小剂量乙酰半胱氨酸治疗慢性肝损伤作用及其机制

目的 研究小剂量乙酰半胱氨酸（N-acetylcysteine,NAC）对CCl₄所致慢性肝损伤的疗效及其作用机制。方法 将大鼠分为正常对照组、模型组、小剂量NAC低、中、高剂量组和阳性对照组。小剂量NAC低、中、高剂量组分别给予45,90,180 mg·kg^-1,阳性对照组给予阿拓莫兰54 mg·kg^-1,正常对照组和模型组腹腔注射等容积灭菌生理盐水。采用CCl₄复制大鼠慢性肝损伤模型,末次给药后24 h麻醉大鼠,腹主动脉取血,检测血清ALT、AST含量以及肝组织中SOD、MDA、GSH和Hyp含量,观察肝脏组织病理学变化,免疫组化检测肝组织Nrf2、HO-1的表达。结果 与正常组比较,模型组大鼠血清ALT、AST、MDA和Hyp含量明显升高（P<0.01）,SOD、GSH虽有下降趋势,但结果无统计学差异,Nrf2、HO-1蛋白表达均增加,但差异无统计学意义。与模型组比较,小剂量NAC低、中、高剂量组ALT、AST水平明显降低（P<0.01）,低、中剂量组SOD、GSH、Hyp含量差异均有显著性（P<0.01或P<0.05）,高剂量组GSH、Hyp含量差异均有显著性（P<0.01或P<0.05）,各剂量组MDA均有下降趋势,但无统计学意义,低、中、高剂量组Nrf2、HO-1蛋白表达均增加,其中低剂量组差异有统计学意义（P<0.01或P<0.05）。结论 小剂量乙酰半胱氨酸对CCl₄诱导大鼠慢性肝损伤具有较好的治疗作用,其作用机制可能通过Nrf2/HO-1通路发挥抗氧化应激作用。     

胃舒散对四氯化碳慢性肝损伤大鼠的保护作用

目的　观察胃舒散对四氯化碳 (CCl4)所致大鼠慢性肝损伤的影响。方法　采用CCl4诱导大鼠慢性肝损伤模型 ,测定血清丙氨酸氨基转移酶 (ALT)、天门冬氨酸氨基转移酶 (AST)、血清白蛋白 (ALB)、透明质酸(HA)、肝组织羟脯氨酸 (Hyp)含量 ,并进行肝脏病理组织学检查。结果　CCl4慢性肝损伤大鼠血清ALT、AST、HA、肝组织Hyp含量升高 (与正常组比较P <0 0 1～ 0 0 0 1) ,血清ALB含量降低 (与正常组比较P <0 0 1) ,肝细胞坏死程度和肝组织纤维化程度显著增加 ,造模成功。胃舒散能显著降低血清ALT、AST、HA、肝组织Hyp含量(与模型组比较P <0 0 5～ 0 0 1) ,升高血清ALB值 (与模型组比较P <0 0 5～ 0 0 1) ,并能使肝细胞坏死程度和肝组织纤维化程度减轻。结论　胃舒散对大鼠CCl4慢性肝损伤有明显的保护作用。     

黄根片对四氯化碳致大鼠慢性肝损伤的影响

目的：探讨黄根片对大鼠慢性肝损伤的防治作用.方法：50只Wistar大鼠随机分为空白对照组、模型组、阳性对照组（联苯双酯滴丸,0.2 g·kg-1）、黄根片高、低剂量（36 g·kg-1,9 g·kg-1）组.除空白对照组外,其余各组大鼠每周2次皮下注射四氯化碳复制慢性肝损伤模型,同时每天灌胃给药1次,连续12周,观察黄根片对慢性肝损伤大鼠血液生化指标以及肝组织病理变化的影响.结果：与空白对照组比较,模型组大鼠造模后12周体质量、残留肝组织百分率显著降低,肝脏系数、肝组织Hyp含量、血清ALT、AST含量显著升高,血清TP、Alb含量显著降低（P＜0.05或0.01）.与模型组比较,黄根片高、低剂量组灌胃给药12周能够显著提高大鼠血清TP含量和残留肝组织百分率（P＜0.05）.结论：黄根片对四氯化碳致大鼠慢性肝损伤模型有一定的保护作用.     

Protective Effect of Ebselen on Aflatoxin B1‐Induced Cytotoxicity in Primary Rat Hepatocytes

Recent studies have shown that aflatoxin B₁ enhances reactive oxygen species formation and causes oxidative damage, which may ultimately contribute to the cytotoxicity and carcinogenic effect of aflatoxin B₁. Ebselen, 2‐phenyl‐1,2‐benzoisoseleazol‐3(H)‐one, a synthetic seleno‐organic compound has been shown to possess glutathione peroxidase‐like activity and free radical scavenging ability. Thus present study was designed to investigate the protective effect of ebselen on aflatoxin B₁‐induced cytotoxicity in primary rat hepatocytes. Aflatoxin B₁‐induced cytotoxicity and lipid peroxidation were determined by lactate dehydrogenase leakage and malondialdehyde generation, respectively. Intracellular reactive oxygen species level was measured using the fluorescent probe 2′,7′‐dichlorofluorescin diacetate, and the intracellular reduced glutathione concentration was determined with a fluorometric method. Ebselen was found to display a dose‐dependent protective effect on lactate dehydrogenase leakage and malondialdehyde generation caused by aflatoxin B₁ exposure. The results also demonstrate that ebselen efficiently inhibits the intracellular reactive oxygen species formation in aflatoxin B₁‐treated hepatocytes in a dose and time‐dependent manner. It was also noted that ebselen was able to increase the intracellular reduced glutathione concentration, both in the control and in aflatoxin B₁‐treated hepatocytes. The protection of ebselen against aflatoxin B₁ cytotoxicity, however, was not affected by lowering the concentration of intracellular reduced glutathione. The overall data indicate that ebselen possesses a potent protective effect against aflatoxin B₁‐induced cytotoxicity, and the main mechanism involved in the protection may be its strong capability in inhibiting intracellular reactive oxygen species formation and preventing oxidative damage.     

低蛋白饮食联合α-酮酸对慢性肾脏病早期蛋白尿的影响研究

目的探讨早期应用低蛋白饮食联合α-酮酸能否减少蛋白尿、延缓肾脏病进展。方法将应用激素联合免疫抑制剂治疗12周后尿蛋白定量仍大于2g/d的慢性肾脏病患者分为两组:低蛋白饮食组(LPD组,蛋白0.6～0.8g.kg-1.d-1并给α-酮酸0.09g.kg-1.d-1)和正常蛋白饮食组(NPD组,蛋白1.0～1.2g.kg-1.d-1)。每月监测血压、肾功能、血清白蛋白、尿蛋白定量等指标。结果同NPD组比较,LPD组肾小球滤过率明显升高,尿蛋白定量明显下降,血清白蛋白明显升高。结论低蛋白饮食联合α-酮酸能显著减少慢性肾脏病(1～2期)蛋白尿水平,更好维持肾脏功能和营养状态。     

小剂量初次腹膜透析对慢性肾衰竭的疗效研究

目的:分析对慢性肾衰竭患者实施小剂量初次腹膜透析治疗的效果.方法:择取32例慢性肾衰竭患者,对照组16例接受常规剂量初次腹膜透析,研究组16例接受小剂量初次腹膜透析.结果:研究组血肌酐水平低于对照组,血红蛋白水平、肾皮质厚度、尿量均高于对照组(P<0.05);研究组总尿素整体清除率高于对照组(P<0.05);研究组并发...     

重组鲨肝刺激物质类似物对CCl4诱导的急性肝损伤的保护作用

探讨重组鲨肝刺激物质类似物（r-sHSA）对CCl₄急性肝损伤模型的保护作用。采用CCl₄花生油溶液（0.15%,ip）诱导小鼠急性肝损伤,用改良赖氏法测定血清ALT、AST、MDA水平,并观察病理变化。结果显示r-sHSA能显著降低CCl₄所致小鼠ALT和AST升高,恢复AST/ALT比值,降低MDA的含量。病理切片显示r-sHSA能明显减轻CCl₄对肝组织的损伤。r-HSA对CCl₄急性肝损伤小鼠具有一定的保护作用。     

Prolonged Attenuation of the Reinforcing Strength of Cocaine by Chronic d-Amphetamine in Rhesus Monkeys

Chronic treatment with the indirect dopamine agonist d-amphetamine can reduce cocaine use in clinical trials and, in preclinical studies in laboratory animals, attenuates daily cocaine self-administration. The present study extended previous results to conditions designed to reflect a more clinically relevant experience of cocaine exposure and d-amphetamine treatment. Each morning, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement. After determining a dose-response curve for cocaine (0.003–0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule of reinforcement in the evening, cocaine self-administration sessions were suspended and d-amphetamine (0.01–0.056 mg/kg/h, i.v.) was administered continuously for at least 24 days, except during cocaine self-administration sessions, which were conducted using the PR schedule once every 8 days. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was redetermined. Cocaine- and food-maintained responding were also examined after discontinuation of d-amphetamine. Although individual differences in sensitivity were observed, d-amphetamine produced selective, qualitatively similar decreases in the reinforcing strength of cocaine in all monkeys that persisted at least 4 weeks. Moreover, cocaine dose-effect curves were shifted downward and/or to the right. For 2 weeks following discontinuation of d-amphetamine treatment, the reinforcing strength of cocaine varied within and across individuals, however, on the whole no increased sensitivity was apparent. These data provide further support for the use of agonist medications for cocaine abuse, and extend the conditions under which such treatment is successful to those that incorporate clinically relevant patterns of cocaine use and drug treatment.     

低蛋白饮食对糖尿病肾病治疗效果的评价研究

目的 评价低蛋白饮食对糖尿病肾病的治疗效果.方法 选取2015年3月-2017年1月解放军白求恩国际和平医院收治的糖尿病肾病64例,随机分为研究组及对照组,每组32例.2组均进行常规饮食指导,研究组在此基础上给予优质低蛋白饮食,治疗周期为3个月.观察并比较2组治疗前后体重指数(BMI)、平均动脉压(MAP)、血红蛋白(Hb)、白蛋白(ALB)、尿素(BUN)、肌酐(Cr)、尿酸、肾小球滤过率(GFR)、24 h尿白蛋白、糖化血红蛋白(HbAlc)、空腹血糖(FPG)、餐后2h血糖(2 h PG)、血清甘油三酯(TG)、血清总胆固醇(TC)水平.结果 研究组BMI、MAP、Hb、ALB、BUN、Cr、尿酸、GFR、24 h尿白蛋白、HbAlc、FPG、2hPG、TG、TC均优于治疗前及对照组(P＜0.05).结论 优质低蛋白饮食可改善GFR,减轻肾小球硬化,提高血清ALB水平,延缓肾功能损伤.     

灵五颗粒对四氯化碳诱导大鼠慢性肝损伤的影响

目的 研究灵五颗粒对四氯化碳(carbon tetrachloride,CCl4)致大鼠慢性肝损伤的防治作用,并探讨其可能的作用机制. 方法 将Wistar大鼠随机分为6组,正常组自由饮水,其余5组给予350 mg&#8226;L^-1苯巴比妥水溶液2周诱导肝药酶.实验第3周,用CCl4复制慢性肝损伤动物模型［50% CCl4橄榄油溶液,灌胃,首次剂量0.08 mL,以后按0.08 mL&#8226;(100 g)-¹,每周1次,连续5周］.自造模之日开始,灌胃给药,qd,连续5周.末次给药后禁食16 h,取大鼠血、肝脏、脾、胸腺,检测血清肝功能［丙氨酸氨基转移酶(alanine aminotransferase,ALT), 天冬氨酸氨基转移酶(aspartate aminotransferase,AST), 碱性磷酸酶(alkaline phosphatase,ALP)、清蛋白(albumin,ALB)、总蛋白(total protein,TP)］指标、肝组织中羟脯氨酸(hydroxyproline,Hyp)、丙二醛(malonaldehyde,MDA)含量和超氧化物歧化酶(superoxide dismutase,SOD)活性,另取肝脏做病理组织学检查,计算脏器指数. 结果 模型组大鼠有明显肝损伤表现,各给药组肝损伤均有不同程度的改善(P<0.01或P<0.05).病理组织学检查 结果 表明,肝脏病变程度均较模型组明显减轻. 结论 灵五颗粒对CCl4所致慢性肝损伤具有较好的防治作用,保肝降酶效果明显,其机制可能与抑制Hyp增多,降低MDA和升高SOD的抗氧化作用有关.     

Effect of 3-Methylcholanthrene Pretreatment on Aflatoxin B1 Metabolism in Hamster Liver

Abstract

The effects of 3-methylcholanthrene (MC) pretreatment of hamsters on the hepatic metabolism of aflatoxin B₁ (AFB₁) have been investigated in studies with subcellular, isolated hepatocytes and in vivo. Pretreatment of hamsters with MC (2.5 mg/100 g body wt.) 24 hr. before sacrifice not only increased microsomal cytochrome P-450 content by 70% but also increased the specific activity of cytochrome P-450 dependent metabolic activation of AFB₁ as judged by AFB₁-DNA binding by 65%. Even in isolated hepatocytes, AFB₁-DNA binding was elevated by 65% in MC-treated hepatocytes. The ratios of AFB₁-glutathione (AFB₁-SG) to AFB₁-DNA were about the same in both hepatocyte system. Hepatic AFB₁-DNA binding was also increased by 85% in intact animals after MC treatment. It appears that the increased hepatic AFB₁-DNA binding after MC treatment of hamsters is a result of higher specific activity and higher levels of cytochrome P-450 species involved in the activation of AFB₁.     

复方甘草酸苷对慢性乙型肝炎患者肝功能和肝纤维化指标的影响

目的:观察复方甘草酸苷对慢性乙型肝炎患者肝功能和肝纤维化指标的影响。方法:33例慢性乙型肝炎患者静脉注射复方甘草酸苷注射液80ml,1次/d,连用4wk,观察治疗前、后肝功能、肝纤维化指标的变化和临床疗效。结果:轻度、中度、重度患者的总有效率分别为100%、92·3%、91·7%;治疗前、后比较,患者丙氨酸氨基转移酶、总胆红素有显著性差异(P<0·05),中度、重度患者的Ⅲ型前胶原、玻璃酸、层粘蛋白亦有显著性差异(P<0·05)。结论:复方甘草酸苷治疗慢性乙型肝炎疗效好,可明显改善其肝功能和肝纤维化指标。     

小剂量甲状腺素对低T3代偿期肝硬化的影响

目的探讨代偿期肝硬化甲状腺激素水平的变化及小剂量甲状腺素对低T1代偿期肝硬化患者肝纤维化的影响。方法60名伴有T3降低的代偿期肝硬化患者,随机分为两组,给予相同的保肝、营养支持治疗,治疗组另加左旋甲状腺素片25m#d,连续1个月,观察两组临床疗效、肝功能及肝纤维化指标的变化。结果治疗组同对照组临床疗效无差异,治疗组血清AST、ALT、血清透明质酸（HA）、层粘连蛋白（LN）、Ⅲ型前胶原肽（PC-Ⅲ）、Ⅳ型胶原（C-Ⅳ）水平低于对照组,ALB无变化,A／G比值高于对照组。结论外源性甲状腺素对T3代偿期肝硬化患者能减轻肝纤维化的发展。     

Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

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Effects of Inhalation Exposures to an M1-Receptor Agonist on Ventilation in Rhesus Monkeys

ABSTRACT

Information was needed on effects of possible occupational inhalation exposure to an M]-receptor agonist (xanomeline) such as might occur during the manufacturing process. Both acute and repeated inhalation exposures to xanomeline were carried out in six male rhesus monkeys using a head-dome exposure system. Exposure concentrations ranged from 0.3 to 10 mg/m³. The exposure durations were up to 2 weeks. Decreases in tidal volume and increases in respiratory frequency were both time and concentration related during acute exposures. These effects were blocked with atropine pre-treatment. Correlation with pulmonary resistance measurements in two monkeys suggested that these were bronchoconstrictive changes that increased with severity with time at a given concentration and with concentration when measured after a constant exposure time. The dose-response was relatively steep with 10 mg/m³ becoming intolerable to the monkeys after approximately 15 minutes, but no measurable effects were observed at 0.3 mg/m³ after up to 4 hours of exposure. To investigate the effects of repeated exposures, monkeys were exposed for 4 hr/day, 5 days/wk for 2 weeks to 0.0 (air only), 0.3, and 1.2 mg xanomeline/m³ of air. When compared to the air-only exposure, 0.3 mg/m³ caused no significant changes in tidal volume. in contrast, 1.2 mg/m³ caused a rapid and significant decrease in tidal volume that was sustained throughout the 4-hr exposure. A slower rise in breathing frequency also occurred. Repeated exposures did not alter the effects seen after a single exposure. It is concluded that xanomeline, a M₁ - receptor agonist, can acutely alter normal ventilation in non-human primates at airborne concentrations ≥0.6 mg/m³ and should be carefully controlled in a manufacturing environment. The no-observed-effect concentration was 0.3 mg/m³.     

空心莲子草醇提物抗CCl4肝损伤的实验研究

目的观察空心莲子草醇提物对CCl4肝损伤的保护作用.方法给小鼠腹腔注射CCl4制成肝损伤模型,分为3组,每组10只.分别经口给予生理盐水、空心莲子草醇提物(0.02 g/g)和联苯双酯(0.2 mg/g).连续用药6天后,第7天将小鼠断头处死,取血和肝脏,分别测定空白对照组、空心莲子草组和联苯双酯组小白鼠的血清ALT和血清AST、肝指数及肝细胞镜检,并进行比较.结果空心莲子草组能明显对抗CCl4引起的血清ALT和血清AST增高,减轻CCl4对肝细胞的损伤.空白对照组与联苯双酯组和空心莲子草组比较均有显著性差异(P＜0.01).结论空心莲子草醇提物对CCl4致肝损伤有保护作用.     

Adsorbents Reduce Aflatoxin M1 Residue in Milk of Healthy Dairy Cow Exposed to Moderate Level Aflatoxin B1 in Diet and Its Exposure Risk for Humans

This study investigated the effect of moderate risk level (8 µg/kg) AFB₁ in diet supplemented with or without adsorbents on lactation performance, serum parameters, milk AFM₁ content of healthy lactating cows and the AFM₁ residue exposure risk in different human age groups. Forty late healthy lactating Holstein cows (270 ± 22 d in milk; daily milk yield 21 ± 3.1 kg/d) were randomly assigned to four treatments: control diet without AFB₁ and adsorbents (CON), CON with 8 μg/kg AFB₁ (dry matter basis, AF), AF + 15 g/d adsorbent 1 (AD1), AF + 15 g/d adsorbent 2 (AD2). The experiment lasted for 19 days, including an AFB₁-challenge phase (day 1 to 14) and an AFB₁-withdraw phase (day 15 to 19). Results showed that both AFB₁ and adsorbents treatments had no significant effects on the DMI, milk yield, 3.5% FCM yield, milk components and serum parameters. Compared with the AF, AD1 and AD2 had significantly lower milk AFM₁ concentrations (93 ng/L vs. 46 ng/L vs. 51 ng/L) and transfer rates of dietary AFB₁ into milk AFM₁ (1.16% vs. 0.57% vs. 0.63%) (p < 0.05). Children aged 2–4 years old had the highest exposure risk to AFM₁ in milk in AF, with an EDI of 1.02 ng/kg bw/day and a HI of 5.11 (HI > 1 indicates a potential risk for liver cancer). Both AD1 and AD2 had obviously reductions in EDI and HI for all population groups, whereas, the EDI (≥0.25 ng/kg bw/day) and HI (≥1.23) of children aged 2–11 years old were still higher than the suggested tolerable daily intake (TDI) of 0.20 ng/kg bw/day and 1.00 (HI). In conclusion, moderate risk level AFB₁ in the diet of healthy lactating cows could cause a public health hazard and adding adsorbents in the dairy diet is an effective measure to remit AFM₁ residue in milk and its exposure risk for humans.     

枯否细胞在高脂诱导的肝脏胰岛素抵抗中的作用

【摘要】目的探讨枯否细胞在高脂诱导的肝脏胰岛素抵抗中的作用。方法将C57BL/6J小鼠84只,分为普食组和高脂组,其中1组普食和1组高脂小鼠在喂养后1、2、4、8、12、16周行葡萄糖耐量检测,另外6组普食和6组高脂小鼠分别在上述时间处死取肝脏;Western blot检测肝脏胰岛素受体底物1（IRS1）-ser307、蛋白激酶B（Akt）-ser473、核糖体蛋白S6激酶1（S6K1）-thr389、磷酸化c-Jun氨基末端激酶（p-JNK）表达;实时定量PCR检测肝脏炎性因子单核细胞趋化蛋白（MCP）-1、肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-10mRNA的表达。结果与普食喂养相比,高脂喂养小鼠1周后葡萄糖耐量检测显示葡萄糖代谢异常（P<0.05）,Western blot显示高脂组肝脏IRS1-ser307、S6K1-thr389（第4~16周）、p-JNK（2~16周）表达增强,Akt-ser473（8~16周）表达减弱,蛋白相对表达量与之一致（均P<0.05）。第2~16周高脂组肝脏炎性因子MCP-1、TNF-α、IL-1βmRNA表达高于普食组（均P<0.01）,抗炎因子IL-10mRNA在第4~16周时低于普食组（均P<0.01）。结论高脂饮食可能通过调节M1型枯否氏细胞分泌炎性因子和抑制M2型枯否细胞分泌抗炎因子在肝脏胰岛素抵抗中发挥作用。     

天丹强肝胶囊对急慢性肝损伤的作用

目的：观察天丹强肝胶囊对急慢性肝损伤的作用。方法：用D－氨基半乳糖和CCl4致小鼠和大鼠急慢性肝损伤，比较天丹强肝胶囊与护肝胶囊、联苯双脂滴丸对急慢性肝损伤动物血清谷丙转氨酶（GOT）、谷草转氨酶（GCT）、总蛋白（TP）、白蛋白（ALB）、白蛋白／球蛋白比值（A／G）及其肝纤维增生程度的影响。结果：与生理盐水组比较，天丹强肝胶囊两个剂量组均可明显降低慢性肝损伤大鼠血清GPT、GOT（P＜0．05），明显降低其肝纤维增生程度(P＜0．05），高剂量组能升高其血清TP、ALB值及A／G比值；与护肝胶囊比较，天丹强肝胶囊的上述保肝作用指标无明显的统计学差异；与联苯双脂比较，该药降低慢性肝损伤大鼠的血清GPT、GOT的作用较弱，升高其血清TP、ALB和A／G比值及降低其肝纤维增生程度无明显的统计学差异，而该药降低急性肝损小鼠血清GPT作用优于联苯双酯。结论：天丹强肝胶囊对急慢性肝损伤有明显改善作用。