Nature Communications
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2024
·Vol. 15
·期 1
·1-16
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IF 14.7
Zhuang Tao,Chen Mei-Hua,Wu Ruo-Xi,Wang Jing,Hu Xi-De,Meng Ting,Wu Ai-Hua,Li Yan,Yang Yong-Feng,Lei Yu,Hu Dong-Hua,Li Yan-Xiu,Zhang Li,Sun Ai-Jun,Lu Wei,Zhang Guan-Nan,Zuo Jun-Li,Ruan Cheng-Chao
Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.
研究领域:
心脏病学
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分子生物学
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免疫学
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Nature Aging
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2026
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IF 25
Wu Meng,Zhu Qingqing,Xiong Jiaqiang,Tang Weicheng,Chen Dan,Xue Liru,Feng Yourong,Dai Yun,Wu Tong,Wu Chuqing,Guo Yican,Wei Simin,Huang Yibao,Zheng Peizhe,Li Yuting,Song Yiqing,Ding Ting,Wu Mingfu,Li Zifu,Rong Yueguang,Wang Wenwen,Li Yan,Dai Jun,Wang Shixuan,Zhang Jinjin
Recent studies have highlighted the crucial role of mechanical properties in the ovarian microenvironment for ovarian function. However, the mechanisms that cause ovarian matrix stiffening during aging remain incompletely understood. Here we utilized atomic force microscopy (AFM) to demonstrate that human ovarian matrix stiffness increases with aging and in pathophysiological conditions, such as chemotherapy-induced premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS) and ovarian endometriosis. By integrating proteomic analysis of human ovarian tissue with transcriptomic profiling of human ovarian fibroblasts, we identified that IL-11, which is elevated in aging ovaries of mice, rats and humans, activates fibroblasts to secrete extracellular matrix (ECM), thereby increasing ovarian matrix stiffness. Genetic deletion of Il11ra1 in mice mitigated the increase in ovarian matrix stiffness and the decline in ovarian function associated with aging, chemotherapy-induced POI and PCOS. Single-nuclei RNA sequencing (snRNA-seq) revealed that blocking Il11r a 1 reduces the proportion of activated fibroblasts. Furthermore, administration of si Il11 nanoparticles to aged mice and rats enhanced fertility and reduced ovarian matrix stiffness. Together, these findings highlight the pro-inflammatory factor IL-11 in regulating ovarian matrix stiffness. We propose that anti-IL-11 therapy represents a promising translational strategy for delaying ovarian aging.
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ACS Applied Materials & Interfaces
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2024
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IF 8.3
Hao Jiang,Ying Luo,Bo Li,Chunbiao Wu,Da Wang,Yingye Xin,Wei Xu,Jianru Xiao
Osteosarcoma (OS) is a lethal malignant orthotopic bone tumor that primarily affects children and adolescents. Biomimetic nanocarriers have attracted wide attention as a new strategy for delivering chemotherapy agents to the OS. However, challenges such as rapid clearance and limited targeting hinder the effectiveness of OS chemotherapy. In this study, we designed reactive oxygen species (ROS)-responsive nanoparticles (NPs) coated with an interleukin (IL)11-engineered macrophage membrane (MM). The camouflage by MMs prevents clearance of IL-11-engineered MM-coated NPs loaded with doxorubicin (IL-11/MM@NPs/Dox) by the immune system. Moreover, the macrophage membrane combined with surface-expressed IL-11 not only directed IL-11/MM@NPs/Dox to OS tissues but also selectively identified IL-11 receptor alpha (IL-11Rα)-enriched OS cells. Within these cells, elevated levels of ROS triggered the controlled release of Dox from the ROS-responsive NPs. The synergistic modification of targeted ligand conjugation and cell membrane coating on the ROS-responsive NPs enhanced drug availability and reduced toxic side effects, thereby boosting the efficacy of OS chemotherapy. In summary, our findings suggest that IL-11/MM@NPs/Dox represents a promising approach to improving OS chemotherapy efficacy while ensuring excellent biocompatibility.
研究领域:
癌症研究
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纳米医学
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药物递送系统
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生物医学工程
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BRITISH JOURNAL OF PHARMACOLOGY
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2026
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IF 7.5
Yufen Xu,Xiaoli Tan,Xiaodong Lv,Qi Yang,Xingxing Ke,Wenyu Chen
Background and Purpose IGF2BP1 stabilizes oncogenic mRNAs via m6A binding to drive lung adenocarcinoma (LUAD) progression, yet how this modification orchestrates immune evasion remains unclear. Experimental Approach Bioinformatics, RT-qPCR and Western Blotting (WB) first profiled IGF2BP1 expression in LUAD. RNA pull-down, IL-11 stability assays, ELISA and confocal imaging screened and validated IGF2BP1/IL-11 as the key oncogenic axis. ELISA, cytotoxicity experiments and flow cytometry were applied in the exploration of the function of the IGF2BP1/IL-11 axis in LUAD. Bioinformatics analysis, IGF2BP1 half-life detection, WB and ubiquitination experiments were employed to identify the interaction between KCTD10 and IGF2BP1. Allograft experiments were conducted to validate the impact of the KCTD10/IGF2BP1/IL-11 axis on tumour immune escape. Clinical correlation analysis was based on samples of LUAD patients before and after PD-1/PD-L1 inhibitor treatment. Key Results IGF2BP1 was up-regulated in LUAD, exhibiting an association with adverse prognosis. Mechanistically, we observed that IGF2BP1 stabilized IL-11 mRNA in an N6-methyladenosine (m6A)-dependent manner, leading to higher protein expression of IL-11, thereby dampening the cytotoxicity and proliferation of CD8 + cells as well as the expression of TNF-α, IFN-γ and IL-2. Furthermore, KCTD10 overexpression facilitated ubiquitination and degradation of IGF2BP1, and its combination with an anti-IL-11 monoclonal antibody dramatically enhanced therapeutic efficacy. Conclusion and Implications These findings reveal that KCTD10 degrades IGF2BP1 by ubiquitination, regulates m6A modification of IL-11, and restrains immune evasion in LUAD. Our study identifies potential targets for immunotherapy and proffers new therapeutic options for LUAD patients.
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ACS Nano
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2024
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IF 15.8
Chenshuang Zhang,Yilong Teng,Xin Bai,Maoping Tang,William Stewart,Jake Jinkun Chen,Xiaoyang Xu,Xue-Qing Zhang
Chronic exposure of the liver to multiple insults culminates in the development of metabolic dysfunction-associated steatohepatitis (MASH), a complicated metabolic syndrome characterized by hepatic steatosis and inflammation, typically accompanied by progressive fibrosis. Despite extensive clinical evaluation, there remain challenges in MASH drug development, which are primarily due to unsatisfactory efficacy and limited specificity. Strategies to address the unmet medical need for MASH with fibrosis before it reaches the irreversible stage of decompensated cirrhosis are critically needed. Herein, we developed an mRNA-mediated liver-specific antibody therapy for MASH and hepatic fibrosis using a targeted lipid nanoparticle (LNP) delivery system. When encapsulated with IL-11 single-chain variable fragment (scFv)-encoded mRNA, the targeted AA3G LNP (termed mIL11-scFv@AA3G) specifically accumulated in the liver and secreted IL-11 scFv to neutralize overexpressed IL-11 in hepatic environments, thus inhibiting the IL-11 signaling pathway in hepatocytes and hepatic stellate cells. As a preventative regimen, systemic administration of mIL11-scFv@AA3G reversed MASH and prevented the progression to fibrosis in a murine model of early MASH. Notably, mIL11-scFv@AA3G exhibited superior efficacy compared to systemic administration of IL-11 scFv alone, attributed to the sustained antibody expression in the liver, which lasted 18-fold longer than that of IL-11 scFv. When tested in the MASH model with fibrosis, mIL11-scFv@AA3G effectively ameliorated steatosis and resolved fibrosis and inflammation. These findings present a versatile LNP platform targeting liver cell subtypes for the sustained expression of therapeutic antibodies to treat MASH and fibrosis. The developed mRNA-mediated liver-specific antibody therapy offers a promising approach for addressing MASH and holds the potential for expansion to various other diseases.
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研究领域:
肝病学
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药理学
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分子生物学
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治疗学
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