维甲酸中毒骨质疏松动物模型椎骨流变特性的研究

研究正常大鼠椎骨和维甲酸所致大鼠骨质疏松L4椎骨的粘弹性性质,为临床提供生物粘弹性力学参数.选用175～245 g,6月龄wistar大鼠30只,随机分为正常对照组15只,模型组15只.对模型组大鼠每日灌服维甲酸(70mg·kg-1·d-1),实验动物于第12周末处死大鼠.取L4椎骨进行压缩应力松弛、蠕变实验.得出了正常对照组和模型组L4椎骨应力松弛,蠕变数据和曲线.对应力松弛蠕变实验数据进行归一化处理,得出归一化应力松弛函数、蠕变函数及曲线.模型组的7 200 s应力松弛、蠕变量指标显著低于正常对照组(P＜0.05).     

骨质疏松动物模型的研究现状

背景：骨质疏松的发病机制十分复杂,但又不能直接在人体上进行实验,需要复制类似人类骨质疏松的动物模型进行研究。 目的：全面分析各种骨质疏松动物模型的造模方法及优缺点,为今后研究骨质疏松症,在模型选择上提供参考。 方法：电子检索中国知识资源总库(CNKI)系列数据库和ESBCO Medline数据库1990-01/2010-07收录的骨质疏松模型的相关综述和论文报告。中文检索词为“骨质疏松,动物模型”;英文检索词为“osteoporosis,animal models”。共检索到469篇相关文献,对文章进行初审,纳入文献主题内容与此文联系紧密;原创、论点论据可靠的试验文章;观点明确,分析全面的文章。排除内容陈旧或重复文献及试验设计中不是采用随机对照试验的文章。 结果与结论：共纳入符合标准的38篇文献。目前用于骨质疏松症研究的动物模型主要有诱发性动物模型和转基因动物模型。各种骨质疏松动物模型可能只侧重于表现该疾病的某种病因、某一阶段、某些主要症状及某些病理生理变化,必须根据研究目的,选择合适的造模方法和实验动物。     

金天格胶囊治疗维甲酸诱导骨质疏松大鼠的蛋白质组学分析

背景：金天格胶囊抗原发性骨质疏松症的疗效已得到临床研究证据证实和临床应用指南推荐,但其抗继发性骨质疏松症的作用及靶点仍未明确。目的：探讨金天格胶囊治疗继发性骨质疏松症的药效靶点与作用机制。方法：将24只雌性SD大鼠随机分为4组,每组6只：空白组不做任何处理;模型组通过灌胃给予维甲酸建立骨质疏松模型,造模14 d后灌胃给予生理盐水;金天格组和阳性对照组通过灌胃给予维甲酸建立骨质疏松模型,造模14 d后分别灌胃给予金天格、阿仑膦酸钠,各组连续给药14 d。给药结束后,取股骨做micro-CT扫描和串联质谱标签定量蛋白质组学,采用生物信息学分析差异蛋白涉及的功能、信号通路及蛋白互作关系,并筛选核心蛋白。结果与结论：(1)与空白组相比,模型组大鼠股骨骨体积分数、骨小梁厚度和骨小梁数量显著降低(P <0.05),骨小梁分离度增高(P <0.05);与模型组相比,阳性对照组与金天格组大鼠股骨骨体积分数、骨小梁厚度和骨小梁数量增高(P <0.05),骨小梁分离度降低(P <0.05);(2)共筛选出模型组与空白组间差异蛋白2 749个,涉及ATP代谢过程、缺氧反应、细胞铁离子...     

海藻酸多糖衍生物治疗大鼠骨质疏松

背景：作者既往研究发现海藻酸多糖衍生物有促进骨细胞生长的作用。 目的：探索海藻酸多糖衍生物治疗骨质疏松的效果。 方法：60只Wistar雌性大鼠随机分成对照组,治疗组和模型组,每组20只。治疗组和模型组大鼠用维甲酸诱导产生骨质疏松模型。治疗组大鼠每只每公斤每天10 mg多糖衍生物灌胃,模型组每只每公斤每天10 mg葡萄糖灌胃,持续2周。观察大鼠股骨病理形态学和骨组织形态计量学变化。 结果与结论：与对照组相比,模型组大鼠股骨骨小梁面积、平均骨小梁厚度、骨小梁密度显著降低,而髓腔质间隔宽度则明显增加;经过海藻多糖衍生物治疗后,治疗组大鼠股骨平均骨小梁密度,平均骨小梁厚度和骨小梁面积较模型组均显著上升,同时髓腔质间隔宽度明显下降;说明海藻酸性多糖能有效促进骨细胞生长,可治疗和预防骨质疏松。     

维甲酸致骨质疏松大鼠椎骨压缩、弯曲、扭转、冲击实验研究

研究正常大鼠与维甲酸致骨质疏松大鼠椎骨的力学性质,为临床提供生物力学参数。选用280~360g8、个月龄wistar雄性大鼠88只,随机分为正常对照组44只,骨质疏松模型组44只。对模型组大鼠每日灌服维甲酸(700mg.Kg-1),对2组大鼠饲养14周,以腹主动脉放血法处死大鼠,取大鼠L1-L4椎骨进行扭转、弯曲、冲击实验,取大鼠L4椎骨进行压缩实验。得出了正常对照组和模型组大鼠L4椎骨压缩最大载荷、最大应力、最大位移、最大应变及弹性模量,得出了正常对照组和模型组大鼠L1-L4椎骨三点弯曲最大载荷、最大弯矩、最大应力、弹性模量等数据,得出了正常对照组和模型组大鼠L1-L4椎骨扭转最大扭矩、扭转角、扭转剪应力、冲击实验最大冲击功、冲击韧性指标。模型组各项力学性能指标小于正常对照组(P<0.05)。     

地塞米松致严重精神障碍

糖皮质激素临床应用极为广泛,对其不良反应时有报道。但引起严重精神障碍致自杀和躁狂者很少见。现将本院近年来发现的3例报道如下。1病例报告例1．男36岁。入院诊断为哮喘型支气管炎、肺气肿。既往无精神异常史。住院后给予抗感染、扩张支气管、祛痰综合治疗，并给予地塞米松20mg静脉点滴，连用7天；治疗后喘息状态缓解，随之出现欣快感、多语不安等精神症状。考虑为激素的不良反应，故将地塞米松减量至10mg／日静滴．于第10天夜间,患者突然自床上跃起,破窗冲出楼外，坠接身亡。事后追问其家属是否有不良刺激因素，其家属否认有任何不良刺…     

培哚普利对维甲酸所致骨质疏松模型大鼠骨代谢的影响

BACKGROUND: Renin-angiotensin-aldosterone system existed in bone tissue. Recent studies on antihypertensive drugs found that angiotensin converting enzyme inhibitor type antihypertensive drug was possibly effective for osteoporosis. Perindopril is one of the commonly used antihypertensive drugs. Whether perindopril affected bone metabolism or could be used in anti-osteoporosis has not been reported.     

构建骨质疏松动物模型建模方法的改进及评价

BACKGROUND: Animal models of osteoporosis play an important role in the research of the pathogenesis, occurrence and development of osteoporosis, as well as in the clinical diagnosis, prevention and treatment of osteoporosis.   OBJECTIVE: To summarize and discuss the establishment and research ideas of osteoporosis models, explore the current situation and advance of osteoporosis models, compare the advantages and disadvantages of various methods, and provide evidence for clinical investigation. METHODS: A computer-based online search was conducted in SinoMed, VIP, Wanfang and PubMed databases by using the key words of “animal model, osteoporosis” from January 1969 to October 2015. The language was limited to both Chinese and English. Relevant articles were screened according to inclusion and exclusion criteria. The documents about the methods of osteoporosis model preparation, method improvement as well as their advantage and disadvantage were summarized. RESULTS AND CONCLUSION: A total of 576 articles were included. Among them, articles published earlier, duplicated, and similarly were excluded, and 53 articles were finally included. Various animal models of osteoporosis may only focus on the certain causes, certain stage, some of the main symptoms and some pathophysiological changes of disease. Accordingly, appropriate modeling methods and experimental animals should be selected based on research objective. Rat undergoing castration is the most commonly used model in the modeling of osteoporosis. Among drug methods for constructing osteoporosis model, glucocorticoids is the most commonly used one. Disuse method and nutritional method have limitations, and always combined with castration and drug methods. The effects of gene transfer, gene mutation and brain-derived model deserve further investigation.       

维甲酸治疗搏莱霉素诱发大鼠肺间质纤维化

观察维甲酸（ＲＡ）的抗纤维化作用并初步探讨其作用机理。ＲＡ治疗搏莱霉所致肺纤维化大鼠２８天后,病理观察及形态定量分析示肺纤维化程度明显减轻,肺组织胶原蛋白含量较同期纤维化对照组（ＢＬＭ组）减少（１１３．８６±１３．８６ｍｇ／ｇ ｌｕｎｇ;１５２．４０±１１．００ｍｇ／ｇ ｌｕｎｇ,Ｐ〈０．０１）。ＲＡ组支气民灌洗液中转化因子β１（ＴＧＦ－β１）含量在第７、１４天时则较同期ＢＬＭ组显著下降（Ｐ均〈０     

地塞米松诱导大鼠胸腺细胞凋亡

细胞凋亡是细胞受到特异刺激后启动内在“自杀”程序而引起的一种控制性死亡。为观察糖皮质激素对免疫器官──胸腺的调节作用,本文加地塞米松与大鼠胸腺细胞共同孵育,胸腺细胞是现了凋亡的典型形态学改变;提取该培养细胞的ＤＮＡ进行琼脂糖凝胶电泳可见典型“阶梯状”条带,提供了该细胞发生凋亡的生物化学依据。本研究结果表明糖质激素能诱导胸腺细胞凋亡。     

咪达普利对实验性骨质疏松大鼠的骨代谢和生物力学的影响

目的:探讨咪达普利对维甲酸所致的实验性骨质疏松的大鼠骨代谢和生物力学的影响.方法:将60只SD雌性大鼠随机分为3组:对照组(Ⅰ组)、维甲酸诱导骨质疏松模型组(Ⅱ组)、咪达普利组(Ⅲ组),每组20只.对Ⅱ组和Ⅲ组的大鼠用维甲酸80mg/(kg.d)连续灌胃21d建立实验性骨质疏松模型.造模后,Ⅲ组给予按大鼠体重10 mg/(kg.d)咪达普利灌胃,Ⅰ组和Ⅱ组采用生理盐水对照,持续7d后处死大鼠,分别检测各组大鼠的体重、股骨骨密度和干湿重、骨代谢指标和骨生物力学指标.结果:与Ⅰ组相比,Ⅱ组在大鼠体重、股骨骨密度、股骨干湿重、骨代谢指标上差异均有统计学意义(P＜0.05).咪达普利干预后,与Ⅱ组相比,Ⅲ组大鼠的体重增加,股骨干湿重增加,差异有统计学意义(p＜0.05);股骨中钙和磷的含量明显增加,差异有统计学意义(p＜0.05),血清中骨钙素(bone gamma-carboxyglutamic-acid-containing proteins,BGP)浓度降低,差异有统计学意义(P＜0.05);抗酒石酸酸性磷酸酶(tartrate resistant acid phosphatase,TRAP)浓度下降,差异有统计学意义(P＜0.05);肱骨生物力学最大载荷(Pmax)、最大挠度(Lmax)、最大弯矩(Mmax)、骨应力(σ)和骨应变增加,差异有统计学意义(P＜0.05).结论:咪达普利能增加维甲酸所致的实验性骨质疏松大鼠骨密度,增加股骨干湿重,减少骨质流失,促进骨形成和矿物质的沉积,增加骨的生物力学强度,减少骨折的发生,对骨质疏松具有保护作用.     

维甲酸诱导HL-60细胞分化过程中WT1基因表达及其异构体比例变化的研究

目的 探讨全反式维甲酸(ATRA)诱导HL-60细胞分化过程中WT1基因及其异构体表达水平及比例变化.方法 采用ATRA诱导HL-60细胞分化,以硝基四氮唑蓝(NBT)还原实验及细胞免疫标记CD11b检测判断细胞分化程度;即时荧光定量RT-PCR方法检测HL-60细胞在诱导分化过程中总WT1、WT1(17AA+)及WT1(KTS+)的表达,并计算出WT1(+/+)、WT1(+/-)、WT1(-/+)、WT1(-/-)四种异构体的比例.结果 ATRA诱导HL-60细胞分化过程中NBT阳性率及CD11b表达阳性率与诱导分化前(0 h)相比均显著增加(P<0.05,P<0.001).随着细胞分化,WT1表达水平由0 h的(4.17±2.21)× 10~(-3)降低至96 h的(7.53±2.30)×10~(-4);17AA+和KTS+两类异构体的比例也逐渐下降,17AA+异构体比例由0 h的0.60±0.05降到96 h的0.42±0.08(P<0.05).KTS+异构体比例由0.53±0.08降至96 h的0.41±0.04(P<0.05);四种异构体的比例变化表现不一致,WT1(+/+)比例由0 h的0.32±0.06降至96 h的0.17±0.03,而WT1(-/-)比例由0 h的0.19±0.04升至96 h的0.34±0.05,另外两类异构体比例变化差异无统计学意义.结论 ATRA诱导HL-60细胞分化过程中总WT1表达水平逐渐降低,分化前异构体以WT1(+/+)为主,而分化后以WT1(-/-)为主,提示WT1基因可能通过调节四种异构体比例而发挥抑制或促进分化的作用.     

Pigs are relatively resistant to dexamethasone induced immunosuppression

Dexamethasone administration has been widely used as a model of immunosuppression in various species. The objective of the work reported here was to evaluate immune function in pigs treated with dexamethasone. Experiment 1 pigs were assigned to either control (n = 10) or 2 mg/kg dexamethasone (n = 10) treated groups. Treatments were administered 48 and 24 h before immune function testing. The dexamethasone-treated pigs received the drug on 22 of 72 experimental days. Pigs in experiment 2 were assigned to one of three groups: control (n = 10), 2 mg/kg dexamethasone (n = 10), or 6 mg/kg dexamethasone (n = 10). Treatments were given once and immune functions were evaluated 3 and 27 h after treatment. Lymphocyte blastogenesis, total and differential white blood cell count, and several measures of in vitro neutrophil function were measured in both experiments. Antigen specific antibody production, growth rate, and organ weights at necropsy were also measured in experiment 1. There were no consistent changes in neutrophil functions in these experiments. Lymphocyte blastogenesis to concanavalin A and pokeweed mitogen was significantly (p <0.05) enhanced during experiment 1 in dexamethasone-treated pigs; antigen specific antibody production was not altered by treatment. Dexamethasone treatment (both 2 and 6 mg/kg) in experiment 2 caused a profound (p <0.02–0.01) decrease in lymphocyte blastogenesis to all three mitogens tested at 3 h after treatment. Lymphocyte proliferation returned to control levels by 27 h after treatment in experiment 2. Dexamethasone treatment was also associated with a relative neutrophilia and lymphopenia in both experiments. Dexamethasone-treated pigs in experiment 1 grew slower, had larger livers and kidneys , but smaller spleens than control animals. The transient decrease in lymphocyte blastoenesis lack of consistent , changes in neutrophil function, and unaltered antibody production despite treatment with large doses of dexamethasone indicate that pigs are remarkably resistant to immunosuppression by this drug.     

大剂量地塞米松诱导的脑细胞死亡机制

目的　探讨大剂量地塞米松诱导的大鼠的脑细胞死亡机制。 方法　将SD大鼠分为对照组和实验组（包括7、9、11 d,3个时间点）。对照组腹腔注射生理盐水,实验组连续腹腔注射5 mg/kg地塞米松, 每日1次。利用光镜和电镜技术观察大脑组织形态结构变化,采用免疫组化和免疫印迹方法检测大脑顶叶皮质Active Caspase-3、PARP-1、pULK1的表达情况。 结果　（1）对照组大鼠大脑组织结构清晰,脑细胞排列整齐,形态完整,染色清晰;7d实验组大鼠大脑组织未见明显病理改变;9d实验组部分脑细胞死亡;11d实验组部分脑细胞可见凋亡和胀亡。（2）对照组Active Caspase-3、PARP-1、pULK1均呈阴性表达。与对照组比较,实验组脑细胞胞质内可见明显的Active Caspase-3、pULK1表达,细胞核内可见明显的PARP-1阳性表达,各实验组脑组织内Active Caspase-3、PARP-1、pULK1表达量随着处理时间的延长而增高。 结论　地塞米松诱导的脑细胞死亡可能通过Active Caspase-3、PARP-1、pULK1的活化所致。     

淫羊藿水提液防治去势大鼠骨质疏松症的实验研究

目的 探讨淫羊藿水提液防治去势大鼠骨质疏松症的疗效。方法 采用3月龄SD雌性大鼠30只，随机分为正常对照组(1组)、去势组(2组)和实验组(3组)。2组及3组均切除双侧卵巢，3组给予淫羊藿水提液灌胃处理；1组给予假手术处理。分别于手术后4周、12周，随机处死三组大鼠中各5只，取第五腰椎，脱钙后包埋切片。Van Gieson染色，图像分析骨小梁结构；HE染色，计数多核巨噬细胞／破骨样细胞。结果去势组与正常对照组比较，4周时出现骨小梁厚度下降，12周时骨小梁面积百分比下降明显，骨小梁分离度增加。实验组在骨小梁计量上与对照组相似，与去势组比较具有显差异。去势组多核巨噬细胞／破骨样细胞计数多于正常对照组及实验组，有显意义。结论 淫羊藿水提液通过抑制破骨细胞的生成，能有效地预防大鼠卵巢切除后所致骨质疏松症的发生。     

Timing determines dexamethasone and rituximab induced synergistic cell death

Dysregulation of cell death signaling pathways in many cell types such as B lymphocytes (B-cells) can lead to cancer, for example to B-cell lymphomas. Rituximab (RTX) and glucocorticoids such as dexamethasone (Dex) are widely used to treat hematological malignancies including B-cell lymphomas. Although the combination of Dex and RTX improves the treatment outcome of lymphoma patients, most lymphomas remain incurable diseases. Therefore, a detailed investigation of Dex- and RTX-induced signaling might provide new insights into the therapeutic benefits of these drugs. In this paper, we describe Dex- and RTX-induced signaling pathways and their downstream target proteins/cells. In addition, we also overview how the signaling initiated by Dex and RTX modulate the outcome of Dex- and RTX-mediated cell death in lymphoma cells.The combination of Dex and RTX results in massive cell death in lymphoma cells. However, pretreatment of lymphoma cells or mononuclear cytotoxic cells with Dex followed by RTX leads to a decrease in apoptosis or it impairs antibody-dependent cellular cytotoxicity (ADCC). RTX-mediated ADCC is impaired by Dex-induced depletion of cytotoxic cells, whereas RTX-mediated short-term ERK1/2 activation decreases Dex-induced apoptosis. Therefore, the timing of the combination of Dex and RTX is a determining factor for the synergistic effect of these cell death inducing agents.     

全反式维甲酸对大鼠残余肾功能的保护作用及其机制

目的：研究全反式维甲酸(atRA)能否延缓大鼠残余肾功能的丧失，并探讨其可能机制。 方法： Wistar大鼠40只，采用5/6肾大部切除大鼠模型，分别给予5 mg·kg-1·d-1（A1组，n=8）、10 mg·kg-1·d-1（A2组，n=8）、20 mg·kg-1·d-1（A3组，n=8）的atRA灌胃，单纯肾大部切除非干预组（NX组，n=8）和假手术组（sham组，n=8）为对照。采用反相高效液相色谱检测大鼠血浆atRA浓度；肾脏病理切片采用PAS染色，计算肾小球硬化指数；应用免疫组化和Western blotting等方法观察转化生长因子β1（TGFβ1）在残余肾组织上的分布水平。 结果： 3个不同剂量的atRA组血药浓度高出NX和sham组10倍以上，并呈现出同给药剂量相吻合的浓度梯度。肾小球硬化评分结果表明，atRA 干预的大鼠肾小球硬化明显轻于NX组，其中A3组硬化程度明显轻于A1组和A2组，P<0.05；A1组和A2组无显著差异，sham组无硬化表现； NX组肾小球TGFβ1表达量最多，atRA干预的3个组明显少于sham组，但A1、A2、A3组间无差异。 结论： atRA能减轻5/6肾大部切除大鼠残余肾硬化，可能是通过抑制TGFβ1起作用。     

Acute release of t-pa in rats and mice is inhibited by endotoxin and dexamethasone but is not affected by retinoic acid

To investigate the contribution of acute release of tissue type plasminogen activator (t-PA) on blood fibrinolytic activity, the ability to modulate the PAF-induced release of t-PA in perfused hindquarters of rats, mice, and hamsters was studied. Effects on t-PA release were compared with effects on ex vivo blood clot lysis. Animals were orally pretreated with dexamethasone (0.1–1 mg/kg) or retinoic acid (3 mg/kg) for a period of 5 days or intravenously with lipopolysaccharide (LPS: 0.03–50 μg/kg) for a period of 4 h. Maximum release of t-PA in response to PAF was 150, 40, and 6 U/kg in rats, mice, and hamsters, respectively, at concentrations of 2, 30, and 20 μM of PAF, respectively. Retinoic acid pretreatment had no effect on acute t-PA release in any of the species. Pretreatment with dexamethasone resulted in a dose-dependent decrease of the t-PA release in rats and mice to 25 ± 7% and 48 ± 6% (relative to vehicle treated animals), respectively at a dose of 1 mg/kg. LPS pretreatment resulted in about 45 % inhibition of t-PA release in both species at a dose of 50 μg/kg. No effects of dexamethasone or LPS were detected on acute release of t-PA in hamsters. In vivo acute release of t-PA in rats was inhibited by about 75% after dexamethasone pretreatment (I mg/kg) and by about 35% after LPS pretreatment (50 μg/kg). Pretreatment of rats with retinoic acid (3 mg/kg) had no effect on in vivo acute release of t-PA. LPS treatment resulted in complete inhibition of ex vivo measured blood clot lysis at doses of 0.3, 10, 0.1 μg/kg for rats, mice, and hamsters, respectively. Dexamethasone and retinoic acid affected the lysis rate of rat blood clots^1,2 but no effects on the lysis rates of murine or hamster blood clots were observed. It is concluded that in rats and mice but not in hamsters acute release of t-PA can be inhibited by pretreatment with dexamethasone or endotoxin. These effects do not parallel with effects on the rate of normal blood clot lysis.     

Midkine and retinoic acid reduce cerebral infarction induced by middle cerebral artery ligation in rats

The present study investigates the neuroprotective effects of midkine (MK) and retinoic acid (RA) against ischemia in the CNS. Primary cortical neurons, derived from rat E15 embryos (DIV9), were treated with 9-cis-RA (9cRA), all-trans-RA (atRA) or vehicle. Using quantitative PCR, the level of MK mRNA was significantly increased at 4h after 9cRA application. The protective effect of RA and MK was also investigated in adult Sprague-Dawley rats. 9cRA, atRA, MK, or vehicle was injected into the lateral ventricle prior to a 60-min-MCA ligation. Pretreatment with 9cRA or MK attenuated cerebral infarction in stroke animals. Application of a similar dose of atRA did not reduce the size of infarction. In conclusion, our data suggest that 9cRA has neuroprotective effects against ischemia-related brain injury which may involve upregulation of midkine.