黄连素对精神分裂症患者胰岛素抵抗与细胞因子的影响

目的 探讨黄连素对利培酮单药治疗的精神分裂症患者胰岛素抵抗与血清细胞因子水平的影响。 方法 将 64 例利培酮单药治疗的精神分裂症患者随机分为研究组（合并黄连素治疗）31 例和对照组（合并安慰剂治疗）33 例, 测定 2 组患者治疗前及治疗 12 周后的空腹血糖（FBG）、空腹胰岛素（Fins）, 采用稳态模型公式计算胰岛素抵抗指数（HOMA-IR）。 采用酶联免疫吸附法测定血清白细胞介素（IL）-1β、IL-6、肿瘤坏死因子（TNF）-α 水平。 结果 研究组治疗后的 FBG、Fins、HOMA-IR、IL-1β、IL-6、TNF-α 水平较自身治疗前和对照组治疗后均显著降低（P < 0.05）; 而对照组治疗后较治疗前 FBG 水平则显著升高（P < 0.01）, IL-1β、IL-6、TNF-α 水平降低（P < 0.01）, Fins、HOMA-IR 水平无明显变化（P > 0.05）。 研究组患者 HOMA-IR 与血清 IL-1β、IL-6、TNF-α 均呈正相关（r 分别为 0.316、 0.351 及 0.401, P < 0.01）。 结论 黄连素能显著降低利培酮单药治疗的精神分裂症患者 FBG、 Fins、 HOMA-IR、IL-1β、IL-6、TNF-α 水平, 且 HOMA-IR 水平与 IL-1β、IL-6、TNF-α 密切相关。     

Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice

Background: Inhaled ozone (O₃) has been demonstrated as a harmful pollutant and associated with chronic inflammatory diseases such as diabetes and vascular disorders. However, the underlying mechanisms by which O₃ mediates harmful effects are poorly understood.

Objectives: To investigate the effect of O₃ exposure on glucose intolerance, immune activation and underlying mechanisms in a genetically susceptible mouse model.

Methods: Diabetes-prone KK mice were exposed to filtered air (FA), or O₃ (0.5?ppm) for 13 consecutive weekdays (4?h/day). Insulin tolerance test (ITT) was performed following the last exposure. Plasma insulin, adiponectin, and leptin were measured by ELISA. Pathologic changes were examined by H&E and Oil-Red-O staining. Inflammatory responses were detected using flow cytometry and real-time PCR.

Results: KK mice exposed to O₃ displayed an impaired insulin response. Plasma insulin and leptin levels were reduced in O₃-exposed mice. Three-week exposure to O₃ induced lung inflammation and increased monocytes/macrophages in both blood and visceral adipose tissue. Inflammatory monocytes/macrophages increased both systemically and locally. CD4?+?T cell activation was also enhanced by the exposure of O₃ although the relative percentage of CD4?+?T cell decreased in blood and adipose tissue. Multiple inflammatory genes including CXCL-11, IFN-γ, TNFα, IL-12, and iNOS were up-regulated in visceral adipose tissue. Furthermore, the expression of oxidative stress-related genes such as Cox4, Cox5a, Scd1, Nrf1, and Nrf2, increased in visceral adipose tissue of O₃-exposed mice.

Conclusions: Repeated O₃ inhalation induces oxidative stress, adipose inflammation and insulin resistance.     

Biochemical efficacy of vitamin D in ameliorating endocrine and metabolic disorders in diabetic rats

Context: Due to the biochemical role of vitamin D (Vit D) in the endocrine system, especially its potential anti-inflammatory and immune-modulating properties, there is an increased interest in its potential role in the prevention and control of diabetes mellitus.

Objective: This study evaluated the potential therapeutic efficacy of Vit D in averting the detrimental effects of both types of diabetes mellitus.

Materials and methods: A total of 50 male Wistar rats were allotted into five groups: a placebo group; a nongenetic model of type 1 diabetes in rats (T1D), injected with a single dose of streptozotocin (STZ; 65?mg/kg, ip); a nongenetic model of type 2 diabetes in rats (T2D), given a short-term high-fat diet followed by a single low dose of STZ (35?mg/kg, ip); fourth and fifth groups that were gastrogavaged with Vit D (10?IU/kg) three days after the induction of T1D and T2D, respectively, which was continued daily throughout the experiment.

Results: Vit D (10?IU/kg/60 days) significantly (p?p?Discussion and conclusion: Vit D ameliorated the deleterious biochemical impact of diabetes mellitus, likely by increasing insulin secretion and sensitivity, ameliorating the β-cell function, and decreasing the number of pro-inflammatory cytokines and insulin resistance.     

葛根素对高脂饮食大鼠胰岛素敏感性的影响

目的观察葛根素(puerarin,pue)对高脂饮食诱导的胰岛素抵抗(insulin resistance,IR)大鼠胰岛素敏感性的影响。方法以尾静脉注射小剂量链脲菌素(streptozotocin,STZ)和高脂饲料喂养诱导IR大鼠模型,给药治疗8wk后,采用改良的高血浆胰岛素-正常血糖钳夹技术,评价葛根素对大鼠胰岛素敏感性的影响。结果高脂饲料喂养诱导IR大鼠基础血糖值(BBG)、基础血浆胰岛素(BINS)、稳态血浆胰岛素(SINS)均较正常组明显增高,而葛根素治疗组BBG、BINS、SINS较IR模型组均明显降低;高血浆胰岛素-正常血糖钳夹试验中60~120min的平均葡萄糖输注率(GIR60-120),IR模型组明显低于正常组,而葛根素高、中剂量组较IR模型组升高。结论葛根素可降低实验性IR大鼠的血糖和血浆INS水平,改善机体对胰岛素的敏感性。     

海地瓜海参胶对胰岛素抵抗模型小鼠慢性炎症的改善作用

目的 研究海地瓜海参胶对胰岛素抵抗模型小鼠慢性炎症的改善作用。方法 建立高脂高果糖饮食诱导胰岛素抵抗小鼠模型。雄性C57BL/6J小鼠随机分为正常对照组、模型对照组、海地瓜海参胶低剂量组（100 mg · (kg ·bw· d)-1）、海地瓜海参胶高剂量组（200 mg · (kg ·bw· d)-1）。饲喂9周后,检测小鼠空腹血糖、胰岛素、促炎因子游离脂肪酸、肿瘤坏死因子-α、白介素6及抗炎因子脂联素、白介素10水平;qRT-PCR 检测小鼠肝脏炎症因子mRNA表达水平。结果 海地瓜海参胶显著降低胰岛素抵抗模型小鼠空腹血糖、空腹胰岛素水平;显著降低血清促炎因子含量,升高抗炎因子含量;显著下调肝脏肿瘤坏死因子-α、白介素6 mRNA表达,上调脂联素、白介素10 mRNA表达。结论 海地瓜海参胶可显著改善胰岛素抵抗小鼠的慢性炎症。     

Profiling of hepatic metabolizing enzymes and nuclear receptors in rats with adjuvant arthritis by targeted proteomics

Inflammatory conditions alter the expression and activity of factors influencing pharmacokinetics, such as metabolizing enzymes. The study examined alterations of hepatic protein levels of cytochrome P450 (CYP), UDP‐glucuronosyltransferase (UGT) and nuclear receptors in rats with adjuvant‐induced arthritis (AA rats), an inflammatory animal model, by liquid chromatography–tandem mass spectrometry‐based targeted proteomics. The protein levels of CYP1A1, CYP1A2, CYP2A1, CYP2A3, CYP2C6, CYP2C12, CYP2D3, CYP2E1, CYP3A9, UGT1A1 and UGT1A2/3 in liver microsomes of AA rats were significantly lower than those in control rats. The protein levels of constitutive androstane receptor (CAR) and retinoid X receptor α (RXRα) in the cytoplasm and nucleus were also significantly decreased, to approximately 60% of the control levels. The decreased protein levels of CYP1A2, CYP2C6, CYP2D3, CYP2E1 and UGT1A1 were potentially associated with downregulation of CAR or RXRα expression in the nucleus.     

Determination of heavy metals for the quality control in argentinian herbal medicines by ETAAS and ICP-OES

The determination of trace elements in Hypericum perforatum leaves and flowers, their teas, tinctures and tablets was carried out by Electrothermal Atomic Absorption Spectrometry (ETAAS) and Ultrasonic Nebulization System coupled to Inductively Coupled Plasma Optical Emission Spectrometry (USN-ICP-OES). Hypericum perforatum (St. John’s wort), is a phytomedicine used for the treatment of depression. Samples were collected from different sources in the argentinian market. Heavy metals contents in the investigated samples were found at different levels. Chromium and cobalt were undetectable above their limits of detection in both liquid and solid samples; while aluminum, cadmium, lead, iron and vanadium were present in the majority of samples.     

Obesity-related colon cancer: dietary factors and their mechanisms of anticancer action

Overweight/obesity is an epidemic in the US as well as in other developed countries, affecting two-thirds of Americans and an estimated 2.3 billion people worldwide. Obesity increases the risk for Type 2 diabetes, cardiovascular disease and cancer. For example, epidemiological studies have established a strong association between obesity and colon cancer. It is generally accepted that metabolic changes associated with overweight/obesity, particularly abdominal obesity and changes in adipocyte function, contribute to the increased risk of colon cancer. Understanding the mechanisms underlying this association is important for the development of preventive strategies for colon cancer. Part of these preventive strategies may be based on dietary factors, such as vitamins, minerals (e.g. selenium), fibre, phytochemicals and phenolic compounds. These anticancer nutrients may counteract the molecular changes associated with obesity. The present article reviews the evidence that inflammation and insulin resistance induced by obesity are the molecular mediators of the association between obesity and colon cancer. We also evaluate the evidence for the ability of dietary factors to target the obesity-induced changes and, thus, protect against colon cancer.     

PPAR及其激动剂与脂肪酸代谢及胰岛素抵抗

过氧化物酶体增殖物激活受体(PPAR)在脂肪细胞分化、脂肪酸代谢中起重要作用,PPAR及其所调控基因的激活可促进脂肪细胞分化、减少脂质产生、增加脂肪酸氧化,从而减少脂质的异位沉积,进一步改善损伤的胰岛素信号转导通路,逆转胰岛素抵抗。针对脂肪酸合成及氧化的关键调控点的药物可能是今后治疗胰岛素抵抗引发的一系列代谢异常的新的靶点。     

Effect of acute administration of certain heavy metals and their combinations on the spontaneous and evoked cortical activity in rats

The aim of this study was to see the effect of acutely administered inorganic lead, mercury, manganese, and their combinations, on the electrical activity in the somatosensory system of rats. Male Wistar rats were anaesthetised with urethane, the head was fixed in a stereotaxic frame and the left hemisphere was exposed. Weak electric shocks to the whiskers and the tail served as stimuli. Spontaneous and stimulus-evoked activity was recorded from the primary projection area of the whiskers and the tail. After an hour of control recording, one of the following was given to the rat i.p.: 1000 mg/kg Pb²⁺, 7 mg/kg Hg²⁺, 50 mg/kg Mn²⁺, 500 mg/kg Pb²⁺ + 25 mg/kg Mn²⁺, or 500 mg/kg Pb²⁺ + 3.5 mg/kg Hg²⁺. Lead caused a massive increase in the cortical response amplitude, starting immediately after administration and developing in the next 40–50 min. Latency showed a minimal increase. The spontaneous activity was moderately shifted to lower frequencies. The effect of Hg²⁺ on the response amplitude and on the ECoG was similar but stronger than that of Pb²⁺. The effect of Mn²⁺ on the evoked activity was marked but less strong than with Pb²⁺. The ECoG shift was moderate. With Hg²⁺ and Mn²⁺, the response amplitude showed first a decrease than an increase. The effect of the Pb²⁺ + Mn²⁺ combination on the activities was not additive but the correlation between the alteration of the ECoG and the evoked potential was stronger than with any of the metals alone. With Pb²⁺ + Hg²⁺, the effect of Pb²⁺ dominated on the evoked and that of Hg²⁺ on the spontaneous activity. In the peripheral nerve, action potential amplitude and conduction velocity were decreased.

These alterations of the spontaneous and stimulus-evoked cortical activity probably reflected a specific action of the heavy metals on the nervous activity.     

孕期脂多糖刺激对子代大鼠胰岛素抵抗的影响

目的 探讨孕期脂多糖（LPS）对子代成年大鼠胰岛素抵抗的影响。方法 SD 孕鼠 20 只随机分为 2 组,每组 10 只。LPS 组孕期第 8、 10、 12 天腹腔注射 LPS 0.40 mg/kg, 对照组腹腔注射无菌生理盐水 0.5 mL。子鼠 3 月龄时测血糖、 血胰岛素的浓度和瘦素（Leptin）水平, 计算稳态胰岛素抵抗指数（HOMA-IR）和胰岛素敏感指数（QUICKI）。结果 与对照组相比, 3 月龄 LPS 组子鼠血糖 （mmol/L：7.72±0.42 vs 7.02±0.42）、 血胰岛素 （mIU/L： 8.78± 4.10 vs 1.51±0.27）、 血 Leptin 水平 （μg/L： 3.88±1.40 vs 1.00±0.33）、 HOMA-IR 值 （3.01±1.41 vs 0.47±0.09） 明显高于对照组; LPS 组 QUICKI 值明显低于对照组 （0.57±0.07 vs 0.99±0.08）。结论 孕期 LPS 刺激会引起子代大鼠胰岛素抵抗。     

Antihyperglycaemic effect of Cassia auriculata in experimental diabetes and its effects on key metabolic enzymes involved in carbohydrate metabolism

1. In experimental diabetes, enzymes of glucose and fatty acid metabolism are markedly altered. Persistent hyperglycaemia is a major contributor to such metabolic alterations, which lead to the pathogenesis of diabetic complications. To our knowledge, there are no available reports on the enzymes of hepatic glucose metabolism of Cassia auriculata flower against diabetes. The present study was designed to study the effect of Cassia auriculata flower extract (CFEt) on hepatic glycolytic and gluconeogenic enzymes. 2. Streptozotocin diabetic rats were given CFEt (0.15, 0.30 and 0.45 g/kg) or 600 microg/kg glibenclamide for 30 days. At the end of 30 days, blood glucose, plasma insulin, haemoglobin, glycosylated haemoglobin, glycolytic and gluconeogenic enzymes were assessed. 3. Administration of CFEt at 0.45 g/kg significantly decreased blood glucose, glycosylated haemoglobin and gluconeogenic enzymes and increased plasma insulin, haemoglobin and hexokinase activity. Similarly, administration of glibenclamide showed a significant effect; however, CFEt at 0.15 and 0.30 g/kg did not show any significant effect. 4. In conclusion, the observations show that the aqueous extract of CFEt possesses an antihyperglycaemic effect and suggest that enhanced gluconeogenesis during diabetes is shifted towards normal and that the extract enhances the utilization of glucose through increased glycolysis. The effect of CFEt was more prominent than that of glibenclamide.     

蜕皮甾酮对胰岛素抵抗细胞模型胰岛素敏感性和糖代谢的影响

目的应用高胰岛素体外诱导培养建立的胰岛素抵抗HepG2细胞模型探讨蜕皮甾酮对其胰岛素敏感性和糖代谢的影响。方法采用3H-D-葡萄糖的参入试验评价细胞的胰岛素敏感性,在诱导胰岛素抵抗HepG2细胞模型的过程中或模型建立后,培养液中加入蜕皮甾酮及吡格列酮共同孵育,观察蜕皮甾酮及吡格列酮对HepG2细胞葡萄糖参入率,同时观察蜕皮甾酮对胰岛素抵抗细胞模型葡萄糖消耗量的影响。结果含有蜕皮甾酮(浓度为1×10-6~10-4mol·L-1)的胰岛素抵抗HepG2细胞的葡萄糖参入率与葡萄糖消耗量明显高于不含蜕皮甾酮的胰岛素抵抗HepG2细胞(对照细胞,P<0·01)。蜕皮甾酮与吡格列酮对胰岛素抵抗模型细胞的葡萄糖参入率与葡萄糖消耗量差异无显著性(P>0·05)。结论蜕皮甾酮在胰岛素抵抗细胞模型中能提高胰岛素介导的葡萄糖摄取和利用能力,即增加胰岛素的敏感性;并能明显改善糖代谢。     

溴隐停与罗格列酮和二甲双胍对PCOS大鼠拮抗胰岛素抵抗及调整性激素作用的研究

目的观察溴隐停、二甲双胍、罗格列酮分别对多囊卵巢综合征(polycystic ovary syndrome,P-COS)大鼠胰岛素抵抗和性激素作用。方法采用十一酸睾酮加绒促性素(human chorionic gonado-tropin,HCG)建立PCOS大鼠模型,连续经口给予溴隐停、二甲双胍、罗格列酮6周,测定大鼠空腹血糖(fasting blood glucose,FBG)、经口给予葡萄糖后2 h血糖(2-hours blood glucose after oral glucosetolerance test,OGTT-2hBG)、胰岛素(insulin,Ins)、肿瘤坏死因子-α(tumor necrosis factor,TNF-α)、睾酮(testosterone,T)、胰岛素样生长因子(insulin growth factor-I,IGF-I)、雌激素(estradiol,E2)、孕酮(progesterone,P)、泌乳素(prolactin,PRL)等含量,并计算胰岛素敏感指数(insulin sensitivity index,ISI)的变化。结果 PCOS大鼠FBG、OGTT-2hBG、Ins、TNF-α、IGF-I、T、E2和PRL水平明显升高,而ISI和P显著降低,与空白对照组比较,差异有高度显著性(P<0.01);溴隐停、二甲双胍、罗格列酮均能不同程度地改善PCOS大鼠的上述病理改变(P<0.01~0.05)。结论溴隐停、二甲双胍、罗格列酮均能不同程度地改善PCOS大鼠胰岛素抵抗(insulin resistance,IR)和性激素分泌异常,降低T含量。     

Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation

Background and purpose:

Nutrient overload leads to obesity and insulin resistance. Pioglitazone, a selective peroxisome proliferator-activated receptor (PPAR)γ agonist, is currently used to manage insulin resistance, but the specific molecular mechanisms activated by PPARγ are not yet fully understood. Recent studies suggest the involvement of suppressor of cytokine signalling (SOCS)-3 in the pathogenesis of insulin resistance. This study aimed to investigate the hepatic signalling pathway activated by PPARγ activation in a non-genetic insulin-resistant animal model.

Experimental approach:

Male Wistar rats were maintained on a high-cholesterol fructose (HCF) diet for 15 weeks. Pioglitazone (3 mg·kg⁻¹) was administered orally for the last 4 weeks of this diet. At the end of the treatment, serum was collected for biochemical analysis. Levels of PPARγ, SOCS-3, pro-inflammatory markers, insulin receptor substrate-2 and Akt/glycogen synthase kinase-3β phosphorylation were assesed in rat liver.

Key results:

Rats fed the HCF diet exhibited hyperlipidemia, hyperinsulinemia, impaired glucose tolerance and insulin resistance. Pioglitazone administration evoked a significant improvement in lipid metabolism and insulin responsiveness. This was accompanied by reduced hepatic expression of SOCS-3, interleukin-6, tumour necrosis factor-α and markers of neutrophil infiltration. Diet-induced PPARγ expression was unaffected by the pioglitazone treatment.

Conclusion and implications:

Chronic pioglitazone administration reduced hepatic inflammatory responses in rats fed a HCF diet. These effects were associated with changes in hepatic expression of SOCS-3, which may be a crucial link between the reduced local inflammation and the improved insulin signalling.This article is commented on by Chatterjee, pp. 1889–1891 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00739.x     

卡维地洛对高血压的降压作用及对胰岛素抵抗的影响

目的探讨卡维地洛的降压作用及对胰岛素抵抗的影响。方法对58例高血压病Ⅰ期或Ⅱ期患者服用卡维地洛10 mg,bid,疗程为6 wk;治疗前后观察血压、空腹血糖(FBS)、血脂和胰岛素敏感性(ISI)的变化。结果服药前收缩压(158．3±13．5)mm Hg,舒张压(92．3±5．7)mm Hg;服药后收缩压(141．5±12．7)mm Hg,舒张压(81．8±6．4)mm Hg,服药前后比较(P< 0．05),治疗前后血糖、血脂无显著性改变(P>0．05),胰岛素敏感性增加(P<0．05)。结论卡维地洛能有效地降低收缩压和舒张压,能显著改善胰岛抵抗。     

小檗碱对高脂血症伴胰岛素抵抗大鼠糖脂代谢的影响

目的:观察小檗碱对高脂血症伴胰岛素抵抗(IR)大鼠糖脂代谢的影响,探讨其调脂和改善IR的机理.方法:通过喂养高脂饲料和小剂量静注链脲佐菌素(STZ)建立高脂血症伴IR大鼠模型,测定各不同处理组血糖、脂、胰岛素水平和脂代谢关键酶活性.结果:小檗碱组大鼠总胆固醇(TC)、甘油三酯(TG)、载脂蛋白B(ApoB)、低密度脂蛋白-胆固醇(LDL-C)、游离脂肪酸(FFA)均比模型组明显降低(P＜0.05或P＜0.01),而高密度脂蛋白-胆固醇(HDL-C)、载脂蛋白A(ApoAI)、胰岛素敏感指数(ISI)显著升高;血脂蛋白脂酶(LPL)活性显著升高(P＜0.05或P＜0.01).结论:小檗碱可能通过降低血FFA而改善IR,其调脂功效可能与升高LPL活性有关.     

Proteomic analysis for the impact of hypercholesterolemia on expressions of hepatic drug transporters and metabolizing enzymes

1. Our objective is to investigate the alterations of hepatic drug transporters and metabolizing enzymes in hypercholesterolemia. Male Sprague–Dawley rats were fed high-cholesterol chows for 8 weeks to induce hypercholesterolemia. Protein levels of hepatic drug transporters and metabolizing enzymes were analyzed by iTRAQ labeling coupled with LC TRIPLE-TOF.

2. Total 239 differentially expressed proteins were identified using proteomic analysis. Among those, protein levels of hepatic drug transporters (MRP2, ABCD3, OAT2, SLC25A12, SCL38A3, SLC2A2 and SLC25A5) and metabolizing enzymes (CYP2B3, CYP2C7, CYP2C11, CYP2C13, CYP4A2 and UGT2B) were markedly reduced, but the levels of CYP2C6 and CYP2E1 were increased in hypercholesterolemia group compared to control. Decreased expressions of drug transporters MRP2 and OAT2 were further confirmed by real time quantitative PCR (RT-qPCR) and western blot.

3. Ingenuity pathway analysis revealed that these differentially expressed proteins were regulated by various signaling pathways including nuclear receptors and inflammatory cytokines. One of the nuclear receptor candidates, liver X receptor alpha (LXRα), was further validated by RT-qPCR and western blot. Additionally, LXRα agonist T0901317 rescued the reduced expressions of MRP2 and OAT2 in HepG2 cells in hypercholesterolemic serum treatment.

4. Our present results indicated that hypercholesterolemia affected the expressions of various drug transporters and metabolizing enzymes in liver via nuclear receptors pathway. Especially, decreased function of LXRα contributes to the reduced expressions of MRP2 and OAT2.     

Thiazolidinediones: effects on insulin resistance and the cardiovascular system

Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years. They may delay the development of type 2 diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. TZDs act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) primarily in adipose tissue. PPAR-gamma receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Clinically, TZDs have been shown to reduce measures of atherosclerosis such as carotid intima-media thickness (CIMT). However, in spite of beneficial effects on markers of cardiovascular risk, TZDs have not been definitively shown to reduce cardiovascular events in patients, and the safety of rosiglitazone in this respect has recently been called into question. Dual PPAR-alpha/gamma agonists may offer superior treatment of insulin resistance and cardioprotection, but their safety has not yet been assured.