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Are androgen receptor agonists a treatment option in bladder cancer? 雄激素受体激动剂是治疗膀胱癌的一种选择吗?
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.jsbmb.2024.106623
Michael L. De Ieso , Ahmed Faris Aldoghachi , Wayne D. Tilley, Amy R. Dwyer
Sex-related differences in bladder cancer incidence and progression infer a role for sex hormones and their cognate receptors in this disease. In part due to the oncogenic role of androgen receptor signaling in prostate cancer, the focus of most preclinical and clinical research to-date has been on the potential pro-tumorigenic action of androgens in urothelial cancers. However, clinical studies of androgen receptor antagonism have yielded minimal success. In this review, we explore the tumor suppressor role of androgen receptor in bladder cancer and discuss how it might be harnessed therapeutically.
膀胱癌的发病率和发展过程中与性别有关的差异推断出性激素及其同源受体在这种疾病中的作用。部分由于雄激素受体信号在前列腺癌中的致癌作用,迄今为止,大多数临床前和临床研究的重点都是雄激素在泌尿系统癌症中的潜在促肿瘤作用。然而,雄激素受体拮抗剂的临床研究收效甚微。在这篇综述中,我们将探讨雄激素受体在膀胱癌中的肿瘤抑制作用,并讨论如何利用雄激素受体进行治疗。
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引用次数: 0
Unique sterol metabolite shifts in inflammatory bowel disease and primary sclerosing cholangitis 炎症性肠病和原发性硬化性胆管炎中独特的甾醇代谢转变
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.jsbmb.2024.106621
Silke Matysik , Tanja Elger , Muriel Huss , Gerhard Liebisch , Marcus Höring , Johanna Loibl , Arne Kandulski , Martina Müller , Hauke Christian Tews , Christa Buechler
Inflammatory bowel disease (IBD) triggers chronic intestinal inflammation and is linked to primary sclerosing cholangitis (PSC). Cholesterol homeostasis, tightly regulated under normal conditions, becomes disrupted in both inflammation and chronic liver disease. We analyzed fecal and serum levels of cholesterol synthesis precursors, oxysterols, and phytosterols in 87 patients with IBD (81 for serum analysis) including patients with Crohn's disease (CD) and ulcerative colitis (UC), 11 patients with PSC, 21 patients with PSC-IBD (18 for serum analysis), and 16 healthy controls (17 for serum analysis). Cholesterol was analysed by flow injection analysis on a high-resolution hybrid quadrupole-Orbitrap mass spectrometer and further serum sterols and all fecal sterols were analysed by a gas chromatograph mass spectrometer. Serum levels of lanosterol, 7-dehydrocholesterol, 7-beta-hydroxycholesterol, 27-hydroxycholesterol, and the plant sterols campesterol, stigmasterol, and sitosterol were similar across control and patient groups. Notably, serum lathosterol was elevated in CD patients compared to those with UC, PSC, PSC-IBD, and healthy controls. All other serum and fecal sterols showed no differences between CD and UC. Cholesterol synthesis precursors in serum, serum cholesterol levels, and both serum and fecal plant sterol levels decreased with increasing IBD severity. Consequently, serum cholesterol, campesterol, sitosterol, and fecal 5-beta sitostanol and 5-alpha sitostanol were negatively correlated with C-reactive protein and fecal calprotectin. The conversion of cholesterol to coprostanol in feces was impaired in IBD, PSC, and PSC-IBD, independent of bowel inflammation severity or liver disease extent. Patients with PSC, and to a lesser extent PSC-IBD, had elevated serum plant sterol levels, positively correlating with liver disease markers. In conclusion, in patients with IBD, cholesterol biosynthetic precursors, serum cholesterol levels, and fecal plant sterols decrease with intestinal inflammation. An inverse association of serum plant sterols with intestinal inflammation was observed in patients with IBD and a direct association of serum phytosterols with liver injury in patients with PSC. The conversion of fecal cholesterol to coprostanol was impaired in all patient cohorts. IBD and PSC alter serum sterol levels differently, whereas changes in fecal sterols are not disease specific and are moderate.
炎症性肠病(IBD)会引发慢性肠道炎症,并与原发性硬化性胆管炎(PSC)有关。胆固醇平衡在正常情况下受到严格调控,但在炎症和慢性肝病中却会受到破坏。我们分析了包括克罗恩病(CD)和溃疡性结肠炎(UC)患者在内的 87 名 IBD 患者(81 人进行了血清分析)、11 名 PSC 患者、21 名 PSC-IBD 患者(18 人进行了血清分析)和 16 名健康对照组(17 人进行了血清分析)的粪便和血清中胆固醇合成前体、氧基甾醇和植物甾醇的水平。胆固醇通过高分辨率混合四极杆-轨道阱质谱仪上的流动注射分析法进行分析,血清固醇和所有粪便固醇则通过气相色谱仪质谱仪进行分析。对照组和患者组的血清中羊毛甾醇、7-脱氢胆固醇、7-beta-羟基胆固醇、27-羟基胆固醇以及植物甾醇莰酯醇、豆甾醇和西固醇的水平相似。值得注意的是,与 UC、PSC、PSC-IBD 患者和健康对照组相比,CD 患者的血清 Lathosterol 有所升高。所有其他血清和粪便固醇在 CD 和 UC 之间没有差异。血清中的胆固醇合成前体、血清胆固醇水平以及血清和粪便中的植物固醇水平随着 IBD 严重程度的增加而降低。因此,血清胆固醇、坎贝酯醇、西固醇以及粪便中的 5-beta 西托烷醇和 5-α 西托烷醇与 C 反应蛋白和粪便钙蛋白呈负相关。在 IBD、PSC 和 PSC-IBD 患者中,粪便中胆固醇向共烷醇的转化受到影响,这与肠道炎症严重程度或肝病程度无关。PSC患者的血清植物固醇水平升高,PSC-IBD患者的血清植物固醇水平较低,与肝病指标呈正相关。总之,IBD 患者的胆固醇生物合成前体、血清胆固醇水平和粪便中的植物固醇会随着肠道炎症而降低。在 IBD 患者中观察到血清植物固醇与肠道炎症呈反向关系,而在 PSC 患者中观察到血清植物固醇与肝损伤直接相关。在所有患者群中,粪便中胆固醇向共烷醇的转化都受到了影响。IBD 和 PSC 会以不同的方式改变血清中的固醇水平,而粪便中固醇的变化则不具有疾病特异性,变化程度适中。
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引用次数: 0
Synthesis and characterization of targeted 17β-hydroxysteroid dehydrogenase type 7 inhibitors. 靶向 17β- 羟类固醇脱氢酶 7 型抑制剂的合成与表征。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-05-14 DOI: 10.1016/j.jsbmb.2024.106544
Jean-Yves Sancéau, René Maltais, Ming Zhou, Sheng-Xiang Lin, Donald Poirier

Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer. The chemical synthesis, molecular characterization, and preliminary biological evaluation as 17β-HSD7 inhibitors of novel carbamate derivatives 3 and 4 are described. Like previous 17β-HSD7 inhibitors 1 and 2, compounds 3 and 4 bear a hydrophobic nonyl side chain at the C-17β position of a 4-aza-5α-androstane nucleus, but compound 3 has an oxygen atom replacing the CH2 in the steroid A-ring C-2 position, while compound 4 has a C17-spiranic E-ring containing a carbamate function. They both inhibited the in vitro transformation of estrone (E1) into E2 by 17β-HSD7, but the introduction of a (17 R)-spirocarbamate is preferable to replacing C-2 methylene with an oxygen atom since compound 4 (IC50 = 63 nM) is an inhibitor 14 times more powerful than compound 3 (IC50 = 900 nM). Furthermore, when compared to the reference inhibitor 1 (IC50 = 111 nM), the use of a C17-spiranic E-ring made it possible to introduce differently the hydrophobic nonyl side chain, without reducing the inhibitory activity.

雌激素雌二醇(E2)和雄激素双氢睾酮(DHT)等性类固醇激素与激素依赖性癌症的发病有关。阻断短链脱氢酶/还原酶超家族成员 17β- 羟类固醇脱氢酶 7 型(17β-HSD7)被认为会降低 E2 水平,同时增加 DHT 水平。因此,其独特的双重作用使该酶成为治疗乳腺癌的一个有趣的药物靶点。本文介绍了新型氨基甲酸酯衍生物 3 和 4 作为 17β-HSD7 抑制剂的化学合成、分子表征和初步生物学评价。与之前的 17β-HSD7 抑制剂 1 和 2 一样,化合物 3 和 4 在 4-aza-5α 雄甾烷核的 C-17β 位上带有疏水性壬基侧链,但化合物 3 中的氧原子取代了类固醇 A 环 C-2 位上的 CH2,而化合物 4 中的 C17-spiranic E 环含有氨基甲酸酯功能。它们都能抑制 17β-HSD7 在体外将雌酮(E1)转化为 E2,但引入 (17R)- 螺氨甲酸酯比用氧原子取代 C-2 亚甲基更好,因为化合物 4(IC50 = 63nM)的抑制作用比化合物 3(IC50 = 900nM)强 14 倍。此外,与参考抑制剂 1(IC50 = 111nM)相比,使用 C17-spiranic E 环可以在不降低抑制活性的情况下引入不同的疏水壬基侧链。
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引用次数: 0
Latent Class Analysis Reveals, in patient profiles, COVID-19–related better prognosis by calcifediol treatment than glucocorticoids 潜类分析显示,在患者资料中,与 COVID-19 相关的降钙素治疗比糖皮质激素治疗预后更好。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-31 DOI: 10.1016/j.jsbmb.2024.106609
Marta Entrenas-Castillo , Luis Manuel Entrenas-Costa , María P. Pata , Bernabe Jurado Gamez , Cristina Muñoz-Corroto , Cristina Gómez-Rebollo , Estefanía Mira-Padilla , Roger Bouillon , Jose Manuel Quesada-Gomez
Calcifediol and glucocorticoids have been repositioned for the treatment of COVID-19 and may reduce severity, the need for intensive care unit admission and death.

Objective

to identify class or profiles of patients hospitalized and treated with COVID-19 pneumonia using latent class clustering methods to assess the clinical and prognostic relevance of the resulting patients’ profiles. Poor prognosis was defined as death or need for ICU admission, good prognosis, the opposite. With special interest in differential responses to calcifediol.

Setting

Reina Sofia University Hospital, Córdoba Spain.

Patients

Retrospective observational cohort study of patients admitted for COVID-19. ClinicalTrials.gov public database (NCT05819918). Inclusion criteria: (i) Age ≥ 18 and ≤ 90 years, (ii) Pneumonia characterized by the presence of infiltrates on chest X-ray or CT scan, (iii) SARS-CoV-2 infection, confirmed, and (iv) CURB Scale 65 >1.

Design

Latent class analysis, for obtaining homogeneous clusters, without specifying a priori the belonging group, and selecting the optimal number of clusters by minimizing information criteria. Evaluating the differences between groups for each variable by means of chi-square, Fisher's exact test and Kruskal-Wallis test.

Results

707 patients hospitalized from 10 March 2020 until 4 March 2022 were included. For the treatment variable, differences were found between class 3 (60 % treated with calcifediol only) and classes 1 (less than 1 % calcifediol only vs. 82 % treated with both), 2 (less than 1 % calcifediol only vs. 82 % treated with both) and 4 (1 % calcifediol only vs. 84 % treated with both). Class 3, (60 % with calcifediol), had a significantly better prognosis compared to patients treated with glucocorticoids alone (OR: 15.2, 95 % CI: [3.73–142], p<0.001) or no treatment (OR: 7.38, 95 % CI: [2.63–30.2], p<0.001).

Conclusions

our real-life study shows that calcifediol treatment significantly reduces the need for ICU admission and improved prognosis in patients hospitalized for COVID-19 pneumonia, especially in the profile of patients receiving it without glucocorticoids.
COVID-19肺炎的治疗已重新定位为降钙素和糖皮质激素,这两种药物可减轻病情严重程度,减少入住重症监护室的需要和死亡。目的:使用潜类聚类方法识别住院治疗的COVID-19肺炎患者的类别或特征,评估由此得出的患者特征的临床和预后相关性。预后差的定义是死亡或需要入住重症监护室,预后好的则相反。特别关注对降钙素的不同反应:地点: 西班牙科尔多瓦索菲亚王后大学医院。患者 COVID-19 入院患者的回顾性观察队列研究。Clinicaltrials: gov 公共数据库(NCT05819918):纳入标准:(i) 年龄≥ 18 岁且≤ 90 岁;(ii) 胸部 X 光片或 CT 扫描显示有浸润的肺炎;(iii) 已确诊感染 SARS-CoV-2;(iv) CURB Scale 65 >1:设计:潜类分析法,用于获得同质群组,不预先指定所属组别,并通过最小化信息标准选择最佳群组数量。通过卡方检验(chi-square)、费雪精确检验(Fisher's exact test)和 Kruskal-Wallis 检验(Kruskal-Wallis test)评估各变量在组间的差异:共纳入了 707 名从 2020 年 3 月 10 日至 2022 年 3 月 4 日住院的患者。在治疗变量方面,3级(60%的患者仅接受了钙化二醇治疗)与1级(82%的患者仅接受了低于1%的钙化二醇治疗,而82%的患者同时接受了两种治疗)、2级(82%的患者仅接受了低于1%的钙化二醇治疗,而82%的患者同时接受了两种治疗)和4级(84%的患者仅接受了1%的钙化二醇治疗,而84%的患者同时接受了两种治疗)之间存在差异。与仅接受糖皮质激素治疗的患者相比,3级患者(60%接受过钙泊三醇治疗)的预后明显更好(OR:15.2,95% CI:[3.73 - 142],p结论:我们的实际研究表明,钙泊三醇治疗可显著减少因COVID-19肺炎住院的患者入住ICU的需求,并改善预后,尤其是在接受钙泊三醇治疗而不使用糖皮质激素的患者中。
{"title":"Latent Class Analysis Reveals, in patient profiles, COVID-19–related better prognosis by calcifediol treatment than glucocorticoids","authors":"Marta Entrenas-Castillo ,&nbsp;Luis Manuel Entrenas-Costa ,&nbsp;María P. Pata ,&nbsp;Bernabe Jurado Gamez ,&nbsp;Cristina Muñoz-Corroto ,&nbsp;Cristina Gómez-Rebollo ,&nbsp;Estefanía Mira-Padilla ,&nbsp;Roger Bouillon ,&nbsp;Jose Manuel Quesada-Gomez","doi":"10.1016/j.jsbmb.2024.106609","DOIUrl":"10.1016/j.jsbmb.2024.106609","url":null,"abstract":"<div><div>Calcifediol and glucocorticoids have been repositioned for the treatment of COVID-19 and may reduce severity, the need for intensive care unit admission and death.</div></div><div><h3>Objective</h3><div>to identify class or profiles of patients hospitalized and treated with COVID-19 pneumonia using latent class clustering methods to assess the clinical and prognostic relevance of the resulting patients’ profiles. Poor prognosis was defined as death or need for ICU admission, good prognosis, the opposite. With special interest in differential responses to calcifediol.</div></div><div><h3>Setting</h3><div>Reina Sofia University Hospital, Córdoba Spain.</div></div><div><h3>Patients</h3><div>Retrospective observational cohort study of patients admitted for COVID-19. ClinicalTrials.gov public database (NCT05819918). Inclusion criteria: (i) Age ≥ 18 and ≤ 90 years, (ii) Pneumonia characterized by the presence of infiltrates on chest X-ray or CT scan, (iii) SARS-CoV-2 infection, confirmed, and (iv) CURB Scale 65 &gt;1.</div></div><div><h3>Design</h3><div>Latent class analysis, for obtaining homogeneous clusters, without specifying a priori the belonging group, and selecting the optimal number of clusters by minimizing information criteria. Evaluating the differences between groups for each variable by means of chi-square, Fisher's exact test and Kruskal-Wallis test.</div></div><div><h3>Results</h3><div>707 patients hospitalized from 10 March 2020 until 4 March 2022 were included. For the treatment variable, differences were found between class 3 (60 % treated with calcifediol only) and classes 1 (less than 1 % calcifediol only vs. 82 % treated with both), 2 (less than 1 % calcifediol only vs. 82 % treated with both) and 4 (1 % calcifediol only vs. 84 % treated with both). Class 3, (60 % with calcifediol), had a significantly better prognosis compared to patients treated with glucocorticoids alone (OR: 15.2, 95 % CI: [3.73–142], p&lt;0.001) or no treatment (OR: 7.38, 95 % CI: [2.63–30.2], p&lt;0.001).</div></div><div><h3>Conclusions</h3><div>our real-life study shows that calcifediol treatment significantly reduces the need for ICU admission and improved prognosis in patients hospitalized for COVID-19 pneumonia, especially in the profile of patients receiving it without glucocorticoids<del>.</del></div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106609"},"PeriodicalIF":2.7,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fast and reliable quantification of aldosterone, cortisol and cortisone via LC-MS/MS to study 11β-hydroxysteroid dehydrogenase activities in primary cell cultures 通过 LC-MS/MS 对醛固酮、皮质醇和可的松进行快速可靠的定量,以研究原代细胞培养物中 11β- 羟类固醇脱氢酶的活性。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.jsbmb.2024.106610
Sonja Kunz , Yao Meng , Holger Schneider , Laura Brunnenkant , Michaela Höhne , Tim Kühnle , Martin Reincke , Marily Theodoropoulou , Martin Bidlingmaier

Cell culture experiments can support characterization of enzymatic activities in healthy and tumorous human tissues. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) enables simultaneous measurement of several steroids from a single sample, facilitating analysis of molecular pathways involved in steroid biosynthesis. We developed a reliable but fast method for quantification of cortisol, cortisone and aldosterone in cell culture supernatant. Validation, including investigation of matrix-matched calibration, was performed for two different cell types. Utility of the method was demonstrated in the study of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity under conditions of glucocorticoid and mineralocorticoid excess in different cell types. Aldosterone, cortisol and cortisone were extracted by liquid-liquid extraction (LLE) with methyl tert-butyl ether from 1 mL of cell culture supernatant. Steroids were separated on a Kinetex biphenyl column (50 ×2.1 mm, 2.6 µm) with gradient elution of water and methanol containing 2 mM ammonium format and analysed in multiple reaction monitoring mode after positive electrospray ionization. Application of the method included cell culture experiments with two different primary cell types, human coronary artery smooth muscle cells (HCSMC) and human coronary artery endothelial cells (EC). Cells were treated with different concentrations of cortisol, aldosterone and mifepristone, a glucocorticoid receptor antagonist and quantitative PCR was performed. The method exhibits high precision (CV ≤ 6 %) and accuracy (deviation from nominal concentration ≤ 6 %) for concentrations above the limit of quantification (LoQ) which is 0.11, 0.56 and 0.69 nmol/L for aldosterone, cortisone and cortisol, respectively. Calibration curves did not differ when prepared in media or solvent. The method enabled us to confirm activity of HSD11B2 and concentration dependent conversion of cortisol to cortisone in HCSMC (median conversion ratio at 140 nM cortisol = 1.46 %). In contrast we did not observe any HSD11B2 activity in EC. Neither addition of high aldosterone, nor addition of 1 µM mifepristone had impact on glucocorticoid concentrations. Quantitative PCR revealed expression of HSD11B1 and HSD11B2 in HCSMC but not in EC. We present a fast and reliable method for quantification of cortisol, cortisone and aldosterone in cell culture supernatants. The method enabled us to study HSD11B2 activity in two different cell types and will support future experiments investigating mechanisms of target organ damage in conditions of glucocorticoid and mineralocorticoid excess.

细胞培养实验有助于确定健康和肿瘤人体组织中酶活性的特征。液相色谱-串联质谱法(LC-MS/MS)可同时测定单个样品中的多种类固醇,有助于分析类固醇生物合成的分子途径。我们开发了一种可靠而快速的方法,用于定量检测细胞培养上清液中的皮质醇、可的松和醛固酮。我们对两种不同类型的细胞进行了验证,包括基质匹配校准调查。在研究不同类型细胞中糖皮质激素和矿质皮质激素过量条件下的 11β- 羟类固醇脱氢酶 2 型(HSD11B2)活性时,证明了该方法的实用性。用甲基叔丁基醚液液萃取法(LLE)从 1 毫升细胞培养上清液中提取醛固酮、皮质醇和可的松。类固醇经 Kinetex 联苯柱(50 ×2.1mm,2.6µm)分离,水和甲醇(含 2mM 氨格式)梯度洗脱,电喷雾正离子后在多反应监测模式下进行分析。该方法的应用包括两种不同原代细胞类型的细胞培养实验,即人冠状动脉平滑肌细胞(HCSMC)和人冠状动脉内皮细胞(EC)。用不同浓度的皮质醇、醛固酮和米非司酮(一种糖皮质激素受体拮抗剂)处理细胞,然后进行定量 PCR 分析。该方法的精密度(CV ≤ 6%)和准确度(与标称浓度的偏差 ≤ 6%)都很高,醛固酮、可的松和皮质醇的定量限(LoQ)分别为 0.11、0.56 和 0.69 nmol/L。在介质或溶剂中制备的校准曲线没有差异。通过该方法,我们确认了 HSD11B2 的活性以及皮质醇在 HCSMC 中转化为可的松的浓度依赖性(140nM 皮质醇时的中位转化率 = 1.46%)。相比之下,我们在 EC 中没有观察到任何 HSD11B2 活性。添加高浓度醛固酮或添加 1µM 米非司酮都不会影响糖皮质激素的浓度。定量 PCR 发现 HCSMC 中有 HSD11B1 和 HSD11B2 的表达,而 EC 中没有。我们提出了一种快速可靠的方法来定量检测细胞培养上清液中的皮质醇、可的松和醛固酮。该方法使我们能够研究两种不同类型细胞中 HSD11B2 的活性,并将支持未来研究糖皮质激素和矿质类固醇过量条件下靶器官损伤机制的实验。
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引用次数: 0
Steroids and Mass Spectrometry: A Personal Story 类固醇与质谱分析:一个个人故事。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-27 DOI: 10.1016/j.jsbmb.2024.106608
Cedric H.L. Shackleton
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引用次数: 0
GPER expression prevents estrogen-induced urinary retention in obese mice GPER 的表达可防止肥胖小鼠因雌激素引起的尿潴留。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-27 DOI: 10.1016/j.jsbmb.2024.106607
Donna F. Kusewitt , Geetanjali Sharma , Christine D. Woods , Emmanuel Rosas , Helen J. Hathaway , Eric R. Prossnitz

Long-term administration of exogenous estrogen is known to cause urinary retention and marked, often fatal, bladder distention in both male and female mice. Estrogen-treated mice have increased bladder pressure and decreased urine flow, suggesting that urinary retention in estrogen-treated mice is due to infravesicular obstruction to urine outflow. Thus, the condition is commonly referred to as bladder outlet obstruction (BOO). Obesity can also lead to urinary retention. As the effects of estrogen are mediated by multiple receptors, including estrogen receptors ERα and ERβ and the G protein-coupled estrogen receptor (GPER), we sought to determine whether GPER plays a role in estrogen-induced BOO, particularly in the context of obesity. Wild type and GPER knockout (KO) mice fed a high-fat diet were ovariectomized or left ovary-intact (sham surgery) and supplemented with slow-release estrogen or vehicle-only pellets. Supplementing both GPER KO and wild type obese mice with estrogen for 8 weeks resulted in weight loss, splenic enlargement, and thymic atrophy, as expected. However, estrogen-treated obese GPER KO mice developed abdominal distension, debilitation, and ulceration of the skin surrounding the urogenital opening. At necropsy, these mice had prominently distended bladders and hydronephrosis. In contrast, estrogen-treated obese wild type mice only rarely displayed these signs. Our results suggest that, under conditions of obesity, estrogen induces BOO as a result of ERα-driven pathways and that GPER expression is protective against BOO.

众所周知,长期服用外源性雌激素会导致雄性和雌性小鼠出现尿潴留和明显的膀胱膨胀,而且往往是致命的。经雌激素处理的小鼠膀胱压力升高,尿流减少,这表明经雌激素处理的小鼠尿潴留是由于膀胱下部尿液流出受阻所致。因此,这种情况通常被称为膀胱出口梗阻(BOO)。肥胖也会导致尿潴留。由于雌激素的作用由多种受体介导,包括雌激素受体ERα和ERβ以及G蛋白偶联雌激素受体(GPER),我们试图确定GPER是否在雌激素诱导的BOO中发挥作用,尤其是在肥胖的情况下。对以高脂饮食喂养的野生型小鼠和GPER基因敲除(KO)小鼠进行卵巢切除或卵巢不切除(假手术),并补充缓释雌激素或仅含载体的颗粒。给GPER KO和野生型肥胖小鼠补充雌激素8周后,正如预期的那样,小鼠体重减轻、脾脏增大、胸腺萎缩。然而,经雌激素处理的 GPER KO 肥胖小鼠出现腹胀、衰弱和尿道口周围皮肤溃疡。尸体解剖时,这些小鼠的膀胱明显膨胀并出现肾积水。相比之下,喂食高脂肪食物的野生型小鼠经雌激素处理后很少出现这些症状。我们的研究结果表明,在肥胖的条件下,雌激素会通过ERα驱动的途径诱发BOO,而GPER的表达对BOO具有保护作用。
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引用次数: 0
Sex hormone-binding globulin and its critical role in prostate cancer: A comprehensive review 性激素结合球蛋白及其在前列腺癌中的关键作用:全面回顾。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-23 DOI: 10.1016/j.jsbmb.2024.106606
Anirban Goutam Mukherjee, Abilash V G

Prostate cancer (PC) is a common and widespread cancer that affects men globally. A complicated interaction of hormonal variables influences its development. Sex hormone-binding globulin (SHBG) is a crucial element in controlling the availability of sex hormones, especially androgens, which have a notable impact on the development and progression of PC. SHBG controls the levels of free, active androgens in the body, which helps regulate androgen-dependent processes associated with PC. The equilibrium between SHBG and androgens plays a critical role in maintaining the stability of the prostate. When this balance is disrupted, it is associated with the development and advancement of PC. The processes responsible for SHBG's role in PC are complex and have multiple aspects. SHBG primarily binds to androgens, preventing them from interacting with androgen receptors (ARs) in prostate cells. It reduces the activation of androgen signaling pathways essential for tumor development and survival. In addition, SHBG can directly affect prostate cells by interacting with specific receptors on the cell surface. This review thoroughly examines the role of SHBG in PC, including its physiological activities, methods of action, and clinical consequences.

前列腺癌(PC)是一种影响全球男性的常见且普遍的癌症。荷尔蒙变量之间复杂的相互作用影响着它的发展。性激素结合球蛋白(SHBG)是控制性激素(尤其是雄激素)供应的关键因素,而雄激素对前列腺癌的发展和恶化有着显著的影响。SHBG 可控制体内游离的活性雄激素水平,有助于调节与 PC 相关的雄激素依赖过程。SHBG 和雄激素之间的平衡对维持前列腺的稳定起着至关重要的作用。一旦这种平衡被打破,就会导致 PC 的发展和恶化。SHBG 在 PC 中发挥作用的过程十分复杂,涉及多个方面。SHBG 主要与雄激素结合,阻止雄激素与前列腺细胞中的雄激素受体 (AR) 发生作用。它能减少对肿瘤发生和存活至关重要的雄激素信号通路的激活。此外,SHBG 还能与细胞表面的特定受体相互作用,从而直接影响前列腺细胞。这篇综述深入探讨了 SHBG 在 PC 中的作用,包括其生理活性、作用方法和临床后果。
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引用次数: 0
OBHSA, a novel selective estrogen receptor degrader, overcomes tamoxifen resistance through cell cycle arrest and unfolded protein response-mediated apoptosis in breast cancer OBHSA是一种新型选择性雌激素受体降解剂,可通过细胞周期停滞和未折叠蛋白反应介导的细胞凋亡克服乳腺癌对他莫昔芬的耐药性。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.jsbmb.2024.106599
Rong Shen , Jiawei Zhou , Lilan Xin , Hai-Bing Zhou , Jian Huang

Breast cancer (BC) is a highly heterogeneous tumor that has surpassed lung cancer as the most frequently diagnosed cancer in women. In clinical practice,the primary approach for treating estrogen receptor alpha (ERα)-positive BC is through endocrine therapy, which involves targeting the ERα using medications like tamoxifen and fulvestrant. However, the problem of de novo or acquired resistance poses a significant clinical challenge, emphasizing the critical need for the development of novel therapeutic strategies. In this regard, we have successfully designed and developed a novel selective estrogen receptor degrader (SERD) called OBHSA, which specifically targets and degrades ERα, demonstrating remarkable efficacy. Our findings revealed the effectiveness of OBHSA in inhibiting the proliferation of various BC cells, including both tamoxifen-sensitive and tamoxifen-resistant BC cells, indicating its great potential to overcome endocrine resistance. In terms of mechanism, we discovered that OBHSA overcame tamoxifen resistance through two distinct pathways. Firstly, OBHSA degraded cyclin D1 in an ERα-dependent manner, thereby blocking the cell cycle. Secondly, OBHSA induced an elevation in intracellular reactive oxygen species, triggering an excessive activation of the unfolded protein response (UPR) and ultimately leading to apoptotic cell death. In summary, our finding demonstrated that OBHSA exerts anti-tumor effects by inducing cell cycle arrest and UPR-mediated apoptosis. These findings hold promise for the development of novel therapeutic drugs targeting endocrine-resistant BC.

乳腺癌(BC)是一种高度异质性肿瘤,已超过肺癌成为女性最常确诊的癌症。在临床实践中,治疗雌激素受体α(ERα)阳性乳腺癌的主要方法是内分泌治疗,包括使用他莫昔芬和氟维司群等药物靶向ERα。然而,新发或获得性耐药性问题给临床治疗带来了巨大挑战,强调了开发新型治疗策略的迫切需要。在这方面,我们成功设计并开发了一种名为OBHSA的新型选择性雌激素受体降解剂(SERD),它能特异性地靶向并降解ERα,显示出显著的疗效。我们的研究结果表明,OBHSA能有效抑制多种BC细胞的增殖,包括他莫昔芬敏感和他莫昔芬耐药的BC细胞,这表明它在克服内分泌耐药方面具有巨大潜力。在机制方面,我们发现OBHSA通过两种不同的途径克服他莫昔芬耐药性。首先,OBHSA以ERα依赖的方式降解细胞周期蛋白D1,从而阻断细胞周期。其次,OBHSA 诱导细胞内活性氧的升高,引发未折叠蛋白反应(UPR)的过度激活,最终导致细胞凋亡。总之,我们的研究结果表明,OBHSA 通过诱导细胞周期停滞和 UPR 介导的细胞凋亡发挥抗肿瘤作用。这些研究结果为开发针对内分泌耐药 BC 的新型治疗药物带来了希望。
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引用次数: 0
In memory of V. Craig Jordan (1947–2024): “Father of tamoxifen” and discoverer of SERMs 纪念 V. Craig Jordan(1947-2024 年):"他莫昔芬之父 "和 SERMs 的发现者。
IF 2.7 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-10 DOI: 10.1016/j.jsbmb.2024.106598
Philipp Y. Maximov
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引用次数: 0
期刊
Journal of Steroid Biochemistry and Molecular Biology
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