ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
LiYao Ma,Xin Yin,Yan Zhang,Yidan Ma,Yanqing Geng,Xinyi Mu,Rufei Gao,Xuemei Chen,Junlin He
Cetylpyridinium chloride (CPC), a widely used surfactant, functions as an antimicrobial agent in pharmaceuticals and personal care products (PPCPs). However, its effect on the female reproductive system remains largely unknown. Herein, female mice were gavaged with 0.01, 0.1, or 1 mg CPC/kg body weight (bw)/d during adolescence. Results showed reduced body and ovarian weights, decreased primordial follicle numbers, and increased atretic follicles. Additionally, CPC disrupted serum hormone levels, reduced cell viability and proliferation, and increased apoptosis in granulosa cells. Transcriptomic analysis of primary granulosa cells revealed altered genes in homologous recombination (HR) repair pathway, including the downregulation of FOXM1 and the MRN complex. Further validation demonstrated decreased expression of HR repair components and increased DNA damage in both in vivo and in vitro . Mechanistically, CPC inhibited the FOXM1/CREBBP interaction and inhibited HR repair gene transcription, including MRE11 and NBS1 . Finally, FOXM1 overexpression partially reversed the detrimental effects of CPC on HR repair and cell proliferation. These results indicate that CPC-induced ovarian dysfunction during adolescence is mediated through FOXM1/CREBBP complex inhibition and homologous recombination repair impairment, potentially increasing the risk for the development of diminished ovarian reserve (DOR) and providing new experimental evidence to assess the reproductive toxicity effects of CPC.
研究领域:
生殖生物学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Chemical Information and Modeling
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2024
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IF 5.6
Xinpei Wang,Xu Chen,Zhidong Chen,Wanting Xu,Ruizhi Lai,Xiaohui Qiu,Zekai Zeng,Chenglin Wang,Zhe Wang,Junqing Wang
Despite recent success in the computational approaches of cyclic peptide design, current studies face challenges in modeling noncanonical amino acids and nonstandard cyclizations due to limited data. To address this challenge, we developed an integrated framework for the tailored design of stapled peptides (SPs) targeting the bromodomain of CREBBP (CREBBP-BrD). We introduce a powerful combination of anchored stapling and hierarchical molecular dynamics to design and optimize SPs by employing the MultiScale integrative conformational dynamics assessment (MSICDA) strategy, which involves an initial virtual screening of over 1.5 million SPs, followed by comprehensive simulations amounting to 154.54 μs across 5418 of instances. The MSICDA method provides a detailed and holistic stability view of peptide–protein interactions, systematically isolated optimized peptides and identified two leading candidates, DA#430 and DA#99409, characterized by their enhanced stability, optimized binding, and high affinity toward the CREBBP-BrD. In cell-free assays, DA#430 and DA#99409 exhibited 2- to 12-fold greater potency than inhibitor SGC-CBP30. Cell studies revealed higher peptide selectivity for cancerous versus normal cells over small molecules. DA#430 combined with (+)-JQ-1 showed promising synergistic effects. Our approach enables the identification of peptides with optimized binding, high affinity, and enhanced stability, leading to more precise and effective cyclic peptide design, thereby establishing MSICDA as a generalizable and transformative tool for uncovering novel targeted drug development in various therapeutic areas.
研究领域:
药学科学
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计算化学
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分子生物学
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癌症研究
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药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Environmental Sciences
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2024
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IF 5.9
Zhijin Zhang,Wentao Zhang,Huan Wang,Haotian Chen,Hong Wang,Yang Yu,Danjing Shen,Man Pi,Yang Wu,Ming Luo,Yanyan He,Shiyu Mao,Jiang Geng,Wei Li,Guangchun Wang,Changcheng Guo,Daqiang Yin,Xudong Yao
Epidemiological studies indicate that prostate cancer (PCa) is the second prevalent malignant tumor affecting men globally. Environmental pollution such as cigarette smoke is one of the important risk factors for the development of prostate cancer. However, as one of the main carcinogens in cigarette smoke, the role of benzo[a]pyrene (BaP) in prostate cancer is still unclear. The current study aimed to investgate the impacts of BaP exposure on the progression of PCa toward malignancy and the regulation of the immune microenvironment. We verified that BaP exposure can promote the proliferation, migration, and apoptosis of prostate cancer cells through in vitro experiments. We constructed a subcutaneous xenograft tumor model of BaP exposure mouse and found that can promote the proliferation of tumors in vivo . Organoids-driven by PCa patients showed higher growth rate under BaP exposure. Flow cytometric analysis demonstrated a remarkable decrease in CD4 + T and CD8 + T cell infiltration levels. Moreover, we identified four genes ( Mdm2, Ar, Foxo1, Crebbp ) were strongly associated with BaP exposure by combining mouse tumor RNA-seq and CTD database. Additionally, a nomogram integrating clinicopathological features was constructed to assess the prognosis of prostate cancer patients under BaP exposure. This study systematically proved that BaP exposure promotes malignant progression of PCa and suppresses the immune microenvironment, in which Mdm2, Ar, Foxo1, Crebbp may play a crucial role in inhibiting apoptosis. These findings offer novel insights into the mechanisms via which BaP exposure contributes to PCa development.
研究领域:
肿瘤学
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免疫学
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环境医学
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产品关联
DOI
高影响因子
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