JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
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2025
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IF 2.5
Yu Pan,Rui Li,Huanhuan Ma,Xiaolei Hu,Jun Zhao,Juanjuan Qiao,Xiyao Dou,Yanan Wang,Yanzhi Zhang,Xiuli Wang,Lin Wang
Expression of the critical pyroptosis protein gasdermin E (GSDME) has been reported to be regulated by DNA methylation and negatively correlated with expression of estrogen receptor (ER) in breast cancer tissues, suggesting that estrogen-induced target gene methylation may be involved in the regulation of GSDME expression in breast cancer cells. To test this hypothesis, we treated MCF-7 and T47D ER-positive breast cancer cells with 17-β-estradiol (E 2 ), either alone or in combination with selective ERα antagonist AZD9496, selective ERβ antagonist PHTPP, DNA methyltransferase (DNMT) inhibitor RG108, and selective ER degrader Fulvestrant (Ful). Then, GSDME protein and mRNA expression were examined with western blot and RT-qPCR. Pyroptosis was induced by short-wave ultraviolet (UV-C) and detected with morphological observation, lactate dehydrogenase (LDH) release assay, and propidium iodide-Annexin V-FITC fluorescence staining. The methylation status of the GSDME promoter was tested with methylation-specific PCR. The results demonstrated that 100 nM E 2 significantly decreased GSDME protein and mRNA expression in MCF-7 and T47D cells, and significantly inhibited UV-C-induced pyroptosis. AZD9496 but not PHTPP significantly attenuated the down-regulatory effect of E 2 on GSDME expression. E 2 induced DNA methylation in the GSDME promoter region and up-regulated DNMT1 expression. RG108 strengthened UV-C-induced pyroptosis, and Ful reversed the inhibitory effects of E 2 on UV-C-induced pyroptosis of MCF-7 and T47D cells . Taken together, our study suggests that E 2 down-regulated GSDME expression in ERα-positive breast cancer by promoting GSDME promoter methylation, and inhibited UV-C-induced pyroptosis.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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细胞死亡研究
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Yongyan Chen,Xu Han,Yuxuan Hao,Xu Wang,Fupeng Wu,Sheng Tan,Huijing Ye,Yang Hong,Xiaoyan Shen
Background Vascular calcification is a major cause of death in chronic kidney disease (CKD), with osteoblastic transdifferentiation of vascular smooth muscle cells (VSMCs) considered to be the crucial pathologic process. However, there remains a significant deficiency in effective prevention and treatment strategies. Purpose In an in vitro calcification screening model, we observed an inhibitory activity of Emodin on osteoblastic transdifferentiation of VSMCs. In the present study, we therefore aimed to evaluate its efficacy in CKD-induced medial vascular calcification in vitro and in vivo, and to further explore the underlying mechanisms. Study design A7R5 and MOVAS cells were treated with sodium phosphate to induce osteogenic transdifferentiation as in vitro models, while mice were fed with adenine and a high-phosphorus diet, and additionally received an intraperitoneal injection of 10,000 IU Vitamin D3 to induce chronic kidney disease (CKD) as an in vivo model. Vitamin K2 served as a positive control. Methods Alizarin Red S staining and VON-KOSSA staining were used to evaluate the effects of Emodin on osteogenic transdifferentiation. Western blotting, RT-qPCR and Von-Kossa staining were used to detect the effects of Emodin on aortic calcification in CKD mice in vivo. Chemical biology techniques including ITC, fluorescence titration, dual fluorescein reporter genes, CETSA, and DARTS, were used to detect the binding activity of Emodin to ERα and SYVN1. Immunoprecipitation, immunostaining, etc. were used to explore the mechanisms, and small molecule inhibitors and small RNA interference were used to verify the target of Emodin. Results Emodin could effectively inhibit the osteogenic transdifferentiation of A7R5 and MOVAS cells in vitro, and alleviate aortic calcification in CKD mice in vivo. Mechanism study revealed that Emodin could act as a molecular glue that binds directly to ERα and SYVN1 and enhances their interaction, thereby accelerating the ubiquitination degradation process of ERα. The decrease in ERα diminished the inhibition of ERα on the deacetylation of HIF-1α by SIRT6, thereby inhibiting VSMC osteogenic transdifferentiation and relieving the vascular cells calcification. Conclusion Our study demonstrates that ERα has a non-genomic effect to inhibit the deacetylation of HIF-1α by SIRT6, which can be abrogated by Emodin through SYVN1-mediated ERα degradation. These results provide evidences for Emodin to serve as a candidate drug for controlling clinical vascular calcification in CKD.
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Yuan Liu,Jingjing Bu,Jiahui Wang,Yufang Zhao,Shuaijun Peng,Liming Liu,Pan Su,Ming Bai,Jiduo Shen,Erping Xu,Yucheng Li
Depression is frequently accompanied by myelin damage in the prefrontal cortex (PFC), and promoting remyelination may alleviate depressive symptoms. This study investigated the antidepressant mechanism of formononetin (FMN), a natural isoflavone phytoestrogen, in a corticosterone (CORT)-induced depression mouse model. FMN significantly improved depression-like behaviors and alleviated demyelination in the PFC. Proteomic analysis suggested the involvement of estrogen signaling in the antidepressant effects of FMN. Molecular docking, target capture, drug affinity responsive target stability (DARTS), and surface plasmon resonance (SPR) identified estrogen receptor alpha (ERα) as a direct target of FMN. FMN promoted ERα nuclear translocation and upregulated myelin basic protein (MBP). Edu assays indicated that FMN promoted oligodendrocyte precursor cells (OPCs) differentiation without affecting cell proliferation. Notably, its pro-differentiation effects were abolished by the ERα antagonist methylpiperidino pyrazole (MPP). Moreover, FMN did not induce proliferation or metastasis in breast cancer cells or promote tumor growth in vivo. These findings support FMN as a promising and safe therapeutic candidate for depression by targeting ERα to promote remyelination.
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DOI
PubMed
高影响因子
Journal of Natural Medicines
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2023
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IF 3.3
He Dongjie,Song Yanli,Xiao Huidongzi,Shi Shaoqi,Song Hongyan,Cui Tianwei,Ni Tingting,Wang Jing,Ren Xingxing,Wei Aiwu
Ligustilide (LIG) is the main active ingredient of Angelica sinensis (Oliv.) Diels, which could promote focal angiogenesis to exert neuroprotection. However, there was no report that verified the exact effects of LIG on endometrial angiogenesis and the pregnancy outcomes. To explore the effects of LIG on low endometrial receptivity (LER) and angiogenesis, pregnancy rats were assigned into Control (saline treatment), LER (hydroxyurea-adrenaline treatment), LIG 20 mg/kg and LIG 40 mg/kg groups. Hematoxylin and eosin (H&E) staining was performed to evaluate endometrial morphology. Quantitative real-time PCR, immunofluorescence staining, western blot and immunohistochemistry staining were employed to assess the expression of endometrial receptivity factors and angiogenesis-related gene/protein, respectively. RNA sequencing was used to analyze the effects of LIG on LER caused by Kidney deficiency and blood stasis. We found that endometrial thickness and the implanted embryo number were substantially reduced in the hydroxyurea-adrenaline-treated pregnancy rats. At the same time, the gene and protein expressions of ERα, LIF, VEGFA and CD31 in the endometrium were markedly reduced, while the expressions of MUC1, E-cadherin were increased in the LER group. Administration of LIG raised the endometrial thickness and implanted embryos, as well as reversed the expressions of these factors. Collectively, our findings revealed that LIG could facilitate embryo implantation via recovery of the endometrium receptivity and promotion of endometrial angiogenesis.
研究领域:
药理学
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生殖生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ChemMedChem
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2016
·Vol. 12
·期 3
·235-249
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IF 2.98
Silong Zhang,Zhiyong Wang,Zhiye Hu,Changhao Li,Chu Tang,Kathryn E. Carlson,Junjie Luo,Chune Dong,John A. Katzenellenbogen,Jian Huang,Hai-Bing Zhou
Graphical Add a new element ! This is the first report of selenophene-core compounds as estrogen receptor (ER) ligands. In transcription assays, several selenophenes were profiled as superagonists for ERα; moreover, a few selenophenes exhibited antiproliferative activity similar to that of 4-hydroxytamoxifen in MCF-7 breast cancer cells while being nontoxic toward normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the ER. The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure–activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene ( 2 f ) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene ( 2 b ), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene ( 6 f ), and 2,3,5-tris(hydroxyphenyl)thiophenes ( 8 b and 8 d ) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor.
研究领域:
药理学
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化学
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癌症研究
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分子生物学
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DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
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2023
·Vol. 30
·期 5
·1260-1278
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IF 12.4
Sun Ge,Wei Yuntao,Zhou Baosheng,Wang Manlin,Luan Ruina,Bai Yu,Li Hao,Wang Shan,Zheng Dantong,Wang Chunyu,Wang Shengli,Zeng Kai,Liu Shuchang,Lin Lin,He Mingcong,Zhang Qiang,Zhao Yue
The estrogen receptor alpha (ERα) signaling pathway is a crucial target for ERα-positive breast cancer therapeutic strategies. Co-regulators and other transcription factors cooperate for effective ERα-related enhancer activation. Recent studies demonstrate that the transcription factor CTCF is essential to participate in ERα/E2-induced enhancer transactivation. However, the mechanism of how CTCF is achieved remains unknown. Here, we provided evidence that BAP18 is required for CTCF recruitment on ERα-enriched enhancers, facilitating CTCF-mediated chromatin accessibility to promote enhancer RNAs transcription. Consistently, GRO-seq demonstrates that the enhancer activity is positively correlated with BAP18 enrichment. Furthermore, BAP18 interacts with SMARCA1/BPTF to accelerate the recruitment of CTCF to ERα-related enhancers. Interestingly, BAP18 is involved in chromatin accessibility within enhancer regions, thereby increasing enhancer transactivation and enhancer-promoter looping. BAP18 depletion increases the sensitivity of anti-estrogen and anti-enhancer treatment in MCF7 cells. Collectively, our study indicates that BAP18 coordinates with CTCF to enlarge the transactivation of ERα-related enhancers, providing a better understanding of BAP18/CTCF coupling chromatin remodeling and E-P looping in the regulation of enhancer transcription.
研究领域:
癌症生物学
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分子生物学
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转录调控
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染色质结构
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2020
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IF 9.038
Naima Hamid,Muhammad Junaid,Rakia Manzoor,Pan-Pan Jia,De-Sheng Pei
Phthalate esters (PAEs) pose prominent ecological risks owing to their multiplex toxicity potentials and ubiquitous detection in the environment. Therefore, this study aims to prioritize the individual and mixtures of six PAEs based on their toxicological implications using in vitro and vivo models exposed at environmentally relevant concentrations. Results were further confirmed using in silico Combination index (CI) and Independent action (IA), and molecular docking models. Among PAEs, DEHP revealed prominent in vitro/vivo toxicity followed by DEP, DBP, and DMP. Importantly, binary mixtures particularly C2-C6 and C11-C15 exhibited greater developmental toxicity, apoptosis, and perturbed the HPG pathway. The CI and IA models forecasted antagonistic and additive effects at Fa = 0.5 and Fa = 0.9 using in vitro Acinetobacter sp. Tox2. Conversely, in zebrafish, the IA model predicted mixture effects in the following order: additive > synergistic > antagonistic on the regulation of the HPG pathway, which was consistent with experimental results from Acridine Orange (AO) staining and apoptosis gene expression. Molecular docking for estrogen receptors (ERα, ERβ) revealed the highest binding energy scores for DEHP, compared to other PAEs. In short, our findings confirm that individual and mixtures of PAEs behave as xenoestrogens in the freshwater ecosystem with DEHP as a priority compound.
研究领域:
环境毒理学
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计算生物学
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分子生物学
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水生生态学
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DOI
PubMed
高影响因子
Inorganic Chemistry Frontiers
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2022
·Vol. 9
·期 14
·3470-3483
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IF 7.779
Xiao-Meng Liu,Zhe Li,Xin-Rui He,Rui-Ping Liu,Zhong-Ying Ma,Xin Qiao,Shu-Qing Wang,Jing-Yuan Xu
The combination of endocrine therapy and chemotherapy is an attractive approach for treating breast cancers. Aromatase inhibitors (AIs) are the first-line drugs for postmenopausal ER-positive breast cancer and adjuvant therapy drugs for early stages of breast cancer. In this paper, we employed the FDA-approved aromatase inhibitor aminoglutethimide (AG) to design and prepare a new class of multi-targeting Pt(IV) prodrugs (aminoplatins 1–3) by utilizing the targeting, estrogen-manipulating, and chemo-sensitizing effects of the aromatase inhibitor. Aminoplatin 3, as a representative, exhibited an enhanced anticancer activity up to 190-fold greater than the parent Pt(II) drug cisplatin, and 3 had less toxicity to normal cells, displaying higher anticancer efficacy and a superior therapeutic index compared to those of cisplatin. Moreover, aminoplatin 3 could enhance intracellular accumulation, induce remarkable DNA damage, inhibit migration and metastasis, and result in S phase cell cycle arrest and apoptosis in ER-positive MCF-7 cells. Besides, molecular docking results showed that 3 simultaneously occupies the heme iron-binding domain and the ASD-binding site of aromatase by a highly efficient dual-binding pattern to aromatase, which further displayed a striking anti-estrogenic effect by significant downregulation of CPY19A1 and ERα in ER-positive MCF-7 cells. Most strikingly, our in vivo anticancer evaluation data also provided evidence that 3 effectively inhibited tumor growth and attenuated kidney toxicity compared to cisplatin in MCF-7 xenografted BALB/c nude mice. Our results suggest that the anticancer activity of aminoplatins is mechanistically distinct from that of the conventional platinum drugs, and modifying platinum drugs with aromatase inhibitors may represent an improved modality for the treatment of advanced postmenopausal breast cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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DOI
高影响因子
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