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。

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。

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。

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。

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。

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。

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。

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。

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。

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）。

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。

BACKGROUND & AIMS: :The purpose of this study was to determine whether the renin-angiotensin system (RAS), nitric oxide (NO), atrial natriuretic peptide (ANP), blood pressure (BP), ultrastructural characteristics, and endothelium-dependent relaxation of thoracic aorta were modulated by the estrogen level. Rats were divided into 3 groups: ovariectomized (OVX); not ovariectomized (sham); and ovariectomized and treated with subcutaneous 17beta-estradiol (15 microg/kg/day, OVX+E(2)) (n=15-17 per group). For 13 weeks after surgery, blood pressure, serum estrogen, NO, plasma angiotensin II (Ang II), ANP, and renin activity levels were monitored. Thirteen weeks after surgery, the vasodilator responses of the aortic rings to acetylcholine and the ultrastructural characteristics of the thoracic aorta were determined. In the 9th and 13th week, OVX rats had a significantly higher blood pressure than the other two groups (p<0.05). Ovariectomy led to a significant decrease in plasma Ang II level and a significant increase in renin activity in OVX rats compared to sham rats; this effect could be reversed by estrogen treatment. In the 5th, 9th, and 13th weeks, the serum NO level was significantly lower in the OVX group than in the sham group (p<0.05); this effect could be reversed by estrogen treatment. Plasma ANP levels in the 9th and 13th weeks were significantly lower in the OVX group (p<0.05), and plasma ANP levels could be completely restored by estrogen treatment. Ovariectomy markedly reduced endothelium-dependent relaxation in response to acetylcholine in isolated rat thoracic aortic rings; chronic estrogen treatment significantly restored endothelium-dependent relaxation in response to acetylcholine. Under electron microscopy, the endothelial cells in OVX rats were swollen, even necrosed; estrogen treatment inhibited these changes. These results strongly suggest that estradiol protects rats from the development of hypertension and has a protective effect on the endothelium by increasing NO and ANP levels while decreasing renin activity. However, there was a discordance between the effects that estradiol had on angiotensin II and on blood pressure. This might be the result of negative feedback that ultimately results in the overall suppression of the RAS.

背景与目标： ：本研究的目的是确定是否存在肾素-血管紧张素系统（RAS），一氧化氮（NO），心房利钠肽（ANP），血压（BP），超微结构特征和胸主动脉内皮依赖性舒张由雌激素水平调节。将大鼠分为3组：去卵巢的（OVX）；去卵巢的（OVX）。未切除卵巢（假）；并经皮下注射17β-雌二醇（15微克/千克/天，OVX E（2））进行去卵巢和处理（每组n = 15-17）。术后13周，监测血压，血清雌激素，NO，血浆血管紧张素II（Ang II），ANP和肾素活性水平。术后十三周，确定主动脉环对乙酰胆碱的血管舒张反应和胸主动脉的超微结构特征。在第9周和第13周，OVX大鼠的血压明显高于其他两组（p <0.05）。与假手术大鼠相比，卵巢切除术可导致OVX大鼠血浆Ang II水平显着降低，肾素活性显着提高。这种作用可以通过雌激素治疗来逆转。在第5、9和13周，OVX组的血清NO水平显着低于假手术组（p <0.05）。这种作用可以通过雌激素治疗来逆转。 OVX组第9周和第13周的血浆ANP水平显着降低（p <0.05），并且通过雌激素治疗可以完全恢复血浆ANP水平。卵巢切除术显着降低了离体大鼠胸主动脉环对乙酰胆碱的内皮依赖性舒张反应；慢性雌激素治疗可显着恢复对乙酰胆碱的内皮依赖性舒张反应。在电子显微镜下，OVX大鼠的内皮细胞肿胀甚至坏死。雌激素治疗抑制了这些变化。这些结果强烈表明，雌二醇可保护大鼠免于高血压的发展，并通过增加NO和ANP的水平同时降低肾素的活性而对内皮具有保护作用。但是，雌二醇对血管紧张素II和血压的影响之间存在分歧。这可能是负反馈的结果，最终导致对RAS的整体抑制。

BACKGROUND & AIMS: :Modulation of dopamine (DA) receptors by cations (Na+, K+, Mg2+, Ca2+) was compared in 7315a, MtTW15, and estradiol valerate-induced (EV-T) pituitary tumors, and intact adenohypophysis. In 7315a tumors, the affinity of [3H]spiperone binding measured at 25 degrees remained unchanged in the presence of each cation individually or all these cations together (IONS) compared to the affinity obtained using a buffer without ions; the density (Bmax) was not affected by monovalent cations or Mg2+ and was decreased by Ca2+ or IONS. When binding experiments were done at 37 degrees, monovalent cations increased affinity whereas divalent cations or IONS did not modify it, and none of these cations affected Bmax values. In MtTW15 tumors, the affinity of [3H]spiperone binding measured at 25 degrees was not changed by Na+ or IONS and was decreased by K+ or divalent cations; the density was decreased by K+ and unchanged by all the other cations. When binding experiments were done at 37 degrees, Na+ increased the affinity, whereas all the other cations did not affect it: the density was unaffected by all the cations studied. In EV-T assayed at 37 degrees, the affinity was increased by monovalent cations or Mg2+ and was unchanged by Ca2+; monovalent cations did not affect the density of [3H]spiperone binding and divalent cations increased it. In binding experiments performed at 25 degrees and 37 degrees, choline chloride did not change the affinity or the density of [3H]spiperone binding to DA receptors in the three pituitary tumors investigated, suggesting that the effect of cations was specific and not due to differences in ionic strength. In the rat normal anterior pituitary, Na+ increased the affinity of [3H]spiperone for the DA receptors, whereas the affinity was unchanged by Ca2+; the density of [3H]spiperone binding was unaffected by these cations. Our results suggest that DA receptors in 7315a and MtTW15 tumors are regulated abnormally by sodium, potassium, magnesium and calcium. In contrast, DA receptors in EV-T are regulated normally by monovalent cations and abnormally by divalent cations as compared to these receptors in intact pituitary tissue.

背景与目标： 在7315a，MtTW15和戊酸雌二醇诱发的垂体瘤（EV-T）和完整的腺垂体中比较了阳离子（Na，K，Mg2，Ca2）对多巴胺（DA）受体的调节作用。在7315a肿瘤中，与使用无离子缓冲液获得的亲和力相比，在每个阳离子单独存在或所有这些阳离子在一起（IONS）的情况下，在25度下测得的[3H]哌酮结合的亲和力保持不变。密度（Bmax）不受单价阳离子或Mg2影响，而受Ca2或IONS降低。当在37度下进行结合实验时，单价阳离子增加了亲和力，而二价阳离子或IONS却没有对其进行修饰，并且这些阳离子都没有影响Bmax值。在MtTW15肿瘤中，在25度测量的[3H]哌咯酮结合的亲和力没有被Na或IONS改变，而被K或二价阳离子降低了。密度降低了K，而所有其他阳离子均未改变。当在37度下进行结合实验时，Na增加了亲和力，而所有其他阳离子均不影响它：密度不受所有研究阳离子的影响。在37度的EV-T中，单价阳离子或Mg2增加了亲和力，而Ca2没有改变亲和力。一价阳离子不影响[3H]哌咯酮结合的密度，而二价阳离子则增加了它的密度。在25度和37度进行的结合实验中，氯化胆碱并未改变所研究的三个垂体肿瘤中[3H]哌咯酮与DA受体的亲和力或密度，这表明阳离子的作用是特异性的，而不是由于差异离子强度。在大鼠正常的垂体前叶，Na增加了[3H] spiperone对DA受体的亲和力，而Ca2却没有改变亲和力。 [3H] spiperone结合的密度不受这些阳离子的影响。我们的结果表明，钠，钾，镁和钙异常调节7315a和MtTW15肿瘤中的DA受体。相反，与完整的垂体组织中的这些受体相比，EV-T中的DA受体通常由单价阳离子调节，而由二价阳离子异常调节。

BACKGROUND & AIMS: :TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median tmax , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV-1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing.

背景与目标： ：TV-1106是人血清白蛋白，与重组人生长激素基因融合，旨在为GH缺乏症患者的日常生长激素（GH）注射提供长效替代品。这项研究调查了日本（n = 44）和高加索人（n = 44）健康受试者单次皮下注射TV-1106（7.5、15、50和100 mg）的药代动力学，药效学和安全性。在日本和白种人中，TV-1106的药代动力学和药效学相当。 TV-1106表现出相对较慢的吸收（tmax中位数为10-30小时），平均消除半衰期为26-36小时。在两个人群中，表观清除率和分布体积均随着TV-1106剂量的增加而降低，并且似乎在整个测试剂量中的增加均大于剂量比例。胰岛素样生长因子-1（IGF-1）和IGF结合蛋白-3（IGFBP-3）以剂量相关的方式增加，分别在33-96和42-109小时观察到最大反应。 IGF-1和IGFBP-3在7.5和15 mg TV-1106服用后168小时以及在50和100 mg TV-1106服用后336小时回到基线值。 TV-1106在两种人群中均显示安全。没有证据表明日本人和白种人之间的药代动力学，药效学或TV-1106的安全性存在差异。数据还证明了TV-1106的长效生长激素特性，并支持其每周一次给药的潜力。

BACKGROUND & AIMS: IMPORTANCE:After menopause, estradiol (E2) is predominately an intracrine hormone circulating in very low serum concentrations. OBJECTIVE:The objective of this work is to examine determinants of E2 concentrations in women beyond age 70 years. DESIGN AND SETTING:A cross-sectional, community-based study was conducted. PARTICIPANTS:A total of 5325 women participated, with a mean age of 75.1 years (± 4.2 years) and not using any sex steroid, antiandrogen/estrogen, glucocorticoid, or antiglycemic therapy. MAIN OUTCOME MEASURES:Sex steroids were measured by liquid chromatography-tandem mass spectrometry. Values below the limit of detection (LOD; E2 11 pmol/L [3 pg/mL] were assigned a value of LOD/√2 to estimate total E2. RESULTS:E2 and estrone (E1) were below the LOD in 66.1% and 0.9% of women, respectively. The median (interdecile ranges) for E1 and detectable E2 were 181.2 pmol/L (range, 88.7-347.6 pmol/L) and 22.0 pmol/L (range, 11.0-58.7 pmol/L). Women with undetectable E2 vs detectable E2 were older (median age 74.1 years vs 73.8, P = .02), leaner (median body mass index [BMI] 26.8 kg/m2 vs 28.5, P < .001), and had lower E1, testosterone and DHEA concentrations (P < .001). A linear regression model, including age, BMI, E1, and testosterone, explained 20.9% of the variation in total E2, but explained only an additional 1.2% of variation over E1 alone. E1 and testosterone made significant contributions (r2 = 0.162, P < .001) in a model for the subset of women with detectable E2. CONCLUSIONS:Our findings support E1 as a principal circulating estrogen and demonstrate a robust association between E1 and E2 concentrations in postmenopausal women. Taken together with prior evidence for associations between E1 and health outcomes, E1 should be included in studies examining associations between estrogen levels and health outcomes in postmenopausal women.

背景与目标： 重要提示：绝经后，雌二醇（E2）主要是一种血清中浓度非常低的循环内分泌激素。
目的：这项工作的目的是检查70岁以上女性中E2浓度的决定因素。
设计与设置：进行了一项基于社区的横断面研究。
参与者：共有5325名妇女参加，平均年龄75.1岁（±4.2岁），未使用任何性类固醇，抗雄激素/雌激素，糖皮质激素或抗血糖治疗。
主要观察指标：用液相色谱-串联质谱法测定性类固醇。低于检测极限的值（LOD； E2 11 pmol / L [3 pg / mL]）被分配为LOD /√2的值，以估算总E2。
结果：E2和雌酮（E1）分别低于LOD，分别为66.1％和0.9％的女性。 E1和可检测到的E2的中位数（十分位数范围）分别为181.2 pmol / L（范围88.7-347.6 pmol / L）和22.0 pmol / L（范围11.0-58.7 pmol / L）。 E2检出与E2检出的女性年龄较大（中位年龄为74.1岁vs 73.8，P = .02），较苗条（中位体重指数[BMI] 26.8 kg / m2 vs 28.5，P <.001），并且E1较低，睾丸激素和脱氢表雄酮的浓度（P <.001）。包括年龄，BMI，E1和睾丸激素在内的线性回归模型解释了总E2变异的20.9％，但仅解释了单独E1变异的1.2％。 E1和睾丸激素在可检测到E2的女性子集中的模型中做出了显着贡献（r2 = 0.162，P <.001）。
结论：我们的研究结果支持E1作为主要的循环雌激素，并证明绝经后妇女的E1和E2浓度之间存在稳固的联系。与E1和健康结局之间的关联的现有证据一起，应将E1纳入检查绝经后妇女雌激素水平与健康结局之间的关联的研究中。