Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression

The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague–Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16α-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(α)pyrene (B(α)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(α)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity.     

Serum IL-21 levels are elevated in atopic dermatitis patients with acute skin lesions

Background

Interleukin (IL)-21 is a member of the type I cytokine family and plays a role in the pathogenesis of T helper type 2 allergic diseases. It has been reported that IL-21 expression is upregulated in acute skin lesions in atopic dermatitis (AD) patients; however, little is known about the serum IL-21 levels of AD patients. The aim of this study was to quantify the serum IL-21 levels of AD patients and to evaluate the relationships between the serum IL-21 level and disease severity, laboratory markers, and eruption type in AD patients.

Ammonium accumulation and chemokine decrease in culture media of Gcdh−/− 3D reaggregated brain cell cultures

Glutaric Aciduria type I (GA-I) is caused by mutations in the GCDH gene. Its deficiency results in accumulation of the key metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body tissues and fluids. Present knowledge on the neuropathogenesis of GA-I suggests that GA and 3-OHGA have toxic properties on the developing brain.We analyzed morphological and biochemical features of 3D brain cell aggregates issued from Gcdh^?/? mice at two different developmental stages, day-in-vitro (DIV) 8 and 14, corresponding to the neonatal period and early childhood. We also induced a metabolic stress by exposing the aggregates to 10 mM l-lysine (Lys).Significant amounts of GA and 3-OHGA were detected in Gcdh^?/? aggregates and their culture media. Ammonium was significantly increased in culture media of Gcdh^?/? aggregates at the early developmental stage. Concentrations of GA, 3-OHGA and ammonium increased significantly after exposure to Lys. Gcdh^?/? aggregates manifested morphological alterations of all brain cell types at DIV 8 while at DIV 14 they were only visible after exposure to Lys. Several chemokine levels were significantly decreased in culture media of Gcdh^?/? aggregates at DIV 14 and after exposure to Lys at DIV 8.This new in vitro model for brain damage in GA-I mimics well in vivo conditions. As seen previously in WT aggregates exposed to 3-OHGA, we confirmed a significant ammonium production by immature Gcdh^?/? brain cells. We described for the first time a decrease of chemokines in Gcdh^?/? culture media which might contribute to brain cell injury in GA-I.     

Potential function of TGF-β isoforms in maturation-stage ameloblasts

Objectives

To investigate potential functions of transforming growth factor-beta (TGF-β) isoforms in maturation-stage ameloblasts during amelogenesis.

不同麻醉方法对开胸手术患者红细胞糖代谢限速酶活性的影响

目的 探讨开胸手术患者红细胞内糖代谢限速酶活性的变化及不同麻醉方法对其的影响。方法 48例ASAI～Ⅱ级择期开胸手术患者,按麻醉方式随机分成三组,每组16例。Ⅰ组采用地氟醚吸入为主的全身麻醉;Ⅱ组采用异氟醚吸入为主的全身麻醉;Ⅲ组采用异氟醚吸入联合连续硬膜外阻滞。于麻醉前、手术90min、术后60min及术后第1、2天共五个时点分别测定血糖浓度及红细胞6-磷酸葡萄糖脱氢酶(G-6PD)、磷酸果糖激酶(PFK)和醛糖还原酶(AR)活性。结果 与麻醉前比较,三组患者血糖浓度自术中90min开始,至术后第2天升高显著(P<0.05);Ⅰ、Ⅱ两组术后第1天PFK活性显著下降(P<0.05),G-6PD、AR活性显著升高(P<0.05),而Ⅲ组各时点红细胞内糖代谢限速酶活性的变化与麻醉前比较均无统计学差异(P>0.05),且Ⅲ组术后第1天PFK值远低于Ⅰ组相应值。结论 开胸手术中、手术后存在明显的高血糖反应。术后第1天,红细胞内会出现糖酵解途径受抑制,磷酸戊糖途径、多元醇通路相应活跃现象。采用异氟醚吸入联合硬膜外阻滞可在一定程度上调控手术创伤对红细胞糖代谢的影响。     

人结直肠癌组织中胸腺嘧啶核苷磷酸化酶和二氢嘧啶脱氢酶的活性变化及其意义

目的研究人结直肠癌组织及癌旁正常组织胸腺嘧啶核苷磷酸化酶(thymidinephosphorylase,TP)和二氢嘧啶脱氢酶(dihydropyrimidinedehydrogenase,DPD)活性与结直肠癌临床病理特征以及与5-FU化疗效果的关系。方法应用酶联免疫吸附法(ELISA)检测68例结直肠癌患者肿瘤组织和癌旁正常组织TP和DPD活性,其中40例患者术后接受5-FU结合甲酰四氢叶酸钙化疗。结果(1)结直肠癌肿瘤组织TP活性(120±102)U/mg明显高于癌旁正常组织(60±49)U/mg,P<0·01;组织分型差(低分化、黏液腺癌)、Dukes分期晚(C期和D期)、有淋巴转移的肿瘤组织TP活性明显增高;(2)在术后接受5-FU化疗的患者中,肿瘤DPD活性低和TP/DPD比值高的患者术后生存期明显好于DPD活性高和TP/DPD比值低的患者。结论人结直肠癌组织TP活性明显高于癌旁正常组织;肿瘤TP活性与结直肠癌恶性潜能相关,可能在肿瘤的发展中起一定作用;肿瘤DPD活性和TP/DPD比值可能是预测结直肠癌对5-FU化疗敏感性的指标之一。     

大鼠脑外伤后LDH和Caspase-9的表达及意义

目的:探讨大鼠脑外伤后乳酸脱氢酶(LDH)和Caspase-9 的表达及其时序性变化,并探讨脑损伤的分子机制.方法:采用改良的自由落体法,制备成脑损伤模型.采用分光光度法检测指标LDH,Caspase-9 的活性测定.结果:LDH 1h 检测到下降,6h降低到最低,从6h后开始升高,到24h达到高峰,之后又开始下降.Caspase-9 检测到,1h低表达,3h开始升高,12h 达到高峰,1d 时开始显著下降.结论:大鼠脑外伤后可诱发LDH,Caspase-9的表达,随着时间的增加呈现一定的变化趋势.     

大鼠舌白斑癌变过程中线粒体琥珀酸脱氢酶活性变化的研究

目的:探讨大鼠口腔癌变过程中线粒体琥珀酸脱氢酶(Succinate dehydrogenase,SDH)的活性变化及其生物学意义.方法:2×10-5 4-硝基喹啉-1-氧化物(4NQO)饮水喂养Wistar大鼠9~32周建立大鼠舌癌变模型,提取30例大鼠舌癌变过程不同病理阶段的舌背组织线粒体,酶标仪检测SDH酶活性的变化.结果:在大鼠舌白斑癌变过程中,线粒体SDH活性呈逐渐下降趋势,其中,重度异常增生、鳞癌组织中SDH酶活性显著低于正常黏膜(P<0.05). SDH的基因表达及酶活性变化趋势较为一致. 结论:SDH酶活性和mRNA表达水平的下降与口腔癌发生发展相关,三羧酸循环在口腔黏膜癌变过程可能起到重要作用.     

Direct electron transfer between the heme of cellobiose dehydrogenase and thiol modified gold electrodes

Cellobiose dehydrogenase (CDH) is an extracellular fungal enzyme with two domains, one containing flavin adenine dinucleotide (FAD) and one containing heme. The electrochemistry of CDH, as well as its cleaved FAD- and heme-subunits, was studied using a membrane electrode, i.e. the enzyme was trapped under a permselective membrane on a cystamine or 3-mercaptopropionic acid modified gold electrode. Direct un-mediated electron transfer (ET) between the heme of CDH and thiol modified gold electrodes was demonstrated using cyclic voltammetry. At low sweep rate (10 mV s^?1) and low pH (pH 4.3) up-hill ET from heme to FAD in CDH was observed. The formal potential of the heme in CDH and in the cleaved heme-subunit was found to be the same and equal to ?41 mV versus Ag ∣ AgCl at pH 5.1. The dependence of the formal potential on the pH (in the pH range 3.6–6.0) indicates the presence of one redox-linked ionisable functional group. Entropy and enthalpy changes were determined in variable temperature experiments as follows, ΔS°′=?194±14 J mol^?1 K^?1 and ΔH°′=?74±6 kJ mol^?1. The electrocatalytic behaviour of the CDH electrodes was demonstrated by addition of the enzyme substrate, cellobiose. The catalytic current was shown to decrease upon increased pH, in accordance with previous kinetic data in solution. The model of electron transport from the substrate (cellobiose) to FAD, and then through the heme domain to the electrode was confirmed in the experiments.