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Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2137-2152页

作者： Tarik Zahr Vijay K.Boda Jian Ge Lexiang Yu Zhongzhi Wu Jianwen Que Wei Li Li Qiang Naomi Berrie Diabetes Center Columbia UniversityNew YorkNY 10032USA Department of Molecular Pharmacology and Therapeutics Columbia UniversityNew YorkNY 10032USA Department of Pharmaceutical Sciences College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA Drug Discovery Center College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA Division of Digestive and Liver Diseases Columbia UniversityNew YorkNY 10032USA Center for Human Development Columbia UniversityNew YorkNY 10027USA Department of Pathology and Cell Biology Columbia UniversityNew YorkNY 10032USA Department of Medicine Columbia UniversityNew YorkNY 10032USA

estrogen is imperative to mammalian reproductivity,metabolism,and ***,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain *** contrast,ERβis more broadly expressed in metabolic tissues and the ***,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERα***,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or *** of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in *** further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound ***,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

关键词： estrogen receptorβ Aging Metabolism Skin injury Muscle metabolism Small molecule conjugates Regeneration Adiposity

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ERβ-activated LINC01018 promotes endometriosis development by regulating the CDC25C/CDK1/CyclinB1 pathway

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Journal of Genetics and Genomics 2024年第6期51卷 617-629页

作者： Ruihui Lu Jingwen Zhu Xin Li Cheng Zeng Yan Huang Chao Peng Yingfang Zhou Qing Xue Department of Obstetrics and Gynecology Peking University First HospitalBeijing 100034China

Endometriosis refers to as an estrogen-dependent *** receptorβ(ERB),the main estrogen receptor subtype which is encoded by the estrogen receptor 2(ESR2)gene,can mediate the action of estrogen in *** selective estrogen receptor modulators can target the ERβ,they are not specific due to the wide distribution of ERβ.Recently,long noncoding RNAs have been implicated in ***,we aim to explore and validate the downstream regulatory mechanism of ERβ,and to investigate the potential role of long intergenic noncoding RNA 1018(LINC01018)as a nonhormonal treatment for *** study demonstrates that the expression levels of ESR2 and LINCo1018 are increased in ectopic endometrial tissues and reveals a significant positive correlation between the ESR2 and LINCo1018 ***,ERβdirectly binds to an estrogen response element located in the LINCO1018 promoter region and activates LINC01018 ***,ERβcan regulate the CDC25C/CDK1/CyclinB1 pathway and promote ectopic endometrial stromal cell proliferation via LINC01018 in *** with these findings,the knockdown of LINC01018 inhibits endometriotic lesion proliferation in *** summary,our study demonstrates that the ERβ/LINC01018/CDC25C/CDK1/CyclinB1 signaling axis regulates endometriosis progression.

关键词： estrogen receptorβ Long intergenic noncoding RNA 1018 (LINC01018) Endometriosis Cell cycle Proliferation

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Combined treatment with valproic acid and estrogen has neuroprotective effects in ovariectomized mice with Alzheimer’s disease

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Neural Regeneration Research 2021年第10期16卷 2078-2085页

作者： Yan-Zhen Li Yuan-Jie Liu Wei Zhang Shi-Fang Luo Xin Zhou Gui-Qiong He Chongqing Key Laboratory of Neurobiology Chongqing Medical UniversityChongqingChina Department of Anatomy Chongqing Medical UniversityChongqingChina Department of Galactophore Chongqing University Cancer HospitalChongqingChina

Postmenopausal women with Alzheimer’s disease exhibit dramatically reduced sensitivity to estrogen replacement therapy,which is though to be related to an estrogen receptor(ER)α/ERβratio imbalance arising from a significantly decreased level of ERs of the *** aim of our study was to investigate whether valproic acid(VPA)can enhance the beneficial effects of estrogen on cognitive function through restoration of ERαand ERβexpression in the *** removed the ovaries of female APP/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA(30 mg/kg,intraperitoneal injection,once daily),17β-estradiol(E2)(2.4μg,intraperitoneal injection,once daily),liquiritigenin(LG)(50μg/kg,intragastric infusion,once daily),VPA+E2,or VPA+LG for 4 successive *** with treatment with a single drug,treatment with VPA+E2 or VPA+LG significantly increased the level of glycogen synthase kinase 3β,increased the expression of estrogen receptorα,reduced the expression of small ubiquitin-like modifiers,and increased the level of estrogen receptorβ.This resulted in enhanced sensitivity to estrogen therapy,reduced amyloidβaggregation,reduced abnormal phosphorylation of the tau protein,reduced neuronal loss,increased dendritic spine and postsynaptic density,and significantly alleviated memory loss and learning impairment in Alzheimer’s *** study was approved by the Chongqing Medical University Animal Protection and Ethics Committee,China on March 6,2013.

关键词： 17β-estradiol amyloidβ dementia estrogen receptorα estrogen receptorβ glycogen synthase kinase-3β liquiritigenin menopause neuron loss tau

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Differentiation of Human Adipose-Derived Stem Cells into Endometrial Epithelial Cells

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Reproductive and Developmental Medicine 2020年第3期4卷 137-145页

作者： Fang Yang Wan-Lin Zhang Shu-Qiang Chen Hui-Jun Sun Jie Lu Xi-Feng Xiao Xiao-Hong Wang Department of Obstetrics and Gynecology Reproductive Medical CenterTangdu HospitalThe Fourth Military Medical UniversityXi’an 710038China

Objective:This study aimed to investigate the differentiation of human adipose-derived stem cells(hASCs)into endometrial epithelial cells(EECs)under certain induction conditions and to a further step provide a promising approach for ASCs in clinical practice to the treatment of severe intrauterine ***:Four groups of hASCs were separately cultured as follows:in Group 1,hASCs were cultured in a control medium(5%fetal bovine serum[FBS]+α-minimum Eagle’s medium[α-MEM]);in Group 2,hASCs were cultured in an induction medium(5%FBS+α-MEM+[1×10-7 mol/L 17β-estradiol]+10 ng/mL transforming growth factorβ1[TGF-β1]+10 ng/mL epidermal growth factor[EGF]+10 ng/mL platelet-derived growth factor BB[PDGF-BB]);in Group 3,hASCs and human endometrium cells(hEMCs)were cocultured in the control medium;and in Group 4,hASCs and hEMCs were cocultured in the induction ***:When cocultured with hEMCs,the morphology of hASCs became similar with EECs,and the addition of factors such as EGF,TGFβ,PDGF-BB,and 17β-estradiol promoted *** study,for the first time,demonstrated estrogen receptor(ER)αand ERβexpression in hASCs and preliminarily explored changes in ERα,ERβ,β-catenin,and H19 mRNA expression during hASC ***,we concluded that H19 mRNA expression was negatively correlated with differentiation,which is seemingly related to the estrogen signaling ***:hASCs revealed the potential for differentiating to EECs when cocultured with hEMCs.

关键词： Adipose-derived Stem Cell Endometrial Epithelial Cell estrogen receptorα estrogen receptorβ H19 β-catenin

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雌激素受体亚型、HER2、VEGF与子宫内膜异位症复发的相关性研究

雌激素受体亚型、HER2、VEGF与子宫内膜异位症复发的相关性研究

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作者：孙贤华青岛大学

学位级别：硕士

目的:探讨雌激素受体亚型、血管内皮生长因子及HER2的表达与子宫内膜异位症EMs复发的关系。方法:采用免疫组化PV-6000通用二步法检测79例子宫内膜异位症(EMs):其中复发15例,未复发64例患者以及10例卵巢单纯性囊肿患者病变组织中VEGF、ER... 详细信息

目的:探讨雌激素受体亚型、血管内皮生长因子及HER2的表达与子宫内膜异位症EMs复发的关系。方法:采用免疫组化PV-6000通用二步法检测79例子宫内膜异位症(EMs):其中复发15例,未复发64例患者以及10例卵巢单纯性囊肿患者病变组织中VEGF、ER-α、ER-β、及HER2的表达情况,同时结合患者临床病例记录及随访资料加以分析。结果:***在异位内膜的阳性表达率为79.75%,单纯性囊肿中阳性表达率为10%,两者之间差异显著(P＜0.01)。2.异位内膜组织与单纯性囊肿组织中ER-α的阳性表达率分别为45.57%和30%,差异无统计学意义(P＞0.05)。3.异位内膜组织ER-β的阳性表达率(49.36%)高于单纯性囊肿(20%),两者之间差异无显著意义(P＞0.05)。***2蛋白在异位内膜组织及单纯性囊肿中均无表达。5.复发组异位内膜组织VEGF与未复发组异位内膜组织VEGF的阳性表达率分别为86.67%和78.12%,两者之间差异无统计学意义(P＞0.05)。但复发组VEGF的高表达率却明显高于未复发组,差异显著(P＜0.05)。6.异位内膜ERα高表达者其VEGF表达率亦相应较高,ERα低表达者其VEGF表达率亦相应较低(r=0.54,P＜0.01);ERβ与VEGF的表达却无此趋势(r=0.35,P＞0.05)。***α在复发组较未复发组异位内膜组织中的阳性表达率高,但无统计学意义(P＞0.05);复发组异位内膜组织ER-α高表达率与未复发组异位内膜组织ER-α高表达率有差异但亦无统计学意义(P＞0.05)。8.复发组异位内膜组织ER-β与未复发组异位内膜组织ER-β的阳性率虽有差异但无统计学意义(P＞0.05);复发组异位内膜组织ER-β高表达率与未复发组异位内膜组织ER-β高表达率之间有差异但亦无统计学意义(P＞0.05)。结论:***在EMs发生、发展及复发中可能起重要作用,检测VEGF的表达对于估计内异症的复发可能有重要临床意义。2.雌激素受体亚型ER-α、ER-β可能与EMs异位内膜血管的生成有关,可能参与了异位内膜血管生成的调节过程,其中ER-α可能在异位内膜血管生成的调节中发挥了重要作用。3.雌激素受体亚型ER-α、ER-β在子宫内膜异位症发生发展的病理过程中发挥重要作用,但可能与子宫内膜异位症复发与否的关系不大。***2可能不参与EMs异位内膜血管生成的调节及其发生发展的病理过程。与子宫内膜症复发亦无关联。

关键词：子宫内膜异位症免疫组织化学 estrogen receptorα estrogen receptorβ HER2 预后

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