• 【糖皮质激素诱导的人子宫上皮细胞和鼠子宫中GILZ表达的雌二醇拮抗作用。】 复制标题 收藏 收藏
    DOI:10.1210/en.2012-1748 复制DOI
    作者列表:Whirledge S,Cidlowski JA
    BACKGROUND & AIMS: :Sex hormone signaling regulates a variety of functions in the uterine endometrium essential for embryo implantation and immunity. Epithelial cells of the uterine endometrium are the target of the coordinated actions of estradiol (E(2)) and progesterone. However, little information exists regarding the interplay of estrogens with glucocorticoids in this tissue. Using the human uterine epithelial cell line ECC1, E(2) was found to antagonize induction of the glucocorticoid-induced leucine zipper (GILZ) gene expression, which is associated with several of the immune-related functions of glucocorticoids. Interestingly, E(2) antagonizes glucocorticoid regulated nascent RNA GILZ expression within 1 h of hormone treatment. Repression of glucocorticoid-induced GILZ expression requires the estrogen receptor (ER), because both treatment with the ER-antagonist ICI 182,780 and small interfering RNA knockdown of ERα block E(2)'s ability to repress GILZ gene expression. Antagonism of glucocorticoid-induced GILZ expression may not be unique to ERα, as the ERβ agonist Liquiritigenin is also able to antagonize glucocorticoid signaling. Transcriptional regulation appears to be at the level of promoter binding. Both the glucocorticoid receptor and ERα are recruited to regions of the GILZ promoter containing glucocorticoid response elements and the transcriptional start site. Glucocorticoid receptor binding to these regions in the presence of dexamethasone decreases with E(2) treatment. GILZ gene expression was also found to be repressed in the whole mouse uterus treated with a combination of dexamethasone and E(2). Regulation of the antiinflammatory gene GILZ by glucocorticoids and E(2) suggests cross talk between the immune modulating functions of glucocorticoids and the reproductive actions of estradiol signaling.
    背景与目标: :性激素信号传导调节子宫内膜的多种功能,对胚胎着床和免疫至关重要。子宫内膜的上皮细胞是雌二醇(E(2))和孕酮协同作用的目标。然而,关于该组织中雌激素与糖皮质激素相互作用的信息很少。使用人类子宫上皮细胞系ECC1,发现E(2)拮抗糖皮质激素诱导的亮氨酸拉链(GILZ)基因表达的诱导,这与糖皮质激素的几种免疫相关功能有关。有趣的是,E(2)在激素治疗后1小时内拮抗糖皮质激素调节的新生RNA GILZ表达。抑制糖皮质激素诱导的GILZ表达需要雌激素受体(ER),因为用ER拮抗剂ICI 182,780进行的治疗和对ERα的小干扰RNA敲低均可阻止E(2)抑制GILZ基因表达的能力。糖皮质激素诱导的GILZ表达的拮抗作用可能不是ERα特有的,因为ERβ激动剂Liquiritigenin也能够拮抗糖皮质激素信号传导。转录调控似乎在启动子结合的水平。糖皮质激素受体和ERα均被募集到含有糖皮质激素应答元件和转录起始位点的GILZ启动子区域。在地塞米松的存在下,糖皮质激素受体与这些区域的结合随E(2)处理而降低。还发现在地塞米松和E(2)联合治疗的整个小鼠子宫中,GILZ基因表达受到抑制。糖皮质激素和E(2)对抗炎基因GILZ的调节表明,糖皮质激素的免疫调节功能与雌二醇信号传导的生殖作用之间存在串扰。
  • 【唾液中雌二醇-17β的直接比色单克隆抗体酶免疫测定。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Tamate K,Charleton M,Gosling JP,Egan D,Ishikawa M,Fottrell PF,Kane MM
    BACKGROUND & AIMS: We developed a direct microtiter plate enzyme immunoassay to measure estradiol-17 beta in saliva. The assay has a commercially available monoclonal antibody, raised against estradiol-17 beta-6-carboxymethyloximebovine serum albumin, and a homologous horseradish peroxidase conjugate measured colorimetrically. The detection limit (equivalent to B0-3 SD) is 365 amol/well or 7.3 pmol/L when 50-microL samples are assayed. Cross-reactivity with estrone and estriol, testosterone, or progesterone is < 0.2%. Estradiol-17 beta was measured in daily samples over five natural menstrual cycles and eight cycles stimulated as a preliminary to in vitro fertilization, and the concentrations and fluctuations found agreed with previously published data. This method gives results in approximately 3 h and may be useful for fertility monitoring and management.

    背景与目标: 我们开发了一种直接的微量滴定板酶免疫测定法,用于测量唾液中的雌二醇-17β。该测定法具有针对雌二醇-17β-6-羧甲基肟肟牛血清白蛋白的市售单克隆抗体,以及用比色法测定的同源辣根过氧化物酶结合物。当检测50微升样品时,检出限(相当于B0-3 SD)为365 amol /孔或7.3 pmol / L。与雌酮和雌三醇,睾丸激素或孕酮的交叉反应性<0.2%。在体外受精的五个自然月经周期和刺激的八个周期中,对每日样品中的雌二醇17β进行了测量,发现其浓度和波动与先前公布的数据一致。该方法可在约3小时内得出结果,可能对生育力监测和管理有用。

  • 【雌二醇和孕酮在非妊娠绵羊宫颈中对前列腺素酶系统的调节。】 复制标题 收藏 收藏
    DOI:10.1530/REP-06-0328 复制DOI
    作者列表:Zhang Q,Collins V,Chakrabarty K,Rose JC,Wu WX
    BACKGROUND & AIMS: :In the present study, we examined the in vivo effects of estradiol (E(2)) and progesterone on cyclooxygenase (COX) 2, prostaglandin F synthase (PTGFS, also known as PGFS), and membrane-associated prostaglandin E synthase 1 (mPTGES1) expression at both mRNA and protein levels using a nonpregnant ovariectomized (OVX) sheep model. Sixteen ewes were OVX shortly after ovulation. After 40 days, ewes were treated with saline (Cont, n=5), or E(2) infused intravenously for 2 days (50 microg/day, n=5) or intravaginal progesterone (P) sponges for 10 days (0.3 g P, n=6). Cervical COX2, PTGFS, and mPTGES1 mRNA and protein were quantified by northern and western blot analyses respectively. In situ hybridization and/or immunocytochemistry were used to localize the cellular distribution of COX2, PTGFS, and mPTGES1 mRNAs and proteins. COX2 mRNA abundance increased significantly in the cervix after E(2) treatment (P<0.05). However, progesterone was a more potent stimulator than E(2) of COX2 mRNA and protein abundance in the cervix (P<0.01). In contrast, PTGFS and mPTGES1 mRNA and protein concentrations did not change after E(2) or progesterone treatment (P>0.05). COX2, PTGFS, and mPTGES1 mRNA and protein were only localized in cervical glandular epithelial cells. This study shows that increased cervical COX2 mRNA and protein, but not PTGFS and mPTGES1 mRNA and protein, were associated with E(2) and progesterone treatment in nonpregnant sheep. More strikingly, progesterone was a more potent stimulator of cervical COX2 expression than E(2). The expression of COX2, PTGFS, and mPTGES1 mRNA and/or protein was confined in the cervical glandular epithelial cells of nonpregnant sheep.
    背景与目标: :在本研究中,我们研究了雌二醇(E(2))和孕酮对环氧合酶(COX)2,前列腺素F合酶(PTGFS,也称为PGFS)和膜相关的前列腺素E合酶1( mPTGES1)使用非妊娠卵巢切除(OVX)绵羊模型在mRNA和蛋白水平上的表达。排卵后不久,有16头母羊经OVX处理。 40天后,母羊用生理盐水(Cont,n = 5)或E(2)静脉输注2天(50 microg / day,n = 5)或阴道黄体酮(P)海绵处理10天(0.3 g)。 P,n = 6)。通过Northern和Western印迹分析分别定量宫颈COX2,PTGFS和mPTGES1 mRNA和蛋白。原位杂交和/或免疫细胞化学用于定位COX2,PTGFS和mPTGES1 mRNA和蛋白质的细胞分布。 E(2)治疗后子宫颈中COX2 mRNA的丰度显着增加(P <0.05)。但是,黄体酮比宫颈中COX2 mRNA和蛋白质丰度的E(2)更有效(P <0.01)。相比之下,E(2)或孕激素治疗后PTGFS和mPTGES1 mRNA和蛋白质浓度没有变化(P> 0.05)。 COX2,PTGFS和mPTGES1 mRNA和蛋白仅位于宫颈腺上皮细胞中。这项研究表明,子宫颈COX2 mRNA和蛋白的增加,但与PTGFS和mPTGES1 mRNA和蛋白的增加无关,与未怀孕绵羊的E(2)和孕激素治疗有关。更惊人的是,黄体酮比E(2)更有效地刺激宫颈COX2表达。 COX2,PTGFS和mPTGES1 mRNA和/或蛋白的表达被限制在非妊娠绵羊的子宫颈腺上皮细胞中。
  • 【17β-雌二醇可防止卵巢切除大鼠的氧化应激并降低血压。】 复制标题 收藏 收藏
    DOI:10.1152/ajpregu.2000.279.5.R1599 复制DOI
    作者列表:Hernández I,Delgado JL,Díaz J,Quesada T,Teruel MJ,Llanos MC,Carbonell LF
    BACKGROUND & AIMS: :In this study, we tested whether estrogen deficiency is associated with oxidative stress and decreased nitric oxide (NO) production, which could be responsible for an increased blood pressure in ovariectomized rats. Hemodynamic studies were performed on conscious, chronically instrumented rats. Chronic estrogen replacement on ovariectomized rats lowered blood pressure approximately 13 mmHg, from 119 +/- 3 mmHg in ovariectomized rats to 106 +/- 3 mmHg in ovariectomized-treated rats; it was also accompanied by an increase in cardiac index and vascular conductance, achieving hemodynamic values similar to those shown by sham-operated rats. N(G)-nitro-L-arginine methyl ester administration lowered significantly less the vascular conductance (0.14 +/- 0.01 vs. 0.22 +/- 0.03 and 0.26 +/- 0.01 ml. min(-1). mmHg(-1)/100 g; P < 0.05) in ovariectomized rats than in the sham-operated and estrogen-treated ovariectomized rats, respectively. Estrogen replacement prevented the lower plasma levels of nitrites/nitrates observed in ovariectomized rats. The lower plasma total antioxidant status and reduced thiol groups and the increase in plasma lipoperoxides presented in ovariectomized animals were reestablished with the estrogen treatment. These results show that estrogen administration decreases blood pressure and increases vascular conductance in ovariectomized rats. This effect may be related to an increase in NO synthesis and/or preventing oxidative stress, then improving endothelial function.
    背景与目标: :在这项研究中,我们测试了雌激素缺乏症是否与氧化应激和一氧化氮(NO)产生减少有关,这可能是卵巢切除大鼠血压升高的原因。在有意识的,长期使用仪器的大鼠上进行了血流动力学研究。去卵巢大鼠的慢性雌激素替代使血压降低约13 mmHg,从去卵巢大鼠的119 /-3 mmHg降低到去卵巢治疗大鼠的106 /-3 mmHg;它也伴随着心脏指数和血管导度的增加,达到了与假手术大鼠相似的血液动力学值。 N(G)-硝基-L-精氨酸甲酯给药显着降低了血管电导(0.14 /-0.01 vs. 0.22 /-0.03和0.26 /-0.01 ml.min(-1)。mmHg(-1)/ 100 g; P <0.05)分别比去假手术和经雌激素治疗的去卵巢大鼠低。雌激素替代可防止在去卵巢大鼠中观察到较低的血浆亚硝酸盐/硝酸盐水平。通过雌激素治疗,可以降低卵巢切除动物体内血浆总抗氧化剂状态的降低和硫醇基团的减少以及血浆脂过氧化物的增加。这些结果表明,雌激素给药可降低去卵巢大鼠的血压并增加血管电导。此作用可能与NO合成增加和/或防止氧化应激,进而改善内皮功能有关。
  • 【药物基因组学,药代动力学和药效学:男女之间生物学差异的相互作用。】 复制标题 收藏 收藏
    DOI:10.1111/bph.12362 复制DOI
    作者列表:Franconi F,Campesi I
    BACKGROUND & AIMS: :Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns.
    背景与目标: :药理反应取决于多种因素,其中之一是性别。有关性别对药代动力学的特定作用以及多种药物的安全性和有效性的数据开始出现。然而,招募女性从事临床研究是不够的,特别是在第一阶段。通常,雄性和雌性之间的药代动力学差异比药效学上的差异更为广泛和一致。但是,现在越来越多地在分子水平上发现性别药效差异。现在甚至变得很明显,性别会影响药物基因组学和药物遗传学。已经报道了几个参数的性别相关差异,并且始终表明,女性的安全性较差,与男性相比,女性的药物不良反应更为频繁和严重。总体而言,与男性相比,女性的药理状况研究较少,应引起更多关注。临床和临床前研究的设计应采用基于性别的方法,目的是根据个体的需要和关注量身定制疗法。
  • 【人体中可利用的雌二醇:与年龄和睾丸激素的关系。】 复制标题 收藏 收藏
    DOI:10.1016/j.cca.2008.09.005 复制DOI
    作者列表:Dolomie-Fagour L,Gatta B,Nguyen TD,Corcuff JB
    BACKGROUND & AIMS: :Sex hormones undergo decreases in aging men. Several studies have shown the association of low levels of bioavailable estradiol with osteoporosis in man. To allow a better approach of sex hormones influences, we evaluated bioavailable estradiol concentrations in men and its correlation with age and testosterone. We show that bioavailable estradiol decreases significantly with age. We provide reference values in men with normal testosterone levels.
    背景与目标: :性激素在衰老的男性中减少。几项研究表明,人体可利用的雌二醇水平低与骨质疏松症有关。为了更好地控制性激素的影响,我们评估了男性体内可利用的雌二醇浓度及其与年龄和睾丸激素的相关性。我们显示,随着年龄的增长,生物利用雌二醇显着降低。我们为睾丸激素水平正常的男性提供参考值。
  • 【别嘌醇和羟嘌呤的临床药代动力学和药效学。】 复制标题 收藏 收藏
    DOI:10.2165/00003088-200746080-00001 复制DOI
    作者列表:Day RO,Graham GG,Hicks M,McLachlan AJ,Stocker SL,Williams KM
    BACKGROUND & AIMS: :Allopurinol is the drug most widely used to lower the blood concentrations of urate and, therefore, to decrease the number of repeated attacks of gout. Allopurinol is rapidly and extensively metabolised to oxypurinol (oxipurinol), and the hypouricaemic efficacy of allopurinol is due very largely to this metabolite. The pharmacokinetic parameters of allopurinol after oral dosage include oral bioavailability of 79 +/- 20% (mean +/- SD), an elimination half-life (t((1/2))) of 1.2 +/- 0.3 hours, apparent oral clearance (CL/F) of 15.8 +/- 5.2 mL/min/kg and an apparent volume of distribution after oral administration (V(d)/F) of 1.31 +/- 0.41 L/kg. Assuming that 90 mg of oxypurinol is formed from every 100mg of allopurinol, the pharmacokinetic parameters of oxypurinol in subjects with normal renal function are a t((1/2)) of 23.3 +/- 6.0 hours, CL/F of 0.31 +/- 0.07 mL/min/kg, V(d)/F of 0.59 +/- 0.16 L/kg, and renal clearance (CL(R)) relative to creatinine clearance of 0.19 +/- 0.06. Oxypurinol is cleared almost entirely by urinary excretion and, for many years, it has been recommended that the dosage of allopurinol should be reduced in renal impairment. A reduced initial target dosage in renal impairment is still reasonable, but recent data on the toxicity of allopurinol indicate that the dosage may be increased above the present guidelines if the reduction in plasma urate concentrations is inadequate. Measurement of plasma concentrations of oxypurinol in selected patients, particularly those with renal impairment, may help to decrease the risk of toxicity and improve the hypouricaemic response. Monitoring of plasma concentrations of oxypurinol should also help to identify patients with poor adherence. Uricosuric drugs, such as probenecid, have potentially opposing effects on the hypouricaemic efficacy of allopurinol. Their uricosuric effect lowers the plasma concentrations of urate; however, they increase the CL(R) of oxypurinol, thus potentially decreasing the influence of allopurinol. The net effect is an increased degree of hypouricaemia, but the interaction is probably limited to patients with normal renal function or only moderate impairment.
    背景与目标: :别嘌呤醇是最广泛用于降低血尿酸盐浓度的药物,因此可减少痛风的反复发作次数。别嘌呤醇被迅速广泛地代谢为氧嘌呤醇(oxipurinol),别嘌呤醇的降尿血药功效在很大程度上归因于这种代谢产物。口服后别嘌醇的药代动力学参数包括79 /-20%(平均/-SD)的口服生物利用度,1.2 /-0.3小时的消除半衰期(t((1/2))),明显的口腔清除率( CL / F)为15.8 /-5.2 mL / min / kg,口服后的表观分布体积(V(d)/ F)为1.31 / 0.41 L / kg。假设每100mg别嘌呤醇可形成90mg羟嘌呤醇,那么在肾功能正常的受试者中,氧嘌呤醇的药代动力学参数为((1/2))为23.3 /-6.0小时,CL / F为0.31 /-0.07 mL / min / kg,V(d)/ F为0.59 /-0.16 L / kg,相对于肌酐清除率的肾清除率(CL(R))为0.19 /-0.06。氧嘌呤醇几乎全部通过尿排泄清除,多年来,建议在肾功能不全时应减少别嘌呤醇的剂量。降低肾功能不全的初始目标剂量仍然是合理的,但是有关别嘌呤醇毒性的最新数据表明,如果血浆尿酸盐浓度的降低不足,则可以将剂量增加到当前指导值以上。在选定的患者中,特别是患有肾功能不全的患者中,测定氧嘌呤醇的血浆浓度可能有助于降低中毒的风险并改善低尿毒症反应。监测氧嘌呤醇的血浆浓度也应有助于确定依从性差的患者。尿酸药物,如丙磺舒,对别嘌呤醇的降尿血药功效具有潜在的相反作用。它们的尿尿排尿作用降低了血浆尿酸盐的浓度。但是,它们会增加氧嘌呤醇的CL(R),因此有可能降低别嘌呤醇的影响。净效应是低尿酸血症程度的增加,但这种相互作用可能仅限于肾功能正常或仅有中度损害的患者。
  • 【社会从属改变了雌二醇引起的成年雌性恒河猴的皮质-边缘脑体积的变化。】 复制标题 收藏 收藏
    DOI:10.1016/j.psyneuen.2020.104592 复制DOI
    作者列表:Reding KM,Styner MM,Wilson ME,Toufexis D,Sanchez MM
    BACKGROUND & AIMS: :Women have a higher risk of developing stress-related disorders compared to men and the experience of a stressful life event is a potent risk-factor. The rodent literature suggests that chronic exposure to stressors as well as 17β-estradiol (E2) can result in alterations in neuronal structure in corticolimbic brain regions, however the translation of these data to humans is limited by the nature of the stressor experienced and issues of brain homology. To address these limitations, we used a well-validated rhesus monkey model of social subordination to examine effects of E2 treatment on subordinate (high stress) and dominant (low stress) female brain structure, including regional gray matter and white matter volumes using structural magnetic resonance imaging. Our results show that one month of E2 treatment in ovariectomized females, compared to control (no) treatment, decreased frontal cortex gray matter volume regardless of social status. In contrast, in the cingulate cortex, an area associated with stress-induced emotional processing, E2 decreased grey matter volume in subordinates but increased it in dominant females. Together these data suggest that physiologically relevant levels of E2 alter cortical gray matter volumes in females after only one month of treatment and interact with chronic social stress to modulate these effects on brain structure.
    背景与目标: :与男性相比,女性罹患与压力有关的疾病的风险更高,并且经历过压力大的生活事件是一个潜在的危险因素。啮齿动物的文献表明,长期暴露于应激源以及17β-雌二醇(E2)可能会导致皮质小脑区的神经元结构发生改变,但是这些数据对人类的翻译受到所经历的应激源的性质和问题的限制。脑同源性。为了解决这些局限性,我们使用了一种经过验证的社会从属恒河猴模型,研究了E2治疗对从属(高压力)和显性(低压力)女性大脑结构(包括区域灰质和白质体积)的影响,采用结构磁学共振成像。我们的研究结果表明,与对照(无)治疗相比,卵巢切除的女性接受E2治疗一个月后,无论社会地位如何,额叶皮层灰质体积均减少。相反,在扣带回皮层(与压力诱导的情绪处理相关的区域)中,E2降低了下属的灰质体积,但增加了占优势雌性的灰质体积。这些数据加在一起表明,在仅治疗一个月后,生理相关的E2水平会改变女性皮质灰色物质的体积,并与慢性社会压力相互作用以调节这些对大脑结构的影响。
  • 【Tafluprost,一种新型的强效类前列腺素受体激动剂:对健康志愿者的药效学和耐受性的剂量反应研究。】 复制标题 收藏 收藏
    DOI:10.5414/cpp46400 复制DOI
    作者列表:Sutton A,Gouws P,Ropo A
    BACKGROUND & AIMS: OBJECTIVE:Prostaglandin receptor analogs lower intraocular pressure (IOP) and are used for the treatment of glaucoma. This study aimed to compare the safety, tolerability and pharmacodynamics of four doses of the new, selective-prostanoid receptor agonist, tafluprost (AFP-168) in a Phase I placebo-controlled study. METHODS:Healthy volunteers (n = 16) received sequentially ascending doses of tafluprost (0.0001%, 0.0005%, 0.0025% and 0.005%) in one eye, and placebo in the other. Each treatment period consisted of 2 days of treatment, with 5 days between the treatment periods. Safety and tolerability assessments, as well as IOP measurements, were performed at defined intervals. RESULTS:Tafluprost was generally well tolerated and no volunteer discontinued due to adverse events (AEs). The most common ocular AE was ocular hyperemia, which was mild-to-moderate, and highly concentration-dependent. All doses of tafluprost decreased IOP, with the maximum effect occurring 12 hours after treatment. The decrease in IOP relative to placebo was significantly more effective with tafluprost 0.0025% and 0.005%, compared with tafluprost 0.0001% (p pound 0.005). CONCLUSION:Tafluprost was well tolerated and effective in lowering IOP. These data support further testing of tafluprost 0.0025% and 0.005%.
    背景与目标: 目的:前列腺素受体类似物可降低眼压(IOP),用于治疗青光眼。这项研究旨在在I期安慰剂对照研究中比较四种剂量的新型选择性前列腺素受体激动剂tafluprost(AFP-168)的安全性,耐受性和药效学。
    方法:健康志愿者(n = 16)在一只眼睛中依次接受塔氟前列素(0.0001%,0.0005%,0.0025%和0.005%)的剂量,而另一只则接受安慰剂。每个治疗期包括2天的治疗,每个治疗期之间有5天。安全性和耐受性评估以及IOP测量均按规定的时间间隔进行。
    结果:塔夫前列素一般耐受良好,没有志愿者因不良事件(AE)而停药。最常见的眼部AE是眼部充血,轻度至中度且高度依赖浓度。所有剂量的tafluprost均可降低IOP,最大作用发生在治疗后12小时。相对于安慰剂,IOP的降低在使用Tafluprost为0.0025%和0.005%时显着更有效,而在Tafluprost中为0.0001%(P磅为0.005)。
    结论:Tafluprost具有良好的耐受性,可有效降低眼压。这些数据支持进一步对他氟普罗斯特进行0.0025%和0.005%的测试。
  • 【在高剂量雌二醇治疗的去卵巢大鼠中,海马中一氧化氮水平的降低可能在学习和记忆障碍中起作用。】 复制标题 收藏 收藏
    DOI:10.1590/s0004-282x2012001100010 复制DOI
    作者列表:Sadeghian R,Fereidoni M,Soukhtanloo M,Azizi-Malekabadi H,Hosseini M
    BACKGROUND & AIMS: :The effects of a high estradiol dose on memory and on nitric oxide metabolites in hippocampal tissues were investigated. Sham-Est and OVX-Est Groups were treated with 4 mg/kg of estradiol valerate for 12 weeks. Time latency and path length were significantly higher in the Sham-Est and OVX-Est Groups than in the Sham and OVX Groups, respectively (p<0.001). The animals in the Sham-Est and OVX-Est Groups spent lower time in the target quadrant (Q1) than those of the Sham and OVX Groups during the probe trial test (p<0.05 and <0.001, respectively). Significantly lower nitric oxide metabolite levels in the hippocampi of the Sham-Est and OVX-Est Groups were observed than in the Sham and OVX ones (p<0.001). These results suggest that decreased nitric oxide levels in the hippocampus may play a role in the learning and memory deficits observed after treatment with a high dose of estradiol, although the precise underlying mechanisms remain to be elucidated.
    背景与目标: :研究了高雌二醇剂量对海马组织记忆力和一氧化氮代谢产物的影响。 Sham-Est和OVX-Est组分别用4 mg / kg的戊酸雌二醇处理12周。 Sham-Est和OVX-Est组的时间延迟和路径长度分别比Sham和OVX组高(p <0.001)。在探针试验过程中,Sham-Est和OVX-Est组的动物在目标象限(Q1)上花费的时间比Sham和OVX组的动物低(分别为p <0.05和<0.001)。与Sham和OVX组相比,Sham-Est和OVX-Est组海马中的一氧化氮代谢产物水平显着降低(p <0.001)。这些结果表明,海马中一氧化氮水平的下降可能在大剂量雌二醇治疗后观察到的学习和记忆障碍中起作用,尽管确切的潜在机制尚待阐明。
  • 【雌二醇和孕酮对促性腺激素LβT2细胞中促性腺激素LHβ和FSHβ亚基启动子活性的影响。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Kanasaki H,Purwana IN,Mijiddorj T,Sukhbaatar U,Oride A,Miyazaki K
    BACKGROUND & AIMS: OBJECTIVES:Sex steroid hormones play roles in the regulation of pituitary hormone synthesis and secretion. Here we investigated the role of estradiol (E2) and progesterone (P4) on pituitary gonadotropin luteinizing hormone (LH)β- and follicle stimulating hormone (FSH)β-transcriptional activity in a single colony of gonadotroph LβT2 cells. METHODS:Pituitary gonadotroph cell line, LβT2 cells were used in this study. Cells were transfected with LHβ- or FSHβ-subunit promoter region-linked luciferase vector, and stimulated with gonadotropin-releasing hormone (GnRH) in the presence or absence of sex steroids. Transcriptional activity for LHβ- and FSHβ-subunit were determined by luciferase assay. Effects of sex steroids on cell proliferation was also determined by measurement of 5-bromoe-2'-deoxyuridine (BrdU) incorporation. RESULTS:The basal promoter activity of the LHβ subunit was not modulated by 10 nM E2, but gonadotropin releasing hormone (GnRH)-induced LHβ promoter activity was significantly increased by the same concentration of E2. Similarly, although the basal FSHβ promoter was not modulated by 10 nM E2, GnRH-induced FSHβ promoters were significantly potentiated in the presence of E2. One micromole E2 modulated neither basal nor GnRH-induced LHβ and FSHβ promoters. On the other hand, basal LHβ promoter activity was enhanced by 1 µM P4, but the stimulatory response of GnRH on LHβ promoters was significantly inhibited in the presence of 1 µM P4. Similar to LHβ promoters, the basal activity of the FSHβ promoter was increased by 1 µM P4; however, the response to GnRH was not modulated in the presence of P4. Ten micromoles P4 modified neither basal nor GnRH-induced promoter activity for LHβ and FSHβ. E2 had no antagonistic effect on P4-induced basal promoter activities of LHβ or FSHβ. A cell proliferation assay showed that neither E2 nor P4 modulated the growth of LβT2 cells, even in the presence or absence of GnRH. CONCLUSION:These observations suggest that both E2 and P4 uniquely modulate basal and GnRH-stimulated gonadotropin promoters without affecting cell growth.
    背景与目标: 目的:性类固醇激素在垂体激素合成和分泌的调节中发挥作用。在这里,我们研究了雌二醇(E2)和孕酮(P4)在促性腺激素LβT2细胞单个菌落中对垂体促性腺激素促黄体生成激素(LH)β-和促卵泡激素(FSH)β-转录活性的作用。
    方法:采用垂体促性腺激素细胞系LβT2。用LHβ-或FSHβ-亚基启动子区域连接的荧光素酶载体转染细胞,并在存在或不存在性类固醇的情况下用促性腺激素释放激素(GnRH)刺激细胞。通过荧光素酶测定法测定LHβ-和FSHβ-亚基的转录活性。性类固醇对细胞增殖的影响还可以通过测量5-溴2'-脱氧尿苷(BrdU)的掺入来确定。
    结果:10 nM E2不能调节LHβ亚基的基础启动子活性,但是在相同浓度的E2下,促性腺激素释放激素(GnRH)诱导的LHβ启动子活性显着增加。类似地,尽管基础FSHβ启动子不受10 nM E2调节,但在E2存在下,GnRH诱导的FSHβ启动子显着增强。一微摩尔E2既不调节基础也不刺激GnRH诱导的LHβ和FSHβ启动子。另一方面,基础LHβ启动子活性被1μMP4增强,但是在1μMP4存在下,GnRH对LHβ启动子的刺激反应被显着抑制。与LHβ启动子相似,FSHβ启动子的基础活性增加1 µM P4。然而,在P4存在下,对GnRH的反应没有被调节。十微摩尔P4既不改变基础也不改变GnRH诱导的LHβ和FSHβ启动子活性。 E2对P4诱导的LHβ或FSHβ的基础启动子活性没有拮抗作用。细胞增殖试验表明,即使存在或不存在GnRH,E2和P4均不能调节LβT2细胞的生长。
    结论:这些观察结果表明,E2和P4均可唯一调节基础和GnRH刺激的促性腺激素启动子,而不会影响细胞生长。
  • 【依多昔芬和雌二醇对体外培养的氧化应激大鼠肝细胞中NF-κB活化的影响。】 复制标题 收藏 收藏
    DOI:10.1034/j.1600-0676.2001.021003183.x 复制DOI
    作者列表:Omoya T,Shimizu I,Zhou Y,Okamura Y,Inoue H,Lu G,Itonaga M,Honda H,Nomura M,Ito S
    BACKGROUND & AIMS: BACKGROUND/AIMS:Idoxifene is a tissue-specific selective estrogen receptor modulator. Estradiol is a potent endogenous antioxidant, and nuclear factor kappaB (NF-kappaB) is a key transcription factor that induces multiple genes in response to inflammation or oxidative stress. The aim of this study was to explore the inhibitory effects of idoxifene and estradiol on NF-kappaB activation in hepatocytes in a state of oxidative stress. METHODS:Lipid peroxidation was induced in cultured rat hepatocytes by incubation with ferric nitrilotriacetate solution. NF-kappaB activity was evaluated by electrophoretic mobility shift assay. RESULTS:The oxidative stress-induced activation of NF-kappaB and degradation of IkappaB-alpha were maximal at 3-5 h, with an increase in lactate dehydrogenase (LDH) and malondialdehyde (MDA) secretion into the culture medium. Treatment with idoxifene and estradiol inhibited IkappaB-alpha degradation and NF-kappaB activation through the attenuation of hepatocyte oxidative bursts and decreased extracellular levels of LDH and MDA. In addition, idoxifene and estradiol inhibited lipid peroxidation in rat liver mitochondria. A potent NF-kappaB inhibitor, pyrrolidine dithiocarbamate, prevented NF-kappaB activation by inhibition of IkappaB-alpha degradation and decreased LDH and MDA levels, suggesting that NF-kappaB might be a regulator in a genetic response to increase oxidative stress-induced hepatic injury. CONCLUSIONS:These findings suggest that idoxifene and estradiol function as antioxidants and protect hepatocytes from inflammatory cell injury.
    背景与目标: 背景/目的:伊多昔芬是一种组织特异性的选择性雌激素受体调节剂。雌二醇是一种有效的内源性抗氧化剂,核因子κB(NF-κB)是一种关键的转录因子,可响应炎症或氧化应激而诱导多个基因。这项研究的目的是探讨在氧化应激状态下伊多昔芬和雌二醇对肝细胞中NF-κB活化的抑制作用。
    方法:用次氮基三乙酸铁溶液孵育可诱导大鼠肝细胞脂质过氧化。通过电泳迁移率变动分析评估NF-κB活性。
    结果:氧化应激诱导的NF-κB活化和IkappaB-α降解在3-5 h达到最大,同时乳酸脱氢酶(LDH)和丙二醛(MDA)向培养基中的分泌增加。用伊多昔芬和雌二醇治疗可通过减轻肝细胞氧化爆发和降低LDH和MDA的细胞外水平来抑制IkappaB-alpha降解和NF-kappaB活化。此外,伊多昔芬和雌二醇抑制大鼠肝线粒体脂质过氧化。一种有效的NF-κB抑制剂吡咯烷二硫代氨基甲酸酯可通过抑制IkappaB-α降解并降低LDH和MDA水平来阻止NF-kappaB活化,这表明NF-kappaB可能是遗传反应中的调节因子,可增加氧化应激诱导的肝损伤。 。
    结论:这些发现表明,伊多昔芬和雌二醇起抗氧化剂的作用,并保护肝细胞免受炎性细胞损伤。
  • 【TX-004HR的阴道雌二醇对雌二醇的极低全身吸收微不足道。】 复制标题 收藏 收藏
    DOI:10.1097/GME.0000000000000790 复制DOI
    作者列表:Archer DF,Constantine GD,Simon JA,Kushner H,Mayer P,Bernick B,Graham S,Mirkin S,REJOICE Study Group.
    BACKGROUND & AIMS: OBJECTIVE:To evaluate the pharmacokinetics of TX-004HR vaginal estradiol softgel capsules when used for treating moderate-to-severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy. METHODS:A substudy of the REJOICE trial (multicenter, double-blind, placebo-controlled, phase 3) evaluated the pharmacokinetics of 4, 10, and 25-μg TX-004HR doses once/d for 2 weeks, followed by twice/wk for 10 weeks. Serum samples obtained at 2, 4, 6, 10, and 24 hours postdose on days 1 and 14, and once on day 84, were analyzed for area under the serum concentration-time curve, tmax, Cmin, Cavg, and Cmax for estradiol, estrone, and estrone conjugates. RESULTS:Seventy-two women (mean 59 y) participated. TX-004HR 4 μg showed no statistical differences from placebo in estradiol pharmacokinetic (PK) parameters. At 10 μg, estradiol Cmax was statistically higher than placebo on day 1, but was not different from placebo on day 14. With 25 μg, estradiol PK parameters were statistically higher than placebo. Estradiol Cavg values for 25 μg were 9.1 pg/mL on day 1 and 7.1 pg/mL on day 14. Estrone and estrone conjugate PK parameters with TX-004HR were lower than or similar to placebo across all doses. No drug accumulation was observed. CONCLUSIONS:Vaginal TX-004HR resulted in negligible to very low systemic absorption of estradiol. No statistical differences in estradiol PK parameters were observed on day 14 with 4 and 10 μg, and only minor increases were observed with 25 μg (within the normal postmenopausal range). This PK substudy, in conjunction with the primary efficacy results, demonstrated that TX-004HR provided local benefits of estradiol with limited systemic exposure.
    背景与目标: 目的:评估TX-004HR阴道雌二醇软胶囊用于治疗绝经后外阴和阴道萎缩妇女中度至重度性交往不良的药代动力学。
    方法:REJOICE试验的一个子研究(多中心,双盲,安慰剂对照,3期)评估了4、10和25μgTX-004HR剂量的药代动力学,每天一次,持续2周,然后每周两次。持续10周。在给药后第1、4天的第2、4、6、10和24小时以及第84天一次获得的血清样品分析血清浓度-时间曲线下的面积,雌二醇的tmax,Cmin,Cavg和Cmax。 ,雌酮和雌酮共轭物。
    结果:72名妇女(平均59岁)参加了研究。 TX-004HR4μg在雌二醇的药代动力学(PK)参数方面与安慰剂无统计学差异。在第10天,雌二醇的Cmax在统计学上高于安慰剂,但在第1天与安慰剂没有统计学差异。在10μg时,雌二醇PK参数在统计学上高于安慰剂。第1天的25μg雌二醇Cavg值在第1天为9.1μpg/ mL,第14天为7.1μpg/ mL。在所有剂量下,具有TX-004HR的雌酮和雌酮共轭PK参数均低于或类似于安慰剂。没有观察到药物蓄积。
    结论:阴道TX-004HR导致雌二醇的极低全身吸收可忽略不计。在第4天和第10μg的情况下,雌二醇PK参数无统计学差异,而在第25天,绝经后范围仅25μg,仅观察到少量增加。这项PK子研究与主要功效结果相结合,证明TX-004HR在全身暴露受限的情况下提供了雌二醇的局部益处。
  • 【17,β-雌二醇主要通过干扰其生命周期的释放阶段来抑制丙型肝炎病毒。】 复制标题 收藏 收藏
    DOI:10.1111/liv.13303 复制DOI
    作者列表:Magri A,Barbaglia MN,Foglia CZ,Boccato E,Burlone ME,Cole S,Giarda P,Grossini E,Patel AH,Minisini R,Pirisi M
    BACKGROUND & AIMS: BACKGROUND & AIMS:Oestrogen and oestrogen-mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of hepatitis C virus life cycle is/are affected by oestrogens. METHODS:Huh7 cells infected with the JFH1 virus (genotype 2a) were exposed to dehydroepiandrosterone, testosterone, progesterone and 17β-estradiol (tested with/without its receptor antagonist fulvestrant). Dose-response curves were established to calculate half maximal inhibitory concentration values. To dissect how 17β-estradiol interferes with phases of hepatitis C virus life cycle, its effects were measured on the hepatitis C virus pseudo-particle system (viral entry), the subgenomic replicon N17/JFH1 and the replicon cell line Huh7-J17 (viral replication). Finally, in a dual-step infection model, infectious supernatants, collected from infected cells exposed to hormones, were used to infect naïve cells. RESULTS:Progesterone and testosterone showed no inhibitory effect on hepatitis C virus; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17β-estradiol inhibited infection by 64%-67% (IC50 values 140-160 nmol/L). Fulvestrant reverted the inhibition by 17β-estradiol in a dose-dependent manner. 17β-estradiol exerted only a slight inhibition (<20%) on hepatitis C virus pseudo-particles, and had no effect on cells either transiently or stably (Huh7-J17 cells) expressing the N17/JFH1 replicon. In the dual-step infection model, a significant half maximal inhibitory concentration decline occurred between primary (134 nmol/L) and secondary (100 nmol/L) infections (P=.02), with extracellular hepatitis C virus RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart. CONCLUSIONS:17β-estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle.
    背景与目标: 背景与目的:雌激素和雌激素介导的信号转导机制尚不完全清楚,可预防丙型肝炎病毒。我们旨在确定丙型肝炎病毒生命周期的哪个阶段受到雌激素的影响。
    方法:将感染JFH1病毒(基因型2a)的Huh7细胞暴露于脱氢表雄酮,睾丸激素,孕酮和17β-雌二醇(经/不经其受体拮抗剂氟维司汀测试)。建立剂量反应曲线以计算最大抑制浓度的一半。为了剖析17β-雌二醇如何干扰丙型肝炎病毒生命周期的各个阶段,测量了其对丙型肝炎病毒假颗粒系统(病毒进入),亚基因组复制子N17 / JFH1和复制子细胞系Huh7-J17(病毒)的影响。复制)。最后,在两步感染模型中,从暴露于激素的感染细胞中收集的感染上清液被用于感染幼稚细胞。
    结果:孕酮和睾丸激素对丙型肝炎病毒无抑制作用。脱氢表雄酮仅具有轻度抑制作用。相比之下,17β-雌二醇可将感染抑制64%-67%(IC50值为140-160nmol / L)。氟韦斯特兰以剂量依赖的方式逆转了17β-雌二醇的抑制作用。 17β-雌二醇仅对C型肝炎病毒假颗粒产生轻微抑制作用(<20%),对表达N17 / JFH1复制子的细胞(瞬时或稳定)(Huh7-J17细胞)没有影响。在双步感染模型中,主要(134nmol / L)和继发性(100nmol / L)感染(P = .02)之间出现最大抑制浓度显着降低一半(P = .02),细胞外丙型肝炎病毒RNA和感染力降低与细胞内对应物相比,程度更高。
    结论:17β-雌二醇通过其细胞内受体抑制丙型肝炎病毒,主要干扰丙型肝炎病毒生命周期的后期阶段(组装/释放)。
  • 【雌二醇的17alpha衍生物作为甾族硫酸酯酶抑制剂的构效关系。】 复制标题 收藏 收藏
    DOI:10.1021/jm0001166 复制DOI
    作者列表:Boivin RP,Luu-The V,Lachance R,Labrie F,Poirier D
    BACKGROUND & AIMS: :The steroid sulfatase or steryl sulfatase is a microsomal enzyme widely distributed in human tissues that catalyzes the hydrolysis of sulfated 3-hydroxy steroids to the corresponding free active 3-hydroxy steroids. Since androgens and estrogens may be synthesized inside the cancerous cells starting from dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E(1)S) available in blood circulation, the use of therapeutic agents that inhibit steroid sulfatase activity may be a rewarding approach to the treatment of androgeno-sensitive and estrogeno-sensitive diseases. In the present study, we report the chemical synthesis and biological evaluation of a new family of steroid sulfatase inhibitors. The inhibitors were designed by adding an alkyl, a phenyl, a benzyl, or a benzyl substituted at position 17alpha of estradiol (E(2)), a C18-steroid, and enzymatic assays were performed using the steroid sulfatase of homogenized JEG-3 cells or transfected in HEK-293 cells. We observed that a hydrophobic substituent induces powerful inhibition of steroid sulfatase while a hydrophilic one was weak. Although a hydrophobic group at the 17alpha-position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17alpha-decyl-E(2) and 17alpha-dodecyl-E(2), a long flexible side chain prevents adequate fitting into the enzyme catalytic site, thus decreasing capacity to inhibit the steroid sulfatase activity. In the alkyl series, the best compromise between hydrophobicity and steric hindrance was obtained with the octyl group (IC(50) = 440 nM), but judicious branching of side chain could improve this further. Benzyl substituted derivatives of estradiol were better inhibitors than alkyl analogues. Among the series of 17alpha-(benzyl substituted)-E(2) derivatives studied, the 3'-bromobenzyl, 4'-tert-butylbenzyl, 4'-butylbenzyl, and 4'-benzyloxybenzyl groups provided the most potent inhibition of steroid sulfatase transformation of E(1)S into E(1) (IC(50) = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E(2) nucleus to inhibit the steroid sulfatase by 3000-fold, and it also inhibits similarly the steroid sulfatase transformations of both natural substrates, E(1)S and DHEAS. Interestingly, the newly reported family of steroid sulfatase inhibitors acts by a reversible mechanism of action that is different from the irreversible mechanism of the known inhibitor estrone sulfamate (EMATE).
    背景与目标: :类固醇硫酸酯酶或固醇硫酸酯酶是广泛分布于人体组织中的微粒体酶,可催化硫酸化的3-羟基类固醇水解为相应的游离活性3-羟基类固醇。由于雄激素和雌激素可能是从血液中可用的脱氢表雄酮硫酸盐(DHEAS)和硫酸雌酮(E(1)S)开始在癌细胞内合成的,因此使用抑制类固醇硫酸酯酶活性的治疗剂可能是一种有益的方法。雄激素敏感性和雌激素敏感性疾病的治疗。在本研究中,我们报告了甾族硫酸酯酶抑制剂新家族的化学合成和生物学评估。通过添加在雌二醇(E(2))的17α位上取代的烷基,苯基,苄基或苄基,C18-类固醇来设计抑制剂,并使用均质的JEG-3的类固醇硫酸酯酶进行酶促测定细胞或转染到HEK-293细胞中。我们观察到,疏水取代基可强烈抑制类固醇硫酸酯酶,而亲水取代基则较弱。尽管在17α-位的疏水基团增加了抑制活性,但位阻因素却起到了相反的作用。如17alpha-癸基-E(2)和17alpha-十二烷基-E(2)所示,较长的柔性侧链会阻止酶催化位点的适当装配,从而降低了抑制类固醇硫酸酯酶活性的能力。在烷基系列中,疏水性和空间位阻之间的最佳折衷是使用辛基(IC(50)= 440 nM),但是明智的侧链支化可以进一步改善这一点。雌二醇的苄基取代衍生物是比烷基类似物更好的抑制剂。在研究的一系列17α-(苄基取代)-E(2)衍生物中,3'-溴苄基,4'-叔丁基苄基,4'-丁基苄基和4'-苄氧基苄基提供了对甾族硫酸酯酶的最有效抑制作用E(1)S转换为E(1)(IC(50)分别为24、28、25和22 nM)。例如,叔丁基苄基可将E(2)核抑制类固醇硫酸酯酶的能力提高3000倍,并且还可以类似地抑制两种天然底物E(1)S和DHEAS的类固醇硫酸酯酶转化。有趣的是,新报道的甾族硫酸酯酶抑制剂家族通过可逆的作用机理起作用,该作用机理不同于已知的抑制剂氨基磺酸雌酮(EMATE)的不可逆机理。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录