NO-1886对高糖高脂饲料喂养新西兰兔糖代谢的影响

合成药NO-1886是脂蛋白脂肪酶(LPL)的激动剂，能降低血浆甘油三酯(TG)并升高高密度脂蛋白胆固醇(HDL-c)水平。我们曾发现NO-1886还具有降低血糖的作用。本研究主要观察NO-1886对糖尿病兔胰岛素抵抗及β-细胞功能方面的影响。用高糖高脂饲料诱导，使新西兰兔血浆葡萄糖升高，发生胰岛素抵抗。在高糖高脂饲料中添加1％NO-1886进行治疗。结果：发现NO-1886可抑制血清葡萄糖升高，经糖耐量和胰岛素敏感性试验检测，NO-1886可保护胰岛素的急性相分泌，增强胰岛素对葡萄糖的清除能力。研究结果提示NO-1886具有改善胰岛素抵抗、降低血糖的作用。     

NO-1886降低脂负荷新西兰兔血清甘油三酯和游离脂肪酸

目的观察NO1886(ibrolipim)对脂肪餐后血脂水平的影响。方法将25只♂新西兰兔随机分为5组正常对照组、脂负荷组、脂负荷+NO1886(05g·kg-1)组、脂负荷+NO1886(10g·kg-1)组、脂负荷+NO1886(15g·kg-1)组;分别在给予20%脂肪乳和相应剂量NO1886前后第1、2、4、6、8、24h从兔耳缘静脉采血,离心收集血清,测定血清甘油三酯和游离脂肪酸。结果NO1886能有效地降低脂负荷后新西兰兔血清甘油三酯和游离脂肪酸水平,呈剂量依赖性,并能使游离脂肪酸恢复到正常。结论NO1886具有调节脂肪餐后血脂水平的作用。     

GABA transporter-1 inhibitor NO-711 alters the EEG power spectra and increases non-rapid eye movement sleep in mice

GABA transporter subtype 1(GAT1) constructs high affinity reuptake sites for GABA in the CNS and regulates GABAergic transmission.Compounds that inhibit GAT1 are targets for epilepsy treatment.Sedation has been reported as a side effect of these agents,indicating possible sedative or hypnotic potential.To elucidate the role of GAT1 in sleep-wake regulation,we observed the sleep behaviors of mice treated by NO-711,a selective GAT1 inhibitor.The current data reveal that NO-711(10 mg·kg-1) causes a marked enhancement of EEG power density in theta(4-10 Hz) and the high frequency range EEG activity during the wakefulness and REM sleep,which were quite differed from those induced by zolpidem,a widely used hypnotic that binds preferentially to α1 GABAA receptor.NO-711 administered ip at doses of 1,3 or 10 mg·kg-1 significantly increased the amount of non-rapid eye movement(non-REM,NREM) sleep and shortened the sleep latency to NREM sleep.NO-711 at doses of 3 and 10 mg·kg-1 increased the number of NREM bouts and prolonged the mean duration at 10 mg·kg-1,and increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness.NO-711 did not affect the architecture of REM sleep.Immunohistochemistry study showed that NO-711 dose-dependently increased c-Fos expression in neurons of the ventrolateral preoptic area(VLPO) and median preoptic nucleus(MnPO),which have been proposed to have a role in sleep-related processes.While the c-Fos expression in wakefulness-related processes nucleus,such as tuberomammillary nucleus(TMN),lateral hypothalamus(LH),and locus ceruleus(LC),were decreased by NO-711 treatment.These results indicated that NO-711 induced NREM sleep by modulating the sleep-wake related nucleus.Suggests GAT1 may be a potential target for hypnotic in treatment of insomnia.     

氢化物原子荧光法检测大米中汞存在的干扰及消除

目的:本文针对微波消解-氢化物原子荧光法测定大米中汞时,干扰因素的存在,如氮氧化物,亚硝酸根等,及其影响因子的消除进行了研究,优化前处理条件。方法:采用了模拟实际可能存在干扰因素的实验,并通过加入一定比例氨基磺酸后水浴的方法相关消除干扰因素。结果:分析测试汞时,就消解时溶解的氮氧化物和亚硝酸根分别进行了探讨:1μg.L-1标准溶液中一定体积亚硝酸根(0.3%m/VNaNO2)可造成90%的负偏差;酸消解过程中产生的NOx带来的干扰不固定。通过实验发现,只通过水浴消解液或在室温条件下加入氨基磺酸都不能完全恢复Hg的测试信号;但通过加入一定比例的氨基磺酸(0.3%)后,水浴1.5 h可以彻底消除上述干扰。结论:利用论文中提供的方法,可消解并分析相关的植物标准样品,可以得到满意的结果。     

NO-1886 ameliorates glycogen metabolism in insulin-resistant HepG2 cells by GSK-3β signalling

Objectives The aim of the study was to elucidate the possible role and mechanism of NO‐1886 (ibrolipim, a lipoprotein lipase activator) in ameliorating insulin resistance induced by high palmitate. Methods HepG2 cells were cultured in RPMI 1640 medium and were treated with palmitate to induce insulin resistance. Free fatty acids (FFAs), glucose, glycogen, cell viability and mRNA and protein levels were analysed separately. Key findings We found that HepG2 cells treated with 0.5 mm palmitate for 48 h led to a significant decrease of insulin‐induced glucose consumption (from 2.89 ± 0.85 mm in the control to 0.57 ± 0.44 mm in palmitate). Insulin resistance (IR) of HepG2 cells was induced by 0.5 mm palmitate for 48 h. NO‐1886 stimulated glucose consumption, glycogen synthesis and FFA absorption in insulin‐resistant HepG2 cells. Maximum stimulation effects were observed with 10 µm NO‐1886 for 24 h. Compared with the dimethyl sulfoxide‐treated group, 2.5 µm NO‐1886 or higher could induce the mRNA expression of lipoprotein lipase. Meanwhile, NO‐1886 increased the protein content of P‐GSK‐3βser⁹ and decreased the protein level of GSK‐3β in insulin‐resistant HepG2 cells, but NO‐1886 didn't change the protein levels of PI3‐Kp85 and Akt2. Conclusion Lipoprotein lipase activator NO‐1886 could increase glycogen synthesis in HepG2 cells and could ameliorate the insulin resistance, which was associated with GSK‐3 signalling.     

脂蛋白脂酶活化剂NO-1886抑制糖尿病兔动脉粥样硬化的形成

目的　合成化合物NO 1886 ,一种脂蛋白脂酶活化观察脂蛋白脂酶活化剂是否降低高脂 /高蔗糖饲料诱发的糖尿病新西兰兔的血浆葡萄糖并减轻其动脉粥样硬化。方法　给予高脂 /高蔗糖饲料升高新西兰兔血浆总胆固醇 ,甘油三酯和葡萄糖及降低高密度脂蛋白胆固醇而导致动脉粥样硬化。饲料中加入 1 0 %NO 1886进行治疗观察。分别在 0、4、8、12、16、2 0及 2 4wk从禁食过夜的兔耳静脉抽取血样测定葡萄糖和脂质水平。第 2 4周末 ,处死动物 ,分离主动脉 ,经苏丹Ⅳ染色固定脂质后 ,计算脂纹病变面积。结果　应用NO 1886后 ,实验动物血浆葡萄糖 ,总胆固醇和甘油三酯降低 ,高密度脂蛋白胆固醇增加。对动脉粥样硬化的发展具有抑制作用。结论　NO 1886不仅可改善脂质紊乱 ,而且可降低血浆葡萄糖 ,减轻糖尿病兔动脉粥样硬化     

艾溴利平降低巴马小型猪脂负荷后血清三酰甘油和游离脂肪酸*

 目的：观察脂蛋白酯酶活化剂艾溴利平（ibrolipim,别名NO-1886）对高脂高蔗糖高胆固醇喂养的巴马小型猪餐后三酰甘油代谢的影响。方法：将10头巴马小型猪随机分为正常对照组和高脂高糖高胆固醇喂养组,分别用正常饲料、高脂高糖高胆固醇饲料喂养5个月,每个月末监测其空腹血糖、血清总胆固醇、高密度脂蛋白胆固醇、三酰甘油和游离脂肪酸水平。第5个月末从2组动物中分别随机选取3头进行脂肪耐量试验,分别经胃管给予以下4种处理：生理氯化钠溶液（10 mL·kg^-1）,20％脂肪乳剂（10 mL·kg^-1）,20％脂肪乳剂+艾溴利平（0.3 g·kg^-1）,20％脂肪乳剂+相似文献   

GM1对缺氧缺血（HI）新生大鼠脑损伤后NO水平及海马CA1区p-ERK表达的影响

目的：观察新生大鼠缺氧缺血性（HI）脑损伤后NO水平及海马细胞外信号调节激酶（ERK）的变化,探讨单唾液酸四己糖神经节苷脂（GM1）对其的影响。方法：选择新生7日龄Sprague-Dawley大鼠108只,随机分为三组：缺氧缺血组（HI组）,假手术对照组（Control组）,缺氧缺血＋神经节苷脂组（GM1组）每组36只。采用结扎右侧颈总动脉并吸入低氧混合气体制备缺氧缺血性脑损伤（HIBD）模型。采用镀铜镉还原法测定颈总动脉血浆一氧化氮（NO）水平,免疫组化SP法检测大脑海马CA1区p-ERK的表达。结果：对照组、HI组和GM1组新生大鼠血浆NO-2/NO-3含量分别为（41.6±8.9）、（60.9±14.7）和（43.8±10.6）μmol/L,HI组明显高于对照组和GM1组（P〈0.05）;GM1组与对照组比较,无明显差异（P〉0.05）。HI组和GM1组p-ERK表达皆为阳性,两组比较HI组表达更强（P〈0.05）。对照组未见有p-ERK表达。结论：GM1能抑制新生大鼠缺氧缺血性（HI）脑损伤后NO生成,影响p-ERK表达,对缺氧缺血（HI）新生大鼠的脑具有保护作用。     

NO-1886 Up-regulates Niemann–Pick C1 Protein (NPC1) Expression Through Liver X Receptor α Signaling Pathway in THP-1 Macrophage-Derived Foam Cells

Background  The Niemann–Pick C1 (NPC1) protein regulates the transport of cholesterol from late endosomes/lysosomes to other compartments responsible for maintaining intracellular cholesterol homeostasis. Liver X receptors (LXRs) operate as cholesterol sensors which may protect from cholesterol overload by increasing the amount of free cholesterol in the plasma membrane through inducing NPC1 expression. NO-1886 has been proven to be highly effective at increasing liver X receptor α expression and promoting cellular cholesterol efflux. In this study, the effects of NO-1886 on NPC1 expression were investigated in THP-1 macrophage-derived foam cells. Methods and results  Results showed that NO-1886 markedly increased expression of NPC1 at both mRNA level and protein level in a dose-dependent and time-dependent manner. Cellular cholesterol content was decreased while cholesterol efflux was increased by NO-1886 treatment. In addition, LXR α was also up-regulated by NO-1886 treatment. And LXR α small interfering RNA completely abolished the promotion effect which was induced by NO-1886. Conclusion  These results provide evidence that NO-1886 up-regulates expression of NPC1 through LXR α pathway in THP-1 macrophage- derived foam cells. Xin Ma and Yan-Wei Hu contributed equally to this study.     

Effects of NO-1886 on inflammation-associated cytokines in high-fat/high-sucrose/high-cholesterol diet-fed miniature pigs

Inflammation, closely associated with obesity, is emerging as an important risk factor for the pathophysiological development of atherosclerosis and diabetes mellitus. Fat balance is critical in the aetiology of obesity. Lipoprotein lipase is an important enzyme in lipid metabolism. The aim of this study was to investigate the long-term effect of the lipoprotein lipase activator, NO-1886, on inflammation cytokines, adiposity and related diseases in miniature pigs fed a high-fat/high-sucrose/high-cholesterol diet (HFSC diet). Chinese Bama-miniature pigs were fed a control diet or HFSC diet with or without NO-1886 for 5 months. The levels of inflammation-associated cytokines were determined using the antibody arrays. Feeding of the HFSC diet to miniature pigs markedly increased the expression of inflammatory cytokines. On the other hand, supplementation of NO-1886 to HFSC diet decreased the expression of inflammatory cytokines significantly, protecting against the development of atherosclerosis and diabetes mellitus. NO-1886 may have a beneficial effect on the most inflammation-associated cytokines, and this effect may contribute to improving atherosclerosis and diabetes mellitus.