MOLECULAR MEDICINE
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2025
·Vol. 31
·期 1
·1-15
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IF 6.4
Pei Lipeng,Zhu Yan,Li Wenpeng,Xu Bin,Sun Jingli
Background Uterine corpus endometrial carcinoma (UCEC) is one of the most frequent female genital malignant tumors. Targeting DNA damage and cell apoptosis are regarded as effective ways for UCEC therapy. Celastrol is a natural anti-cancer product from the Celastraceae plant family, while its role in UCEC has not been investigated. Methods UCEC cell lines Ishikawa and HEC-1-A were applied and treated with different concentrations of Celastrol. The appropriate and nontoxic concentrations were used for the subsequent experiments. Functional experiments analyzed the cell viability, cell cycle distribution, DNA damage, apoptosis and the expression of related proteins. We determined tumor growth in xenograft nude mice. Bioinformatic analysis, protein coimmunoprecipitation (Co-IP), luciferase assay, cell experiments were performed to reveal the relationship of Celastrol/KAT2B/RBPJ/MCM4 in UCEC. Results Treatment of Celastrol inhibited cell viability in a dose-dependent manner, and caused cell cycle arrest, accompanied by the downregulation of CDK2 and cyclin E expression and the upregulation of p21. Celastrol treatment resulted DNA damage and apoptosis in cultured cells, as demonstrated by increased number of TUNEL-positive cells, activity of caspase-3 and expression of cleaved-caspase-9, cleaved PARP1 and γ-H2AX. In xenograft nude mice, Celastrol also repressed tumor growth. Furthermore, lysine acetyltransferase KAT2B was a putative target of Celastrol, and its expression was upregulated by Celastrol in vitro and in vivo. Overexpression of KAT2B in UCEC inhibited cell proliferation and increased DNA damage and apoptosis. KAT2B knockdown overcame the anti-proliferative and pro-apoptotic roles of Celastrol. Moreover, Co-IP demonstrated that KAT2B bound to RBPJ, a transcriptional repressor, and increased the acetylation of RBPJ. RBPJ could bind to the MCM4 promoter to suppress the luciferase activity. Further functional analysis revealed that the functions of KAT2B in UCEC cell proliferation, DNA damage and apoptosis were mediated by MCM4, and Celastrol enhanced RBPJ acetylation and reduced MCM4 expression. Conclusions These results underscore that Celastrol is a promising anti-cancer agent in UCEC with preferential anti-proliferative, pro-apoptotic and DNA damage effects through the KAT2B/RBPJ/MCM4 axis, and KAT2B is a promising therapeutic target for UCEC. Graphical abstract
研究领域:
肿瘤学
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分子生物学
·
细胞生物学
·
药理学
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Mei Feng,Xin Yang,Kuo Yao,Ke-Fan Yang,Xiang-Yi Zhan,Ming-Sheng Zhou,Hui Jia
Background and Purpose Previous studies have found that activation of the γ-secretase/NICD-PXR/Notch pathway can induce Taxol resistance in triple-negative breast cancer (TNBC) to limit its therapeutic effect. Accordingly, inhibition of the γ-secretase/Notch pathway maybe an effective strategy to enhance Taxol chemosensitivity in TNBC. We have already found that cimigenoside (CG), the active ingredient of Cimicifuga dahurica (Turcz.) Maxim, can inhibit γ-secretase activity. Experimental Approach The dynamic interaction between the natural γ-secretase inhibitor CG and γ-secretase catalytic core presenilin-1 (PSEN-1) was revealed by molecular dynamics simulations and in vitro enzyme activity experiments. The biological characterisation and in vivo role of CG in increasing Taxol sensitivity of TNBC were investigated. The regulatory effect of CG on the γ-secretase/RBPJ-PXR axis was studied through dual luciferase reporter gene assays, nuclear cytoplasmic separation experiments, and western blot assays. Key Results CG stably binds to the PSEN-1 protein cavity to inhibit γ-secretase activity. In vitro studies showed that CG significantly enhanced the inhibition of cell proliferation, migration and invasion, as well as the promotion of apoptosis of MDA-MB-231/Taxol cells by Taxol. CG enhanced the inhibitory effect of Taxol on subcutaneous tumours and lung metastatic TNBC in vivo. Mechanistically, CG inhibited the transcriptional activity of RBPJ by targeting γ-secretase, interfered with the interaction between RBPJ and pregnane X receptor (PXR), down-regulated the expression of PXR-regulated metabolic enzymes and transport proteins, and enhanced the sensitivity of TNBC to Taxol. Conclusions and Implications We show that CG enhances the chemical sensitivity of TNBC by regulating the γ-secretase/RBPJ-PXR axis. Graphical
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高影响因子
POULTRY SCIENCE
·
2026
·
IF 4.5
Yuling Niu,Yujie Zhang,Chunmei Fa,Xintong Qian,Zhijun Wang,Xiaolong Zhou,Hui Yu,Ayong Zhao,Xue Du
The recombinant signal binding protein for immunoglobulin kappa J region (RBPJ) is the central effector of the Notch signaling pathway, which is a highly conserved pathway that regulates developmental and differentiation processes impacting tissue development, morphology, and function. The duck oviduct undergoes dramatic morphological and functional remodeling as laying egg or not, wherein fibroblasts play critical roles in extracellular matrix (ECM) remodeling and tissue homeostasis. However, the regulatory role of RBPJ in duck oviduct fibroblasts remains poorly understood. This study investigated the effects of RBPJ on the proliferation and molecular networks of duck fibroblasts using a RBPJ-overexpression model combined with RNA-seq and LC-MS/MS-based proteomic analysis. A RBPJ -overexpressing fibroblast model was successfully established. Compared to the control group (C), RBPJ overexpression (OE) significantly increased cell proliferation at 24 h ( P < 0.01), as verified by CCK-8 and EdU assays. RNA-seq identified 130 differentially expressed genes (DEGs; |log2(fold change) | ≥ 1, P < 0.05), with significant enrichment of the Cytoskeleton in muscle cells pathway. Proteomic analysis detected 569 differentially expressed proteins (DEPs; |Fold change| ≥1.5, P < 0.05), primarily enriched in ECM-receptor interaction. Integrated transcriptome-proteome analysis revealed 12 key molecules. Among which, EGF is well-documented regulators of cell proliferation; ACTN2 (Actinin alpha 2), MYPN (Myopalladin) and COL21A1 (Collagen type XXI alpha 6 chain) were significantly enriched in pathways including ECM–receptor interaction, Cytoskeleton in muscle cells, and Focal adhesion. Collectively, these results indicate that RBPJ promotes fibroblast proliferation and regulates structural modulating by EGF, ACTN2, MYPN and COL21A1 at both the transcriptional and protein levels. Tissue-level verification demonstrated that the mRNA and protein expression levels of RBPJ in the oviduct of laying ducks were significantly elevated compared to ceased laying ducks ( P < 0.05). Furthermore, the expression patterns of the 12 key DEGs in tissues aligned with the findings from cell study. This study provides novel molecular insights into RBPJ-mediated regulation of oviduct fibroblast function, offering a better understanding of duck oviduct remodeling during the laying cycle.
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