地龙活性蛋白对实验性高脂血症大鼠的调脂作用及其机制

目的:研究地龙活性蛋白(Earthworm active protein,EWAP)对实验性高脂血症SD大鼠的调脂作用并探讨可能的降脂作用机制。方法:通过高脂饲料及维生素D2联合应用法建立SD大鼠高脂血症模型,以EWAP进行治疗28 d,末次给药后测定大鼠血清中总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL-c)、低密度脂蛋白(LDL-c)水平、脂蛋白脂酶(LPL)、肝脂酶(HL)活性、粪便胆汁酸(FBA)含量以及大鼠体质量变化。结果:EWAP高、中剂量组与模型组比较,TC、TG、LDL-c水平显著降低,同时HL,LPL活性及粪便中FBA排泄量均显著提高,并且EWAP高剂量组大鼠体质量相比模型组增加趋势明显。结论:EWAP对实验性高脂血症大鼠血脂代谢有调节作用,其作用机制可能与提高脂蛋白脂酶、肝脂酶活性,加强肠内胆固醇代谢转化有关。     

银杏叶提取物对实验性高脂血症大鼠的调脂机制

目的 研究银杏叶提取物对实验性高脂血症大鼠的调脂机制.方法 预防给药,即以高脂饲料造模的同时连续给药28 d,于末次给药后测定大鼠血浆中总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)的含量和脂蛋白脂酶(LPL)、肝脂酶(HL)的活性及大鼠粪便中胆汁酸(FBA)的排泄量;治疗给药,即给予高脂饲料喂养28 d,造模成功后连续给药28 d,测定大鼠血浆中TC、TG、HDL-C、LDL-C的含量和LPL、HL的活性及大鼠FBA的排泄量.结果 预防性给药后,银杏叶提取物高、中剂量组与高脂模型组比较,能显著降低血浆中TC、LDL-C,显著升高HDL-C,同时可显著提高HL和LPL的活性及增加大鼠FBA的排泄量;治疗性给药后,银杏叶提取物高、中剂量组与高脂模型组比较,能显著降低已形成高脂血症大鼠血浆中的TC、LDL-C,显著升高HDL-C,同时可显著提高HL、LPL的活性及增加大鼠FBA的排泄量.结论 银杏叶提取物对大鼠实验性高脂血症具有显著的预防和治疗作用.其作用机制可能与药物提高LPL和HL的活性并加速体内胆固醇的代谢有关.     

伊贝沙坦对胰岛素抵抗大鼠脂蛋白脂酶的影响

目的探讨伊贝沙坦改善胰岛素抵抗（IR）、减少动脉粥样硬化疾病发生的危险因素的作用。方法用果糖喂养6周龄雄性SD大鼠8周造成IR,并给予伊贝沙坦干预后,行空腹血糖（FPG）、空腹血清胰岛素（FINS）、血清甘油三脂（TG）、胆固醇（TC）、极低密度脂蛋白（VLDL）、游离脂肪酸（FFA）和血浆脂蛋白脂酶（LPL）活性的测定,分别与对照组比较。结果果糖喂养组的血压、FINS、TG、TC、VLDL及FFA均高于对照组和药物处理组（P〈0.05或P〈0.01）,而胰岛素敏感指数（ISI）及LPL活性却均低于对照组和药物处理组（P〈0.05）。结论伊贝沙坦可以减轻果糖饲料喂养SD大鼠的IR、降低血压、明显提高LPL的活性及减轻机体脂质代谢紊乱。     

小檗碱对胆固醇代谢及肝脏Insig-2基因表达的影响

目的研究小檗碱(berberine,Ber)对高脂模型大鼠胆固醇代谢的影响,并探讨其可能的机制是否与胰岛素诱导基因-2(insulin-induced gene 2,Insig-2)基因表达有关。方法♂清洁级SD大鼠40只,随机分为普食组(Normal diet,ND)、高脂饲料组(High fat diet,HFD)、高脂饲料+洛伐他汀组(Lovastatin diet,LD)、高脂饲料+低剂量小檗碱干预组(Berlow dose diet,BLD)、高脂饲料+高剂量小檗碱干预组(Berhigh dose diet,BHD)。Ber干预18 wk后测定大鼠血清总胆固醇(TC)、甘油三脂(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)等血生化指标的含量。RT-PCR和Western blot技术检测各组大鼠肝脏Insig-2 mRNA和蛋白表达变化。结果Ber干预呈剂量依赖性降低高脂模型大鼠血清TC和LDL-C水平;低剂量Ber明显上调高脂血症大鼠肝脏Insig-2基因mRNA和蛋白表达水平,而高剂量Ber则反馈性下调Insig-2基因mRNA和蛋白的表达。结论Ber干预具有明显的调血脂作用,其机制可能是通过上调肝脏Insig-2基因表达,从而抑制肝脏中胆固醇的合成代谢。     

厄贝沙坦和罗格列酮对胰岛素抵抗SD大鼠脂蛋白脂酶的影响

目的比较厄贝沙坦与罗格列酮对胰岛素抵抗(IR)SD大鼠血压、胰岛素敏感性及脂蛋白脂酶(LPL)含量的变化。方法 6周龄SD大鼠30只用果糖喂养4周,造成IR之后随机分为3组,其中2组分别给予厄贝沙坦和罗格列酮治疗4周。8周后行收缩压、空腹血糖、空腹血清胰岛素(FINS)、三酰甘油(TG)、胆固醇(TC)、极低密度脂蛋白(VLDL)、游离脂肪酸(FFA)及LPL含量测定。结果果糖喂养组的血压、FINS、TG、及FFA均高于药物治疗组(P<0.01),而胰岛素敏感指数(ISI)及LPL含量均低于药物治疗组(P<0.01)。厄贝沙坦组的血压降低较罗格列酮组明显(P<0.01),而血脂高于罗格列酮组(P<0.01),低于果糖喂养组(P<0.01)。结论厄贝沙坦较罗格列酮降压作用明显,罗格列酮改善IR和降脂作用优于厄贝沙坦。     

Mechanism and Effect of Telmisartan on Improving Insulin Resistance in OLETF Rats

目的:研究血管紧张素Ⅱ1型(AT1)受体阻滞剂替米沙坦对改善OLETF大鼠胰岛素抵抗(IR)的作用.方法:OLETF大鼠47只,高脂喂养14周诱导建立IR大鼠模型并将其随机分为5组:IR对照组(IR组)、二甲双胍(MET)组、吡格列酮(P)组、替米沙坦(L)组、低剂量替米沙坦(VL)组,12只LETO大鼠为正常对照(NC)组.干预26周后测定空腹胰岛素(FINS)、游离脂肪酸(FFA)、网膜素、视黄醇结合蛋白4(RBP4)、内脂素、空腹血糖(FBG)及血脂,计算胰岛素抵抗指数(IIOMA-IR)和胰岛素敏感性指数(ISI).结果:L组较IR组的血清网膜素、ISI升高(P＜0.05或P＜0.01);RBP4、内脂素、FBG、HOMA-IR、TC、LDL-C和FFA降低(P＜0.05或P＜0.01).多元线性逐步回归分析显示网膜素、ISI是RBP4水平的影响因素;网膜素、HOMA-IR是内脂素水平的影响因素.结论:替米沙坦可能通过提高血清网膜素、降低血清RBP4和内脂素调节血脂水平,从析改善IR.     

多廿醇降胆固醇及抗氧化作用的实验研究

目的 观察多廿醇对高脂血症大鼠的降胆固醇和抗氧化作用.方法 将大鼠随机分为正常对照组、多廿醇预防组和高脂造模组.多廿醇预防组喂饲高脂饲料的同时给予多廿醇灌胃10周;高脂造模组先给予高脂饲料4周制备大鼠高脂血症模型,再按照总胆固醇水平分为多廿醇低、中、高剂量组和阳性药物洛伐他汀对照组,灌胃给予相应药物6周后采血,测定血清中总胆固醇(TC)、甘油三脂(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平,并计算LDL-C/HDL-C、TG/HDL-C比值和动脉硬化指数(AI);测定血清中丙二醛(MDA)含量,超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)活性.结果 与高脂模型组比较,多廿醇预防组、多廿醇低、中、高剂量组和阳性对照组大鼠的血清中TC、LDL-C含量显著性下降(P＜0.01);阳性对照组大鼠的血清中TG水平显著性降低(P＜0.05);多廿醇预防组、多廿醇高剂量组和阳性对照组大鼠血清中HDL-C水平显著性升高(P＜0.05);多廿醇预防组,多廿醇低、中、高剂量组和阳性对照组LDL-C/HDL-C比值显著性下降(P＜0.01);AI显著性下降(P＜0.01);血清中MDA含量显著性下降(P＜0.05或P＜0.01);多廿醇中、高剂最组和阳性对照组的血清中SOD活性显著性升高(P＜0.05或P＜0.01);多廿醇中和高剂量组的血清中GSH-Px活性显著性升高(P＜0.01).结论 多廿醇对高脂血症模型大鼠具有明显降胆固醇的作用,且可增强机体的抗氧化作用.     

小檗碱改善多囊卵巢综合征大鼠卵巢功能及其机制

目的研究小檗碱对多囊卵巢综合征大鼠模型血清胰岛素水平及卵巢组织中胰岛素受体(IR)表达影响。方法构建多囊卵巢综合征大鼠模型, SD大鼠分为:正常组、模型组、小檗碱组(终浓度为 200 mg/kg的小檗碱灌胃)、二甲双胍组(终浓度为 170 mg/kg的二甲双胍灌胃),每组 20只。测定大鼠体质量和卵巢、子宫质量, HE染色法测定卵巢组织中成熟卵泡及黄体数,酶联免疫吸附法(ELISA)测定血清中黄体生成素(LH)、促卵泡生成素(FSH)、睾酮、瘦素(Leptin)、胰岛素水平, qPCR测定卵巢组织中胰岛素样生长因子(I IGF?I)、瘦素、胰岛素样生长因子 I受体(IGF?IR)、 IR mRNA相对表达量水平。结果模型组多囊卵巢综合征大鼠体质量和卵巢质量明显升高,成熟卵泡数明显降低,子宫质量和黄体数减少,同时血清中 LH、FSH、睾酮、瘦素水平升高,胰岛素水平( 4 569.81±528.96)pg/mL也升高,卵巢组织中 IGF?I、瘦素、 IGF?IR升高, IR mRNA相对表达量(1.95±0.12)水平升高,与正常组大鼠相比,均差异有统计学意义(P＜0.05)。小檗碱组灌胃以后,大鼠体质量和卵巢质量明显降低,成熟卵泡数明显升高,子宫质量和黄体数增多,同时血清中 LH、FSH、睾酮、瘦素水平降低,胰岛素水平［(2 741.21±247.68)pg/mL］也降低,卵巢组织中 IGF?I、瘦素、 IGF?IR、IR mRNA相对表达量( 1.62±0.10)水平降低,与模型组大鼠相比,差异有统计学意义( P＜0.05);与二甲双胍组差异无统计学意义(P＞0.05)。结论小檗碱可以改善多囊卵巢综合征大鼠激素分泌,调节胰岛素水平,促进排卵,改善卵巢功能。     

消瘀化痰饮对非酒精性脂肪肝大鼠胰岛素抵抗的影响

目的 观察中药消瘀化痰饮对非酒精性脂肪肝(NAFLD)大鼠胰岛素抵抗的影响,探讨其防治NAFLD的作用机制.方法 采用喂饲高脂饲料的方法复制大鼠胰岛素抵抗模型,以东宝肝泰为对照药,检测各组大鼠血清总胆固醇(TG)、甘油三酯(TG)、游离脂肪酸(FFA)、血清胰岛素(INS)、血糖(FBG)和肝组织中TC、TG的含量,计算胰岛素抵抗(IR)、胰岛素敏感指数(ISI)并观察肝组织形态学的变化.结果:消瘀化痰饮能明显降低IR,增强ISI敏感性,降低模型大鼠血清TC、TG、FFA、FBG、INS及肝脏组织中TC、TG的含量(P＜0.05或P＜0.01),改善肝组织的病变程度.结论 改善胰岛素抵抗、增强胰岛素敏感性可能是消瘀化痰饮防治NAFLD的作用机制之一.     

小檗碱对胰岛素抵抗大鼠糖脂代谢影响的研究

目的研究小檗碱对胰岛素抵抗大鼠糖脂代谢相关指标的影响及其酶学机制。方法选用雄性Wistar大鼠,以高脂高热量饲料喂养8周,复制胰岛素抵抗大鼠模型,造模成功后随机分成模型组、小檗碱组、二甲双胍组,各组干预4周,同时设置健康对照组;比较各组葡萄糖耐量试验(GTT)各时间点血糖水平、总胆固醇(TC)、甘油三酯(TG)、游离脂肪酸(FFA)、胰岛素敏感性指数(ISI)、肝脏葡萄糖激酶(GK)活性的差异。组间均数比较采用方差分析和LSD-t检验。结果与模型组比较,小檗碱组餐后60min血糖水平下降[分别为(7.2±1.4)mmol/L,(8.0±1.2)mmol/L,P<0.05],FFA水平下降[分别为(258±29)mmol/L,(479±34)mmol/L,P<0.05],ISI增强[分别为(-4.9±0.3),(-5.4±0.4),P<0.05],GK活性增强[分别为(13.6±1.7),(5.6±0.8),P<0.05];二甲双胍阳性对照组取得类似结果。结论小檗碱能调节胰岛素抵抗大鼠的糖脂代谢水平,增强胰岛素敏感性;其调节糖代谢机制可能与提高GK活性水平有关。     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

Synthesis and anti-inflammatory and analgesic activities of pyridyloxy- and phenoxyalkanoic acid derivatives

Synthesis of pyridyloxy-, pyridyloxyphenoxy- and phenoxylphenoxyalkanate derivatives and their anti-inflammatory and analgesic activities were investigated. Analysis of structure-activity relationships showed that in pyridyloxyalkanoic acid derivatives anti-edematous potency was associated with the presence of chlorophenoxypropionic acid moiety and 2-nitrated methyl propionates contributed to the analgesic activity.