MATERIALS & DESIGN
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2023
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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.
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DOI
高影响因子
JOURNAL OF FOOD AND DRUG ANALYSIS
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2020
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IF 4.727
Li Li,Meng-Lin Fan,Ya-Nan Li,Ya-Xuan Huang,Xiu-Feng Liu,Ji-Hua Liu
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an attractive target for new cholesterol-lowering drug development. Here, we developed a method integrating ligand fishing, HPLC-Q-TOF-MS and interdisciplinary assay, aiming to explore potential PCSK9 inhibitors from mixtures rapidly and accurately. PCSK9 was expressed and purified firstly, and then the recombined PCSK9 was coated on the surface of magnetic beads (MBs). The PCSK9-immobilized MBs (PCSK9-MBs) were used for ligand fishing combined with HPLC and Q-TOF-MS/MS. Ginkgo biloba leaves (GBL), an herbal medicine widely used in Asia and Europe with good efficacy in treatment of hypercholesterolemia, were chosen as an illustration for ligand fishing. Two PCSK9 ligands were discovered from GBL and identified as kaempferol-3-O-rutinoside (1) and kaempferol 3-O-26″-(6‴-p-coumaroyl) glucosylrhamnoside (KCGR) (2). In order to verify fishing results and pick out more powerful PCSK9 inhibitors, molecular docking assay was further performed and KCGR was optimized to be an excellent PCSK9 inhibitor by the confirmation of affinity and activity bioassay. These results suggested that the developed approach could be applied to screen and analysis potential bioactive constituents from mixtures, which may improve the efficiency of drug discovery. Moreover, KCGR separated from GBL was expected to be a potential candidate of PCSK9 inhibitors.
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2024
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IF 6.8
Yun Zhao,Guobin Zheng,Shu Yang,Shangjing Liu,Yifan Wu,Yaodong Miao,Zhen Liang,Yunqing Hua,Jing Zhang,Jia Shi,Dan Li,Yanfei Cheng,Yunsha Zhang,Yuanli Chen,Guanwei Fan,Chuanrui Ma
Background and purpose Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS ( Panax notoginseng saponins ), containing the main active ingredients of Panax notoginseng , exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s). Experimental approach The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE −/− mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2 −/− macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2 −/− mice treated with high-fat diet (HFD) and AAV-PCSK9. Key results PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro. Conclusion and implications PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS. Graphical
研究领域:
心血管疾病
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药理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
BIOMATERIALS
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2024
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IF 12.8
Weihan Zhang,Shijun Yuan,Zipeng Zhang,Shunli Fu,Shujun Liu,Jinhu Liu,Qingping Ma,Zhenxing Xia,Panpan Gu,Shuying Gao,Zhiyue Zhang,Xinke Zhang,Yongjun Liu,Na Zhang
Tumor cells transmit various immunosuppressive signals and induce a dysfunctional state in T cells, which essentially leads to immune escape and tumor progression. However, developing effective strategies to counteract the domestication of T cells by tumor cells remains a challenge. Here, we prepared pH-responsive lipid nanoparticles (NL/PLDs) co-loaded with PCSK9 shRNA, lonidamine (LND), and low-dose doxorubicin (DOX). NL/PLDs can awaken domesticated T cells function by sending pro-activation, pro-recognition, and pro-killing signals by increasing tumor immunogenicity, increasing the expression of major histocompatibility complex I (MHC-I) on tumor cells, and alleviating the suppression effect of tumor-secreted lactic acid (LA) on the T cell effector function, respectively. In melanoma-bearing mice, NL/PLDs effectively relieved tumor immunosuppressive microenvironment (TIME) and enhanced the antitumor immunity mediated by CD8 + T cells. Furthermore, when combined with aPD-1, NL/PLDs demonstrated strong antitumor effects and increased immunotherapeutic efficacy. This regulatory strategy provides new insights for enhancing immunotherapy by regulating tumor immunosuppressive signals and shows significant potential for clinical tumor treatment.
研究领域:
肿瘤学
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免疫学
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纳米技术
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药理学
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PubMed
高影响因子
ACS Nano
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2024
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IF 15.8
Shiji Fang,Liyun Zheng,Gao-Feng Shu,Chen Xiaoxiao,Xiaoju Guo,Yiming Ding,Wenjing Yang,Jiale Chen,Zhongwei Zhao,Jianfei Tu,Minjiang Chen,Jian-Song Ji
Immunotherapy is the most promising systemic therapy for hepatocellular carcinoma. However, the outcome remains poor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in altering cell-surface protein levels, potentially undermining the efficacy of immunotherapy against tumors. This highlights its potential as a target for antitumor therapy. Herein, CaCO3-based nanoparticles coencapsulated with DOX, an immunogenic cell death (ICD) inducer, and evolocumab was developed to enhanced the efficacy of immunotherapy. The obtained DOX/evolocumab-loaded CaCO3 nanoparticle (named DECP) exhibits a good capacity of acid neutralization and causes ICD of cancer cells. In addition, DECP is able to evaluate the cell-surface level of MHC-I, a biomarker that correlates positively with patients’ overall survival. Upon intravenous injection, DECP accumulates within the tumor site, leading to growth inhibition of hepa1-6 bearing subcutaneous tumors. Specifically, DECP treatment causes augmented ratios of matured dendritic cells, tumor-infiltrating CD8+ T cells and natural killing cells, while concurrently depleting Foxp3+ regulatory T cells. Peritumoral delivery of DECP enhances the immune response of distant tumors and exhibits antitumor effects when combined with intravenous αPD-L1 therapy in a bilateral tumor model. This study presents CaCO3-based nanoparticles with multiple immunomodulatory strategies against hepatocellular carcinoma by targeting PCSK9 inhibition and modulating immune homeostasis in the unfavorable TME.
研究领域:
肿瘤学
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免疫学
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纳米技术
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药理学
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DOI
PubMed
高影响因子
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