Nanomedicine-Nanotechnology Biology and Medicine
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2023
·
IF 5.4
Yan Zhu,Yanni Xu,Dong Han,Xiujin Zhang,Cheng Qin,Jing Liu,Lei Tian,Mengqi Xu,Yan Fang,Yang Zhang,Yabin Wang,Feng Cao
ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in atherosclerotic formation through mediated cholesterol efflux in macrophage-derived foam cells . In this study, a scavenger receptors AI (SR-AI) targeted theranostic nanoparticles was constructed for atherosclerosis regression via ABCA1 activation in foam cells. ABCA1-upregulator 5242331 and IR780 were encapsulated in PLGA-PEG micelles which were conjugated with SR-AI targeting peptide (PP1) to formulate the nanoparticles (SAU-NPs). Immunostaining revealed that SR-AI was highly expressed both in macrophage foam cells and in atherosclerotic plaque of ApoE −/− mice. The SAU-NPs have shown more active targeting to plaque lesion with higher stability compared with non-SR-AI targeted nanoparticles. The transformation from macrophage to foam cells was inhibited by SAU-NPs carried 5242331. Cholesterol deposition was effectively reduced in foam cells by SAU-NPs through activating the LXRα-ABCA1/ABCG1/SR-BI pathway. In conclusion, theranostic SAU-NPs which carried ABCA1-upregulator 5242331 exert beneficial effects on atherosclerosis regression via LXRα activation.
研究领域:
心脏病学
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纳米医学
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分子生物学
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DOI
PubMed
高影响因子
Foods
·
2025
·Vol. 14
·期 24
·4267
·
IF 5.1
Jing Xu,Wen-Zhao Wen,Jun-Hui Zhao,Jun-Rong Guo,Zhuo-Ya Zhang,Ping Xiong
Citri grandis exocarpium ( Citri grandis ) has been consumed by human beings for fifteen hundred years. It is commonly consumed as a health drink and dietary supplement in China. However, its nutritional and healthcare functions are still not fully understood. Objective: Our previous study found that oral administration of Citri grandis extract can significantly decrease the blood lipid levels of hyperlipidemic mice fed a high-fat diet. The aim of this study was to confirm the preventative effects of Citri grandis extract against atherosclerosis. Methods: Atherosclerotic lesion models were induced in HUVECs and apoE −/− C57BL/6J mice. ApoE −/− mice fed a high-fat diet were orally administered Citri grandis extract (0.4, 0.8, and 1.6 g/kg/d BW) and Simvastatin (1 mg/kg/d BW) on the first day of model establishment. After a 16-week treatment, serum samples and aorta and liver tissues were collected. Observation of pathological changes in aortic and liver tissues was performed using a light microscope with oil red O, H&E, Masson’s trichrome staining, and TEM. Biochemical detection was employed to determine the serum levels of TC, TG, LDL-C, and HDL-C as well as the activities of AST and ALT. In addition, expression studies of TGF-β, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1 were performed via qPCR and Western blot analysis. Results: Compared with cholesterol-induced HUVECs, Citri grandis extract significantly enhanced cell viability, attenuated the morphological changes in HUVECs, and reduced LDH release. Furthermore, after treatment with Citri grandis extract, the levels of TC, TG, and LDL-C significantly decreased in the atherosclerosis model apoE −/− mice after 16 weeks, and aortic plaque, lipid deposition, and endothelial injury were obviously ameliorated. The mRNA and protein expression of TGF-β, PPAR-γ, LXR-α, and ABCA1 in aortic and liver of atherosclerosis apoE −/− mice were upregulated ( p < 0.05, p < 0.01), while those of PI3K and Akt1 were suppressed ( p < 0.05, p < 0.01). Conclusions: Citri grandis extract can significantly decrease the high circulating lipid levels and the liver lipid deposition of high-fat-diet-fed apoE −/− mice and reduce aorta lipid accumulation and atherosclerotic plaques by regulating the expression of TGF-β1, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1. Citri grandis extract can be used as a healthcare dietary supplement for the prevention of abnormal lipid metabolism and atherosclerosis.
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PubMed
高影响因子
MATERIALS & DESIGN
·
2023
·
IF 8.4
Chao-ping He,Wen-juan Quan,Ya-ling Zeng,Hong-yan Zhou,Pei-dong You,Zhen-xian Li,Ya-mei Li,Li-mei Lin,Bin Liu,Duan-fang Liao,Qin-hui Tuo
Reducing lipid uptake of macrophages and stimulating cholesterol efflux are two necessary steps for atherosclerotic plaque regression. In this study, a compound of curcumin nicotinate (CN) was synthesized from nicotinic acid which can raise raising high-density lipoprotein (HDL) and curcumin which can lower lipid. However, the shortcomings of CN, such as poor water solubility and low bioavailability, limit its clinical application. In this article, a CN loaded biomimetic nanosystem was constructed by using Prussian blue nanoparticles (PB NPs) to improve its solubility, thereby changing its administration route. In addition, hyaluronic acid (HA) modification on the biomimetic PB NPs was adopted to prolong circulation time and improve the accumulation of drugs in the plaque region. Mechanism studies have shown that the constructed nanosystem could exert anti-AS effects through the pathway of Proprotein Convertase Subtilisin/Kexin Type 9(PCSK9) /Low-density lipoprotein receptor (LDL-R), ATP Binding Cassette Transporter A1(ABCA1) /Caveolin-1 /Liver X Receptor (LXR). These findings indicated that the designed nano-platform is expected to be used for prevention and targeted therapy of atherosclerosis.
研究领域:
纳米技术
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药学
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心血管疾病
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DOI
高影响因子
Molecular Neurodegeneration
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2026
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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
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 24
·17280
·
IF 5.6
Hui Li,Mingchao Wang,Kai Qu,Ruiming Xu,Haibo Zhu
It is widely recognized that macrophage cholesterol efflux mediated by the ATP-binding cassette transporter A1 (ABCA1) constitutes the initial and rate-limiting step of reverse cholesterol transport (RCT), displaying a negative correlation with the development of atherosclerosis. Although the transcriptional regulation of ABCA1 has been extensively studied in previous research, the impact of post-translational regulation on its expression remains to be elucidated. In this study, we report an AMP-activated protein kinase (AMPK) agonist called ((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-((3-hydroxyphenyl) amino)-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl dihydrogen phosphate (MP), which enhances ABCA1 expression through post-translational regulation rather than transcriptional regulation. By integrating the findings of multiple experiments, it is confirmed that MP directly binds to AMPK with a moderate binding affinity, subsequently triggering its allosteric activation. Further investigations conducted on macrophages unveil a novel mechanism through which MP modulates ABCA1 expression. Specifically, MP downregulates the Cav1.2 channel to obstruct the influx of extracellular Ca2+, thereby diminishing intracellular Ca2+levels, suppressing calcium-activated calpain activity, and reducing the interaction strength between calpain and ABCA1. This cascade of events culminates in the deceleration of calpain-mediated degradation of ABCA1. In conclusion, MP emerges as a potentially promising candidate compound for developing agents aimed at enhancing ABCA1 stability and boosting cellular cholesterol efflux and RCT.Keywords:ATP-binding cassette transporter A1;reverse cholesterol transport;AMP-activated protein kinase;MP;calpain-mediated degradation
研究领域:
心血管研究
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药理学
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分子生物学
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DOI
PubMed
高影响因子
FITOTERAPIA
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2026
·
IF 2.9
Zihan Zhou,Fanxing Zhou,Xudong Xing,Zuguo Zheng,Guangji Wang,Hua Yang
QGJZF reduces aortic plaque in AS mice with PCSK9 overexpression induced by HFD. • 16 blood-absorbed components and 23 metabolites identified from QGJZF in vivo . • Network pharmacology and omics reveal QGJZF modulates lipid metabolism via PI3K-AKT. • QGJZF suppresses macrophage foam cell formation. • QGJZF activates PI3K-AKT pathway and upregulates ABCA1 for cholesterol export. Objective Qigui Jiangzhi Formula (QGJZF) is a traditional Chinese medicine formulation developed based on the principles of regulating Qi, warming Yang, and resolving dampness. All of its herbs have historically been used to treat obesity, hypertension, and hyperlipidemia. However, its therapeutic mechanism in atherosclerosis (AS)-related cardiovascular disease remains unclear. This study aimed to investigate the anti-atherosclerotic activity and explain the mechanism of QGJZF. Methods PCSK9 overexpressing mice induced by high-fat diet were used to establish an in vivo model. Aortic pathology and inflammation were assessed via histology, immunofluorescence, and Enzyme-linked immunosorbent assay. Chemical characterisation was performed by LC-MS. Network pharmacology and multi-omics were combined to elucidate the mechanism of QGJZF, validated by molecular docking and surface plasmon resonance (SPR). An in vitro foam cell model using ox-LDL-induced RAW264.7 macrophages was analysed by qPCR and Western blot. Results QGJZF effectively reduced aortic lipid plaque deposition, ameliorated plaque pathology, and suppressed macrophage infiltration in AS mice. LC-MS identified 93 non-volatile components, including 16 blood-entering constituents and 23 metabolites. Network pharmacology and multi-omics analyses indicated QGJZF regulates lipid metabolism via the PI3K-AKT pathway. Molecular docking and SPR confirmed strong binding of five major blood-entering components to PI3K/AKT proteins. In vitro , QGJZF activates the PI3K-AKT pathway, upregulated ABCA1 expression, inhibited macrophage foam cell formation, and improved lipid metabolism. Conclusion QGJZF inhibits the formation of foam macrophages through the PI3K-AKT-ABCA1 signalling pathway, thereby improving AS. This provides a scientific foundation for the clinical application of QGJZF in AS-related cardiovascular disease. Download: Download high-res image (195KB) Download: Download full-size image
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2012
·Vol. 33
·期 7
·909-917
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IF 1.953
Wang Xin-ting,Li Jia,Liu Li,Hu Nan,Jin Shi,Liu Can,Mei Dan,Liu Xiao-dong
Aim: Diabetes is associated with elevated serum total cholesterol level and disrupted lipoprotein subfractions. The aim of this study was to examine alterations in the tissue cholesterol contents closely related to diabetic complications. Methods: Intraperitoneal injection of streptozotocin was used to induce type 1 diabetes in adult male Sprague-Dawley rats. On d 35 after the injection, liver, heart, intestine, kidney, pancreas, cerebral cortex and hippocampus were isolated from the rats. The content of total and free cholesterol in the tissues was determined using HPLC. The ATP-binding cassette protein A1 (ABCA1) protein and ApoE mRNA were measured using Western blot and QT-PCR analyses, respectively. Results: In diabetic rats, the level of free cholesterol was significantly decreased in the peripheral tissues, but significantly elevated in hippocampus, as compared with those in the control rats. Diabetic rats showed a trend of decreasing the total cholesterol level in the peripheral tissues, but significant change was only found in kidney and liver. In diabetic rats, the level of the ABCA1 protein was significantly increased in the peripheral tissues and cerebral cortex; the expression of ApoE mRNA was slightly decreased in hippocampus and cerebral cortex, but the change had no statistical significance. Conclusion: Type 1 diabetes decreases the free cholesterol content in the peripheral tissues and increases the free cholesterol content in hippocampus. The decreased free cholesterol level in the peripheral tissues may be partly due to the increased expression of the ABCA1 protein.
研究领域:
内分泌学
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代谢学
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药理学
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神经科学
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DOI
PubMed
高影响因子
npj Regenerative Medicine
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2023
·Vol. 8
·期 1
·1-17
·
IF 7.2
Zhao Chuanrong,Yang Qianru,Tang Runze,Li Wang,Wang Jin,Yang Fangfang,Zhao Jianan,Zhu Juanjuan,Pang Wei,Li Ning,Zhang Xu,Tian Xiao Yu,Yao Weijuan,Zhou Jing
Healing of the cutaneous wound requires macrophage recruitment at the sites of injury, where chemotactic migration of macrophages toward the wound is regulated by local inflammation. Recent studies suggest a positive contribution of DNA methyltransferase 1 (Dnmt1) to macrophage pro-informatory responses; however, its role in regulating macrophage motility remains unknown. In this study, myeloid-specific depletion of Dnmt1 in mice promoted cutaneous wound healing and de-suppressed the lipopolysaccharides (LPS)-inhibited macrophage motility. Dnmt1 inhibition in macrophages eliminated the LPS-stimulated changes in cellular mechanical properties in terms of elasticity and viscoelasticity. LPS increased the cellular accumulation of cholesterol in a Dnmt1-depedent manner; cholesterol content determined cellular stiffness and motility. Lipidomic analysis indicated that Dnmt1 inhibition altered the cellular lipid homeostasis, probably through down-regulating the expression of cluster of differentiation 36 CD36 (facilitating lipid influx) and up-regulating the expression of ATP-binding cassette transporter ABCA1 (mediating lipid efflux) and sterol O-acyltransferase 1 SOAT1 (also named ACAT1, catalyzing the esterification of cholesterol). Our study revealed a Dnmt1-dependent epigenetic mechanism in the control of macrophage mechanical properties and the related chemotactic motility, indicating Dnmt1 as both a marker of diseases and a potential target of therapeutic intervention for wound healing.
研究领域:
免疫学
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细胞生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
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2023
·
IF 4
Feier Cheng,Yaru Yang,Shaojun Yun,Jinling Cao,Mingchang Chang,Yanfen Cheng,Cuiping Feng
Sparassis latifolia polysaccharide (SLP) has broad application prospects as a raw material of functional food. This study aimed to investigate the effects of SLP on liver cholesterol metabolism and its mechanism. Sprague–Dawley rats were fed a high-fat, high-cholesterol diet, and various assessments were conducted including hematoxylin and eosin staining, measurement of liver and metabolic indices, and antioxidant analysis. In addition, fluorescence quantitative reverse transcription-polymerase chain reaction was performed to analyze mRNA expression, and gas chromatography-mass spectrometry was employed for screening differential metabolites. The results demonstrated that SLP reduced the abnormal increase in the liver index caused by high fat and cholesterol and improved liver tissue morphology, metabolism level, and antioxidant-related enzyme activities. The polysaccharide regulated the liver sterol metabolism pathway, decreased the mRNA expression levels of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) and sterol O-acyltransferase 1 (SOAT1), upregulated the mRNA expression levels of cholesterol 7α hydroxylase (CYP7α-1) and ABCA1, and increased the contents of propionic acid and butyric acid in the liver. These findings indicated a novel pathway through which SLP prevented hepatic lipid deposition and ameliorated sterol metabolism via regulating the HMG-CoAR-CYP7α-1 axis.
研究领域:
营养学
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生物化学
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分子生物学
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药理学
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DOI
高影响因子
Nanoscale Advances
·
2023
·
IF 4.7
Chunying Cui,Shuang Zhang,Dandan Li,Danni Liu,Yaoqi Wang,Qi Sun,Ran Sun,Jie Zhang,Xiaoxuan Hong,Ran Huo
Atherosclerosis is a chronic inflammatory disease, characterized by a lipid accumulated plaque. Anti-oxidative and anti-inflammation as well as lipid metabolism promoting therapeutic strategies have been applied for atherosclerosis treatment. However, the therapeutic effect by a single therapeutic method is limited. Combination of the two strategies could for one thing prevent lipid accumulation cause by inflammation and oxidative stress, for another thing promote lipid efflux from atherosclerotic plaque, to normalize arteries maximumly. Hence, a multifunctional liposome co-encapsulating an antioxidant and anti-inflammatory drug epigallocatechin-3-gallate(EGCG) as well as a lipid-efflux promoting gene miR-223 was established. The system (lip@EGCG/miR-223) could encapsulate miR-223 in core areas of the liposomes to provide an effective protective effect for gene drugs. Moreover, lip@EGCG/miR-223 was smaller in size (91.28±2.28 nm characterized by DLS), making it easier to target to AS lesions which had a smaller vascular endothelial spaces. After internalized into cellular efficiently, lip@EGCG/miR-223 exhibited excellent antioxidant and anti-inflammatory effects in vitro by eliminating overproduced ROS and decreasing the level of inflammatory cytokines (TNF-α, IL-1β and MCP-1), which is due to the effect of EGCG. Besides, the lipid-efflux promoting protein ABCA1 was up-regulated when treated with lip@EGCG/miR-223. By the two therapies mentioned, lip@EGCG/miR-223 could effectively inhibit the formation of foam cells, which is a main component of atherosclerotic plaques. In AS model mice, after intravenous (i.v.) administration, lip@EGCG/miR-223 was effectively accumulated in atherosclerotic plaques, and the distribution of drugs in heart and aorta to that in kidney was significantly increased when compared with free drugs (the ratio was 6.27% for free miR-223 treated group, and was increased to 66.10% for lip@EGCG/miR-223 treated group.). By decreasing inflammation level and lipid accumulation, the arterial vessels in AS were normalized with less macrophages and micro-angiogenesis when treated with lip@EGCG/miR-223. Overall, this study demonstrates lip@EGCG/miR-223 can be developed as a potential system for atherosclerosis treatment by a combined treatment of antioxidant, anti-inflammatory and lipid-efflux promoting effects, which provides a novel strategy for safe and efficient management of atherosclerosis.
研究领域:
药理学
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心血管疾病
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纳米技术
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-22
·
IF 10.2
Zhu Li,Li Hongjiao,Li Jiyu,Zhong Yuan,Wu Shuai,Yan Meng,Ni Sheng,Zhang Kun,Wang Guixue,Qu Kai,Yang Deqin,Qin Xian,Wu Wei
A disorder of cholesterol homeostasis is one of the main initiating factors in the progression of atherosclerosis (AS). Metabolism and removal of excess cholesterol facilitates the prevention of foam cell formation. However, the failure of treatment with drugs (e.g. methotrexate, MTX) to effectively regulate progression of disease may be related to the limited drug bioavailability and rapid clearance by immune system. Thus, based on the inflammatory lesion “recruitment” properties of macrophages, MTX nanoparticles (MTX NPs) camouflaged with macrophage membranes (MM@MTX NPs) were constructed for the target to AS plaques. MM@MTX NPs exhibited a uniform hydrodynamic size around ~ 360 nm and controlled drug release properties (~ 72% at 12 h). After the macrophage membranes (MM) functionalized “homing” target delivery to AS plaques, MM@MTX NPs improved the solubility of cholesterol by the functionalized β-cyclodextrin (β-CD) component and significantly elevate cholesterol efflux by the loaded MTX mediated the increased expression levels of ABCA1, SR-B1, CYP27A1, resulting in efficiently inhibiting the formation of foam cells. Furthermore, MM@MTX NPs could significantly reduce the area of plaque, aortic plaque and cholesterol crystals deposition in ApoE−/− mice and exhibited biocompatibility. It is suggested that MM@MTX NPs were a safe and efficient therapeutic platform for AS.Graphical Abstract
研究领域:
纳米技术
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药学
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心血管疾病
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生物医学工程
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DOI
PubMed
高影响因子
Bioactive Materials
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2022
·
IF 16.874
Ting Dai,Wenming He,Shuangshuang Tu,Jinru Han,Bo Yuan,Chenyang Yao,Wenzhi Ren,Aiguo Wu
Given that apoptosis increases the risk of plaque rupture, strategies that reduce intracellular lipid levels without killing foam cells are warranted for safe and effective treatment of atherosclerosis. In this study, a mild phototherapy strategy is carried out to achieve the hypothesis. Foam cell-targeted nanoprobes that allow photothermal therapy (PTT) and/or photodynamic therapy (PDT) were prepared by loading hyaluronan and porphine onto black TiO 2 nanoparticles. The results showed that when temperatures below 45 °C, PTT alone and PTT + PDT significantly reduced the intracellular lipid burden without inducing evidently apoptosis or necrosis. In contrast, the use of PDT alone resulted in only a slight reduction in lipid levels and induced massive apoptosis or necrosis. The protective effect against apoptosis or necrosis after mild-temperature PTT and PTT + PDT was correlated with the upregulation of heat shock protein 27. Further, mild-temperature PTT and PTT + PDT attenuated intracellular cholesterol biosynthesis and excess cholesterol uptake via the SREBP2/LDLR pathway, and also triggered ABCA1-mediated cholesterol efflux, ultimately inhibiting lipid accumulation in foam cells. Our results offer new insights into the mechanism of lipid regulation in foam cells and indicate that the black TiO 2 nanoprobes could allow safer and more effective phototherapy of atherosclerosis.
研究领域:
纳米技术
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光疗
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心血管疾病
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脂质代谢
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细胞生物学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）