Maternal benzo[a]pyrene exposure is correlated with the meiotic arrest and quality deterioration of offspring oocytes in mice

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) in particulate matter that has a diameter of ≤2.5 μm (PM2.5). Studies have demonstrated that BaP exposure causes oocyte meiotic arrest in mice. However, whether BaP exposure also affects oocyte maturation in offspring remains unclear. To test this, female mice were administered BaP before pregnancy to generate BaP-exposed offspring. Our findings showed that BaP exposure reduced the in vitro maturation and increased the abnormalities of meiotic apparatus in offspring oocytes. In addition, BaP exposure reduced the mitochondrial content and intracellular ATP generation, induced early apoptosis, increased reactive oxidative species accumulation and the genomic DNA 5-methylcytosine (5mc) level in offspring oocytes. Along with the abovementioned defective parameters, maternal BaP exposure further compromised the embryo developmental competence of offspring oocytes. In summary, our study demonstrated that maternal BaP exposure compromised offspring oocyte maturation and quality.     

双环[1.1.1]戊烷衍生物的合成研究进展

双环[1.1.1]戊烷（BCP）是一种具有三维立体结构的桥环骨架，其作为苯环、叔丁基和炔烃的生物电子等排体，已经在药物化学领域得到广泛的应用。随着BCP应用范围的扩大，BCP及其衍生物的合成日益成为研究的热点。本文对BCP衍生物的主要合成策略和方法进行总结，旨在为新药研发人员提供参考。     

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

Synthesis,in vivo and in silico evaluation of novel 2,3-dihydroquinazolin-4(1H)-one derivatives as potential anticonvulsant agents

In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED₅₀) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED₅₀ values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABA_A binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.

A facile synthesis of [14C]pyrithiobac‐sodium

Condensation of thiourea 1 with diethyl malonate 2 in the presence of sodium methoxide furnished 4,6‐dihydroxy‐2‐mercaptopyrimidine 3 . Compound 3 on methylation with diazomethane followed by oxidation with H₅IO₆/CrO₃ in ethyl acetate gave 4,6‐dimethoxy‐2‐methylsulphonylpyrimidine 5 . Compound 5 on condensation with 2‐mercapto‐6‐chlorobenzoic acid in the presence of a phase transfer catalyst, tetrabutylammonium bromide and sodium carbonate gave the title compound – pyrithiobac‐sodium 6 with an overall yield of > 35% starting from thiourea. Following the above standardized procedure, using [¹⁴C]‐thiourea in lieu of thiourea, ¹⁴C labelled product 6 , was synthesized with an overall radiochemical yield > 30% (with respect to [¹⁴C]‐thiourea) for further evaluations of environmental fate of 6 , in soils and plants. Copyright © 2006 John Wiley & Sons, Ltd.     

卡托普利对自发性高血压大鼠血管平滑肌细胞增殖及癌基因和抑癌基因的影响

目的：观察卡托普利（CaP）对自发性高血压大鼠（SHR）血管平滑肌细胞（VSMC）增殖的作用及对原癌基因及抑癌基因的影响。方法：氚-胸腺嘧啶核苷（3H－TdR）参入，电镜，原位来交及Northernblot杂交。结果：CaP在降低SHR血压同时，能减少VSMC的线粒体，粗面内质网及3H－TdR参入量（P<0.01），并能逆转c－fos，c－myc，c－sis原癌基因mRNA表达增强（P<0.05或0.01），p53抑癌基因mRNA表达减弱（P＜0．01）。结论：Cap能抑制SHR的VSMC增殖，与癌基因调控的分子生物学机制有关。     

The value of the acoustic analysis of pathological infant cry and breathing noise in everyday practice

During a period of twenty years [1969-1988] the author has observed 614 cases of congenital malformations and noninflammatory diseases of the larynx in infants and young children, Budapest. He summarizes the most characteristic symptoms of laryngeal pathology in infants, and discusses the diagnostic possibilities. Among the latter, spectrographic analyses complemented by auditory evaluation of pathological cry and different breathing noises play an important role. Based on his investigation author differentiates 20 kinds of pathological crying sounds and 4 basic forms of stridor. He describes the acoustic attributes of different pathological sound phenomena and summarizes characteristic voice changes.     

Synthesis of deramciclane* labeled with tritium in various positions

[(1R)‐endo]‐(+)‐3‐bromocamphor was dehalogenated with tritium gas to [3‐³H]camphor and via [3‐³H]phenylborneol converted to [3‐³H]deramciclane isolated as the fumarate salt (specific activity 51.8 GBq/mmol). This three step synthesis from [3‐³H]camphor gave an overall yield of 22%. Benzyloxy‐acetic acid methyl ester was reduced with sodium‐borotritide to 2‐benzyloxy‐ethanol‐[1‐³H], and through a four step procedure was converted to 2‐dimethylaminoethyl‐[2‐³H] chloride. The latter was condensed with the sodium derivative of 2‐phenylborneol giving rise to [2‐dimethylamino‐[2‐³H]ethoxy]deramciclane isolated as the fumarate (specific activity 8.177 GBq/mmol). This six step synthesis from [³H]NaBH₄ gave an overall yield of 6%. Copyright © 2005 John Wiley & Sons, Ltd.     

稳定性核素测定大鼠小肠蛋白质合成

目的：建立稳定性核素（[L-^15N]亮氨酸）测定大鼠小肠蛋白质合成率的方法。方法：分别测定静脉注射相同剂量[L-^15N]亮氨酸不同时相的大鼠小肠^15N丰度及不同剂量[L-^15N]亮氨酸同一时相的大鼠小肠^15N丰度。结果：大鼠小肠游离氨基酸池中^15N核素丰度在注射后0．5h内呈线性上升并达高峰，维持4h后缓慢下降，小肠蛋白质中的^15N丰度0．5h至12h基本维持不变；随着注射剂量的增加，大鼠小肠蛋白质分数合成率（FSR）亦增加，当[L-^15N]亮氨酸剂量在1．0mmol／kg以上，FSR并不随施加[L15N]亮氨酸剂量的加大而增加。结论：在进行大鼠小肠蛋白质合成率测定时，一次性静脉注射的测量最佳时限为0．5h，剂量为1．0mmol／kg。