Comparison of disposition behavior and de-coppering effect of triethylenetetramine in animal model for Wilson's disease (Long-Evans Cinnamon rat) with normal Wistar rat.

The disposition behaviors and de-coppering effect of triethylenetetramine dihydrochloride (trientine), a selective chelating agent for copper and an 'orphan drug' for Wilson's disease, have been evaluated in an animal model, Long-Evans Cinnamon (LEC) rats, and normal rats (Wistar). In LEC rats, urinary excretion of trientine was remarkably lower than that of Wistar rats. The absorption rates from the jejunal loop and in vitro metabolism in the liver S9 fraction (supernatant of 9000 x g) were approximately the same for both strains. The decline of urinary excretion of trientine in LEC rats is thought to be due mainly to the lowering of the functional activity of the kidney, because urinary excretion of creatinine and phenolsulfonphthalein were significantly lower in LEC rats than those in Wistar rats. Both acceleration of urinary excretion of copper and reduction of hepatic copper levels were observed with treatment of trientine in LEC rats aged 6 weeks. In LEC rats aged 13 weeks, however, no de-coppering effect from the liver was observed, though urinary excretion of copper was increased. These results suggest that trientine has a pharmacological effect in disease state, especially in the early stages of hepatitis.     

An iron-deficient diet stimulates the onset of the hepatitis due to hepatic copper deposition in the Long-Evans Cinnamon (LEC) rat

To study effects of dietary Cu and Fe levels on the onset of hepatitis in Long-Evans Cinnamon (LEC) rats, female rats (40 days old) were fed a semipurified diet containing 0.1 or 10 mg Cu/kg and 1.5 or 150 mg Fe/kg in a 2 × 2 factorial arrangement for 35 days. At 75 days after birth, LEC rats (+Cu−Fe) fed a Cu-sufficient but Fe-deficient diet (Cu, 10 mg/kg; Fe, 1.5 mg/kg) showed jaundice, with lethargy, anorexia, and malaise. The biochemical variables relating to liver function were significantly increased compared to three other groups, a Cu- and Fe-deficient (−Cu−Fe) group, a Cu-deficient but Fe-sufficient (−Cu+Fe) group, and a Cu and Fe sufficient (+Cu+Fe) group. Furthermore, the +Cu−Fe rat liver showed massive necrosis with huge nuclei. The other three groups presented no biochemical and histological findings of hepatitis. Hepatic Cu and metallothionein concentrations were 289 ± 87 (mean ± SD) μg/g liver and 8.7 ± 1.8 mg/g liver, respectively, in the +Cu−Fe rats. However, in the +Cu+Fe group the values were 196 ± 28 μg Cu/g liver and 10.8 ± 1.0 mg/g liver. Hepatic Fe deposition was not influenced significantly by the dietary Cu level. The +Cu−Fe group with jaundice showed the highest free Cu concentration in the liver among the four groups, but the hepatic free Fe concentration was similar to those in the −Cu+Fe and +Cu+Fe groups. Our results indicate that an Fe-deficient diet enhances the deposition of hepatic Cu due to increased absorption of Cu from the gastrointestinal tract. This deposition stimulated the onset of hepatitis. Received: 11 March 1999 / Accepted: 11 June 1999     

Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites

The role of multidrug resistance-associated protein 2 (MRP2) on the intestinal disposition and hepatobiliary elimination of tenofovir disoproxil fumarate (DF) and its metabolites [tenofovir (mono)ester and tenofovir] was studied in the Caco-2 system, Ussing chambers and rat in-situ efflux experiments. In the Caco-2 model and Ussing chambers, no statistically significant differences in transport could be observed when the MRP inhibitor probenecid was included. In Ussing chambers, transport was also similar when using intestinal tissue from MRP2-deficient rats. After intravenous administration of tenofovir DF, the excretion of tenofovir [(mono)ester] in bile was significantly decreased in MRP2-deficient rats and in rats treated with probenecid. The area under the blood concentration–time curve was increased in MRP2-deficient rats [1.0?±?0.1 and 0.36?±?0.03?µM.min^?1 for tenofovir and tenofovir (mono)ester, respectively] and rats treated with probenecid (1.42?±?0.04 and 0.36?±?0.02?µM.min^?1) compared with control rats (0.64?±?0.05 and 0.15?±?0.06?µM.min^?1). The appearance of tenofovir [(mono)ester] in intestinal perfusate was similar in control rats upon co-administering probenecid or when using MRP2-deficient rats. In conclusion, MRP2 appeared to have no modulatory effect on the intestinal disposition of tenofovir and tenofovir (mono)ester. However, inhibition (probenecid) or the total absence of MRP2 (MRP2-deficient rats) significantly reduced hepatobiliary elimination, which was accompanied by increased systemic exposure.     

Protection from spontaneous hepatocellular damage by N-benzyl-d-glucamine dithiocarbamate in Long-Evans Cinnamon rats, an animal model of Wilson's disease

The Long-Evans Cinnamon (LEC) rat is a mutant strain that accumulates excessive tissue copper (Cu) and models the clinical symptoms and biological features of Wilson's disease in humans. We compared the effects of three metal chelating agents, N-benzyl-d-glucamine dithiocarbamate (BGD), d-penicillamine (D-PEN), and triethylenetetramine (TETA), on the biliary and urinary excretions of Cu using LEC rats. The animals were treated ip with each chelating agent (1 mmol/kg body weight) and then the bile and urine samples were collected for 3 h. Because single treatment with BGD markedly stimulated biliary excretion of Cu, the protective effect of repeated BGD injection on spontaneous hepatocellular damage was further examined. Separate groups received two weekly injections of BGD starting at 11 weeks of age and were compared to saline-injected controls. Serum alanine aminotransferase (ALT) activity and bilirubin level were significantly increased in control LEC rats by 19 weeks of age and histopathological analysis demonstrated extensive hepatic damage in these rats. However, repeated BGD injections prevented the increases in serum ALT and bilirubin and blocked the histopathological changes in the liver. Furthermore, although Cu rapidly accumulated in the liver, kidney, spleen, and serum of control LEC rats during the test period, repeated BGD injection largely prevented these increases. These results indicate that BGD treatment is effective in blocking excessive Cu accumulation in LEC rats that, in turn, provides protection from spontaneous liver damage.     

Wilson病患者生活质量与社会支持的相关性分析

目的 探讨Wilson病(WD)患者获得的社会支持对其生活质量的影响。方法 采用世界卫生组织生存质量评定量表简表(WHOQOL-BREF)、社会支持评定量表(SSRS)对51例健康者(对照组)和287例WD患者(WD组)进行生活质量问卷调查并对比分析,运用Spearman相关分析统计方法分析相关影响因素。结果 ①SSRS测量结果显示,WD患者的客观支持得分为(8.01±2.87)分、社会利用度得分为(7.79±2.49)分,对照组得分分别为(7.10±1.87)分和(9.16±1.64)分,两组比较,差异有统计学意义(P<0.05);WD患者的社会支持总分(33.30±7.42)分、主观支持得分(17.73±4.99)分,与对照组的(32.47±5.38)分、(17.22±3.98)分相比,差异无统计学意义(P>0.05)。②社会支持总分对患者的生活质量有显著影响(P<0.01)。结论 ①WD患者对社会支持的利用度低于一般人群。②文化程度,社会支持等对WD患者生活质量有影响。要提高其生活质量,须多方位采取干预措施。     

非诺贝特在非酒精性脂肪性肝病大鼠中的作用探讨

目的高脂饮食构建NAFLD大鼠模型,观察非诺贝特对NFALD大鼠血清学肝功、血脂及肝脏病理的影响。方法将27只雄性SD大鼠随机分为正常组(N组)、病理组(B组)及非诺贝特组(F组),每组9只,分别予正常饮食及高脂饮食建立NAFLD模型。于4、8、12周后,每组各处死大鼠3只,称体重、肝湿重,计算肝指数;8周后测定血清天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、三酰甘油(TG)、总胆固醇(TC);肝脏病理切片行HE染色,观察病理改变。F组第5周开始药物干预。结果 8周时B组大鼠体重及肝指数高于N组,差异有统计学意义(P<0.05),F组肝指数低于B组,差异有统计学意义(P<0.05);12周时N组与F组大鼠肝指数组间比较差异无统计学意义(P>0.05),B组大鼠体重和肝指数大于N组,差异有统计学意义(P<0.05)。血清学指标:8周时N组与F组AST、ALT、TG、TC比较差异无统计学意义(P>0.05),B组AST、ALT、TG、TC明显高于N组,且差异有统计学意义(P<0.05)。12周时B组AST、ALT、TG、TC明显高于N组,差异有统计学意义(P<0.05),B组ALT、TG高于F组,差异有统计学意义(P<0.05),F组与N组AST、ALT、TC、TG差异无统计学意义(P>0.05)。结论改良法高脂饮食诱导SD大鼠非酒精性脂肪性肝病,造模成功;非诺贝特对NAFLD大鼠的肝脏酶学、血脂及病理学均有一定改善。     

高血压大鼠尾动脉上κ,σ和苯环利定受体激动剂的效应(英文)

利用电场刺激引起的大鼠尾动脉收缩模型,研究了κ,(?)和苯环利定(Phe)受体在高血压大鼠(SHR)上的变化,结果,埃托啡和U-50 488H在SHR上的抑制作用显著高于非高血压大鼠(WKY)。( )-3-PPP的结果与上述相反,DTG的作用很小,Phe,TCP和MK-801的增强作用在两者间无显著差别。提示在SHR上κ受体的敏感性增高,(?)受体相反,而Phe受体的敏感性变化较少。     

基于网络药理学方法和分子对接技术探讨肝豆灵治疗肝豆状核变性认知障碍的作用机制

目的基于网络药理学方法和分子对接技术探讨肝豆灵治疗肝豆状核变性认知障碍的作用机制。方法通过TCMSP数据库检索肝豆灵六味中药的有效化学成分及潜在靶点,并将所获靶点导入到Uniprot数据库进行标准基因名转化;通过GeneCards、OMIM、PharmGkb、TTD数据库查询肝豆状核变性认知障碍的相关靶点;利用R 4.0.3软件获得肝豆灵与肝豆状核变性认知障碍的交集靶点;借助String数据库和Cytoscape 3.8. 0软件构建PPI网络,筛选核心靶点;应用DAVID数据库进行GO生物功能和KEGG通路富集分析;运用AutoDockTools 1.5. 6及Autodock vina 1.1. 2软件进行分子对接。结果共收集得到肝豆灵的基因靶点218个,肝豆状核变性认知障碍相关靶点4 858个,交集靶点189个,其交集靶点主要富集于2 922个生物功能及175条信号通路上。分子对接结果显示度值排名前3的核心靶点与其对应的化学成分之间均有较强的相互作用,其中JUN与槲皮素的结合性最好。结论肝豆灵治疗肝豆状核变性认知障碍具有多成分、多靶点、多通路的特点,可通过JUN、STAT3、TP53等核心靶点调控PI3K-AKT、AGE-RAGE等信号通路来降低活性氧簇水平,减轻神经炎症反应,抑制神经细胞凋亡,发挥其保护神经细胞、改善认知的效用。     

Mechanism of enhanced lipid peroxidation in the liver of Long-Evans cinnamon (LEC) rats

The Long-Evans Cinnamon (LEC) rat is a mutant strain of rats that accumulate copper (Cu) in the liver in much the same way as individuals who suffer from Wilson's disease (WD) and has been suggested as a model for this disease. Lipid peroxidation (LPO) is considered to be involved in the toxic action of Cu in the livers of LEC rats. We investigated the mechanism of LPO in the livers of LEC rats showing apparent signs of hepatitis. Several-fold higher LPO levels were observed in post-mitochondrial supernatant (S-9) fraction of livers from hepatitic LEC rats than in those from Wistar rats. To mimic living cells, we introduced NADPH-generating system (NADPH-gs) into the S-9 incubation system. Thus was ensured a constant supply of NADPH to vital enzymes that may be directly or indirectly involved in the generation and/or elimination of reactive oxygen species (ROSs), such as glutathione reductase (GSSG-R), which require NADPH for their reactions. The levels of LPO in liver S-9 from hepatitic LEC rats were further increased by incubating liver S-9 at 37 °C in the presence of NADPH-gs. This increase was inhibited by EDTA, butylated hydroxytoluene (BHT), and catalase (CAT), suggesting that some metal, most likely the accumulated Cu, and ROSs derived from hydrogen peroxide (H₂O₂) are involved in the increased levels of LPO in the livers of hepatitic LEC rats. The requirement of NADPH-gs for enhanced LPO in the livers of hepatitic LEC rats indicates the consumption of NADPH during reactions leading to LPO. It is known that H₂O₂, and consequently hydroxyl radical are generated during Cu–catalyzed glutathione (GSH) oxidation. The cyclic regeneration of GSH from GSSG by NADPH-dependent GSSG-R in the presence of NADPH-gs may cause sustained generation of hydroxyl radical in the presence of excess free Cu. The generation of H₂O₂ in S-9 fraction of livers from hepatitic LEC rats was observed to be significantly higher than that in S-9 fraction of livers from non-hepatitic LEC rats and Wistar rats. Moreover, in addition to the reported decrease in glutathione peroxidase (GPX) activity, we found that CAT activity was markedly decreased in LEC rats with hepatitis. The increased generation of H₂O₂ with reduced activities of GPX and CAT may result in cellular accumulation of H₂O₂ in the liver of hepatitic LEC rats. Taken altogether, it is suggested that the accumulated H₂O₂ undergoes the Fenton-type reaction with also accumulated free Cu, thus generating hydroxyl radical in the livers of hepatitic LEC rats and increasing LPO levels in these animals. Received: 20 April 1999 / Accepted: 2 September 1999     

Renal vascular structural properties and their alterations by removal of uraemic toxins in a rat model of chronic kidney disease

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卡托普利和依那普利对血管平滑肌细胞内钙的影响(英文)

目的:检测ACE抑制剂对主动脉平滑肌细胞内Ca~(2 )的影响。方法:用荧光标计和图象处理技术。结果:SHR细胞内Ca~(2 )以及KCl,NE和Ang在SHR细胞引起的Ca~(2 )增加多于WKY细胞。Cap和Ena不影响KCl和Ang在WKY细胞的作用,但Cap,Ena和Nif抑制KCl,NE和Ang在SHR细胞的作用。结论:Cap和Ena阻断功能和特异性已改变的电压依赖性钙通道。     

新生鼠部分输尿管梗阻建立及梗阻解除的动物模型制作

目的探索新生鼠部分输尿管梗阻建立及梗阻解除的动物模型制作,为临床小儿肾积水的研究提供可靠的动物模型。方法生后48h内新生Wistar鼠72只,随机分为6组,每组12只,选择1组行假手术．作为对照组,余各组用腰大肌压迫法制作左侧部分输尿管梗阻性（PUO）肾积水模型,再随机分为组2～组6,作为模型组。3周后解除梗阻,术中观察梗阻肾体积是否增大,皮试针穿刺证实肾盂是否积水。组2梗阻解除后即处死,余各组分别于梗阻解除后第2、6、8、12周处死。实验动物处死后,切取肾脏行病理学检查。结果大体观察：梗阻侧输尿管上段增粗,肾盂扩张积水,梗阻肾外观体积较时侧肾脏及对照组同侧肾脏增大;对侧肾脏体积又较对照组同侧肾脏体积大。镜下观察：梗阻肾皮质变薄,肾单位减少,肾小球萎缩变形,肾小管扩张,出现肾间质纤维化;对侧肾脏肾单位较对照组增多,余形态学无异常改变。随梗阻解除时间延长,病肾肾小球及肾小管结构逐渐恢复,正常形态肾小球数目增多,肾闻质纤维化逐渐减轻。结论本动物模型成功模拟了小儿肾积水梗阻解除前后的病理改变,可作为临床研究小儿肾积水的理想动物模型。     

The spontaneously hypertensive rat: an experimental model of sulfur dioxide-induced airways disease.

Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation, and mucus hypersecretion, features that are common in bronchitis, emphysema, and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisposed spontaneously hypertensive (SH) rats display phenotypes such as systemic inflammation, hypercoagulation, oxidative stress, and suppressed immune function that are also apparent in COPD patients, we hypothesized that SH rat may offer a better model of experimental bronchitis. We, therefore, exposed SH and commonly used Sprague Dawley (SD) rats (male, 13- to 15-weeks old) to 0, 250, or 350 ppm sulfur dioxide (SO(2)), 5 h/day for 4 consecutive days to induce airway injury. SO(2) caused dose-dependent changes in breathing parameters in both strains with SH rats being slightly more affected than SD rats. Increases in bronchoalveolar lavage fluid (BALF) total cells and neutrophilic inflammation were dose dependent and significantly greater in SH than in SD rats. The recovery was incomplete at 4 days following SO(2) exposure in SH rats. Pulmonary protein leakage was modest in either strain, but lactate dehydrogenase and N-acetyl glucosaminidase activity were increased in BALF of SH rats. Airway pathology and morphometric evaluation of mucin demonstrated significantly greater impact of SO(2) in SH than in SD rats. Baseline differences in lung gene expression pattern suggested marked immune dysregulation, oxidative stress, impairment of cell signaling, and fatty acid metabolism in SH rats. SO(2) effects on these genes were more pronounced in SH than in SD rats. Thus, SO(2) exposure in SH rats may yield a relevant experimental model of bronchitis.     

Development and characterization of a rat model of chronic obstructive pulmonary disease (COPD) induced by sidestream cigarette smoke

Cigarette smoke (CS) induced chronic obstructive pulmonary disease (COPD) has been emerging as a great health problem in China. However, lack of appropriate animal model slows down the progress in understanding pathogenesis of the disease. The aim of current study is to establish and evaluate a more adequate rat model of COPD. Study was performed with rats exposed to sidestream cigarette smoke 2 h/d and 7 d/wk for 2, 4, 6, 8, 10, 12, 24 and 36 wk in a CS chamber (carbon monoxide concentration was 231 ± 11 ppm). The lung function was determined by using the forced oscillation technique. Pathologic changes were determined by using histological analyses and mucin measurement. Following 36-wk exposure, airway resistance (Raw) and respiratory system elastance (Ers) in CS group rats was elevated by 28.5% and 37.5%, respectively. Up to 4.1-, 2.3- and 1.4-fold increase in the number of neutrophils, macrophages and lymphocytes was observed in the BALF of CS rats. Using quantitative histomorphology techniques, it was found that mean linear intercept (MLI) and mean alveolar airspace (MAA) of CS rats increased by 44.8% and 43.7%, respectively, indicating the occurrence of emphysema. The characteristics of chronic bronchitis including hyperplasia of bronchial epithelial cells, hypersecretion of mucus and development of peribronchial fibrosis were also found in rat lungs. CS group rats showed 43% body weight gain reduction. To conclude, a more adequate sidestream cigarette smoke rat COPD model was established, which will be beneficial for understanding the pathogenesis of the disease and for evaluation of drug effectiveness.     

Metabolic disposition of pyrazinamide in the rat: identification of a novel in vivo metabolite common to both rat and human

Only limited studies have been reported on the disposition and pharmacokinetics of pyrazinamide (PZA) in both animals and humans. The metabolism of PZA has never been completely elucidated, consequently the metabolites of PZA, pyrazinoic acid (PA), 5-hydroxypyrazinoic acid (5-HOPA), and 5-hydroxypyrazinamide (5-HOPZA) were characterized and the disposition of PZA was examined following administration of 150 mg kg-1 of 14C-PZA to male Wistar rats. Comparable t1/2 for total radiolabel 14C (1.45 +/- 0.06 h) and PZA (1.39 +/- 0.04 h) in the blood compartment were observed. Cumulative 48 h excretion in urine and faeces accounted for 82.6 +/- 3.2 per cent and 11.0 +/- 1.3 per cent, respectively, of the dose administered. In the 0-6 h urine collections PA, 5-HOPA, 5-HOPZA, and PZA, respectively, accounted for 25.4 +/- 1.7, 17.7 +/- 1.2, 11.6 +/- 0.8, and 2.7 +/- 0.2 per cent of the administered dose. In the 6-12 h urine samples the proportions of PA and 5-HOPA increased statistically over the 0-6 h excretion whereas 5-HOPZA decreased. Administration of PZA to humans indicated 5-HOPZA was a major urinary metabolite in human. These data suggested that direct hydroxylation of PZA was an alternative pathway in the oxidation of PZA of importance to both human and rat.     

Distribution and Elimination of 2–MethyI–4–Chlorophenoxyacetic Acid (MCPA) in Male Rats

Abstract The distribution and elimination of 2–methyl–4–chlorophenoxyacetic acid (MCPA) in male rats were studied. 3 mg of ¹⁴C–labelled and non–labelled MCPA in 50 % ethanol was injected into the stomach of male rats and urine, faeces and internal organs or tissues were analyzed for radioactivity. During the first 24 hrs 92.26 ± 5.36 % of the radioactivity was excreted in the urine and 6.76 ± 3.56 % in the faeces. Recovery in the urine and faeces after five days was 102.78 ± 1.10 % of the dose administered, indicating that practically all MCPA is eliminated in the urine and faeces. The maximum concentrations of MCPA in the tissues occurred between 2 to 8 hrs after administration. Thereafter the concentrations declined rapidly. The highest concentrations of MCPA were observed in the blood, kidney, lung, heart, suprarenal gland, liver, thyroid gland and bone marrow. The lowest concentrations were those in the brain, adipose tissue, testis and muscle.     

Mechanistic population modeling of diabetes disease progression in Goto-Kakizaki rat muscle

Pyruvate dehydrogenase kinase 4 (PDK4) is a lipid status responsive gene involved in muscle fuel selection. Evidence is mounting in support of the therapeutic potential of PDK4 inhibitors to treat diabetes. Factors that regulate PDK4 mRNA expression include plasma corticosterone, insulin and free fatty acids. The objective was to determine the impact of those plasma factors on PDK4 mRNA and to develop and validate a population mathematical model to differentiate aging, diet and disease effects on muscle PDK4 expression. The Goto-Kakizaki (GK) rat, a polygenic non-obese model of type 2 diabetes, was used as the diabetic animal model. Muscle PDK4 mRNA expression was examined by real-time QRTPCR. Groups of GK rats along with controls fed with either a normal or high fat diet were killed at 4, 8, 12, 16 and 20 weeks of age. Plasma corticosterone, insulin and free fatty acids were measured. The proposed mechanism-based model successfully described the age, disease and diet effects and the relative contribution of these plasma regulators on PDK4 mRNA expression. Muscle growth reduced the PDK4 mRNA production rate by 14% per gram increase. The high fat diet increased the initial production rate constant in GK rats by 2.19-fold. The model indicated that corticosterone had a moderate effect and PDK4 was more sensitive to free fatty acid than insulin fluxes, which was in good agreement with the literature data.     

Long-term feeding of red algae (Gelidium amansii) ameliorates glucose and lipid metabolism in a high fructose diet-impaired glucose tolerance rat model

This study was designed to investigate the effect of Gelidium amansii (GA) on carbohydrate and lipid metabolism in rats with high fructose (HF) diet (57.1% w/w). Five-week-old male Sprague-Dawley rats were fed a HF diet to induce glucose intolerance and hyperlipidemia. The experiment was divided into three groups: (1) control diet group (Con); (2) HF diet group (HF); and (3) HF with GA diet group (HF + 5% GA). The rats were fed the experimental diets and drinking water ad libitum for 23 weeks. The results showed that GA significantly decreased retroperitoneal fat mass weight of HF diet-fed rats. Supplementation of GA caused a decrease in plasma glucose, insulin, tumor necrosis factor-α, and leptin. HF diet increased hepatic lipid content. However, intake of GA reduced the accumulation of hepatic lipids including total cholesterol (TC) and triglyceride contents. GA elevated the excretion of fecal lipids and bile acid in HF diet-fed rats. Furthermore, GA significantly decreased plasma TC, triglyceride, low density lipoprotein plus very low density lipoprotein cholesterol, and TC/high density lipoprotein cholesterol ratio in HF diet-fed rats. HF diet induced an in plasma glucose and an impaired glucose tolerance, but GA supplementation decreased homeostasis model assessment equation-insulin resistance and improved impairment of glucose tolerance. Taken together, these results indicate that supplementation of GA can improve the impairment of glucose and lipid metabolism in an HF diet-fed rat model.     

高糖高脂诱导大鼠代谢相关脂肪性肝病模型的建立

目的 建立SD大鼠代谢相关脂肪性肝病（metabolic associated fatty liver disease,MAFLD）模型,观察大鼠病理变化。方法 用高糖高脂饲料饲喂雄性SD大鼠20周,检测模型组大鼠血清和肝匀浆相关生化指标的水平、肝脏脏器质量和系数、肝脏组织病理学变化。结果 模型组大鼠饲喂高糖高脂饲料20周后,与对照组比较,血清总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）及肝脏TC和三酰甘油（TG）的水平均显著升高（P<0.01）,血清TG、高密度脂蛋白胆固醇（HDLC）的水平均显著降低（P<0.01）,肝脏质量及系数显著性增加（P<0.01）。肝组织的病理改变为严重肝细胞脂肪变性及多灶性肉芽肿性炎。结论 高糖高脂饲料饲喂成功建立了合适的MAFLD动物模型,肝脏病理改变可见广泛的脂肪变性和大量的肉芽肿性炎症,未见纤维化。     

Hepatoprotective effects of geniposide in a rat model of nonalcoholic steatohepatitis

Objectives Nonalcoholic steatohepatitis (NASH), a metabolic disorder of the liver, may gradually evolve into fibrosis or cirrhosis. Recent studies have suggested that geniposide can effectively inhibit experimental liver fibrosis. Therefore, the aim of this study was to determine whether geniposide can influence the early phase of fibrogenesis in an animal model of NASH. Methods Male Sprague–Dawley rats were given a high fat diet alone or the same diet combined with geniposide at doses of 25, 50 or 100 mg/kg for six weeks. Ten rats received corresponding solvent as a normal control. Key findings Treatment with geniposide could improve liver histology through reducing the elevated liver index (liver weight/body weight), serum alanine aminotransferase and aspartate aminotransferase. Total cholesterol, triglycerides and free fatty acids in serum and liver decreased in geniposide‐treated rats. Furthermore, geniposide increased serum insulin levels but reduced serum tumour necrosis factor‐α level in high‐fat diet rats. In addition, geniposide suppressed expression of CYP2E1 and increased peroxisome proliferator‐activated receptor‐α (PPARα) expression. These benefits may be associated with increased superoxide dismutase and decreased malondialdehyde in liver. Conclusions Geniposide exerts protective effects against hepatic steatosis in rats fed with a high fat diet; the underlying mechanism may be associated with its antioxidant actions or regulation of adipocytokine release and expression of PPARα.