Synthesis and biodistribution studies of two novel radioiodinated areno‐annelated estra‐1,3,5(10),16‐tetraene‐3‐ols as promising estrogen receptor radioligands

Two novel radioiodinated areno‐annelated estra‐1,3,5(10),16‐tetraenes, [¹²⁵I]2‐iodo‐1′‐methoxybenzo[4′,3′:16,17]estra‐1,3,5(10),16‐tetraene‐3‐ol ( 2 ‐[ ¹²⁵ I ]‐ MEBE ) and [¹²⁵I]4‐iodo‐1′‐methoxybenzo[4′,3′:16,17]estra‐1,3,5(10),16‐tetraene‐3‐ol, ( 4 ‐[ ¹²⁵ I ]‐ MEBE ) were synthesized for evaluation as potential ligands for the estrogen receptor. Radioiodination of 1′‐methoxybenzo[4′,3′:16,17]estra‐1,3,5(10),16‐tetraene‐3‐ol at the A ring was accomplished by electrophilic aromatic substitution using [¹²⁵I] sodium iodide and chloramine‐T as oxidant. After purification by reverse phase HPLC, the two radioisomers ( 2 ‐[ ¹²⁵ I ]‐ MEBE and 4 ‐[ ¹²⁵ I ]‐ MEBE ) were obtained in a radiochemical yield of 42 and 48%, respectively, in a radiochemical purity of greater than 95% and a high specific activity. The effect of the site of radioiodination (C₂ vs C₄) on the biological behaviour of the molecules was evaluated through biodistribution studies in immature female Sprague‐Dawley rats. Both 2 ‐[ ¹²⁵ I ]‐ MEBE and 4 ‐[ ¹²⁵ I ]‐ MEBE are stable in vivo and are mainly excreted through the hepatobiliary pathway. Both localize in the uterus and ovaries via a receptor‐mediated process, where the 2 ‐[ ¹²⁵ I ]‐ MEBE isomer has the higher specific ER binding and uterus selectivity. The favourable in vitro/in vivo stability and biodistribution profiles suggest that these radioligands are good candidates for further exploration of their potential clinical application. Copyright © 2006 John Wiley & Sons, Ltd.     

知柏地黄丸对抑那通诱导特发性性早熟小鼠模型的干预作用

目的观察知柏地黄丸对抑那通诱导的特发性中枢性性早熟（ICPP）模型小鼠的影响。方法选用18日龄BALB／c雌性小鼠,随机分为5组：正常对照组,ICPP模型组,知柏地黄丸高、低剂量组（剂量分别为101．4g·kg^-1·d^-1、50．7g·kg^-1·d^-1）。甲地孕酮对照组（剂量为3．9mg·kg^-1·d^-1）;除正常对照组外,其他各组均给予促性腺激素释放激素拟似物抑那通,首次剂量为1573．5雌／kg,第2次、第3次剂量均为1180μg／kg,隔日1次,复制模型;检测各组小鼠阴道开口数,体重,血清雌二醇（E2）和黄体生成素（LH）水平,子宫、卵巢重量,计算子宫指数和卵巢指数,子宫和阴道脱落细胞涂片,卵巢组织病理学变化等。结果知柏地黄丸高剂量组于造模第3_4天对抑那通所致阴道开口提前有抑制作用（P〈0．05,P〈0．01）,知柏地黄丸低剂量组于造模第2-5天对抑那通所致阴道开口提前有抑制作用（均P〈0．05,P〈0．01）,甲地孕酮对照组于造模第3天对抑那通所致阴道开口提前有抑制作用（P〈0．05）;知柏地黄丸高剂量组可降低抑那通所致子宫重量增加（P〈0．05）,知柏地黄丸低剂量组及甲地孕酮对照组均可降低抑那通所致子宫、卵巢重量增加及子宫指数和卵巢指数的升高（P〈0．01）;高、低剂量的知柏地黄丸及甲地孕酮均有抑制抑那通降低E2水平的作用（P〈0．05,P〈0．01）,各给药组对抑那通升高LH水平、诱导阴道角化细胞的出现及排卵后出现的子宫内膜分泌期改变无明显影响。结论知柏地黄丸对抑那通刺激诱导的ICPP模型具有一定的对抗作用,其机制可能是通过抑制HPGA的靶腺（性腺）而起作用。     

补肾除湿方治疗卵巢储备功能低下临床研究

目的:观察自拟补肾除湿方治疗卵巢储备功能低下的临床疗效。方法:136例卵巢储备功能低下患者随机分为观察组(黄芪、菟丝子、陈皮等)68例、对照组(戊酸雌二醇片+黄体酮胶丸)68例,治疗3个月后,比较各组治疗前后性激素变化及临床疗效。结果:观察组治疗前后卵泡刺激素(follicle-stimulating hormone,FSH)、黄体生成素(luteinizing hormone,LH)、雌二醇(estradiol,E2)、FSH/LH比较,差异均有统计学意义(P0.01);对照组治疗前后FSH、E2、FSH/LH比较,差异均有统计学意义(P0.01);观察组FSH、FSH/LH、LH、E2及临床疗效改善与对照组比较,差异均有统计学意义(P0.05)。结论:自拟补肾除湿方治疗卵巢储备功能低下临床疗效显著。     

Role of miR‐21‐5p/FilGAP axis in estradiol alleviating the progression of monocrotaline‐induced pulmonary hypertension

BackgroundAberrant expression of microRNAs (miRNAs) has been associated with the pathogenesis of pulmonary hypertension (PH). It is, however, not clear whether miRNAs are involved in estrogen rescue of PH.MethodsFresh plasma samples were prepared from 12 idiopathic pulmonary arterial hypertension (IPAH) patients and 12 healthy controls undergoing right heart catheterization in Shanghai Pulmonary Hospital. From each sample, 5 μg of total RNA was tagged and hybridized on microRNA microarray chips. Monocrotaline‐induced PH (MCT‐PH) male rats were treated with 17β‐estradiol (E₂) or vehicle. Subgroups were cotreated with estrogen receptor (ER) antagonist or with antagonist of miRNA.ResultsMany circulating miRNAs, including miR‐21‐5p and miR‐574‐5p, were markedly expressed in patients and of interest in predicting mean pulmonary arterial pressure elevation in patients. The expression of miR‐21‐5p in the lungs was significantly upregulated in MCT‐PH rats compared with the controls. However, miR‐574‐5p showed no difference in the lungs of MCT‐PH rats and controls. miR‐21‐5p was selected for further analysis in rats as E₂ strongly regulated it. E₂ decreased miR‐21‐5p expression in the lungs of MCT‐PH rats by ERβ. E₂ reversed miR‐21‐5p target gene FilGAP downregulation in the lungs of MCT‐PH rats. The abnormal expression of RhoA, ROCK2, Rac1 and c‐Jun in the lungs of MCT‐PH rats was inhibited by E₂ and miR‐21‐5p antagonist.ConclusionsmiR‐21‐5p level was remarkably associated with PH severity in patients. Moreover, the miR‐21‐5p/FilGAP signaling pathway modulated the protective effect of E₂ on MCT‐PH through ERβ.     

SPERM DNA FRAGMENTATION IS INCREASED IN COUPLES WITH UNEXPLAINED RECURRENT PREGNANCY LOSS

Previous studies have indicated that sperm quality may be related to unexplained recurrent pregnancy loss. This study evaluated the degree of sperm DNA fragmentation using the TUNEL assay on sperm from 24 couples with unexplained recurrent pregnancy loss (RPL) compared to sperm from 2 control groups: donors of known fertility and unscreened men from the general population. The percentage of sperm staining positive for DNA fragmentation was increased ( p <.001) in the RPL group (38±4.2) compared to the donor (11.9±1.0) or general population (22±2.0) control groups. In the RPL group, no correlation was observed between semen quality parameters and the TUNEL data. These data indicate that some RPL patients have a significant increase of sperm DNA fragmentation, which may be causative of pregnancy loss in some patients.     

妇科止血灵片联合米非司酮治疗功能性子宫出血的Meta分析

目的 利用Meta分析方法对妇科止血灵片联合米非司酮治疗更年期功能性子宫出血的疗效和安全性进行评价分析。方法检索并选取1989—2020年国内、外公开发表的关于妇科止血灵片联合米非司酮治疗更年期功能性子宫出血的临床随机对照试验文献,筛选符合纳入标准的试验进行研究,采用Revman5.1软件统计并分析相关数据。结果 共有5项研究符合纳入标准。与对照组比较,妇科止血灵片联合米非司酮治疗更年期功能性子宫出血的神经功能缺损临床疗效比数比（OR）合并值为4.02(95%可信区间为2.09～7.73)。促黄体生成素水平的加权均数差（WMD）合并值为-1.90(95%可信区间为–2.35～-1.46)。卵泡刺激素水平的WMD合并值为-4.52(95%可信区间为-7.19～-1.85)。雌二醇水平的WMD合并值为–87.91(95%可信区间为-88.78～-87.03)。孕酮水平的WMD合并值为-3.97(95%可信区间为-5.71～-2.77)。用药安全风险OR合并值为0.89(95%可信区间为0.46～1.73)。结论 Meta分析结果显示,妇科止血灵片联合米非司酮治疗更年期功能性子宫出血安全、有...     

雌二醇对强迫游泳实验中大鼠行为及海马和杏仁核5-羟色胺转运体表达的影响

目的观察雌二醇对强迫游泳实验中双侧卵巢切除大鼠行为及海马和杏仁核中5-羟色胺转运体(SERT)蛋白表达的影响。方法将28只成年雌性SD大鼠随机分为对照组、应激组、雌二醇组和氟西汀组(n=7)。手术切除大鼠双侧卵巢后饲养3周,第4周开始慢性给药14 d。第14天时应激组、雌二醇组和氟西汀组大鼠进行15 min强迫游泳实验,评定大鼠行为。免疫荧光组织化学法检测各组大鼠海马和杏仁核中SERT表达。结果雌二醇组和氟西汀组大鼠游泳行为计数分别显著多于应激组,而不动行为计数显著少于应激组,差异均有统计学意义(均P<0.001);免疫荧光组织化学法检测结果显示:应激组大鼠海马和杏仁核中SERT积分吸光度显著高于对照组(均P<0.001),而雌二醇组和氟西汀组海马和杏仁核中SERT积分吸光度均显著低于应激组(P<0.05,P<0.001)。结论雌二醇可使双侧卵巢切除大鼠在强迫游泳实验中的游泳行为增加,不动行为减少;预先给予雌二醇可阻止应激引起海马和杏仁核SERT蛋白含量增加,作用与抗抑郁药物氟西汀相似。     

雌二醇对慢性脑缺血去卵巢大鼠脑病理改变的影响

目的：探讨苯甲酸雌二醇对大鼠额部皮质和海马CA1区细胞形态和数量的影响，初步研究雌激素对血管性痴呆（Vascular dementia,VD)大鼠的神经保护作用。方法：利用双侧颈总动脉持久性结扎及卵巢切除大鼠模型，利用光镜，电镜结合图像分析，观察大鼠额叶皮质和海马CA1区的病理和超微结构变化。结果：手术组较治疗组大鼠额部皮质和海马CA1区细胞形态改变明显，数量减少，统计学分析呈显著差异，结论：雌激素具有一定的神经保护作用，可以为缓解血管性痴呆的症状提供结构基础。     

高血压脑出血患者血清雌二醇、睾酮的变化及临床意义

目的：探讨高血压脑出血患者血清雌二醇、睾酮水平与病情程度及预后的相关性。方法：检测168例高血压脑出血患者（脑出血组）及60例对照组血清雌二醇、睾酮的含量,按美国国立卫生研究院卒中量表标准对患者进行评分,再按病情轻重及病程评分的差值分组比较。结果：男性脑出血组雌二醇和睾酮与对照组差异均有统计学意义（P〈0.01和P〈0.05）,男女脑出血组雌二醇/睾酮比值与对照组差异均无统计学意义（P〉0.05）。男性患者轻度病情组血清雌二醇含量较中、重度组升高（P〈0.05）,男性3种病情组雌二醇/睾酮比值差异均无统计学意义（P〉0.05）。男性患者少量出血组血清雌二醇和睾酮含量均较中量出血组升高（P〈0.05）,男性3种出血组雌二醇/睾酮比值差异均无统计学意义（P〉0.05）。女性脑出血组雌二醇与对照组差异无统计学意义（P〉0.05）,女性脑出血组睾酮与对照组差异有统计学意义（P〈0.05）,女性患者轻度病情组血清睾酮含量均较中、重度组显著升高（P〈0.01）,女性轻度病情组雌二醇/睾酮比值均较中、重度组低（P〈0.01和P〈0.05）。女性患者少量出血组血清睾酮含量均较中、大量出血组明显升高（P〈0.01）,女性患者血清雌二醇和雌二醇/睾酮比值不同出血量组差异均无统计学意义（P〉0.05）。男、女性患者显著好转组雌二醇含量均较无变化组及恶化组升高（P〈0.05~P〈0.01）,男、女性患者显著好转组睾酮含量均较无变化组及恶化组下降（P〈0.05~P〈0.01）,男、女性患者显著好转组雌二醇/睾酮比值均较无变化组及恶化组升高（P〈0.05~P〈0.01）。结论：高血压脑出血患者血清雌二醇、雌二醇/睾酮比值测定有助于判断预后。