Advanced Science
·
2025
·
IF 14.1
Hui Luo,Xiaolu She,Yubo Zhang,Bingfan Xie,Shibo Zhang,Qianqian Li,Yangyang Zhou,Shuang Guo,Shushan Zhang,Yanhui Jiang,Yingying Dong,Jianzhong He,Lijie Wang,Qianqian Zhang,Yuan Zhuang,Panxia Deng,Feng Wang,Jihong Liu,Xin Chen,Huilong Nie,Huanhuan He
A major characteristic of ovarian cancer (OC) is its unique route of metastasis via ascites. The immune microenvironment in ascites remains understudied, leaving the mechanism of ascites-mediated abdominal metastasis obscure. Here, a single-cell transcriptomic landscape of CD45 + immune cells across multiple anatomical sites is depicted, including primary tumors, metastatic lesions, and ascites, from patients diagnosed with high-grade serous ovarian carcinoma (HGSOC). A novel subset of perilipin 2 high (PLIN2 hi ) macrophages are identified that are enriched in ascites and positively correlated with OC progression, hence being designated as “ascites-associated macrophages (AAMs)”. AAMs are lipid-loaded with overexpression of the lipid droplet protein PLIN2. Overexpression or suppression of PLIN2 can enhance or inhibit tumor cell migration, invasion, and vascular permeability in vitro, which is also confirmed in vivo. Mechanistically, it is demonstrated that PLIN2 boosts HIF1α/SPP1 signaling in macrophages, thereby exerting pro-tumor functions. Finally, a PLIN2-targeting liposome is designed to efficiently suppress ascites production and tumor metastasis. Taken together, this work provides a comprehensive characterization of the cancer-promoting function and lipid-rich property of ascites-enriched PLIN2 hi macrophages, establishes a link between lipid metabolism and hypoxia within the context of the ascites microenvironment, and elucidates the pivotal role of ascites in trans-coelomic metastasis of OC.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2024
·
IF 25.5
Yangning Lan,Xiaoxuan Zhang,Shaorui Liu,Chen Guo,Yuxiao Jin,Hui Li,Linyixiao Wang,Jinghong Zhao,Yilin Hao,Zhicheng Li,Zhaoyuan Liu,Florent Ginhoux,Qi Xie,Heping Xu,Jie-Min Jia,Danyang He
Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1（Spp1） to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1 + microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions.
研究领域:
神经科学
·
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Liting Zhu,Linjie Mu,Xiaoqiu Ni,Feng Wang,Xinyi Peng,Yujiu Gao,Tingting Wei,Congcong Zeng,Yongheng Bai,Fangyan Wang,Zhengzhong Yuan,Jinguo Cheng
Ethnopharmacological relevance Xin-Zi-Sheng-Wan Decoction (XZSWD), a formulation rooted in the classic Zi-Sheng Pill first recorded in the Qing-dynasty compendium “ Golden Mirror of Medicine ,” is traditionally employed to resolve turbid pathogenic stagnation and restore metabolic equilibrium. Modern ethnopharmacological studies reveal a marked uric acid–lowering effect, although its precise molecular mechanisms have yet to be fully clarified. Aim of the study This study aimed to evaluate the therapeutic efficacy of XZSWD in hyperuricemia (HUA)-induced kidney injury and to elucidate its molecular mechanisms. Methods UPLC-QTOF/MS was used to identify compounds in XZSWD medicated serum. A HUA mouse model was induced by potassium oxonate and hypoxanthine to evaluate the therapeutic effects of XZSWD on renal injury. RNA-Seq, qRT-PCR, Western blot, immunofluorescence, and flow cytometry were applied to investigate immune infiltration and key signaling pathways. A THP-1/HK-2 co-culture system combined with SPP1 overexpression and knockdown was used to explore the molecular mechanisms. Results 99 compounds were identified in XZSWDS. XZSWD improved renal function, reduced serum uric acid levels, and downregulated macrophage-related inflammatory genes while modulating mixed M1/M2 polarization. XZSWD also inhibited the SPP1-CD44 axis and downstream SRC/FAK/β-Catenin signaling to reduce renal extracellular matrix (ECM) deposition. In vitro, SPP1 was identified as a critical target mediating these effects. Conclusions XZSWD alleviates HUA-induced renal injury by suppressing macrophage-mediated inflammation via regulation of the SPP1–CD44 axis and SRC/FAK/β-Catenin signaling, highlighting its therapeutic potential for HUA-related renal dysfunction.
研究领域:
民族药理学
·
肾脏病学
·
免疫学
·
信号转导
·
植物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-19
·
IF 6.1
Pan Caizhe,Wei Hao,Chen Bi,Wu Lei,Song Jiayao,Zhang Qing,Wu Xinglong,Liang Guibai,Chen Wenhao,Wang Yingshuo,Xie Yicheng
Background Idiopathic pulmonary fibrosis (IPF) stands as a significant contributor to global mortality rates. Presently, there exists a dearth of effective anti-fibrotic treatments for this condition. While itraconazole (ITR) has exhibited potential in mitigating pulmonary fibrosis, its oral administration is hampered by unfavorable pharmacokinetics, which elevate the risk of adverse reactions, thus limiting its clinical utility. Methods An inhalable formulation of ITR were engineered which aimed at enhancing its pulmonary dispersion. First, pharmacokinetics were conducted to investigate the blood concentration and tissue residue of ITR after inhalation administration. In addition, bleomycin induced mouse pulmonary fibrosis model was used to compare the therapeutic effects of ITR administered by inhalation and intragastric administration. Finally, single-cell RNA sequencing (scRNAseq) was used to explore the mechanism of ITR inhalation administration. Results We found that a large amount of drugs accumulated in the lung tissue for a long time after inhalation administration, thus maximizing the therapeutic effect of drugs. Inhalation of ITR daily at for 21 days significantly attenuated bleomycin-induced lung fibrosis and inflammation in murine models. Additionally, our findings revealed that ITR inhalation diminished the proportion of diseased fibroblasts while promoting reparative fibroblast populations in the murine model. Furthermore, it effectively reversed the proportion of activated phagocytic macrophages. Mechanistically, ITR inhalation exerted its effects by regulating SPP1 and C3 signaling pathway pivotal in the interaction between phagocytic macrophages and diseased fibroblasts. Conclusions These insights into the molecular mechanisms underlying ITR’s therapeutic effects on IPF underscore the favorable pharmacokinetic profile conferred by inhalation, thus presenting a promising formulation poised for clinical translation.
研究领域:
呼吸病学
·
药理学
·
分子生物学
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
Cell Reports Medicine
·
2026
·
IF 14
Xiaomeng Dai,Chunyu Lai,Libing Hong,Yuzhi Jin,Jinlin Cheng,Haimeng Yan,Xuqi Sun,Bin Li,Chuan Liu,Hangyu Zhang,Yanwei Lu,Haibo Zhang,Danyang Wang,Peng Zhao,Yu Shi,Weijia Fang,Shan Xin,Xia Yu,Xuanwen Bao
The immunometabolic basis of therapy-resistant colorectal cancer (CRC) peritoneal carcinomatosis with malignant ascites remains poorly defined. Here, we profile ascites immune cells from 20 patients across treatment-naive, chemo/targeted therapy-refractory, and immune checkpoint blockade (ICB)/adoptive T cell therapy (ACT)-resistant CRC. Single-cell RNA sequencing identifies SPP1 + cavity macrophages as drivers of CD8 + T cell dysfunction. Proteomic profiling of 36 patients confirms SPP1 enrichment in ICB/ACT-resistant peritoneal metastases. Mechanistically, SPP1 sustains an M2-like program via PPARγ activation and lipid uptake. SPP1 deficiency reduces PPARγ ligand precursors, triggering NF-κB-driven macrophage reprogramming and reversing CD8 + T cell suppression. Supplementation with 15 d-PGJ 2 and fatty acids restores the M2 phenotype. In vivo , macrophage-specific SPP1 knockout enhances cytotoxic T lymphocyte infiltration and ICB efficacy, while SPP1 neutralization overcomes ICB resistance and augments ACT efficacy. Thus, SPP1 + cavity macrophages are central immunometabolic regulators, and SPP1 inhibition represents a promising strategy to overcome immunotherapy resistance in this lethal disease.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AGING CELL
·
2026
·Vol. 25
·期 2
·e70378
·
IF 7.1
Meiling Wang,Yumin Chang,Aojie He,Jing Yang,Ang Li,Hongqin Wang,Kah-Leong Lim,Xing Guo,Chengwu Zhang,Li Lu
Age-related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)-positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia-specific Spp1 knockout (Spp1-cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age-dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia-specific overexpression of Spp1 partially ameliorates the age-related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age-related memory decline.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2022
·
IF 4.631
Qian-Qian Nie,Zong-Qing Zheng,Juan Liao,Yu-Chao Li,Yan-Ting Chen,Tian-Ye Wang,Gui-Qiang Yuan,Zhong Wang,Qun Xue
Background: Ischemic injury in stroke is followed by extensive neurovascular inflammation and changes in ischemic penumbra gene expression patterns. However, the key molecules involved in the inflammatory response during the acute phase of ischemic stroke remain unclear.Methods: Gene expression profiles of two rat ischemic stroke-related data sets, GSE61616 and GSE97537, were downloaded from the GEO database for Gene Set Enrichment Analysis (GSEA). Then, GEO2R was used to screen differentially expressed genes (DEGs). Furthermore, 170 differentially expressed intersection genes were screened and analyzed for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Candidate genes and miRNAs were obtained by DAVID, Metascape, Cytoscape, STRING, and TargetScan. Finally, the rat middle cerebral artery occlusion-reperfusion (MCAO/R) model was constructed, and qRT-PCR was used to verify the predicted potential miRNA molecule and its target genes.Results: GO and KEGG analyses showed that 170 genes were highly associated with inflammatory cell activation and cytokine production. After cluster analysis, seven hub genes highly correlated with post-stroke neuroinflammation were obtained: Cxcl1, Kng1, Il6, AnxA1, TIMP1, SPP1, and Ccl6. The results of TargetScan further suggested that miR-340-5p may negatively regulate SPP1, AnxA1, and TIMP1 simultaneously. In the ischemic penumbra of rats 24 h after MCAO/R, the level of miR-340-5p significantly decreased compared with the control group, while the concentration of SPP1, AnxA1, and TIMP1 increased. Time-course studies demonstrated that the mRNA expression levels of SPP1, AnxA1, and TIMP1 fluctuated dramatically throughout the acute phase of cerebral ischemia-reperfusion (I/R).Conclusion: Our study suggests that differentially expressed genes SPP1, TIMP1, and ANXA1 may play a vital role in the inflammatory response during the acute phase of cerebral ischemia-reperfusion injury. These genes may be negatively regulated by miR-340-5p. Our results may provide new insights into the complex pathophysiological mechanisms of secondary inflammation after stroke.
研究领域:
神经科学
·
分子生物学
·
基因组学
·
病理生理学
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Shuai-dong Chen,Chen-yu Chu,Chen-bing Wang,Yang Yang,Zhao-yu Xu,Yi-li Qu,Yi Man
Extracellular matrix (ECM) scaffold membranes have exhibited promising potential to better the outcomes of wound healing by creating a regenerative microenvironment around. However, when compared to the application in younger individuals, the performance of the same scaffold membrane in promoting re-epithelialization and collagen deposition was observed dissatisfying in aged mice. To comprehensively explore the mechanisms underlying this age-related disparity, we conducted the integrated analysis, combing single-cell RNA sequencing (scRNA-Seq) with spatial transcriptomics, and elucidated six functionally and spatially distinctive macrophage groups and lymphocytes surrounding the ECM scaffolds. Through intergroup comparative analysis and cell-cell communication, we characterized the dysfunction of Spp1+ macrophages in aged mice impeded the activation of the type Ⅱ immune response, thus inhibiting the repair ability of epidermal cells and fibroblasts around the ECM scaffolds. These findings contribute to a deeper understanding of biomaterial applications in varied physiological contexts, thereby paving the way for the development of precision-based biomaterials tailored specifically for aged individuals in future therapeutic strategies.
研究领域:
生物材料
·
伤口愈合
·
衰老
·
免疫学
·
转录组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）