Cell Reports
·
2022
·
IF 9.995
Da Xu,Yanyan Li,Fengrui Yang,Cai-Rong Sun,Jinheng Pan,Liang Wang,Zhi-Peng Chen,Shu-Cheng Fang,Xuebiao Yao,Wen-Tao Hou,Cong-Zhao Zhou,Yuxing Chen
Summary The reverse cholesterol transport pathway is responsible for the maintenance of human cholesterol homeostasis, an imbalance of which usually leads to atherosclerosis. As a key component of this pathway, the ATP-binding cassette transporter ABCG1 forwards cellular cholesterol to the extracellular acceptor nascent high-density lipoprotein (HDL). Here, we report a 3.26-Å cryo-electron microscopy structure of cholesterol-bound ABCG1 in an inward-facing conformation, which represents a turnover condition upon ATP binding. Structural analyses combined with functional assays reveals that a cluster of conserved hydrophobic residues, in addition to two sphingomyelins, constitute a well-defined cholesterol-binding cavity. The exit of this cavity is closed by three pairs of conserved Phe residues, which constitute a hydrophobic path for the release of cholesterol in an acceptor concentration-dependent manner. Overall, we propose an ABCG1-driven cholesterol transport cycle initiated by sphingomyelin-assisted cholesterol recruitment and accomplished by the release of cholesterol to HDL.
研究领域:
分子生物学
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结构生物学
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心血管疾病
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DOI
PubMed
高影响因子
Genes & Diseases
·
2026
·
IF 14.6
Xinhang Li,Yi Xie,Wenyan Ren,Qing Liu,Qiming Pang,Wenting Liu,Xin Li,Bin He,Dongmei He,Xinyue Wan,Jia Liu,Jie Cai,Baicheng He,Wei Huang,Fang He
Renal osteodystrophy is a debilitating complication of chronic kidney disease characterized by deteriorated bone microarchitecture and impaired bone formation, leading to increased fracture risk. Despite the pressing need for anabolic therapies, the cellular mechanisms by which uremic stress compromises osteoprogenitor function remain poorly defined. Here, metabolomic profiling of renal osteodystrophy patient cohorts revealed a profound depletion of circulating betaine. We show that betaine supplementation not only rescued the osteogenic differentiation of bone marrow-derived mesenchymal stem cells challenged with the uremic toxin indoxyl sulfate but also ameliorated skeletal deterioration in a rat model of chronic kidney disease. Mechanistically, we demonstrated that indoxyl sulfate triggered ferroptosis in bone marrow-derived mesenchymal stem cells—characterized by iron-dependent lipid peroxidation and aberrant HMOX1 up-regulation—thereby arresting osteogenesis. Betaine mitigates this ferroptotic stress through a novel post-transcriptional mechanism. Specifically, betaine down-regulated the RNA-binding protein hnRNP A1, preventing the recruitment of the CNOT1 deadenylase complex. This inhibition stabilized Abcg1 mRNA, leading to restored ABCG1 expression. Functional perturbation studies confirmed that the ABCG1–HMOX1 axis was indispensable for the anti-ferroptotic and osteoprotective effects of betaine. Collectively, our findings delineate a Betaine–hnRNP A1/CNOT1–ABCG1–HMOX1 signaling cascade that links metabolic deficiency to ferroptosis-driven osteogenic failure, positioning betaine as a promising anabolic therapeutic strategy for renal osteodystrophy.
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DOI
高影响因子
Molecular Neurodegeneration
·
2026
·
IF 19.6
Ling Zhipeng,Pan Jun-Ping,Xiao Xianglu,Wu Wenfan,Chen Guisi,Shi Fang,Chen Zehuan,Zhang Haiyi,Huang Yuehao,Tang Qing,Cai Qiwei,Deng Shenglong,Niu Zhangming,Zhang Shi-Qi,Wang He-Ling,Zhang Jianying,Zhou Xuefeng,Mao Lipeng,Li Junliang,Chen Hongming,Lu Guang,Chen Guobing,Fang Evandro Fei,Yang Guang,Wang Guocai,Xiao Fei,Zhang Yubo
Defective mitophagy is a key pathological risk of Alzheimer’s disease (AD), yet available pharmacological agents capable of restoring mitophagy remain clinically limited, largely due to the lack of tools for drug screening and target identification. To address this, we introduce an integrated platform with three novel artificial intelligence (AI)-enabled approaches—the phenotype-based screening model ‘CellAutoFM’, the drug-likeness predictor ‘ADMET Ranker’, and the target deconvolution method ‘PROCAT’. Using this platform together with wet lab validation, Crassifolin A (JGX-1) is identified as a potent natural product-derived mitophagy inducer; structurally, JGX-1 directly binds to ATP-binding cassette sub-family A member 1 (ABCA1) and sub-family G member 1 (ABCG1), triggering enhanced cholesterol efflux which activates PINK1/Parkin-dependent mitophagy. In both in vitro and in vivo AD laboratory models, JGX-1 reduces amyloid-β and Tau pathologies in an autophagy/mitophagy-dependent manner as these benefits are dramatically blunted with key mitophagy genes knocked down. Collectively, we provide an open-access, reproducible AI-assisted platform for rapid compound screening, drug-likeness evaluation, and potential target prediction to advance drug discovery. Through this paradigm, we unveil modulating the ABCA1/ABCG1-mediated cholesterol-mitophagy pathway as a promising anti-AD strategy, with a novel drug candidate JGX-1 identified.
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DOI
高影响因子
NEURON
·
2025
·
IF 15
Tao Qin,Tao Jiang,Zihan Zhou,Mengyuan Wu,Yuanzhen Zhang,Zhenqi Yang,Ziyang Zheng,Jiang Yi,Xiaowei Wang,Mingran Luo,Peng Gao,Jiayun Liu,Yifan Huang,Hao Liu,Qingqing Li,Wei Zhou,Shujun Zhang,Xiaodong Guo,Baorong He,Yongxiang Wang,Jin Fan,Shujie Zhao,Jian Chen,Guoyong Yin
The spatiotemporal dynamics and specific roles of regulatory T (Treg) cells in spinal cord injury (SCI) remain unclear. Using single-cell RNA sequencing, flow cytometry, and immunofluorescence, we found that thymus-derived Treg cells infiltrate the injured spinal cord via peripheral blood around 3 days post-SCI. Treg cell depletion worsened SCI and impaired long-term recovery. Transcriptomic profiling revealed strong anti-inflammatory functions of Treg cells and the potential to regulate cholesterol metabolism in neighboring microglia. Further single-cell RNA sequencing uncovered the clonality of SCI-associated Treg cells. Major histocompatibility complex class II (MHC II) expression on microglia, not macrophages, was crucial for sustaining Treg cell numbers and neuroprotective function, with myelin-phagocytosing microglia-activated Treg cells showing significant neuroprotective effects. Treg cells mitigated microglial inflammation via CTLA-4 and upregulated the ATP-binding cassette transporter G1 (Abcg1) receptor in microglia, helping to manage myelin load and reduce lipid droplet formation. Our findings offer mechanistic insights into SCI-associated Treg cells and lay the groundwork for future Treg-based therapies in SCI treatment.
研究领域:
免疫学
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神经科学
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分子生物学
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转化医学
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炎症与修复
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神经免疫学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
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2016
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IF 3.817
Xu Wang,Yijie Bai,Guyue Cheng,Awais Ihsan,Feng Zhu,Yulian Wang,Yanfei Tao,Dongmei Chen,Menghong Dai,Zhengli Liu,Zonghui Yuan
Quinoxaline 1,4-dioxides (QdNOs) are widely used as a kind of antibacterial growth promoter in animal husbandry. The adrenal cortex was found to be one of the main toxic targets of QdNOs, accompanied by a decreased aldosterone level. However, the way in which QdNOs decrease production of the hormone aldosterone is far from clear. To illustrate the mechanism by which QdNOs damage the adrenal cortex and decrease aldosterone hormone levels, the QdNOs were screened to choose the drug with most toxic effects on aldosterone production, and then to reveal the mechanism between the gene and protein profiles in human adrenocortical cells (NCI-H295R cells). The results found that quinocetone (QCT) showed the highest adrenal toxic effect among QdNOs. After exposing H295R cells to 10 and 20 μM QCT for 24 h, compared with blank cells, the gene and protein expression profiles obtained were analyzed by microarray and MALDI TOF/TOF mass spectrometry, respectively. The results of microarray analysis suggested that ABCG1 and SREBF1, which were involved in the cholesterol biosynthetic and metabolic processes, and CYP17A1, NR4A2 and G6PD, which were related to aldosterone biosynthesis, were important molecular targets. It has been speculated that PKC and ERK pathways might be involved in the reduction of aldosterone production caused by QCT, through enhanced mRNA expression of CYP17A1. Additionally, JNK and p38MAPK signal transduction pathways might participate in apoptosis induced by QCT. Twenty-nine and 32 protein spots were successfully identified when cells were treated with 10 and 20 μM QCT, respectively. These identified proteins mainly included material synthesis and energy metabolism-related proteins, transcription/translation processing-related proteins, signal transduction proteins, cytoskeletal proteins, molecular chaperones, proteins related to response to stress, and transport proteins. Further investigations suggested that oxidative stress caused by QCT was exacerbated through disruption of the Keap1/Nrf2/ARE anti-oxidative stress pathway. Taken together, the data demonstrated for the first time that the Keap1/Nrf2/ARE pathway plays a crucial role in adrenal toxicity, and that CYP17A1 was the key switch to reduce the aldosterone production induced by QCT. Furthermore, large numbers of genes and proteins and entry points for research in the inhibition of aldosterone synthesis induced by QCT were offered, which will provide new insight into the adrenal toxicity of QdNOs and help to provide a theoretical foundation for the formulation of safety controls for products obtained from animals and to design new QdNOs with less harmful effects.
研究领域:
毒理学
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药理学
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内分泌学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2022
·Vol. 478
·期 3
·665-678
·
IF 3.842
Qi Jie,Lv Ying,Zhong Ni-Er,Han Wen-Qi,Gou Qi-Ling,Sun Chao-Feng
Atherosclerotic morbidity is significantly higher in the diabetic population. Hyperglycemia, a typical feature of diabetes, has been proven to accelerate foam cell formation. However, the molecular mechanisms behind this process remain unclear. In this study, LPS and IFN-γ were used to convert THP-1-derived macrophages into M1 macrophages, which were then activated with ox-LDL in either high glucose or normal condition. We identified lipids within macrophages by Oil red O staining and total cholesterol detection. The genes involved in lipid absorption, efflux, inflammation, and metabolism were analyzed using qRT-PCR. The mechanisms of high glucose-induced foam cell formation were further investigated through metabolomics and transcriptomics analysis. We discovered that high glucose speed up lipid accumulation in macrophages (both lipid droplets and total cholesterol increased), diminished lipid efflux (ABCG1 down-regulation), and aggravated inflammation (IL1B and TNF up-regulation). Following multi-omics analysis, it was determined that glucose altered the metabolic and transcriptional profiles of macrophages, identifying 392 differently expressed metabolites and 293 differentially expressed genes, respectively. Joint pathway analysis suggested that glucose predominantly disrupted the glycerolipid, glycerophospholipid, and arachidonic acid metabolic pathways in macrophages. High glucose in the glyceride metabolic pathway, for instance, suppressed the transcription of triglyceride hydrolase (LIPG and LPL), causing cells to deposit excess triglycerides into lipid droplets and encouraging foam cell formation. More importantly, high glucose triggered the accumulation of pro-atherosclerotic lipids (7-ketocholesterol, lysophosphatidylcholine, and glycerophosphatidylcholine). In conclusion, this work elucidated mechanisms of glucose-induced foam cell formation via a multi-omics approach.
研究领域:
心血管疾病
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糖尿病
·
分子生物学
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代谢
·
炎症
·
脂质代谢
✓ 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）