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.     

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.     

西酞普兰与文拉法辛治疗抑郁症对照研究

目的:比较西酞普兰与文拉法辛治疗抑郁症的疗效及安全性。方法:将65例抑郁症患者随机分为两组,分别给予西酞普兰与文拉法辛治疗,疗程6周。用汉密尔顿抑郁量表(HAMD)及汉密尔顿焦虑量表(HAMA)在治疗前及治疗1、2、4、6周评定疗效;用副反应量表(TESS)评定不良反应。结果:两组总体疗效相当,西酞普兰起效稍快。两组不良反应均较轻,安全性好。结论:西酞普兰与文拉法辛均是安全有效的抗抑郁药。     

氯氮平和利培酮对精神分裂症患者体质量的影响

目的:探讨氯氮平和利培酮对精神分裂症患者体质量(体重)的影响及相关因素。方法:选择符合国际疾病分类第10版(ICD-10)精神分裂症的诊断标准,空腹血糖正常,无严重躯体疾病,1周内未用任何抗精神病药的住院患者,共计65例,其中利培酮组32例,氯氮平组33例。两组患者于治疗前和治疗6周末分别做葡萄糖耐量试验,测空腹血胰岛素,测量体质量、身高,计算体质量指数(BMI),评定阳性与阴性症状量表(PANSS)。结果:①治疗后体质量增加者氯氮平组24例(占72.7%),利培酮组19例(占59.4%);氯氮平组体质量平均增加2.5kg,利培酮组1.4kg;②氯氮平组体质量增加与进食量增加、胰岛素水平增加和PANSS评分减分率相关(P<0·05),体质量增加者餐后1h血糖升高;③利培酮组体质量增加与年龄、病程显著相关(P<0·05),与基础BMI存在负相关倾向;④两组治疗后均出现糖耐量减低(IGT)和暂时诊断糖尿病(DM)。结论:氯氮平和利培酮均能导致体质量增加,体质量增加更易对糖代谢造成不良影响。     

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.     

激素间歇冲击及小剂量维持治疗IgA肾病的随机对照研究

目的:探讨激素间歇冲击及小剂量维持与血管紧张素转换酶抑制剂治疗中度蛋白尿IgA肾病的疗效及其影响因素。方法:47例IgA肾病患者随机分为实验组和对照组。对照组(21例)给予ACEI药物治疗,实验组(26例)在此基础上口服泼尼松0.5mg/kg,隔日给药,治疗12个月,并在治疗的第1、3、5个月初分别给予甲基泼尼松龙0.5g/d,冲击3d。对肾脏病理改变进行WHO分级并对各种病变进行半定量分析。结果:两组间在性别、年龄、临床及病理资料间无统计学差异。平均随访14个月后,实验组尿蛋白完全缓解8例(30.8%),部分缓解14例(53.8%),无缓解4例(15.4%);而对照组分别为4例(19.1%),3例(23.8%),12例(57.1%),有统计学差异(P<0.01)。治疗前后,实验组血肌酐分别为(89.9±30.3)μmol/L及(88.2±32.8)μmol/L;对照组分别为(89.5±37.9)μmol/L及(104.0±49.7)μmol/L,但两者比较均无统计学意义(P>0.05)。多因素分析显示疗效与肾小球硬化率及肾小管间质病变呈负相关。结论:激素间歇冲击及小剂量维持治疗能显著减少蛋白尿,维持肾功能稳定。影响疗效的主要因素为肾小球硬化率及肾小管间质病变程度。