Experimental and Therapeutic Medicine
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2022
·Vol. 24
·期 1
·1-11
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IF 2.751
Lingyun Zhang,Shan Zhang,Fangrong Chen
Proteasome 26S subunit, non-ATPase 14 (PSMD14) expression has been previously reported to be reduced in patients with pre-eclampsia (PE). The present study investigated the interaction network associated with the role of PSMD14 in PE. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to determine the transfection efficacy following plasmid-based gene transfer of PSMD14 into HTR-8/SVneo cells. Cell proliferation was measured using an MTT assay and 5-ethynyl-2'-deoxyuridine staining. The expression of proliferation-related proteins, including Ki67 and PCNA, was determined using western blotting. Wound healing and Transwell assays were performed to measure cell invasion and migration, whilst the expression of migration-related proteins, including MMP2 and MMP9, was measured using western blotting. The angiogenesis of HUVECs following treatment with the HTR-8/SVneo cell culture supernatant was examined using tube formation assay. Following overexpression of Hes-related family BHLH transcription factor with YRPW motif 1 (HEY1) by transfection of pcDNA3.1 expression vector containing full-length human HEY1 or knockdown by transfection of shRNA plasmids targeting HEY1, the expression of HEY1 and PSMD14 was detected using RT-qPCR and western blotting. The potential interaction between HEY1 and the PSMD14 promoter was examined using dual-luciferase reporter and chromatin immunoprecipitation assays. PSMD14 overexpression was found to promote the proliferation, invasion, migration of HTR-8/SVneo cells and the angiogenesis of HUVECs following treatment with the HTR-8/SVneo cell culture supernatant, accompanied by enhanced expression of proliferation and migration-related proteins. Furthermore, the transcription factor HEY1 activated the expression of PSMD14. Knocking down HEY1 expression partially reversed the promoting effects of PSMD14 overexpression on the proliferation, invasion, migration, angiogenesis, proliferation and migration-related protein expression in trophoblasts. In conclusion, HEY1-activated PSMD14 promoted trophoblast proliferation, invasion and angiogenesis. Therefore, HEY1 and PSMD14 can be potential targets for PE treatment.
研究领域:
分子生物学
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细胞生物学
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妇产科学
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妇科
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高影响因子
Biomaterials Advances
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2026
·
IF 6.7
Yong Zheng,Yong Tao,Fuqiang Tan,Keyi Feng,Fei Xie,Shasha Shi,Yunsheng Ou
In vitro : CPP reduced 143B cell viability by ~50% at 30 µg/mL with low toxicity to normal osteoblasts. • In vivo : CPP reduced xenograft tumor volume by ~80% and showed good biosafety in histology and serum tests. • Mechanism: CPP induced ROS accumulation, GSH depletion, SLC7A11/GPX4 downregulation, and ferroptotic mitochondrial damage. Ferroptosis induction represents a promising antitumor strategy, yet osteosarcoma cells frequently resist ferroptosis through the PSMD14-mediated stabilization of SLC7A11. Here, we report an acid-responsive cobalt-doped ZIF-8 nanoplatform loaded with 1, 10-phenanthroline and coated with PEG (denoted as CPP) that simultaneously amplifies oxidative stress and dismantles the PSMD14/SLC7A11 antioxidant axis. Upon exposure to the acidic tumor microenvironment, the ZIF-8 framework degrades, releasing Co 2+ ions that catalyze Fenton-like reactions to generate hydroxyl radicals (•OH) and initiate lipid peroxidation. Concurrently, 1, 10-phenanthroline chelates the catalytic Zn 2+ of PSMD14, abolishing its deubiquitinase activity and thereby promoting ubiquitin-dependent degradation of SLC7A11, which depletes intracellular glutathione (GSH). Physicochemical characterization confirmed the successful construction of CPP nanoparticles (~100 nm) with a drug loading efficiency of 14.76% and pH-triggered Co 2+ release. In vitro , CPP was efficiently internalized by 143B osteosarcoma cells and exhibited dose-dependent cytotoxicity with markedly elevated reactive oxygen species (ROS), malondialdehyde (MDA) accumulation, lipid peroxidation, mitochondrial depolarization, and downregulation of SLC7A11 and GPX4, collectively supporting ferroptosis. CPP also significantly suppressed osteosarcoma cell invasion. In a subcutaneous 143B xenograft model, intravenous CPP administration reduced tumor volume by approximately 80% relative to controls, with pronounced tumor necrosis, proliferation inhibition, and decreased SLC7A11/GPX4 expression in tumor tissues, while maintaining favorable biosafety. These findings establish CPP as a dual-action nanoplatform for ferroptosis-based osteosarcoma therapy.
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高影响因子
RSC Chemical Biology
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2026
·
IF 3.9
Zheng Chu,Liting Xu,Honglin Chen,Tianyun Fan,Xueqian Hu,Yin Kwan Wong,Qiaoli Shi,Junzhe Zhang,Chengchao Xu,Jigang Wang,Huan Tang
Treatment of acute promyelocytic leukemia (APL) remains challenged by toxicities associated with current regimens, highlighting the need for novel and safer therapeutic agents. Here, we identify Eupalinolide B (EB), a natural sesquiterpene lactone isolated from Eupatorium lindleyanum DC., as a potent anti-leukemic compound targeting the human APL-derived HL-60 cell line. Through integrated chemoproteomic profiling and functional validation, we demonstrate that EB covalently binds and inhibits 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a deubiquitinase enzyme (DUB) within the 19S proteasome regulatory particle. This inhibition disrupts PSMD14-mediated stabilization of key oncoproteins RAC-alpha serine/threonine-protein kinase 1 (AKT1) and cyclin-dependent kinase 4 (CDK4), promoting their proteasomal degradation. As a result, EB induces G2/M cell cycle arrest and apoptosis in leukemia cells. Both genetic knockdown and pharmacological inhibition of PSMD14 recapitulate EB's effects, confirming its essential role in leukemia cell survival and proliferation. Collectively, these findings uncover a previously unrecognized PSMD14–AKT1/CDK4 regulatory axis in leukemia and position EB as a promising chemical probe and lead compound for the development of targeted covalent inhibitors against oncogenic DUBs.
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