INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Boyuan Gu,Yu Jiang,Zhiwei Huang,Han Li,Wenhao Yu,Tongxi Li,Chen Liu,Pengru Wang,Jiatong Chen,Lei Sun,Peng Tan,Wenguang Fu,Jian Wen
Objective Disorders of lipid oxidation play an important role in organ damage, and lipid metabolites are associated with inflammation and coagulation dysfunction in sepsis. However, the specific molecular mechanism by which lipid metabolism-related proteins regulate sepsis is still unclear. The aim of this study is to investigate the role of mortality factor 4-like protein 1 (MORF4L1, also called MRG15), a hepatic lipid metabolism related gene, in sepsis-induced liver injury. Methods In the mouse sepsis models established by cecal ligation and puncture (CLP) and lipopolysaccharide (LPS), the impact of pretreatment with the MRG15 inhibitor argatroban on sepsis-related liver injury was investigated. In the LPS-induced hepatocyte sepsis cell model, the effects of MRG15 overexpression or knockdown on hepatic inflammation and lipid metabolism were studied. Additionally, in a co-culture system of hepatocytes and macrophages, the influence of MRG15 knockdown in hepatocytes on the synthesis and secretion of inflammation-related protein PCSK9 as well as its effect on macrophage activation were examined. Results Studies have shown that MRG15 expression was increased in septicemia mice and positively correlated with lipid metabolism and inflammation. However, knockdown of MRG15 ameliorates sepsis-induced hepatocyte injury. Increased MRG15 in LPS-stimulated hepatocytes promotes PCSK9 synthesis and secretion, which induces macrophage M1 polarization and exacerbates the inflammatory response. Agatroban, an inhibitor of MRG15, ameliorates sepsis-induced liver injury in mice by inhibiting MRG15-induced lipid metabolism disorders and inflammatory responses. Conclusions In sepsis, increased MRG15 expression in hepatocytes leads to disturbed hepatic lipid metabolism and induces macrophage M1 polarization by secreting PCSK9, ultimately exacerbating liver injury.
研究领域:
免疫学
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肝病学
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药理学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2019
·Vol. 20
·期 2
·1383-1392
·
IF 1.851
Zhewen Dong,Wenxiang Zhang,Siyu Chen,Chang Liu
Hypercholesterolemia is one of the major risk factors for the occurrence and development of atherosclerosis. The most common drugs used to treat hypercholesterolemia are 3‑hydroxy‑3‑methyl‑glutaryl‑CoA reductase inhibitors, known as statins. Statins induce a beneficial increase in the levels of the low density lipoprotein receptor (LDLR) and additionally upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which leads to LDLR degradation. This process causes a negative feedback response that attenuates the lipid lowering effects of statins. Therefore, the development of PCSK9 inhibitors may increase the lipid‑lowering functions of statins. In the present study, a drug‑screening assay was developed using the human PCSK9 promoter, based on data from a dual‑luciferase reporter assay, and the efficacies of various compounds from Traditional Chinese Medicine were examined. Among the compounds examined, SIL was demonstrated to function by targeting PCSK9. It was identified that SIL treatment decreased the expression levels of PCSK9 in HepG2 cells by decreasing the activity of the PCSK9 promoter in a dose‑and time‑dependent manner. Notably, SIL antagonized the statin‑induced phosphorylation of the p38 MAPK signaling pathway. The present study suggested that SIL may be developed as a novel PCSK9 inhibitor that may increase the efficiency of statin treatment.
研究领域:
药理学
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分子生物学
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心血管疾病
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2019
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IF 4.511
Shasha You,Xiaoyu Guo,Xiaomei Xue,Yongyong Li,Haiqing Dong,Haiying Ji,Ting Hong,Yazhong Wei,Xueyin Shi,Bin He
In recent years, various vaccination strategies have shed new light on the treatment of atherosclerosis. Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a hot target in the development of antiatherosclerosis vaccine. However, the efficacy of conventional PCSK9 is largely limited by poor immunogenicity and low hapten density. Therefore, we hypothesized whether a nanostructure synthesized by self-assembled carrier protein accompanied by multicopy hapten display could improve the efficacy of vaccine. In this study, bovine serum albumin (BSA) was self-assembled into sub-100 nm nanoparticles via an intermolecular disulfide network as the inner core. Then, sequences of PCSK9 were conjugated onto the surface of nanoparticles by “click” chemistry to consequently form an orderly structured of nanovaccine with repetitive hapten display. Compared with conventional PCSK9 peptide vaccine, our immunization study demonstrated that the PCSK9 multicopy display nanovaccine (PMCDN) was able to induce higher titers of PCSK9 antibody and more efficient lymph node drainage and improve endocytosis by antigen presenting cells.
研究领域:
药学
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免疫学
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纳米技术
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心血管疾病
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产品关联
DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2025
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IF 5.7
Chuan Wang,Junyue Xing,Huan Zhao,Xiru Chen,Zongfeng Niu,Xiaohan Ma,Yuesheng Gui,Xinkun Qi,Yingchao Shi,Xiaolei Cheng,Dongdong Jian,Chao Shi,Hao Tang,Zhen Li
Elevated levels of low-density lipoprotein cholesterol (LDL-C) play a critical role in the onset and progression of cardiovascular disease (CVD). Inhibitors or monoclonal antibody drugs targeting pro-protein convertase subtilisin/kexin type 9 (PCSK9) are novel cholesterol-lowering medications that can effectively reduce serum LDL-C levels. However, these drugs are usually expensive and require injections, which can reduce patient compliance and increase the financial burden. In this study, we constructed an engineered probiotic strain containing a prokaryotic expression element and a high-affinity fragment of the human PCSK9 nanobody (PCSK9nb). The engineered bacterium was evaluated in vitro and in vivo for its ability to express and release PCSK9nb, as well as for its biocompatibility and stability. The therapeutic potential of the engineered probiotics was confirmed using mouse models of hyperlipidemia and atherosclerosis. We analyzed differences in mouse gut microbiota using high-throughput sequencing and compared the therapeutic efficacy of the engineered bacteria with that of atorvastatin in a mouse model of hyperlipidemia. The engineered bacteria were found to express and release PCSK9nb in vivo after oral administration, achieving the effect of lowering serum cholesterol levels, alleviating atherosclerosis, and reducing body weight. In vivo, PCSK9nb was found to increase hepatic LDL receptor (LDLR) expression levels, decrease serum LDL-C content, regulate the diversity and community structure of gut microbiota, reduce lipid accumulation in the liver, and decrease systemic inflammation. By comparing their efficacy with that of statins, the engineered probiotics demonstrated similar therapeutic effects. The research results provide a new strategy for the development of orally delivered PCSK9 antibody drugs, reducing healthcare costs and minimizing statin drug tolerance.
研究领域:
心血管病学
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分子生物学
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微生物组学
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代谢疾病
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转化医学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BIOCHIMIE
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2023
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IF 3.9
Ya-nan Ou-Yang,Fen-fen Deng,Yun-jia Wang,Meng Chen,Peng-fei Yang,Zhe Yang,Zhongmin Tian
A high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt - induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt - sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL - C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.
研究领域:
营养学
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心血管疾病
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分子生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
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2024
·Vol. 50
·期 1
·1-15
·
IF 3.7
Luo Yuanfei,Yuan Linying,Liu Zhihui,Dong Weichen,Huang Li,Liao Anyu,Xie Yi,Liu Rui,Lan Wenya,Cai Yulong,Zhu Wusheng
Proprotein convertase substilin/kexin type 9 (PCSK9), a pivotal protein regulating lipid metabolism, has been implicated in promoting microthrombotic formation and inflammatory cascades, thereby contributing to cardiovascular ischemia/reperfusion (I/R) injury. However, its involvement in cerebral I/R injury and its potential role in microcirculation protection remain unexplored. In this investigation, we utilized a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate ischemic stroke. Different concentrations of evolocumab (1, 5, 10 mg/kg, i.v.), a PCSK9 inhibitor, were administered to assess its impact. Immunofluorescence staining was employed to analyze changes in the expression of occludin, claudin-5, thrombocyte, ICAM-1, VCAM-1, and CD45, providing insights into blood-brain barrier integrity, platelet adhesion, and immune cell infiltration. Moreover, the Morris water maze and elevated plus maze were utilized to evaluate neurological and behavioral functions in MCAO/R mice, shedding light on the effects of PCSK9 inhibition. Our findings revealed a surge in plasma PCSK9 levels post-MCAO/R, peaking at 24 h post-reperfusion. Evolocumab (10 mg/kg) treatment significantly mitigated brain infarction and neurological deficits, evidenced by enhanced locomotor function and reduced post-stroke anxiety. However, it did not ameliorate cognitive impairment following MCAO/R. Additionally, evolocumab administration led to diminished leakage of evans blue solution and upregulated expression of occludin and claudin-5. Thrombocyte, ICAM-1, VCAM-1, and CD45 levels were notably reduced in the penumbral area post-evolocumab treatment. These protective effects are speculated to be mediated through the inhibition of the ERK/NF-κB pathway. The PCSK9 inhibitor evolocumab holds promise as a therapeutic agent during the acute phase of stroke, exerting its beneficial effects by modulating the ERK/NF-κB signaling pathway.
研究领域:
神经科学
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药理学
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心血管研究
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免疫学
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DOI
高影响因子
Materials Today Bio
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2025
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IF 10.2
Ling Chen,Meng Hu,Hui-min Yan,Xue-Qing Ding,Qiu-xiang Yang,Ling Wang,Hong Pan
The immunosuppressive microenvironment and impaired antigen presentation represent significant challenges in melanoma treatment. This study explores strategies to overcome these barriers by simultaneously inducing tumor cell immunogenic cell death (ICD) and enhancing antigen presentation. We developed hyaluronic acid/R8-RGD dual-modified albumin nanoparticles (HR/LDPP-NPs) designed to co-deliver low-dose paclitaxel (PTX) and the PCSK9 inhibitor PF-06446846. PTX induces ICD, releasing calreticulin (CRT), ATP, and HMGB1 danger signals, thereby transforming tumor cells into an in situ antigen source and initiating dendritic cell-mediated T-cell responses, akin to an intrinsic vaccine effect. Simultaneously, the inhibition of PCSK9 significantly upregulates tumor MHC-I expression, counteracting immune evasion. This synergistic approach, combining in situ vaccination with enhanced antigen presentation, significantly amplifies antitumor immunity. Both in vitro and in vivo experiments demonstrate that these spatiotemporally coordinated dual-targeting nanoparticles achieve substantial therapeutic efficacy with significantly reduced toxicity, presenting a novel chemo-immunotherapeutic strategy for melanoma treatment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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转化医学
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分子药理学
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肿瘤免疫治疗
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2023
·Vol. 15
·期 10
·2377
·
IF 5.4
Hua Cai,Rongrong Zheng,Ningxia Wu,Jiaman Hu,Ruixin Wang,Jianing Chi,Wei Zhang,Linping Zhao,Hong Cheng,Ali Chen,Shiying Li,Lin Xu
Chemotherapy-induced side effects restrain anti-tumor efficiency, with hyperlipidemia being the most common accompanying disease to cause treatment failure. In this work, a chimeric peptide-engineered nanomedicine (designated as PRS) was fabricated for the synergistic suppression of tumor growth and therapy-induced hyperlipidemia. Within this nanomedicine, the tumor matrix-targeting peptide palmitic-K(palmitic)CREKA can self-assemble into a nano-micelle to encapsulate Rapamycin (mTOR inhibitor) and SBC-115076 (PCSK9 inhibitor). This PRS nanomedicine exhibits a uniform nano-distribution with good stability which enhances intracellular drug delivery and tumor-targeting delivery. Also, PRS was found to synergistically inhibit tumor cell proliferation by interrupting the mTOR pathway and reducing Rapamycin-induced hyperlipidemia by increasing the production of LDLR. In vitro and in vivo results demonstrate the superiority of PRS for systematic suppression of tumor growth and the reduction of hyperlipidemia without initiating any other toxic side effects. This work proposes a sophisticated strategy to inhibit tumor growth and also provides new insights for cooperative management of chemotherapy-induced side effects.Keywords:anti-tumor;hyperlipidemia;tumor-targeted peptide;nanomedicine;Rapamycin;proprotein convertase subtilisin/kexin type 9 (PCSK9)
研究领域:
肿瘤学
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药理学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
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.
研究领域:
纳米技术
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药学
·
心血管疾病
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产品关联
DOI
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2017
·
IF 7.78
Yan Li,Junlin He,Jun Chen,Yazhen Niu,Yilin Zhao,Yuchan Zhang,Chao Yu
In this study, a dual-type responsive electrochemical immunosensor was developed for the quantitative detection of proprotein convertase subtilisin/kexin type 9 (PCSK9), a potential biomarker of cardiovascular disease in serum. N-doped graphene nanoribbons (N-GNRs) with good conductivity were used as the sensing matrix modifying the glassy carbon electrode. Palladium platinum alloy (PdPt) nanoparticles with high catalytic performance toward the reduction of hydrogen peroxide (H 2 O 2 ) were reduced onto amino-functionalized fullerene (n-C 60 -PdPt) and significantly amplified the electrochemical signal recorded by the amperometric i-t curve. Furthermore, staphylococcus protein A (SPA) with antibody orientation function was introduced to improve the immunoreaction efficiency. Accordingly, a label-free immunosensor was fabricated based on n-C 60 -PdPt/N-GNRs for the quick detection of PCSK9. Meanwhile, to realize ultrasensitive detection of PCSK9, Pt-poly (methylene blue) (Pt-PMB) nanocomposites synthesized by a one-pot method for the first time were used as a novel signal label, which exhibited uniform morphology as well as good conductivity and produced an electrochemical signal recorded by differential pulse voltammetry (DPV). Herein, a novel sandwich-type immunosensor was designed using n-C 60 -PdPt/N-GNRs as the sensing matrix and Pt-PMB as the signal label for sensitive detection of PCSK9. Under optimal conditions, the label-free immunosensor showed a linear range of 10 pg mL −1 to 100 ng mL −1 with a detection limit of 3.33 pg mL −1 (S/N=3), and the sandwich-type immunosensor exhibited a linear range of 100 fg mL −1 to 100 ng mL −1 with a detection limit of 0.033 pg mL −1 (S/N=3) for PCSK9 detection, indicating its potential application in clinical bioassay analysis.
研究领域:
生物医学工程
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分析化学
·
临床检验
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD AND DRUG ANALYSIS
·
2020
·
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.
研究领域:
药理学
·
分析化学
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分子生物学
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药物发现
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2026
·Vol. 34
·期 3
·1-12
·
IF 5
Chaochu Cui,Jinyu Zhao,Xiaoqian Li,Shengming Huang,Gang Liu,Xinhui Xu,Can Guo,Tiesuo Zhao,Jiang Du,Shipeng Li,Xianwei Wang,Jianbo Yang
Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.
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DOI
PubMed
高影响因子
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