PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α–GLUT2 pathway

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.Key words: Pregnane X receptor, Hepatocyte nuclear factor 4-alpha, Glucose transporter 2, Hepatic glucose uptake, Diabetes, Drug-induced hyperglycemia     

姜黄素对小鼠黑素瘤的抑制作用

目的:研究姜黄素(curcumin)对小鼠黑素瘤的抑制作用及对MT1-MMP基因表达、MMP-2基因活化的影响,探讨姜黄素抑瘤作用的可能机制.方法:将黑素瘤细胞株B16接种于小鼠右大腿外侧皮下,建立小鼠黑素瘤模型,予以腹腔注射姜黄素治疗,观察不同实验组瘤体及瘤重变化,采用Western blotting方法检测MMP-2活化程度,应用反转录(RT)-PCR方法检测MT1-MMP mRNA的表达水平.结果:治疗组小鼠瘤体均较肿瘤对照组缩小,瘤重均减轻,尤以50mg/kg组为著,缩小约55.61%,减轻约55.56%;治疗组MMP-2活性均较肿瘤对照组降低,50 mg/kg组降低50.94%,100 mg/kg组降低45.75%;治疗组MT1-MMP mRNA的表达水平均较肿瘤对照组降低,50 mg/kg组降低52.85%,100 mg/kg组降低48.73%;肿瘤组织MMP-2活性与MT1-MMP mRNA表达水平呈正相关.结论:姜黄素可以抑制小鼠黑素瘤的生长,下调MT1-MMP mRNA表达,从而抑制下游的MMP-2基因活化,这可能是姜黄素治疗黑素瘤的重要机制.     

低剂量纳洛酮对芬太尼镇痛效应的影响

目的 观察低剂量纳洛酮(naloxone)对芬太尼(fentanvyl)镇痛效应的影响.方法 将试验小鼠80只随机分为两组,分别采用扭体法(40只,雌雄各半)和热板法(40只,均为雌性)观察纳洛酮对芬太尼镇痛小鼠热板法痛阈(HPPT)和扭体次数的影响.各组按分层随机设计分为Fs组(芬太尼与生理盐水合用)及FNl、FN2和FN3组(芬太尼分别与纳洛酮100、10、10ng,1n/kg合用组)四组.结果 与Fs组相比,FN2组HPPT在第5 min增大(P＜0.05);扭体次数FN1和FN2组均显著减少(P＜0.05).结论 纳洛酮在一定剂量范围内能够增强芬太尼的镇痛效应.     

异氟烷对幼小鼠自主活动和学习记忆行为的影响

目的观察异氟烷(Iso)对幼小鼠自主活动和学习记忆行为的影响,探讨其与γ-氨基丁酸A受体(GABAA)的关系。方法 360只小鼠分为3大组,分别进行自主活动实验、避暗实验和跳台实验,每大组按分层随机区组设计分为正常对照组,Iso 0.05,0.1和0.2 ml·kg-1组、GABAA受体特异性阻断剂一叶萩碱(Sec)2,4和8 mg.kg-1组和Iso 0.2 m.lkg-1+Sec 2,4和8 mg.kg-1组。小鼠sc给予Sec 10 min后,再ip给予Iso,测试给药后15,30,45和60 min小鼠5 min内活动次数;跳台仪和避暗仪记录小鼠步入、跳下的潜伏期和错误次数。结果与同一时间点的正常对照组相比,Iso可减少小鼠自主活动次数,给予Iso后1 d小鼠避暗实验和跳台实验的步入和跳下潜伏期缩短以及错误次数增加(P<0.05)。正常小鼠单独给Sec(除Sec 8 mg·kg-1组15 min外)对小鼠自主活动、步入和跳下潜伏期和错误次数无明显影响,但Sec可改善Iso导致的小鼠自主活动次数,拮抗Iso对小鼠自主活动的影响,但随着时间延长拮抗作用逐渐减弱,明显低于正常对照组(P<0.05)。Sec延长Iso小鼠的跳下和步入潜伏期,减少错误次数,基本恢复至正常对照组水平,明显改善Iso对幼小鼠学习记忆的影响(P<0.05)。结论 Iso可降低幼小鼠自主活动次数,损害学习记忆能力,GABAA受体可能部分参与了以上作用。     

The effect of apolipoprotein E gene polymorphism and Lp(a) levels on coronary artery disease with atrial fibrillation

ObjectiveTo explore the influence of apolipoprotein E (APOE) genotypes and blood lipid metabolism on coronary artery disease (CAD) with atrial fibrillation (AF).MethodsPatients with suspected CAD were consecutively enrolled and divided into groups with or without CAD and/or AF. Blood lipid levels and APOE genotypes were determined and analysed for associations with CAD and AF.ResultsA total of 2048 patients were included (400 patients without CAD or AF [controls], 126 patients without CAD but with AF, 1294 patients with CAD without AF, and 228 patients with CAD and AF). Age and lipoprotein (a) (Lp[a]) levels were significantly higher in patients with CAD and AF versus those with CAD without AF. Among patients with CAD, the E3/E3 genotype and ε3 allele frequencies were significantly lower in patients with AF than in those without AF, and the E4/E4 genotype and ε4 allele frequencies were significantly increased. Multivariate logistic regression revealed that increased Lp(a) levels and age were independent risk factors for AF in patients with CAD.ConclusionAmong patients with CAD, those with AF had increased age, ε4 frequencies and Lp(a) levels. Age and Lp(a) levels may be independent risk factors for AF in patients with CAD.     

新型抗生素磷酸泰地唑胺的药理作用与临床评价

磷酸泰地唑胺(tedizolid phosphate)为新型第2代唑烷酮类抗生素,美国FDA于2014年6月20日批准其用于治疗金黄色葡萄球菌(包括耐甲氧西林菌株、甲氧西林敏感菌株)和各种链球菌属和粪肠球菌等革兰阳性细菌引起的急性细菌性皮肤和皮肤结构感染(ABSSSI)。临床研究表明,该药与利奈唑胺相比具有非劣效性,且安全性较好。本文对磷酸泰地唑胺的药理学、药动学、临床评价和安全性等作一综述。     

木蹄层孔菌石油醚组分的成分分析及抗肿瘤活性研究

目的:分析木蹄层孔菌(Fomes fomentarius)石油醚组分中甾醇和三萜类等成分及其主要抗肿瘤活性物质。方法:采用95%乙醇回流提取法及拌硅胶淋洗方法得到木蹄层孔菌的石油醚组分。用气相色谱-质谱联用技术对石油醚组分甾体和三萜类成分进行分析和鉴定并计算出其含量。用硅胶柱色谱法分离纯化含量最高的7,22-二烯麦角甾-3-酮。采用Alamar Blue法进行体外抗肿瘤活性检测。结果:从木蹄层孔菌石油醚组分中检测出37个成分,鉴定了其中的35个成分,包括10种甾体和三萜类成分。其主要成分为:7,22-二烯麦角甾-3-酮(37.67%)和5,24(28)-二烯麦角甾-3-醇(27.01%)。石油醚组分对细胞株NCI-H460的IC50为75μg.mL-1,7,22-二烯麦角甾-3-酮对细胞株NCI-H460的IC50为30μg.mL-1,抗肿瘤活性与单体浓度存在明显的量效关系。结论:木蹄层孔菌石油醚组分主要成分为7,22-二烯麦角甾-3-酮和5,24(28)-二烯麦角甾-3-醇,抗肿瘤活性物质最高的为7,22-二烯麦角甾-3-酮。研究结果为木蹄层孔菌的进一步开发提供了依据。     

Comparison of the effects of perineural or intravenous dexamethasone on thoracic paravertebral block in Ivor‐Lewis esophagectomy: A double‐blind randomized trial

Efforts to prolong thoracic paravertebral block (TPVB) analgesia include local anesthetic adjuvants, such as dexamethasone (Dex). Previous studies showed that both perineural (PN) and intravenous (i.v.) routes could prolong analgesia. As PN Dex is an off‐label use, anesthesiologists should be fully informed of the clinical differences, if any, on block duration. This study was designed to evaluate the two administration routes of Dex for duration of analgesia in TPVB. Ninety‐five patients scheduled for Ivor‐Lewis esophagectomy were randomized to receive TPVB (0.5% ropivacaine 15 ml), PN or i.v. Dex 8 mg. The primary end point was the duration of analgesia. The secondary end points included pain scores, analgesic consumption, adverse effects rate, and incidence of chronic pain at 3 months postoperatively. The PN‐Dex group showed better analgesic effects than the i.v.‐Dex group (p < 0.05). Similarly, the visual analogue scale scores in patients at 2, 4, 8, and 12 h postoperatively were lower in the PN‐Dex group than the i.v.‐Dex group (p < 0.05). The analgesic consumption in both the PN‐Dex and i.v.‐Dex groups was significantly lower than that in the control group (p < 0.05). Regarding the incidence of chronic pain, regardless of route, Dex decreased the incidence of chronic postsurgical pain and neuropathic pain at 3 months after surgery (p < 0.05), but there were no clinical differences between the i.v.‐Dex and PN‐Dex groups. Perineural dexamethasone improved the magnitude and duration of analgesia compared to that of the i.v.‐Dex group in TPVB in Ivor‐Lewis esophagectomy. However, there were no clinically significant differences between the two groups in the incidence of chronic pain.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Both perineural (PN) and intravenous (i.v.) dexamethasone (Dex) could prolong the duration of a nerve block, but the superiority of either route is still inconclusive. WHAT QUESTION DID THIS STUDY ADDRESS? The study investigated the effects of the two routes of Dex added to ropivacaine on analgesic effects of thoracic paravertebral block in patients undergoing Ivor‐Lewis esophagectomy. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These results extend the knowledge of the superior analgesic effect of Dex for the management of perioperative pain in the setting of Ivor‐Lewis Esophagectomy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Because PN Dex is an off‐label use, our study conformed the safety of Dex as PN adjuvants and extended its application field in clinical work.     

骨形态发生蛋白7在慢性HBV感染者肝组织中的表达

[目的]通过对不同慢性乙型肝炎病毒（HBV）感染者肝组织中骨形态发生蛋白7（BMP-7）表达的分析,初步探讨BMP-7在肝脏炎症和肝细胞再生过程中可能发挥的作用。[方法]对56例慢性HBV感染者及5例正常对照肝组织进行常规组织学观察,按病理诊断分组。其中病毒性肝炎乙型慢性轻度12例,中度12例,重度6例,重型8例,乙肝肝硬化10例,肝癌8例。进行BMP-7的免疫组织化学染色,观察光镜下分布特点,取部分标本进行图像分析。取8例肝癌患者癌结节及3例癌旁组织进行实时荧光定量RT-PCR,检测BMP-7mRNA的表达。[结果]BMP-7阳性单位在正常人肝脏（7.27±2.88）、病毒性肝炎（乙型）慢性轻度（8.50±3.22）、中度（10.96±2.88）、重度（13.11±1.26）有逐渐增加趋势,重型肝炎（7.50±1.21）、肝硬化（8.24±1.79）较中度、重度低;进一步比较BMP-7阳性区灰度有相似结果（P值均小于0.01）。BMP-7在肝脏既有胞浆型表达,也有胞膜型表达。在慢性中度、重度患者及肝硬化结节内为弥漫性表达;但在重型肝炎患者,仅呈灶状表达;在癌周组织有弥漫或灶状表达,在癌结节表达极少。[结论]在慢性乙型肝炎患者肝组织中BMP-7表达增多,但是在重型肝炎肝组织及肝癌结节中表达减少,值得进一步研究。