详细内容（全部5条）

1. GSE241488 抑制中链脂肪酸受体 GPR84 可增强 CD8 T 细胞的代谢、细胞毒性和抗肿瘤功能

• ✍️ 作者：未知作者
• 🏷️ 关键词：tumor、metabolism
• 📝 描述：Contributors : Phaethon Philbrook ; Matthew J Dean ; Liqin Zheng ; Jovanny Zabaleta ; Julio A Vázquez-Martínez ; Darwin Chang ; Jessica K Mandula ; Timothy I Shaw ; Dorota Wyczechowska ; Jone Garai ; Ramesh T Puttalingaiah ; Maria D Sanchez-Pino ; Satyajit Das ; Shiun Chang ; José R Conejo-Garcia ; Paulo C Rodriguez ; Augusto C OchoaSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusGPR84 is a medium-chain free fatty acid receptor predominately expressed on myeloid cells. Previous studies identified GPR84 as an enhancer of pro-inflammatory myeloid cell response and a regulator of metabolic homeostasis. However, the role of GPR84 on T cell function and metabolism remains wholly unexplored. This study tested the effect of GPR84 modulation on CD8+ T cell function and metabolism in vitro, and examined its effect on anti-tumor function in adoptive cellular therapy models. Inhibition of GPR84 with the antagonist GLPG1205 promoted CD8+ T cell differentiation, proliferation, cytokine production, and cytotoxicity. This effect was confirmed using CRISPR-Cas9 GPR84 deleted CD8+ T cells. In contrast, treatment with the GPR84 agonist DL175 inhibited proliferation, cytokine production and cytotoxicity. These functional changes were paralleled by changes in metabolic activity. GPR84 antagonist GLPG1205 increased glucose uptake, glycolysis, oxidative phosphorylation (OXPHOS) and ATP production, which enhanced the energetic fitness of CD8+ T cells. Furthermore, stimulation of antigen-specific CD8+ T cells with GPR84 antagonist in vitro, or deletion of GPR84 in antigen specific T cells before adoptive cellular therapy resulted in a significantly enhanced anti-tumor effect in vivo. This study is the first demonstration that GPR84 modulation in T cells can enable more effectively killing of tumor cells and reduce tumor growth, and opens a novel approach to significantly enhance the efficacy of adoptive cellular therapies including CAR-T, TIL or CAR-NK cells.
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2. GSE276884 研究发现，在严重的营养不良性心肌病模型中，炎症细胞含有高比例的T细胞，这些T细胞促进了病理的发生。

• ✍️ 作者：未知作者
• 🏷️ 关键词：inflammation
• 📝 描述：Contributors : Arden B Piepho ; Swathy Krishna ; Jill A Rafael-FortneySeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusDuchenne muscular dystrophy (DMD) is a severe neuromuscular disorder characterized by progressive muscle degeneration and cardiomyopathy leading to heart failure. While the inflammatory environment in dystrophic skeletal muscle has been well-studied, little is known about inflammation in the progression of DMD cardiomyopathy due to the lack of adequate animal models. To address this, we developed the Fiona/dko mouse model, which exhibits severe, isolated dystrophic cardiomyopathy. In this study, we used Fiona/dko mice to characterize the immune cell composition in dystrophic heart and investigated the contribution of T-cells to the onset and progression of cardiac pathology. Flow cytometry analysis revealed that T-cells constitute a significant proportion of the immune cell population in Fiona/dko hearts, in contrast to the predominantly myeloid signature observed in dystrophic skeletal muscle. Furthermore, we demonstrated that T-cell infiltration precedes the development of cardiac fibrosis and dysfunction in Fiona/dko mice and that depletion of circulating CD3+ T-cells ameliorates early pathology, suggesting a role for T-cells in the initiation and persistence of dystrophic cardiomyopathy. These findings highlight the distinct inflammatory environment in the dystrophic heart and provide new insights into the pathogenesis of DMD cardiomyopathy, paving the way for the development of targeted anti-inflammatory therapies.
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3. GSE314991 持续的 STING-IRF7 信号传导通过过度生成中性粒细胞胞外陷阱加剧 LPS 诱导的子宫内膜炎症

• ✍️ 作者：未知作者
• 🏷️ 关键词：inflammation
• 📝 描述：Contributors : Min Chu ; Ding Ma ; Zhan Song ; Li Liang ; Fengjuan Xing ; Hongchu BaoSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusThe stimulator of interferon genes (STING) is a central mediator of innate immune sensing and represents a critical regulator of chronic inflammation. Upon persistent infection, excessive neutrophil activation leads to the formation of neutrophil extracellular traps (NETs) that damage the tissues. However, the mechanism by which STING signaling regulates NETs formation under chronic inflammatory conditions remains poorly understood. In this study, using LPS-induced murine endometritis models in wild-type and STING-deficient mice, we demonstrated that STING deficiency significantly suppressed myeloperoxidase activity, and diminished NETs formation. We identified neutrophil surface molecular CD11b as a key downstream target of STING, whose expression was transcriptionally regulated via IRF7. Furthermore, the STING-IRF7 axis was found to drive lipocalin-2 (LCN2) expression, which acted through its receptor MC4R to upregulate intracellular adhesion molecule-1 (ICAM-1), thereby facilitating neutrophil recruitment and NETosis during LPS stimulation. The role of this pathway was validated both in vitro using isolated neutrophils and in vivo using Lcn2-/- mice. Moreover, STING deficiency reprogramed the endometrial immune microenvironment by reducing inflammatory infiltration and restoring receptivity transcription factor homeobox A10 (HOXA10). Our findings revealed a novel mechanism in which the STING-IRF7 pathway exacerbated endometrial inflammation and tissue damage by coordinately upregulating CD11b and activating the LCN2-ICAM-1 axis. Consequently, targeting the STING signaling pathway may offer a promising therapeutic strategy for chronic endometritis.
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4. GSE314956 靶向 mTORC2 依赖性 AKT/FOXO1/RNF125 信号通路利用 c-MET 激活和 β-catenin 突变肝细胞癌的治疗弱点 [SNU449]

• ✍️ 作者：未知作者
• 🏷️ 关键词：carcinoma
• 📝 描述：Contributors : Xue Wang ; Xin ChenSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensBackground and Aims: Approximately 10% of human hepatocellular carcinomas (HCC) exhibit concurrent c-MET activation and β-catenin gain-of-function mutations, representing a clinically relevant HCC subtype. This study aimed to investigate the role of mTORC2/AKT signaling in this subtype and identify potential therapeutic targets. Approach and Results: The mTORC2/AKT cascade was activated in c-Met/β-cateninΔ90 HCC lesions. Genetic ablation of Rictor, the essential mTORC2 subunit, strongly suppressed c-Met/β-cateninΔ90-dependent hepatocarcinogenesis. Mechanistically, both the TSC2/mTORC1 axis and FOXO1 transcription factors functioned as critical downstream effectors of mTORC2/AKT in this model. We further identified RNF125 as a direct transcriptional target of FOXO1. RNF125 overexpression significantly inhibited tumorigenesis in the c-Met/β-cateninΔ90 model and suppressed liver cancer cell growth in vitro. Notably, using an in vivo doxycycline-inducible system, we found that inducing RNF125 expression in established c-Met/β-cateninΔ90 HCC suppressed tumor progression, suggesting that activation of RNF125 may have translational implications for HCC treatment. Conclusions: Our study, for the first time, established the mTORC2/AKT/FOXO1/RNF125 axis as a critical driver and therapeutic vulnerability in c-MET-activated/β-catenin-mutated HCC. Our study filled a critical gap by defining the tumor-suppressive role of FOXO1 specifically in this HCC subtype. Furthermore, our results positioned RNF125 as a promising therapeutic target for this aggressive HCC subtype.
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5. GSE314666 从大戟属植物中发现的紫檀烷二萜类化合物是一种新型抗肝纤维化药物，可通过抑制PI3K-AKT信号通路发挥作用

• ✍️ 作者：未知作者
• 🏷️ 关键词：pathway
• 📝 描述：Contributors : Sheng Yin ; Dong Huang ; Lu Gan ; Wei Liu ; Shuqi WuSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensLiver fibrosis represents an unmet clinical need. Building on the high screening hit rate of Euphorbiaceae diterpenoids in our previous anti-fibrotic campaigns, we constructed a library of 29 myrsinane diterpenoids from the roots of Euphorbia prolifera in the current study. This collection features three skeletal subtypes and includes 13 new compounds, euphpronoids A-M (1-13), whose structures were elucidated by comprehensive spectroscopic analyses, ECD calculations, chemical correlation, and single-crystal X-ray diffraction. Anti-liver fibrosis screening of this library in TGF-β1-stimulated LX-2 cells revealed ten compounds that significantly suppressed fibronectin (FN) expression. The most active hit, compound 11, dose-dependently reduced the protein levels of FN, α-smooth muscle actin, and collagen I. Mechanistic studies indicated that 11 exerts its anti-fibrotic effect by inhibiting the PI3K-AKT signaling pathway. These findings underscore the potential of the myrsinane scaffold as a promising structural motif for anti-liver fibrosis drug development.
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