Assessment of postural stability in women with hip osteoarthritis: A case–control study

Objective

The aim of the study was to assessment the impact of hip osteoarthritis on postural stability.

A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein

P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. The diphenylpropylamine opioids methadone and loperamide are structurally similar, but loperamide has about a 4-fold higher Pgp-mediated transport rate. In addition to these differences, they showed significant differences in their effects on Pgp-mediated adenosine triphosphate (ATP) hydrolysis. The activation of Pgp-mediated ATP hydrolysis by methadone was monophasic, whereas loperamide activation of ATP hydrolysis was biphasic implying methadone has a single binding site and loperamide has 2 binding sites on Pgp. Quenching of tryptophan fluorescence with these drugs and digoxin showed competition between the opioids and that loperamide does not compete for the digoxin-binding site. Acrylamide quenching of tryptophan fluorescence to probe Pgp conformational changes revealed that methadone- and loperamide-induced conformational changes were distinct. These results were used to develop a model for Pgp-mediated transport of methadone and loperamide where opioid binding and conformational changes are used to explain the differences in the opioid transport rates between methadone and loperamide.     

The Influence of In Vivo Metabolic Modifications on ADMET Properties of Green Tea Catechins–In Silico Analysis

The health effects of green tea are associated with catechins: (?)-epigallocatechin-3-O-gallate (EGCG), (?)-epigallocatechin, (?)-epicatechin-3-O-gallate, and (?)-epicatechin. An understanding of compound absorption, distribution, metabolism, excretion, and toxicity characteristics is essential for explaining its biological activities. Herein, absorption, distribution, metabolism, excretion, and toxicity properties of in vivo detected metabolites of green tea catechins (GTCs) have been analyzed in silico. The influence of metabolic transformations on absorption, distribution, metabolism, and excretion profiles of GTCs corresponds to the effects of size, charge, and lipophilicity, as already observed for other small molecules. Mutagenic, carcinogenic, or liver toxic effects were predicted only for a few metabolites. Similar to galloylated GTCs EGCG and (--)-epicatechin-3-O-gallate, the sulfo-conjugates were predicted to bind at the warfarin binding site. The low free plasma concentration of these derivatives may be consequential to their serum albumin binding. The activity cliff detected for methylated conjugates of EGCG indicates that GTCs' pro-oxidative activity in bound state comes primarily from free hydroxyl groups of the pyrogallol ring B.     

Electroreduction of methyl viologen in the presence of nitrite. Its influence on enzymatic electrodes

The electroreduction of methyl viologen (MV) in the presence of nitrite was studied by cyclic voltammetry. A catalytic wave for the reduction of MV²⁺ was observed at ?0.740 V for which an EC catalytic mechanism is proposed. The rate constant for this chemical reaction under pseudo-first-order conditions, evaluated using working curves, was employed in the simulation of the voltammetric response. The second-order rate constant was also evaluated. Influences of the reaction at ?0.800 V on enzymatic electrodes employing nitrate reductase (NR) and MV⁺ as mediator were also analysed by chronoamperometry.     

核桃青皮提取物对食管癌细胞增殖的抑制作用及其分子机制的探讨

目的观察核桃青皮提取物对人食管癌细胞增殖的抑制作用.方法：用MTT法分别测定核桃青皮粗提物和核桃青皮提取物没食子酸、乙酸乙酯、紫杉叶素、7-D-芹菜糖-儿茶酚对食管癌细胞EC9706和KYSE150的增殖抑制率,并用Western Blot检测不同药物处理后食管癌细胞中细胞周期相关蛋白CyclinD1的蛋白表达.结果：核桃青皮粗提物、没食子酸和乙酸乙酯能抑制食管癌细胞的增殖,其作用呈明显剂量依赖性,当药物浓度增加至80 μg/mL时,对KYSE150的抑制率分别为82.75% 、90.51%、88.36%,对EC9706的抑制率分别为85.54% 、87.21%、85.17%.与对照组相比,3种药物均会显著抑制KYSE150和EC9706细胞中CyclinD1的表达.结论：核桃青皮提取物对食管癌细胞系的增殖有较强的抑制作用,其机制可能与引起细胞周期阻滞有关.     

Tamoxifen induces resistance to activated protein C

Introduction

The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet.

Materials and Methods

Blood samples were collected prospectively from women with breast cancer before (n = 25) and monthly after start of adjuvant TAM treatment (n = 75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally.

Results

APC sensitivity decreased by 41% (p = 0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p = 0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed.

Conclusions

This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.