Triton WR-1339对小鼠血脂水平的影响

Triton wR—1339(tyloxaPol，简称Triton)是一种表面活化剂。50年代初就发现它能引起兔、小鼠的血脂升高^[1]，以后在其他动物中发现它亦有该作用，并广泛应用于降脂药物的筛选^[2]，但尚未见对血脂全套指标进行系统的、全面的研究报道。本研究给小鼠尾静脉注射Triton，观察不同时间点小鼠血脂水平的变化，并确定Triton诱导小鼠高脂血症的最佳时间。     

Triton WR-1339诱发小鼠高脂血症模型的研究

<正>由于高脂血症可诱发心脑血管等多种相关疾病,因此人们十分关注对其治疗药物的研发和药效评价方法的建立。表面活性剂Triton WR-1339(tyloxapol)诱发动物高脂血症模型,具有操作简便且药效评价快速等特点而被广泛运用。本实验从基因水平探讨Triton WR-1339诱发高脂血症的机制,旨在为该模型用于降血脂药物筛选和药效评价提供有益的实验依据。     

微粒化非诺贝特对原发性高脂血症病人血脂和血液流变性的影响

目的：观察微粒化非诺贝特的降血脂疗效及是否有改善血液流变性的作用。方法：６７例原发性高脂血症病人（男性５１例,女性１６例;年龄５４ａ±ｓ１１ａ）给微粒化非诺贝特２００ｍｇ,ｐｏ,ｑｎ,疗程８ｗｋ。结果：治疗８ｗｋ后血清三酰甘油、总胆固醇、低密度脂蛋白胆固醇和载脂蛋白Ｂ１００显著低于治疗前水平（Ｐ＜０．０１或Ｐ＜０．０５）,高密度脂蛋白胆固醇与载脂蛋白ＡＩ升高,（Ｐ＜０．０５）;另外血浆粘度、凝血因子Ｉ、血小板粘附率和血细胞比容较治疗前明显下降（Ｐ＜０．０１或Ｐ＜０．０５）。结论：微粒化非诺贝特能有效降低高血脂,同时明显改善了病人的高粘血症。     

非诺贝特酯对非酒精性脂肪肝大鼠模型的影响

目的 探讨非诺贝特酯对非酒精性脂肪肝大鼠模型的影响.方法 用高脂乳液制造SD非酒精性脂肪肝大鼠模型,进行随机划分三组,分别是非诺贝特酯组、对照组、易善复组,进行8周治疗后,检测肝组织生化反应和病理学研究.结果 非诺贝特酯对非酒精性脂肪肝大鼠模型的肝脂水平有明显降低的作用,使脂肪变性得到改善.结论 非诺贝特酯对非酒精性脂肪肝大鼠治疗作用明显.     

非诺贝特通过介导TGF-β1/Smad3信号通路对糖尿病肾病大鼠肾功能的保护作用研究

目的 研究非诺贝特保护糖尿病肾病(DN)大鼠肾功能的作用机制.方法 将30只4周龄SD大鼠分为正常对照组、模型组和非诺贝特组,模型组和非诺贝特组大鼠经高糖高脂饲料饲养联合链脲佐菌素腹腔注射构建DN大鼠模型,非诺贝特组大鼠给予非诺贝特50 mg/kg腹腔注射,连续干预8周.干预8周后检测各组大鼠血脂、肾功能指标水平,取肾...     

福辛普利联合非诺贝特对糖尿病小鼠视网膜病变干预作用的研究

目的 研究福辛普利（Fosinopril）联合非诺贝特（Fenofibrate）对糖尿病小鼠视网膜细胞凋亡的影响及相关基因的表达和视网膜组织中血管内皮生长因子（vascular endothelial growth factor,VEGF）、氧化相关物质的影响,以明确其抑制糖尿病视网膜病变（diabetic retinopathy,DR）的作用机制。方法 选取清洁级性成熟ICR小鼠150只,随机分为5组（每组30只）：A组（假造模组,普通饲料喂养并给予相同体积的生理盐水）、B组（模型组,高脂饲料喂养4 w后给予腹腔注射链脲佐菌素（streptozotocin,STZ）,给予相同体积生理盐水灌胃8 w）、C组（福辛普利对抗组,高脂饲料喂养4 w后给予腹腔注射链脲佐菌素,给予福辛普利干预8 w）、D组（非诺贝特对抗组,高脂饲料喂养4 w后给予腹腔注射链脲佐菌素,给予非诺贝特干预8 w）、E组（福辛普利+非诺贝特联合对抗组,高脂饲料喂养4 w后给予腹腔注射链脲佐菌素,给予福辛普利+非诺贝特干预8 w）,0w和8w时测血糖BG,处死小鼠取眼球制备视网膜组织匀浆取上清检测谷光甘肽过氧化物酶（Glutathione peroxidase,GSH-PX）、超氧化物歧化酶（Superioxide dismutase,SOD）、活性氧类物质（Reactive oxygen species,ROS）、丙二醛（Malondialdehyde,MDA）、VEGF浓度,用RT-PCR法检测视网膜Bax与Bcl-2基因mRNA水平的表达,并用Tunel染色法检测视网膜细胞凋亡情况。结果B、C、D、E组小鼠用药前后血糖无差别(p>0.05); 均较A组明显升高(p<0.05);A组小鼠视网膜组织GSH-PX、SOD活性值及Bcl-2基因mRNA水平表达均高于其他四组（P＜0.05）,而ROS、MDA、VEGF、Bax基因mRNA水平表达与Tunel指数均低于B、C、D组（P＜0.05）;B组小鼠GSH-PX、SOD活性值及Bcl-2基因mRNA水平表达均低于其他四组（P＜0.05）,而ROS、MDA、VEGF、Bax基因mRNA水平表达与Tunel指数均高于其他四组（P＜0.05）;E组小鼠GSH-PX、SOD活性值及Bcl-2基因mRNA水平表达均高于C、D组（P＜0.05）,而ROS、MDA、VEGF、Bax基因mRNA水平表达与Tunel指数均低于C、D组（P＜0.05）;D组小鼠GSH-PX、SOD活性及Bcl-2基因mRNA水平表达均高于C组（P＜0.05）,而ROS、MDA、Bax基因mRNA水平表达与Tunel指数均低于C组（P＜0.05）;C组小鼠VEGF浓度值低于D组（P＜0.05）。结论 福辛普利及非诺贝特均能改善DR,通过抑制凋亡与抗氧化对视网膜起到一定的保护作用,但两药联合应用效果更佳。     

基于脂质代谢组学评价五味子素B诱导的急性高甘油三酯血症小鼠模型

目的利用脂质代谢组学技术对五味子素B(schisandrin B,Sch B)诱导的小鼠高甘油三酯血症模型进行评价和提供新的实验依据。方法♂ICR小鼠分为4组:正常饮食(ND)组; ND+Sch B组;高脂高糖饮食(HFFD)组; HFFD+Sch B组。生化法检测血清甘油三酯(TG)和总胆固醇水平;利用超高效液相色谱-四极杆飞行时间质谱联用仪(UPLCQ-TOF/MS)的代谢组学技术方法测定各组小鼠血清中脂类代谢物的变化。结果 ND+Sch B组与ND组比,筛选出27个差异代谢物,分别为TG类18个、磷脂酰胆碱(PC) 7个、磷脂酰乙醇胺(PE) 2个; HFFD组与ND组比,筛选出27个差异代谢物,分别为神经鞘磷脂6个、PC 13个、胆甾醇酯(CE) 2个、TG类5个、磷脂酰肌醇1个; HFFD+Sch B组与HFFD组比,筛选出25个差异代谢物,分别为TG类14个、CE 1个、PC 6个、PE 4个。结论 Sch B诱导的高甘油三酯血症动物模型涉及血清脂质代谢组学的改变。     

探索用于非临床药效学研究的半抗原诱导小鼠特应性皮炎模型

特应性皮炎(atopic dermatitis, AD)是一种慢性、复发性、炎症性皮肤病,临床表现多样且难以治愈。目前多种治疗AD候选药物进入研发管线,为AD药物临床开发提供技术规范,国家药品监督管理局药品审评中心于2022年11月发布了《AD治疗药物临床试验技术指导原则》(征求意见稿)。非临床药效评价是受试药物进入临床试验前的重要研究内容,噁唑酮(oxazolone, OXA)和2,4-二硝基氟苯(2,4-dinitrofluorobenzene, DNFB)诱导的特应性皮炎小鼠模型是最常用的经典半抗原诱导AD小鼠模型,但在已有报道中,半抗原剂量、致敏部位、攻击次数和皮损严重程度评估方法都存在差异。本研究根据特应性皮炎患者病程和病理表现,结合AD治疗药物临床试验药效学评价要点构建AD小鼠模型,系统考察并比较不同构建方案(致敏部位、半抗原剂量和攻击次数等)与皮损指标间的关系,探索OXA和DNFB两种经典半抗原诱导AD小鼠的病变过程、模型强度和特点,为治疗AD候选药物的非临床药效学研究提供方法学依据。所有动物实验均经过中国医学科学院、北京协和医学院药物研究所实验动物管理与动物福利委员会批...     

白芍总苷通过白细胞介素 -6/信号转导及转录激活蛋白 3信号通路对脂多糖诱导的急性肺炎小鼠炎症反应的影响

目的探讨白芍总苷( TGP)通过白细胞介素 -6/信号转导及转录激活蛋白 3(IL-6/STAT3)信号通路对脂多糖诱导的急性肺炎小鼠炎症反应的影响。方法本研究起止时间为 2019年 10月至 2020年 2月。选择 SPF级雄性小鼠 50只,采用随机数字表法将小鼠随机分为五组,对照组、急性肺炎模型组、 TGP低剂量组、 TGP中剂量组和 TGP高剂量组。采用苏木精 -伊红( HE)染色观察各组小鼠肺组织病理形态学;采用酶联免疫吸附测定( ELISA)检测各组小鼠肺组织肿瘤坏死因子 -α(TNF-α)、白细胞介素( IL)-1β含量;采用蛋白质印迹( Western blotting)检测各组小鼠肺组织 IL-6、STAT3、磷酸化信号转导及转录激活蛋白 3(p-STAT3)的蛋白表达水平;采用实时荧光定量 PCR(qRT-PCR)检测各组小鼠肺组织 IL-6、STAT3 mRNA表达水平。结果模型组小鼠肺组织结构被破坏,肺泡间隔增厚,大量炎性细胞浸润; TGP药物组病理改变较模型组均存在不同程度改善,白芍总苷高剂量组肺组织仅存在少量炎性细胞浸润。与对照组( 45.12±9.73)ng/L、(21.38±2.13)ng/L相比,模型组及 TGP各剂量组小鼠肺组织 TNF-α(89.30±9.26)ng/L,(84.32±5.08)ng/L,(75.36±4.67)ng/L,(64.06±5.90)ng/L、IL-1β含量( 59.69±3.60)ng/L,(56.87±     

Evodiamine improves lipid profile in high-fat diet-fed mice by facilitating reverse cholesterol transport

OBJECTIVE Reverse cholesterol transport(RCT) is a pivotal pathway involved in transporting excess cholesterol from peripheral tissues to the liver for excretion in the bile and eventual y the feces. In the present study we identified the naturally occurring alkaloid evodiamine as alipid-lowing inducer by facilitating RCT in highfat diet(HFD)-fed mice. METHODS Hep G2 cells were first exposed to 0.6 m M FFA(palmitic acid/oleic acid, 1:2)for 24 h to induce the liversteatosis before treated with or without evodiamine foran additional 24 h. Atorvastatin was used as apositive control. Intracellular lipid deposition was analyzed by Oil Red O staining. Male ICR mice were fed HFD initially for 4 weeks to induce hyperlipidemia. After induction of hyperlipidemia, evodiamine was intragastrically administered in the dose of 10 mg · kg~(-1) per day for 4 weeks to the mice. The levels of triglyceride(TG), total cholesterol(TC), high-density lipoprotein cholesterol(HDL-C) and low-density lipoprotein cholesterol(LDL-C)in the serum were determinedto evaluate the metabolic lipid profiles in the HFD-fed mice. Hematoxylin and eosin(H&E) staining was performed for fat accumulation examination. Western blotting and quantitative real time polymerase chain reaction(q RT-PCR) were used to assess the expression of proteins and m RNAs correlated with RCT in the liver and small intestine, including ATP-binding cassette transporter A1(ABCA1), ABCG1, ABCG5,ABCG8, scavenger receptor class B type 1(SR-B1) and Niemann-Pick type C1 Like 1(NPC1L1). RESULTS Oil Red O staining revealed that evodiamine markedly attenuated hepatic fat accumulation caused by FFA in HepG2 cells. In HFD-fed mice, evodiamine significantly reduced serum TG, TC and LDL-C but not HDL-C. Besides, evodiamine significantly decreased hepatic lipid accumulation revealed by H&E staining. Moreover, evodiamine increased ABCG1 expression in the liver and raised NPC1L1 expression in the small intestine. CONCLUSION Evodiamine improves lipid metabolic profile in HFD-fed mice by increasing expression of ABCG1 in liver and NPC1L1 in the small intestine.     

1,3-Dichloro-2-propanol induced hyperlipidemia in C57BL/6J mice via AMPK signaling pathway

1,3-Dichloro-2-propanol (1,3-DCP) is a well-known contaminant that has been detected in a wide range of foods. Dietary intake represents the greatest source of exposure to 1,3-DCP. In the study, we first found 1,3-DCP could induce hyperlipidemia in C57BL/6J mice below 1 mg/kg/day. We investigated serum lipid profile, liver total cholesterol (TC) and triglyceride (TG), histopathology of Liver and adipose tissue. The results showed 1,3-DCP dose dependently increased serum TG, TC and low-density lipoprotein cholesterol (LDL-C), decreased serum high-density lipoprotein cholesterol (HDL-C), increased relative liver weight, liver TG and TC, relative adipose tissue weight and enlarged the size of adipose cells. Because AMPK signal pathway is important in the process of lipid metabolism, we further investigated the effects of 1,3-DCP on AMPK signaling pathway in murine models. The results showed that 1,3-DCP (0.1–1 mg/kg/day) decreased p-AMPK/tAMPK ratio, p-ACC/tACC ratio, PPARα expression, but increased FAT, SREBP1, HMGCR and FAS expression. These observations indicated that 1,3-DCP induced hyperlipidemia in C57BL/6J mice at least partially through regulating AMPK signaling pathway.     

Experimental hyperlipidemia and atherosclerosis induced by cholesterol diet in SPF Japanese white rabbits

Experimental hyperlipidemia and atherosclerosis induced by a cholesterol diet in SPF male and female rabbits (JW/KBL) were investigated by the determination of the lipid contents of the plasma, liver and thoracic aorta; determination of morphological changes of the aortic arch by head angiography; and computer tomography of the brain. Rabbits were fed the diet that contained 1% cholesterol for eight weeks. The plasma lipid levels began to rise from two weeks after the cholesterol diet was started, reached the peak four to six weeks later, and then fell in both males and females at eight weeks. The cholesterol of the high density lipoprotein in male rabbit plasma was slightly increased by the cholesterol diet, but not in female rabbits. An increase in the total cholesterol (TC) and triglyceride contents of the liver and an increase in the TC and phospholipid contents of the thoracic aorta were observed at the eighth week. Histological examination of the aortic arch showed marked lipid vacuoles under the endothelial cells, noticeable lipid inclusions in the smooth muscle cells of the intima and granular prominences on the internal surface of the aorta. Head angiography of rabbits fed the cholesterol diet revealed a constriction of the lumina of several arteries due to the lipid depositions. These results suggest that hyperlipidemia and atherosclerosis can be produced at the eighth week using SPF rabbits fed on a cholesterol diet.     

白藜芦醇对高脂饮食诱导小鼠高脂血症的作用机制研究

目的 考察白藜芦醇对高脂血症小鼠的影响,并探讨其作用机制.方法 按体重将雄性C57BL/6J小鼠随机分为3组:正常组、模型组及实验组,每组10只.正常组正常饲养,模型组及实验组小鼠连续饲喂4周高脂饲料构建高血脂模型.建模后,实验组灌服白藜芦醇(400 mg·kg-1),模型组及空白组灌服等量生理盐水,每天1次,连续干预...     

泊洛沙姆诱导急性高脂血症小鼠模型的药效学研究

目的通过泊洛沙姆诱导建立急性高脂血症小鼠模型。方法 ICR小鼠单次腹腔注射不同剂量的泊洛沙姆407（P-407）（用量依次为0.25 g/kg、0.50 g/kg、1.0 g/kg、2.0 g/kg）,然后在指定的时间点（次）从眼窝丛收集血液样本,测定血清中TG、TC、AST、ALT、HDL、LDL及血糖水平并观察经阿托伐他汀预处理后的血脂水平。结果 P-407可诱发ICR小鼠血脂水平出现异常,其中0.25、0.50和1.0 g/kg剂量组小鼠ALT、AST以及血糖水平并无显著改变,但2.0 g/kg剂量组小鼠ALT水平显著升高;阿托伐他汀能有效改善0.25和0.50 g/kg剂量P-407诱发的血脂异常。结论 0.25和0.50 g/kg剂量的P-407可用于复制急性高脂血症小鼠模型,此模型可用于药物的筛选,其对血糖水平和肝功能不受影响。     

Effects of gamma-oryzanol and cycloartenol ferulic acid ester on cholesterol diet induced hyperlipidemia in rats

Hypolipidemic effects of gamma-oryzanol (OZ) and cycloartenol ferulic acid ester (CAF) on the hyperlipidemia induced by ingestion of a high cholesterol diet (HCD) in male Sprague-Dawley rats were investigated. The test drugs were given orally and intravenously, daily for 12 days with the HCD feeding. The oral administration with OZ and CAF at 100 mg/kg daily for 6 or 12 days did not apparently prevent the hyperlipidemia induced by HCD-feeding. The intravenous administrations with OZ and CAF at 10 mg/kg for 6 days significantly inhibited the increases in serum total cholesterol (TC), phospholipid (PL) and free cholesterol by HCD. OZ and CAF did not inhibit the decreases of TC in high density lipoprotein (HDL-TC) and HDL-PL by HCD. The increases of atherogenic index [( TC-HDL-TC]/[HDL-TC] and [PL-HDL-PL]/[HDL-PL]) with the HCD feeding were reduced by the intravenous administrations of OZ and CAF. Triglyceride, nonesterified fatty acid, lactate dehydrogenase and transaminase (GOT and GPT) markedly decreased below the control level by the intravenous administrations of OZ and CAF for 12 days. These results suggest that the intravenous administrations of OZ and CAF may have accelerated the excretion of lipids in the blood.     

The thienotriazolodiazepine Ro 11-1464 increases plasma apoA-I and promotes reverse cholesterol transport in human apoA-I transgenic mice

BACKGROUND AND PURPOSE

Ro 11-1464 is a thienotriazolodiazepine previously described to selectively stimulate apolipoprotein A-I (apoA-I) production and mRNA level in human liver cells. Here, we studied its effects upon oral administration to human apoA-I transgenic (hapoA-I) mice.

EXPERIMENTAL APPROACH

HapoA-I mice were treated for 5 days with increasing doses of Ro 11-1464. Macrophage reverse cholesterol transport (mph-RCT) was assessed by following [³H]-cholesterol mobilization from pre-labelled i.p. injected J774 macrophages to plasma, liver and faeces. Effects on plasma lipids, apoproteins, lecithin-cholesterol : acyltransferase (LCAT) and liver enzymes, as well as on faecal excretion of cholesterol and bile salts, and on liver lipids and mRNA contents were determined.

KEY RESULTS

Treatment with Ro 11-1464 300 mg·kg⁻¹·day⁻¹ resulted in a nearly 2-fold increase in plasma apoA-I, a 2- to 3-fold increase in the level of large sized-pre-β high-density lipoprotein and a 3-fold selective up-regulation of hepatic apoA-I mRNA, but a marked decrease in all plasma lipids and LCAT activity. Mpm-RCT was decreased in blood but markedly increased in faecal sterols (4-fold) and bile acids (1.7-fold). However, liver weight and liver enzymes in plasma were also increased, in parallel with an increase in liver cholesterol ester content (all these effect being significant).

CONCLUSION AND IMPLICATIONS

In this model Ro 11-1464 causes increased hepatic expression and plasma levels of apoA-I and a suppression of LCAT, and a marked enhancement of reverse cholesterol transport, but also some symptoms of liver toxicity. The compound may therefore be a prototype for a next generation of anti-atherosclerotic medicines.     

Comparative effects of two forms of gamma-oryzanol in different sterol compositions on hyperlipidemia induced by cholesterol diet in rats

Hypolipidemic effects of the usual gamma-oryzanol (gamma-OZ) and a new gamma-OZ (N-gamma-OZ) with a different sterol composition from gamma-OZ were investigated on the hyperlipidemia induced by ingestion of a high cholesterol diet (HCD) containing 1% cholesterol for 12 days in male Sprague-Dawley rats. Treatment with gamma-OZ for 6 days significantly inhibited the increase in serum total cholesterol (TC) and phospholipids (PL) induced by HCD, while the treatment with gamma-OZ for 12 days did not inhibit the increase of TC and PL. Treatment with N-gamma-OZ at 100 or 1000 mg/kg for 6 days slightly inhibited the increase of TC by HCD. The decrease of TC in high density lipoprotein (HDL-TC) was markedly inhibited by treatment with N-gamma-OZ for 12 days, but N-gamma-OZ for 6 days and gamma-OZ for 6 and 12 days did not inhibit the decrease of HDL-TC. Treatment with N-gamma-OZ for 12 days significantly inhibited the increase of PL and free cholesterol (FC) by HCD. gamma-OZ at 1000 mg/kg for 12 days also inhibited the increase of FC. N-gamma-OZ significantly reduced the atherogenic index using TC and HDL-TC by affecting the HDL-TC increase. gamma-OZ at 100 mg/kg and N-gamma-OZ at 100 mg/kg for 6 days reduced the atherogenic index using TC and HDL-TC by the inhibition of TC increase. The atherogenic index using PL and HDL-PL was only reduced by the treatment with N-gamma-OZ at 1000 mg/g for 12 days. The increase of triglyceride (TG) by HCD was inhibited by the treatment of N-gamma-OZ for 6 days (all doses) and 12 days (500, 1000 mg/kg), and gamma-OZ at 500 mg/kg for 6 and 12 days also inhibited the increase of TG by HCD. gamma-OZ and N-gamma-OZ had no effects on liver lipid contents. The hypolipidemic effect of N-gamma-OZ was slightly more potent than that of gamma-OZ.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of SMP-500, a novel acyl-CoA:cholesterol acyltransferase inhibitor,on serum cholesterol level and LDL cholesterol clearance in hamsters with induced hyperlipidemia

The effect of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on serum cholesterol levels was investigated in hyperlipidemic hamsters whose condition had been preestablished by diet. SMP-500 reduced the total serum cholesterol level in a dose-dependent manner. SMP-500 also reduced the hepatic free cholesterol content and markedly reduced the esterified cholesterol content compared with the control group. Interestingly, SMP-500 at a dose of 30 mg/kg increased LDL clearance in vivo. As SMP-500 at this dose potently lowered the total serum cholesterol level, the increased LDL clearance was identified as another mechanism for the cholesterol-lowering effect of SMP-500. However, unlike HMG CoA reductase inhibitors, SMP-500 did not affect cholesterol biosynthesis in HepG2 cells. Therefore the etiology of the increased LDL clearance is not yet clear, but the reduced hepatic free cholesterol may play an important role in this process. These results suggest that the cholesterol-lowering effect of SMP-500 is due, not only to the inhibition of ACAT, but also to the increase in cholesterol clearance from the blood. This finding supports the therapeutic potential of SMP-500 for the treatment of human hypercholesterolemia.