酒石酸美托洛尔片联合左卡尼汀注射剂治疗慢性心力衰竭的临床研究

目的观察酒石酸美托洛尔片联合左卡尼汀注射剂治疗慢性心力衰竭的临床疗效及安全性。方法将98例慢性心力衰竭患者随机分为对照组和试验组,每组49例。对照组予以口服酒石酸美托洛尔片6.25 mg,bid;试验组在对照组的基础上,予以静脉滴注左卡尼汀注射剂2 g,qd,2组均持续治疗10 d。比较2组患者的临床疗效,血清半乳糖凝集素-3(Gal-3)、糖类抗原125(CA125)和N末端脑钠肽前体(NT-proB NP)水平和药物不良反应发生率。结果试验组和对照组总有效率分别为93.87%(46例/49例)和71.42%(35例/49例),差异有统计学意义(P<0.05)。治疗后,试验组和对照组血清Gal-3分别为(4.19±0.59),(5.64±0.73)μg·L^-1;CA125分别为(48.16±5.54),(73.47±8.02)U·L^-1;NT-proB NP分别为(291.93±36.30),(389.61±45.60)μg·L^-1,差异均有统计学意义(均P<0.05)。试验组和对照组的药物不良反应主要有转氨酶上升和头痛,药物不良反应发生率分别为22.44%(11例/49例)和18.37%(9例/49例),差异无统计学意义(P>0.05)。结果酒石酸美托洛尔片联合左卡尼汀注射剂治疗慢性心力衰竭的临床疗效肯定,且安全性高。     

金水宝胶囊中发酵虫草菌粉多糖的指纹图谱研究

目的建立金水宝胶囊发酵虫草菌粉多糖的指纹图谱。方法沸水回流提取金水宝胶囊中的发酵虫草菌粉多糖,经酸水解和1-苯基-3-甲基-5-吡唑啉酮(PMP)衍生化后采用HPLC法分析,色谱条件为Phenomenex OOG-4252-EO C18色谱柱(250 mm×4.6 mm,5μm),以乙腈-0.05 mol/L磷酸盐缓冲液梯度洗脱,体积流量1 m L/min,进样量20μL,检测波长250 nm,柱温30℃。结果对组成发酵虫草菌粉多糖的11种单糖成分进行鉴别,并建立了发酵虫草菌粉多糖指纹图谱。通过指纹图谱分析10批金水宝胶囊中各单糖成分,相似度均大于0.999,无显著性差异。结论建立的发酵虫草菌粉多糖指纹图谱操作简单,专属性强,重复性好,能够客观评价金水宝胶囊的质量。     

Ferrostatin-1通过抑制铁死亡延缓D-gal诱导的心肌细胞衰老的研究

目的 探讨D-半乳糖（D-gal）诱导的心肌细胞衰老是否存在铁死亡及铁死亡抑制剂Ferrostatin-1(Fer-1)能否延缓心肌细胞衰老。方法 通过不同水平（0、5、10、20、40、80、100 g/L）D-gal诱导H9C2心肌细胞损伤从而制备心脏衰老模型,采用MTT法检测细胞活力,确定后续实验采用的D-gal质量浓度。将细胞分为Control组、D-gal组和Fer-1组。MTT法检测细胞活力;DCFH-DA法检测细胞内活性氧（ROS）水平;微板法检测细胞内还原型谷胱甘肽（GSH）含量;硫代巴比妥酸法检测细胞内丙二醛（MDA）含量;Western blot检测溶质载体家族7成员11(SLC7A11)、谷胱甘肽过氧化物酶4(GPx4)、P53蛋白表达水平;微量法检测细胞内β-半乳糖苷酶（β-GAL）活性。结果 MTT法结果显示,细胞活力随D-gal质量浓度升高而降低（P<0.05）,后续实验采用D-gal质量浓度为20 g/L。与D-gal组相比,Fer-1组细胞活力增加（P<0.05）;与Control组相比,D-gal组中ROS、MDA含量、P53蛋白表达水平、...     

HepaRG culture in tethered spheroids as an in vitro three‐dimensional model for drug safety screening

Conventional two‐dimensional (2D) monolayer cultures of HepaRG cells allow in vitro maintenance of many liver‐specific functions. However, cellular dedifferentiation and functional deterioration over an extended culture period in the conventional 2D HepaRG culture have hampered its applications in drug testing. To address this issue, we developed tethered spheroids of HepaRG cells on Arg–Gly–Asp (RGD) and galactose‐conjugated substratum with an optimized hybrid ratio as an in vitro three‐dimensional (3D) human hepatocyte model. The liver‐specific gene expression level and drug metabolizing enzyme activities in HepaRG‐tethered spheorids were markedly higher than those in 2D cultures throughout the culture period of 7 days. The inducibility of three major cytochrome P450 (CYP) enzymes, namely CYP1A2, CYP2B6 and CYP3A4, was improved in both mRNA and activity level in tethered spheroids. Drug‐induced cytotoxic responses to model hepatotoxins (acetaminophen, chlorpromazine and ketoconazole) in tethered spheroids were comparable to 2D cultures as well as other studies in the literature. Our results suggested that the HepaRG‐tethered spheroid would be an alternative in vitro model suitable for drug safety screening. Copyright © 2014 John Wiley & Sons, Ltd.     

Metformin ameliorates the age‐related changes of d‐galactose administration in ovariectomized mice

Metformin (Met) has been shown to have pleiotropic effects such as neuroprotective, antioxidant, and anti‐inflammatory properties making that a potential candidate for the treatment of central nervous system (CNS) disorders. This study was designed to investigate the possible effect of Met on the d ‐galactose (d ‐gal)‐induced aging in ovariectomized mice. The female mice underwent bilateral ovariectomy. d ‐gal was administered orally at a dose of 500 mg/kg, and Met was administrated orally at doses of 1 and 10 mg/kg for 6 weeks. Anxiety‐like behavior was evaluated by the elevated plus‐maze. Physical power was assessed by vertical grid holding test and forced swimming capacity test. The brains were assessed for the level of superoxide dismutase (SOD) and brain‐derived neurotrophic factor (BDNF). Ovariectomy caused anxiety and declined the physical power as well as BDNF and SOD levels. d ‐gal administration in ovariectomized mice exacerbated these deleterious effects. Met hampered the anxiety‐like behavior and strengthened the physical power of d ‐gal‐treated ovariectomized mice. Met also increased the SOD and BDNF levels in the brains of d ‐gal‐treated ovariectomized animals. Based on the obtained results, we suggest Met administration as a novel therapeutic approach for the treatment of age‐related conditions in the absence of female sex hormones.     

Age-dependency of galactose elimination capacity in healthy children and children with chronic liver disease

Abstract

Objective. Galactose elimination capacity (GEC) is used as a quantitative measure of liver metabolic function with prognostic value in adults with acute and chronic liver failure. Almost no data are available regarding GEC in children, however. This study thus aims to meet the previously unmet clinical need for age-related data on GEC in children. Material and methods. We studied galactose elimination in 10 healthy children (median age 10.7 years; range 7 months to 16 years) and 30 children with chronic liver disease (median age 8.6 years; range 3 months to 16 years). GEC was estimated from the linear decrease in concentration of galactose in arterialized capillary blood from the ear following intravenous infusion of galactose. Results. In both groups of children, GEC (μmol/min/kg body weight) was highest in the youngest children and decreased with age, although at a significantly lower level in the children with liver disease (p = 0.05). GEC was significantly higher in healthy children than in healthy adults, diminishing to the adult level by the age of 16 years. Conclusions. GEC was found to be higher in children than in adults until the age of 16 years. Moreover, GEC was significantly lower in children with chronic liver disease than in healthy children, underlining that GEC testing also has potential clinical usefulness as a quantitative measure of liver metabolic function in children.     

13C-methacetin and 13C-galactose breath tests can assess restricted liver function even in early stages of primary biliary cirrhosis

Objective. The ¹³C-methacetin breath test quantitatively evaluates cytochrome P450-dependent liver function. The ¹³C-galactose breath test non-invasively measures the galactose oxidation capacity of the liver. The aim of this study was to find out whether these breath tests are sensitive parameters also in non-cirrhotic patients with primary biliary cirrhosis.

Material and methods. Nineteen patients with early-stage primary biliary cirrhosis (no cirrhotic alterations in the liver biopsy, Ludwig stage I–III) and 20 healthy controls underwent the ¹³C-methacetin and ¹³C-galactose breath tests.

Results. Patients with primary biliary cirrhosis metabolized less ¹³C-methacetin than controls (cumulative recovery within 30 min 7.5±2.4% versus 14.0±2.6%; p<0.001). When a cut-off?>?9.8% was used for the cumulative recovery after 30 min, the methacetin breath test reached 84.2% sensitivity and 95.0 specificity. In the ¹³C-galactose breath test, the percentage recovery at 60 min in patients was 3.1±1.3%/h, and 6.3±1.1%/h in controls (p<0.001). Using a cut-off?>?4.7%/h, the galactose breath test reached 89.5% sensitivity and 95.0 specificity.

Conclusions. In non-cirrhotic, early-stage, primary biliary cirrhosis the ¹³C-methacetin breath test and the ¹³C-galactose breath test reliably indicate decreased liver function. The ¹³C-galactose breath test can also predict the histological score.     

Changes in quantitative measures of hepatic function after 90% hepatectomy in rats

Quantitative measures of liver functions were investigated in rats up to 360 h after 90% hepatectomy and related to total hepatic DNA. Galactose elimination capacity (cytosolic phosphorylation of carbohydrate), p-nitro-anisole demethylase activity (endoplasmic drug hydroxylation) and prothrombin index (protein synthesis at rough endoplasmic membranes) were initially reduced as much as the liver weight, but recovered differently. During hepatic regeneration prothrombin index and galactose elimination were back to control values after an interval of 360 h, while p-nitro-anisole demethylase activity was about 0.4 times control value after that interval. The correlation between total hepatic DNA and liver weight, and between total hepatic protein and liver weight was 0.92 in both cases, indicating their close relationship during hepatic regeneration. Compared to earlier studies on 70% hepatectomy the recovery of metabolic functions after 90% hepatectomy is delayed, as compared to regeneration of total hepatic DNA. The compensatory hyperfunction observed after 70% hepatectomy was not found after 90% hepatectomy, indicating a lost ability to hyperfunction when hepatic function is reduced close to the minimal residual function. This is suggested to be important for the sudden onset of hepatic insufficiency.     

可溶性ST2与半乳糖凝集素-3对缺血性心脏病患者心力衰竭评估价值分析

目的:观察缺血性心脏病患者可溶性ST2(sST2)和半乳糖凝集素-3(Gal-3)水平与心功能的关系。方法:选择缺血性心脏病导致慢性射血分数减低的心力衰竭患者179例(HF组),其中NYHA心功能Ⅱ级60例、Ⅲ级67例、Ⅳ级52例。另入选同期入院治疗的冠心病心功能Ⅰ级患者49例(非HF组)为对照。比较两组及HF组不同心功能分级之间血清sST2和Gal-3水平,分析血清sST2和Gal-3水平对缺血性心脏病患者心力衰竭的评估价值。结果:与非HF组比较,HF组血清sST2[(103.07±45.87)ng/ml比(152.33±48.84)ng/ml]和Gal-3[(84.56±40.54)ng/ml比(119.58±46.86)ng/ml]水平均显著升高(P均=0.001)。与心功能Ⅱ级组比较,Ⅲ级和Ⅳ级组Gal-3水平[(103.74±36.75)ng/ml比(123.56±51.48)ng/ml、(132.72±49.64)ng/ml]均显著升高(P<0.05或<0.01);sST2水平在不同心功能组间差异无显著性(P=0.136)。经ROC分析,sST2及Gal-3诊断缺血性心脏病患者HF的曲线下面积分别为0.769(P=0.001)和0.722(P=0.001)。结论:缺血性心脏病患者血清Gal-3水平随心功能恶化而显著升高,sST2和Gal-3具备评价缺血性心脏病患者心力衰竭的临床价值。