TOXICOLOGY
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2025
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IF 4.6
Yu Zhang,Yanqing Geng,Yan Zhang,Yidan Ma,Xin Yin,Zhuxiu Chen,Xinyi Mu,Rufei Gao,Xuemei Chen,Fangfang Li,Junlin He
Phthalates (PAEs) can impair trophoblast cell and subsequent placental development, adversely affecting pregnancy. The effects of dicyclohexyl phthalate (DCHP), the main PAE homologue in urban household dust, on trophoblast function and placental development are unknown. In this study, we investigated the effects and potential mechanisms of DCHP on trophoblast function and placental development by constructing in vitro trophoblast (10, 20, 30 μM) and in vivo mouse pregnancy (25, 50, 100 mg/kg bw) exposure models. We found that exposure to DCHP during pregnancy led to the accumulation of placental lipid droplets and foetal weight gain. Consistently, DCHP induced the uptake of fatty acids by HTR-8/SVneo cells, leading to intracellular lipid droplet accumulation and mitochondrial dysfunction while inhibiting cell migration and invasion. This suggests that metabolic processes can serve as important links for environmental pollutants to interfere with bodily functions. Knocking down N-myc Downstream-Regulated Gene 1 (NDRG1) can alleviate lipid metabolism abnormalities caused by DCHP exposure while restoring cell migration and invasion abilities. Further research has found that the enhanced transcriptional activity of PPARα:RXRα is an important molecular initiating event for the role of DCHP, which promotes the transcription of downstream target gene NDRG1 by binding to PPARα:RXRα. These findings fill the research gap regarding the effects and related mechanisms of DCHP exposure on the placenta, help explore prevention and treatment strategies for DCHP reproductive toxicity, and provide new insights into toxicological research on environmental pollutants.
研究领域:
毒理学
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生殖生物学
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分子生物学
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PubMed
高影响因子
ONCOGENE
·
2025
·
IF 7.3
Li Honghao,Wu Junfeng,Dai Hua,Li Jiaming,Bai Xiaoyan,Sun Yueli,Lin Jiaxin,Li Yangsi,Li Peng,Shi Lingchao,Wang Zhen,Tu Haiyan,Ke Ee
Indolent lung cancer is characterized by slow progression, and the patient may die of other causes before it becomes symptomatic. The increasing usage of lung cancer screening technologies has increased the detection of early-stage cancers, improved survival, and reduced mortality, but it also brings overdiagnosis or overtreatment for indolent lung cancer patients. In this study, we performed high-throughput whole-exome sequencing in lung adenocarcinoma (LUAD) patients with a tumor doubling time of more than 600 days (the indolent group) and another group with a tumor doubling time of less than 30 days (the aggressive group). We identified a novel germline variation in PDZRN4 , rs74955204 (p.G121E, c.362 G > A) in the indolent group. The rs74955204 variant resulted in upregulated PDZRN4 expression and was positively correlated with the survival of LUAD patients. We confirmed that overexpression of PDZRN4 inhibits the ubiquitylation of HIF-1A mediated by TRIM28, thus activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, restricting lung cancer cell growth in vitro and in vivo. With the EGFR L858R -driven lung cancer mouse model as an example, we found that PDZRN4 knockout promoted, whereas PDZRN4 overexpression suppressed LUAD growth in vivo. In addition, recombinant PDZRN4 or screened small molecules retinoic acid showed potent inhibitory effects on EGFR-driven LUAD growth and amelioration of osimertinib resistance. Overall, our findings suggest that targeted PDZRN4 is a potential therapeutic strategy for treating LUAD. Examination of PDZRN4 rs74955204 variant may be an effective approach for the early detection of indolent lung cancer and to avoid overdiagnosis. Graphical : Germline variation rs74955204 (p.G121E, c.362 G > A) in PDZRN4 significantly upregulated PDZRN4 expression and resulted in indolent growth of LUAD. Overexpressed PDZRN4 inhibits the ubiquitylation of HIF-1A by TRIM28, activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, thus restricting lung cancer cell growth.
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高影响因子
iScience
·
2026
·Vol. 29
·期 3
·
IF 4.5
Yong Chen,Yanchao Zhang,Shen Rui,Bo Dong,Xiangshan Xu,Yuanzhe Jin
Atherosclerosis (AS), a chronic inflammatory disorder initiated by vascular endothelial dysfunction (ED), is prominently triggered by hemodynamic low-shear stress (LSS). Interferon regulatory factor 6 (IRF6) is a transcription factor that regulates the inflammatory response following injury. In this work, the LSS-induced AS model was induced by the partial ligation of the left carotid artery in high-fat diet-fed ApoE −/− mice. After four weeks of feeding, AS mice exhibited higher IRF6 expression and more severe lesions than sham mice. IRF6 suppression alleviated ED, inflammatory response, and oxidative stress in LSS-induced AS mice. In LSS-treated human aortic endothelial cells (HAECs), IRF6 was also highly expressed. Inhibition of IRF6 reduced the expression of pro-inflammatory adhesion molecules and the adhesion of THP-1 cells to HAECs. Mechanistically, IRF6 transcriptionally upregulated NDRG1. NDRG1 upregulation reversed the beneficial effect of IRF6 knockdown. Overall, IRF6 induces ED through the transcriptional activation of NDRG1, aggravating LSS-mediated AS progression.
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高影响因子
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