Frontiers in Cell and Developmental Biology
·
2026
·
IF 5.3
Yuanjie Sun,Haosheng Lin,Wenqian Zhu,Liuchang Niu,Yilin Li,Yuan Huang,Qingxian Chang
Background/Objective Early-onset fetal growth restriction (FGR) is a severe pregnancy complication caused by placental dysfunction. Although superficial trophoblast invasion and sterile inflammation are recognized as characteristics, the specific cellular driving factors and molecular mechanisms that lead to the dysregulation of the immune-trophoblast microenvironment remain unclear. Methods We constructed a high-resolution single-nucleus transcriptomic (snRNA-seq) atlas of placental tissues from patients with early-onset FGR and their matched normal controls. By integrating bioinformatics methods, such as pseudotime trajectory inference, gene regulatory network analysis (SCENIC), and intercellular communication modeling (CellChat), along with in vitro validation approaches, such as hypoxia-induced macrophage models, recombinant protein stimulation, and RT-qPCR, we identified specific changes associated with this disease. Results Our research revealed impaired differentiation trajectories of trophoblast cells, characterized by the absence of a critical intermediate state essential for acquiring invasiveness. At the same time, we identified a pathogenic Hofbauer cell subset (HBC5), which increases in number in FGR and exhibits high regulon activity of FOS and NFKB1. In vitro experiments have confirmed that hypoxia triggers the polarization of HBC5-like macrophages, leading to the upregulation of pro-inflammatory factors such as CCL4. Furthermore, the CellChat analysis combined with functional validation indicates that the CCL4 produced by HBC5 significantly induces mitochondrial stress markers GDF15 and APP in trophoblast cells, resulting in dysregulation of the placental microenvironment. Mechanistically, unlike physiological HBC that provide trophic support, HBC5 shows impaired secretion of IGF1, and implements dual blockade of inflammation and metabolism on Extravillous Trophoblasts (EVT) and the vascular system through CCL chemokines and NAMPT signaling pathways. Moreover, we have elucidated a vicious cycle: trophoblast cells under stress conditions release danger signals such as GDF15 and APP, which may continuously maintain the pathogenic immune polarization state of HBC5, and polarized HBC5 in turn stimulates trophoblast cells. Conclusion Our study reveals that the HBC5 subset with high FOS/NFKB1 regulon activity acts as a key mediator of placental niche dysregulation. The identified HBC5-CCL4-Trophoblast stress axis provides a potential therapeutic target for early-onset FGR.
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2023
·Vol. 28
·期 1
·1-10
·
IF 4.2
Gu Shanshan,Lin Chen,Li Yanguo,Wei Zhengyu,cao Bing,Shen Zhisen,Deng Hongxia
Head and neck squamous carcinoma (HNSCC) is the seventh most common cancer worldwide. Targeted therapeutic drugs for HNSCC are still being explored. Among them, (S)-10-hydroxycamptothecin (10-HCPT), a specific inhibitor of TOP1, functions by DNA double-strand breaks that can inhibit DNA replication and trigger apoptotic cell death subsequently. Previous studies have reported that MLN4924 exerts potent anti-tumor effects by inhibiting cullin–RING ligases and causing substrate accumulation in a variety of cancers. Here, we show that MLN4924 effectively causes dose-dependent accumulation of topoisomerase I (TOP1) and blocks TOP1 ubiquitination. Importantly, neddylation inhibition with MLN4924 acts synergistically with 10-HCPT to suppress cell growth, migration and apoptosis in HNSCC cells. Mechanistically, transcriptome sequencing shows that the cytotoxic effects of the combination of MLN4924 and 10-HCPT may involve activation of the NFKB1 pathway. Taken together, our results suggest that combined treatment with MLN4924 and 10-HCPT may be an effective strategy in HNSCC.
研究领域:
肿瘤学
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分子生物学
·
癌症治疗
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DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 10
·2345
·
IF 4.2
Lingna Xie,Congwei Ma,Xinyu Li,Huixiong Chen,Ping Han,Li Lin,Weiqiang Huang,Menglu Xu,Hailiang Lu,Zhiyun Du
Glycyrrhetinic acid (GA) is a saponin compound, isolated from licorice (Glycyrrhiza glabra), which has been wildly explored for its intriguing pharmacological and medicinal effects. GA is a triterpenoid glycoside displaying an array of pharmacological and biological activities, including anti-inflammatory, anti-bacterial, antiviral and antioxidative properties. In this study, we investigated the underlying mechanisms of GA on acne vulgaris through network pharmacology and proteomics. After the intersection of the 154 drug targets and 581 disease targets, 37 therapeutic targets for GA against acne were obtained. A protein–protein interaction (PPI) network analysis highlighted TNF, IL1B, IL6, ESR1, PPARG, NFKB1, STAT3 and TLR4 as key targets of GA against acne, which is further verified by molecular docking. The experimental results showed that GA inhibited lipid synthesis in vitro and in vivo, improved the histopathological damage of skin, prevented mast cell infiltration and decreased the level of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6. This study indicates that GA may regulate multiple pathways to improve acne symptoms, and the beneficial effects of GA against acne vulgaris might be through the regulation of sebogenesis and inflammatory responses.
研究领域:
药理学
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皮肤科
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分子生物学
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生物信息学
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PubMed
高影响因子
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