成纤维细胞生长因子21在糖脂代谢中的作用机制及其临床研究进展

随着人群中糖脂代谢异常的患病率逐年升高,随之而来的社会经济负担也愈加严重,故对于改善糖脂代谢的机制研究及临床研究也成为了学科热点。近年来成纤维细胞生长因子21(FGF-21)在糖脂代谢中的作用越来越被关注,相关机制研究也逐渐深入。在细胞、动物及临床研究中均发现FGF-21有改善糖脂代谢的作用,但具体分子机制仍未完全揭示,且相关临床研究的有效性及安全性仍缺乏充分且可靠的循证医学证据。本文对FGF-21在糖脂代谢中的作用机制及临床研究现状做一综述。     

腺苷酸活化蛋白激酶调控相关通路与糖脂代谢异常相关疾病的发病机制研究进展

糖脂代谢异常会造成线粒体功能紊乱,从而导致相关疾病的发生发展.研究表明,腺苷酸活化蛋白激酶(AMPK)是体内重要的能量代谢感受器,激活后的AMPK通过调控多条相关通路参与机体糖脂代谢和能量调节活动,以减轻糖脂代谢紊乱对机体的损害或促进机体相关正常功能的恢复.本文对AMPK调控相关通路在糖脂代谢异常相关疾病中的研究进展进...     

法尼醇X受体与糖脂代谢

法尼醇X受体(farnesoid X receptor,FXR)属于核受体超家族,研究证明FXR可调控多种代谢通路,除在胆汁酸代谢中发挥重要作用外,FXR激活后参与维持机体糖脂代谢稳态。随着糖脂代谢异常相关疾病发病率的升高,FXR对糖脂代谢的调节越来越引起研究者的重视。FXR激动剂可能成为治疗2型糖尿病和脂代谢紊乱等代谢性疾病的新型药物靶点。     

Caco-2细胞在药物研究中的应用进展

目的Caco-2细胞模型特征及其在药物研究中的应用。方法概述了近年来Caco-2细胞模型在药物吸收机制、高通量筛选、药物相互作用、代谢及在药物剂型开发中应用情况。结果Caco-2细胞模型与整体吸收具有良好的相关性,可预测药物在体内的吸收、代谢规律。结论Caco-2细胞模型是药物体外研究的良好工具。     

三维重组皮肤模型在体外替代遗传毒性评价中的应用

三维（3D）重组皮肤模型已证实在模拟体内代谢条件、给药浓度及反应靶器官毒性特点方面具有突出优势。近年来已有多家公司构建3D重组人工皮肤模型,且一些制药公司已将3D细胞模型应用于药物的早期毒性筛选。我国动物实验替代方法的研究仍处于起步阶段,利用3D重组皮肤模型进行体外安全性评价成为目前替代方法的研究热点之一。综述人3D重组皮肤模型在遗传毒性评价中体外微核试验和彗星试验的研究进展,并对该模型在外用药物体外替代遗传毒性评价中的应用前景进行探讨。     

AMPK、PPARs在2型糖尿病中的作用机制及药物研究

2型糖尿病（T2DM）在全球范围内广泛流行,其主要特征为胰岛素抵抗和胰腺β细胞分泌的胰岛素减少,糖脂代谢发生紊乱,其发病原因是多因素的。AMPK和PPARs作为体内代谢过程的关键调节因子,对糖脂代谢平衡有着巨大贡献。本文着重综述两者在2型糖尿病发生发展中的作用机制,以及相应的药物对2型糖尿病的治疗效果和作用机制,以期为2型糖尿病药物的研发提供参考。     

六种抗精神病药物对精神分裂症患者糖脂代谢的影响研究

<正>目前,药物治疗是精神分裂症的关键,非典型抗精神病药物因其安全、有效特点被广泛用于精神分裂症的治疗。近年来,由其引发的糖脂代谢不良影响给患者造成一定痛苦并引起临床医生们的关注。国内外有不少关于抗精神病药物对糖脂代谢影响的报道,但缺乏多种药物间的比较。本研究比较了6种非典型抗精神病药物对精神分裂症患者糖脂代谢的影响,现报告如下。1对象与方法1.1研究对象本研究选取2011年2月至2013年12月在山西省荣军     

丝裂原活化蛋白激酶信号通路在糖脂代谢中作用的研究进展

<正>随着生活水平的日益提高,糖脂代谢异常发病率明显上升,已成为我国一个严重的公共卫生问题。糖脂代谢异常是一种代谢性疾病,其与高血压、肥胖等多种疾病统称为代谢综合症,可导致糖尿病和冠心病以及其他心血管病发生的风险明显提高,因而对糖脂代谢异常的早期预防、早期干预显得尤为重要。近年来,有研究发现丝裂原活化蛋白激酶(MAPK)信号通路在糖脂代谢异常的发生     

体外三维肝细胞模型在药物肝毒性评价中的应用

肝毒性是药物治疗过程中常见的副作用,也是导致新药临床试验失败以及药物撤市的主要原因。建立可以有效识别药物肝毒性的体外模型对于新药研发至关重要。传统的二维（2D）模型在培养过程中会逐渐丧失肝脏特异性功能,无法准确评价药物肝毒性。新兴的三维（3D）培养技术可模拟体内细胞微环境,有利于肝细胞的体外组装,从而使3D肝细胞模型表现出与体内肝细胞相似的表型以及药物毒性反应,在肝毒性评价方面具有很大潜力。     

天然药对CYP3A的影响

天然药在我国及东南亚国家应用相当广泛，在欧洲及美国，天然药正日益受到重视。天然药成分虽复杂，但其单体或有效成分与合成药一样，大多数是通过细胞色素P450酶（CYP450）代谢。CYP3A是很重要的CYP450酶系，临床上一半以上药物由其代谢。目前很多体外、体内实验证明多种天然药及其成分广泛影响CYP3A，从而在合并用药时，导致药物间的相互作用。研究天然药对CYP3A的调控不仅对安全合理用药有指导作用，而且对于新药研发和揭示药物相互作用机制都有指导意义。     

Nuclear receptor regulation of lipid metabolism: potential therapeutics for dyslipidemia, diabetes, and chronic heart and liver diseases

Lipids are essential components of biological membranes, fuel molecules and metabolic regulators that control cellular functions, metabolism and homeostasis. The liver plays a central role in regulating lipid metabolism and whole body lipid homeostasis. Sterols, bile acids and fatty acids are the endogenous ligands of the liver orphan receptor, farnesoid X receptor, peroxisome proliferator-activated receptor, vitamin D receptor, constitutive androstane receptor and pregnane X receptor. These metabolic receptors coordinately regulate lipid, glucose, energy and drug metabolism. Alteration of lipid homeostasis causes dyslipidemia, which is a major risk factor contributing to atherosclerotic cardiovascular diseases, diabetes, obesity and liver diseases. Advances in the understanding of the mechanisms of nuclear receptor regulation of lipid homeostasis have provided an opportunity to investigate potential therapeutic drugs targeted to nuclear receptors. This could be useful for the treatment of diabetes, and cardiovascular and chronic liver diseases.     

Metabolic effects of antihypertensive agents: role of sympathoadrenal and renin-angiotensin systems

Reports of beneficial, neutral and adverse impacts of antihypertensive drug classes on glucose and lipid metabolism can be found in human data. Furthermore, mechanisms for these diverse effects are often speculative and controversial. Clinical trial data on the metabolic effects of antihypertensive agents are highly contradictory. Comparisons of clinical trials involving different agents are complicated by differences in the spectrum of metabolic disturbances that accompany hypertension in different groups of patients. Two physiological systems are predominant at the interface between metabolic and cardiovascular regulation: the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). These two systems are major targets of antihypertensive drug actions, and also mediate many of the beneficial and adverse effects of antihypertensive agents on glucose and lipid metabolism. Thiazides and β-adrenergic antagonists can adversely affect glucose and lipid metabolism, which are frequently compromised in human essential hypertension, and increase the incidence of new cases of diabetes. Laboratory studies confirm these effects, and suggest that compensatory activation of the SNS and RAS may be one mechanism. Other antihypertensives directly targeting the SNS and RAS may have beneficial effects on glucose and lipid metabolism, and may prevent diabetes. Resolution of the controversies surrounding the metabolic effects of antihypertensive agents can only be resolved by further laboratory studies, in addition to controlled clinical trials.     

Metabolism of minaprine in human and animal hepatocytes and liver microsomes--prediction of metabolism in vivo

1. The metabolism of minaprine and its major metabolite p-hydroxyminaprine were studied using hepatocytes and liver microsomes from different species. Metabolism of this drug in vitro was then compared with in vivo data already published. 2. Our results showed that the major metabolic route (4-hydroxylation of the aromatic ring) is the same in the two experimental systems. Other in vivo biotransformation pathways (i.e. N-oxidation, reductive ring cleavage, N-dealkylation, oxidation) were also confirmed in hepatocytes. 3. Similar inter-species variability was observed both in vitro and in vivo. The present study has led to the same conclusion as previous in vivo metabolic investigations, namely, that metabolism in the dog quantitatively differs from that observed in other animal species. 4. These results clearly demonstrate that in vitro models (i.e. isolated hepatocytes and liver microsomes) are powerful tools in predicting the metabolic pathways of a drug in man and animal species.     

Use of GLUT-4 null mice to study skeletal muscle glucose uptake

1. The present review focuses on the effects of varying levels of GLUT-4, the insulin-sensitive glucose transporter, on insulin sensitivity and whole body glucose homeostasis. 2. Three mouse models are discussed including myosin light chain (MLC)-GLUT-4 mice which overexpress GLUT-4 specifically in skeletal muscle, GLUT-4 null mice which express no GLUT-4 and the MLC-GLUT-4 null mice which express GLUT-4 only in skeletal muscle. Overexpressing GLUT-4 specifically in the skeletal muscle results in increased insulin sensitivity in the MLC-GLUT-4 mice. In contrast, the GLUT-4 null mice exhibit insulin intolerance accompanied by abnormalities in glucose and lipid metabolism. Restoring GLUT-4 expression in skeletal muscle in the MLC-GLUT-4 null mice results in normal glucose metabolism but continued abnormal lipid metabolism. 3. The results of experiments using these mouse models demonstrates that modifying the expression of GLUT-4 profoundly affects whole body insulin action and consequently glucose and lipid metabolism.     

Use of embryo culture to study normal development and developmental mechanisms.

Mammalian embryo culture techniques have been used to study many aspects of embryonic development. The advantages and limitations of such studies as models for in vivo development are discussed by reference to the following specific examples: development of the paraxial mesoderm, regulation of growth, protein uptake and metabolism, and carbohydrate metabolism. Embryo culture techniques are useful for the study of morphogenesis and growth because the embryo is made accessible for manipulation and observation. Development in vivo and in vitro over equivalent periods can be compared. The limitations of the system have important implications for the interpretation of studies of embryonic metabolism. In vitro metabolic activity can be assessed by assays of the culture media and embryonic tissue at intervals throughout the culture. However, the sensitivity of the metabolic pathways to explantation remains unknown because of the technical difficulties involved in studying embryonic metabolism in vivo.     

Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability

Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.     

体外模型在中药代谢研究中的应用

体内代谢研究对阐明中药药效物质基础及作用机制有重要意义。体外模型由于其替代、简化和精准的特点,已成为中药体内代谢研究的重要手段之一。综述药物体内过程研究中常用的体外模型及其特点,并总结其在中药代谢研究中的应用概况,以期为中药成分代谢研究提供理论和方法学参考。     

Effects of typical and atypical antipsychotics on glucose–insulin homeostasis and lipid metabolism in first-episode schizophrenia

Rationale Glucose and lipid metabolism dysfunction is a significant side effect associated with antipsychotics. Although there are many studies about the linkages between drugs and metabolic dysfunction, most of these studies have compared the effects of two antipsychotics on only one metabolic measure: either glucose or lipid metabolism.Objectives The present study aimed to investigate the effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.Materials and methods One hundred twelve schizophrenics were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index (BMI), waist-to-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol, and triglyceride. All measures were collected at baseline and at the end of the 8-week treatment.Results After treatment, insulin, C-peptide, and IRI were significantly increased in the four groups, but not fasting glucose levels. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. Among the four antipsychotics, the increases of mean BMI from high to low were as follows: clozapine, olanzapine, sulpiride, and risperidone.Conclusions This study confirmed that the four antipsychotic drugs were associated with an increase of insulin, C-peptide, and IRI. It was found that clozapine and olanzapine were associated with an increase in cholesterol and triglyceride levels. The effects of clozapine and olanzapine on the glucose and lipid metabolism outweighed those of risperidone and sulpiride.     

An assessment of human liver-derived in vitro systems to predict the in vivo metabolism and clearance of almokalant.

The ability of various human derived in vitro systems to predict various aspects of the in vivo metabolism and kinetics of almokalant have been investigated in a multicenter collaborative study. Although almokalant has been withdrawn from further clinical development, its metabolic and pharmacokinetic properties have been well characterized. Studies with precision-cut liver slices, primary hepatocyte cultures, and hepatic microsomal fractions fortified with UDP-glucuronic acid all suggested that almokalant is mainly glucuronidated to the stereoisomers M18a and M18b, which is in good agreement with the results in vivo. Both in vivo and in vitro studies indicate that the formation of M18b dominates over that of M18a, although the difference is more pronounced with the in vitro systems. Molecular modeling, cDNA-expressed enzyme analysis, correlation analysis, and inhibition studies did not clearly indicate which P450 enzymes catalyze the oxidative pathways, which may indicate a problem in identifying responsible enzymes for minor metabolic routes by in vitro methods. All of the in vitro systems underpredicted the metabolic clearance of almokalant, which has previously been reported to be a general problem for drugs that are cleared by P450-dependent metabolism. Although few studies on in vivo prediction of primarily glucuronidated drugs have appeared, in vitro models may consistently underpredict in vivo metabolic clearance. We conclude that in vitro systems, which monitor phase II metabolism, would be beneficial for prediction of the in vivo metabolism, although all of the candidate liver-derived systems studied here, within their intrinsic limitations, provided useful information for predicting metabolic routes and rates.     

学龄期肥胖与体质量正常儿童血清25羟维生素D水平及其与儿童肥胖程度及糖脂代谢的关系

目的 探讨学龄期肥胖与体质量正常儿童血清25羟维生素D[25(OH)D]水平及其与儿童肥胖程度及糖脂代谢的关系.方法 从学龄期儿童中选出肥胖儿童100例作为肥胖组,根据肥胖程度将肥胖组分为轻中度肥胖组42例及重度肥胖组58例,并选出年龄相仿、体质量正常儿童100例作为对照组.采用自动生化分析仪检测血液各项生化指标以及采用ELISA检测甲状旁腺素(PTH)及血清25(OH)D的水平,分析血清25(OH)D的水平与儿童肥胖程度及糖脂代谢的关系.结果 (1)三组儿童的体质量、体质量指数(BMI)、臀围、腰围、腰臀比,总能量/每日推荐摄入能量(RDA)和25(OH)D水平的数据比较均差异有统计学意义(P<0.05),经过q检验,以上项目中任意两组之间的数据均差异有统计学意义(P<0.05),而且体质量、BMI、臀围、腰围、腰臀比,总能量/RDA几个项目中,数据均为对照组<轻中度肥胖组<重度肥胖组,但是在25(OH)D水平中,数据为对照组>轻中度肥胖组>重度肥胖组;(2)25(OH)D<50 nmol·L-1组儿童的三酰甘油明显高于25(OH)D≥50 nmol·L-1组,比较差异有统计学意义(t=6.021,P<0.05);(3)血清25(OH)D浓度与儿童三酰甘油呈负相关性,低血清25(OH)D浓度为儿童代谢综合征(MS)的危险因素.结论 学龄期肥胖儿童血清内25(OH)D水平显著低于体质量正常儿童,血清25(OH)D浓度与儿童三酰甘油呈负相关性,由此推断低血清25(OH)D浓度为儿童肥胖及MS的危险因素.