Cell Reports
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2024
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IF 7.5
Zhu Li,Kexin Mao,Lin Liu,Shengyun Xu,Min Zeng,Yu Fu,Jintao Huang,Tingting Li,Guoan Gao,Zhao-Qian Teng,Qinmiao Sun,Dahua Chen,Ying Cheng
Microglia are versatile regulators in brain development and disorders. Emerging evidence links microRNA (miRNA)-mediated regulation to microglial function; however, the exact underlying mechanism remains largely unknown. Here, we uncover the enrichment of miR-137, a neuropsychiatric-disorder-associated miRNA, in the microglial nucleus, and reveal its unexpected nuclear functions in maintaining the microglial global transcriptomic state, phagocytosis, and inflammatory response. Mechanistically, microglial Mir137 deletion increases chromatin accessibility, which contains binding motifs for the microglial master transcription factor Pu.1. Through biochemical and bioinformatics analyses, we propose that miR-137 modulates Pu.1-mediated gene expression by suppressing Pu.1 binding to chromatin. Importantly, we find that increased Pu.1 binding upregulates the target gene Jdp2 (Jun dimerization protein 2) and that knockdown of Jdp2 significantly suppresses the impaired phagocytosis and pro-inflammatory response in Mir137 knockout microglia. Collectively, our study provides evidence supporting the notion that nuclear miR-137 acts as a transcriptional modulator and that this microglia-specific function is essential for maintaining normal adult brain function.
研究领域:
神经生物学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2019
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IF 1.984
Liwen Han,Haotian Kong,Fasheng Liu,Xiaobin Li,Shanshan Zhang,Xuanming Zhang,Yong Wu,Hua Yang,Aiping Zhang,Kechun Liu
The aim of the study is to explore the protective effect of new gelatin (NG, Xin’ejiao in China) on hematopoietic injury caused by chemotherapy. Zebrafish, at 48 hours post fertilization (hpf), was treated with different chemotherapeutic drugs to establish the zebrafish hematopoietic damage model with reduced thrombocytes and erythrocytes. The protecting effects of NG on the thrombocytes and erythrocytes were observed, respectively, on zebrafish models. Then, the RT-PCR method was used to detect the change of mRNA level of the hematopoiesis-related cytokines scl1, c-myb, pu.1, GATA1, and runx1 genes. The results showed that 50 μg·mL−1 and 100 μg·mL−1 NG rescued and increased the thrombocytes numbers induced by vinorelbine (NVB) and chloramphenicol (CHL) and the erythrocytes numbers induced by methotrexate (MTX), doxorubicin (ADM), and mechlorethamine hydrochloride (MH) in zebrafish models. Meanwhile, the mRNA expression of scl1, c-myb, and GATA1 genes in the NG treatment group was raised compared with the MTX treatment group. Also, the mRNA expression of pu.1 and Runx1 in the NG treatment group was reduced compared with the MTX treatment group. In consequence, traditional Chinese medicine NG showed a certain degree protective effect on hematopoiesis injury induced by chemotherapy in this study, which may depend on the promotion of erythrocytes proliferation and the regulation of the hematopoietic genes level.
研究领域:
药理学
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血液学
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分子生物学
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斑马鱼研究
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
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IF 12.6
Leye Yan,Xinyan Hu,Jianan He,Hairun Gan,Yang Shi,Luting Li,Siyu Li,Kunpeng Wei,Jiaxing Wei,Jianxun Cai,Bing Li,Pengfei Pang
Atherosclerosis is a chronic inflammatory disease affecting arterial walls and remains a leading cause of morbidity and mortality worldwide. While anti-inflammatory therapy is widely recognized as a critical component in the management of atherosclerosis, current treatments are often limited by adverse effects and suboptimal efficacy. Membrane-derived nanovesicles have demonstrated excellent biocompatibility and prolonged circulation times, making them effective drug delivery carriers. However, their targeting capabilities remain limited, as only a small fraction of transmembrane proteins possesses intrinsic targeting functions. To overcome these limitations and leverage the targeting capability of folate in inflammatory disease, we designed biomimetic nanovesicles modified with folate by covalently conjugating folate-C 6 -PEG 4 -NHS to nanovesicles under physiological conditions enabling efficient drug delivery to atherosclerotic plaques. Meanwhile we also identified the PU.1 inhibitor DB1976 as an anti-inflammatory target for the treatment of atherosclerosis. Mechanistically, DB1976 suppresses inflammation by inhibiting the IL-1β/NF-κB signaling pathway, reducing reactive oxygen species (ROS) levels, and decreasing apoptosis rates. Folate-modified biomimetic nanovesicles loaded with DB1976 achieved promising therapeutic outcomes. In summary, folate-modified macrophage biomimetic nanovesicles loaded with a PU.1 inhibitor effectively alleviate atherosclerosis by targeting inflammation in atherosclerotic plaques, highlighting their potential as a promising therapeutic strategy for atherosclerosis treatment.
研究领域:
纳米医学
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心血管疾病
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炎症生物学
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药物递送系统
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分子药理学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
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2023
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IF 15.1
Long Fang,Ruofei Zhang,Lin Shi,Jiaying Xie,Long Ma,Yili Yang,Xiyun Yan,Kelong Fan
The success of arsenic in degrading PML-RARα oncoprotein illustrates the great anti-leukemia value of inorganics. Inspired by this, the therapeutic effect of inorganic selenium on t(8; 21) leukemia is studied, which has shown promising anti-cancer effects on solid tumors. A leukemia-targeting selenium nanomedicine is rationally built with bioengineered protein nanocage and is demonstrated to be an effective epigenetic drug for inducing the differentiation of t(8;21) leukemia. The selenium drug significantly induces the differentiation of t(8;21) leukemia cells into more mature myeloid cells. Mechanistic analysis shows that the selenium is metabolized into bioactive forms in cells, which drives the degradation of the AML1-ETO oncoprotein by inhibiting histone deacetylases activity, resulting in the regulation of AML1-ETO target genes. The regulation results in a significant increase in the expression levels of myeloid differentiation transcription factors PU.1 and C/EBPα, and a significant decrease in the expression level of C-KIT protein, a member of the type III receptor tyrosine kinase family. This study demonstrates that this protein-nanocaged selenium is a potential therapeutic drug against t(8;21) leukemia through epigenetic regulation.
研究领域:
肿瘤学
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分子生物学
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纳米技术
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2020
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IF 4.268
Xiaotian Qi,Jing Liu,Xiaoyu Li,Mengyue Fan,Nana Huang,Rong Sun
Background Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical, cancer chemotherapy induced neutropenia (CCIN) infection and infection-related mortality is high for lack of functionally mature neutrophils . Generating functional neutrophils is new therapeutic approaches to reduce CCIN-associated infection and mortality. Saikosaponin a (SSA) is one of the major bioactive components of Radix Bupleuri (RB) and exerts immunoregulatory effects. Purpose The present study aims to investigate the efficacy and mechanism of SSA in CCIN therapy. Methods SSA was applied both in vitro and in vivo to assess the efficacy of CCIN therapy. The differentiation of neutrophils was measured by Nitroblue tetrazolium (NBT) reduction assay and Giemsa staining assay. The neutrophil differentiation related real-time transcription factors were detected by quantitative PCR (RT-qPCR) and Western Blot . Bacteria killing assay was used to assess the ability of fighting infection. Network pharmacology was employed to explore the mechanism network, and the predicted pathways were validated by Western Blot. Results We found that SSA contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo . Network pharmacology prediction showed 55 pathways were predicted involved in SSA against CCIN. Further validation showed that CBL-ERK1/2 pathway was activated by SSA, which could upregulate PU.1 and CEBPβ expression leading to neutrophil differentiation. Conclusions Our findings suggest a natural regimen SSA regenerates microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2 pathway, providing a rationale for future therapeutic approaches.
研究领域:
药理学
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肿瘤学
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免疫学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
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