BMC CANCER
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2025
·Vol. 25
·期 1
·1-16
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IF 3.4
Zhang Mingxiang,Yang Tao,Qian Youcun
Background Dysregulated fatty acid metabolism is a key contributor to poor prognosis in glioma, and targeting cholesterol metabolism represents a promising therapeutic strategy. Apolipoprotein L4 (APOL4), a member of the Apolipoprotein L family, has been implicated in lipid metabolism, but its role in glioma remains unclear. Methods RNA-sequencing were performed to analysis gene expression under exogenous cholesterol treatment. Comprehensive bioinformatics analyses were performed using CGGA datasets to evaluate APOL4 expression, clinical correlations, and prognostic significance in GBM. In vitro experiments, including CRISPR-Cas9 mediated APOL4 knockdown, MTT assays, wound healing assays and immunofluorescence were performed to validate the oncogenic role of APOL4. Xenograft mouse models were employed to validate tumor growth in vivo. Results RNA-sequencing showed that exogenous cholesterol upregulated the expression of APOL4 in U-87 cells. Clinical database analysis revealed that APOL4 was significantly upregulated in human glioblastoma. Genetic depletion of APOL4 markedly suppressed glioblastoma cell proliferation in vitro and impaired xenograft tumor growth in vivo. Furthermore, APOL4 localized to late endosomes and lysosomes, where it likely facilitated the cytoplasmic transport of exogenous cholesterol, supporting tumor cell growth. Conclusions Our study identifies APOL4 as a novel regulator of cholesterol trafficking in glioma cells, promoting glioblastoma progression. These findings highlight APOL4 as a potential therapeutic target for glioma treatment.
研究领域:
肿瘤学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
STRUCTURE
·
2025
·
IF 4.3
Shu-Cheng Fang,Liang Wang,Meng-Ting Cheng,Da Xu,Zhi-Peng Chen,Jie Wang,Wenli Liao,Yanyan Li,Cong-Zhao Zhou,Wen-Tao Hou,Yuxing Chen
The human ATP-binding cassette (ABC) transporter ABCA7 participates in the lipidation of apolipoprotein ApoE, a commonly recognized risk factor for Alzheimer’s disease (AD). How ABCA7 is involved in the molecular pathogenesis of AD remains poorly understood. Using cryoelectron microscopy (cryo-EM), we determined ABCA7 structures in the apo and substrate-bound forms, respectively. Combined with activity assays, we assigned the residues that specifically bind two molecules of phosphatidylserine (PS) that are arranged in a “tail-to-tail” manner. Pull-down assays confirmed that ApoE directly interacts with ABCA7; and moreover, both ATPase and lipid transport activities of ABCA7 were significantly enhanced in the presence of ApoE. We also measured the activities of a familial AD variant and a protective clinically reported variant in the ABCA7 gene. Our findings not only give structural insights into ABCA7-mediated PS translocation, but we also provide first biochemical evidence for its link to AD by forwarding lipids to ApoE.
研究领域:
结构生物学
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神经科学
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分子生物学
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DOI
PubMed
高影响因子
Biotechnology Journal
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2024
·Vol. 19
·期 2
·2300390
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IF 3.2
Yaqiong Guo,Yingying Xie,Jianhua Qin
Organ-on-a-chip technology has shown great potential in disease modeling and drug evaluation. However, traditional organ-on-a-chip devices are mostly pump-dependent with low throughput, which makes it difficult to leverage their advantages. In this study, we have developed a generic, pump-free organ-on-a-chip platform consisting of a 32-unit chip and an adjustable rocker, facilitating high-throughput dynamic cell culture with straightforward operation. By utilizing the rocker to induce periodic fluid forces, we can achieve fluidic conditions similar to those obtained with traditional pump-based systems. Through constructing a gut-on-a-chip model, we observed remarkable enhancements in the expression of barrier-associated proteins and the spatial distribution of differentiated intestinal cells compared to static culture. Furthermore, RNA sequencing analysis unveiled enriched pathways associated with cell proliferation, lipid transport, and drug metabolism, indicating the ability of the platform to mimic critical physiological processes. Additionally, we tested seven drugs that represent a range of high, medium, and low in vivo permeability using this model and found a strong correlation between their P app values and human Fa, demonstrating the capability of this model for drug absorption evaluation. Our findings highlight the potential of this pump-free organ-on-a-chip platform as a valuable tool for advancing drug development and enabling personalized medicine.
研究领域:
生物医学工程
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药理学
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组织工程
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Advanced Research
·
2023
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IF 10.7
Xin Zong,Hao Zhang,Luoyi Zhu,Edward C. Deehan,Jie Fu,Yizhen Wang,Mingliang Jin
Introduction Auricularia auricula is a well-known traditional edible and medical fungus with high nutritional and pharmacological values, as well as metabolic and immunoregulatory properties. Nondigestible fermentable polysaccharides are identified as primary bioactive constituents of Auricularia auricula extracts. However, the exact mechanisms underlying the effects of Auricularia auricula polysaccharides (AAP) on obesity and related metabolic endpoints, including the role of the gut microbiota, remain insufficiently understood. Methods The effects of AAP on obesity were assessed within high-fat diet (HFD)-based mice through obesity trait analysis and metabolomic profiling. To determine the mechanistic role of the gut microbiota in observed anti-obesogenic effects AAP, faecal microbiota transplantation (FMT) and pseudo-germ-free mice model treated with antibiotics were also applied, together with 16S rRNA genomic-derived taxonomic profiling. Results High-fat diet (HFD) murine exposure to AAP thwarted weight gains, reduced fat depositing and enhanced glucose tolerance, together with upregulating thermogenesis proteomic biomarkers within adipose tissue. Serum metabolome indicated these effects were associated with changes in fatty acid metabolism. Intestine-dwelling microbial population assessments discovered that AAP selectively enhanced Papillibacter cinnamivorans , a commensal bacterium with reduced presence in HFD mice. Notably, HFD mice treated with oral formulations of P. cinnamivorans attenuated obesity, which was linked to decreased intestinal lipid transportation and hepatic thermogenesis. Mechanistically, it was demonstrated that P. cinnamivorans regulated intestinal lipids metabolism and liver thermogenesis by reducing the proinflammatory response and gut permeability in a JAK-STAT signaling-related manner. Conclusion Datasets from the present study show that AAP thwarted dietary-driven obesity and metabolism-based disorders by regulating intestinal lipid transportation, a mechanism that is dependent on the gut commensal P. cinnamivorans. These results indicated AAP and P. cinnamivorans as newly identified pre- and probiotics that could serve as novel therapeutics against obesity.
研究领域:
营养学
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药理学
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微生物学
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代谢学
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免疫学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF NUTRITION
·
2021
·Vol. 61
·期 1
·115-126
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IF 5.619
Yan Xin,Liu Xiaoyun,Wang Yu,Ren Xueyang,Ma Jiamu,Song Ruolan,Wang Xiuhuan,Dong Ying,Fan Qiqi,Wei Jing,Yu Axiang,Sui Hong,She Gaimei
Purpose Alcoholic liver disease (ALD) is a major health issue globally. In addition to pharmacotherapy, dietary support is also regarded as reliable strategy for ALD management. As a widely distributed natural constituent within edible plants, the present study aims to investigate the hepatoprotective effects of ursolic acid (UA) against ALD and also to deepen insights into the underlying targets and mechanisms comprehensively. Methods The hepatoprotective activity of UA against chronic alcohol-induced liver injury was investigated on Lieber–DeCarli liquid diet-based mouse model. In-depth RNA-seq transcriptomics and TMT-based proteomics analyses were conducted in parallel. Data integration as well as bioinformatics analysis were also performed to unravel the targets and mechanisms associated with the hepatoprotective activity of UA intake against alcoholic liver injury comprehensively. Results The serum biomarkers and pathological characteristics indicated the hepatoprotective effects of UA intake on alcoholic liver injury. 567 target genes and 377 target proteins related to the hepatoprotective activity of UA were identified in transcriptomics and proteomics analysis respectively, most of which were associated with function of cellular process, cell part and binding. After data integration, 56 co-regulated targets, including ADH4, CYP450 enzymes, NQO1, apolipoproteins, glutathione–S–transferase, etc. which were consistently modulated on both mRNA and protein levels were identified. These co-regulated targets were found to be correlated with 70 KEGG pathways led by carcinogenesis, retinol metabolism and CYP450 metabolism pathways. Conclusion UA intake ameliorated chronic alcohol-induced liver injury. Given the role of the co-regulated targets in ALD and the bioinformatics analysis results, CYP450-, glutathione and redox homeostasis-dependent antioxidation, promotion of lipid transport, and restoration of ethanol metabolic capacity are the potentially underlying mechanisms. This information will further deepen our insights into the hepatoprotective effects of UA-rich edible plants, and provide us valuable instruction for ALD management.
研究领域:
药理学
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分子生物学
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肝病学
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营养基因组学
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DOI
PubMed
高影响因子
Nature Communications
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2024
·Vol. 15
·期 1
·1-19
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IF 14.7
Xue Xiaoyu,Wu Xianming,Fan Yongheng,Han Shuyu,Zhang Haipeng,Sun Yuting,Yin Yanyun,Yin Man,Chen Bing,Sun Zheng,Zhao Shuaijing,Zhang Qi,Liu Weiyuan,Zhang Jiaojiao,Li Jiayin,Shi Ya,Xiao Zhifeng,Dai Jianwu,Zhao Yannan
Spinal cord injury (SCI) leads to fibrotic scar formation at the lesion site, yet the heterogeneity of fibrotic scar remains elusive. Here we show the heterogeneity in distribution, origin, and function of fibroblasts within fibrotic scars after SCI in mice and female monkeys. Utilizing lineage tracing and single-cell RNA sequencing (scRNA-seq), we found that perivascular fibroblasts (PFs), and meningeal fibroblasts (MFs), rather than pericytes/vascular smooth cells (vSMCs), primarily contribute to fibrotic scar in both transection and crush SCI. Crabp2 + /Emb+ fibroblasts (CE-F) derived from meninges primarily localize in the central region of fibrotic scars, demonstrating enhanced cholesterol synthesis and secretion of type I collagen and fibronectin. In contrast, perivascular/pial Lama1 + /Lama2+ fibroblasts (LA-F) are predominantly found at the periphery of the lesion, expressing laminin and type IV collagen and functionally involved in angiogenesis and lipid transport. These findings may provide a comprehensive understanding for remodeling heterogeneous fibrotic scars after SCI.
研究领域:
神经科学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
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