INFLAMMATION
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2023
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IF 5.1
Xing Zeyu,Zhen Yanhua,Chen Jie,Du Mingyang,Li Dongdong,Liu Ruyin,Zheng Jiahe
Atherosclerosis (AS), characterized by a maladaptive inflammatory response, is one of the most common causes of death among the elderly. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, has been reported to play a pro-inflammatory role in various pathological processes by regulating the nuclear translocation of pro-inflammatory transcription factors. However, the function of KPNA2 in AS remains unknown. ApoE −/− mice were fed high-fat diets for 12 weeks to establish an AS mice model. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to establish an AS cell model. We found that KPNA2 was upregulated in the aortic roots of atherosclerotic mice and LPS-stimulated cells. KPNA2 knockdown inhibited LPS-induced secretion of pro-inflammatory factors and monocyte-endothelial adhesion in HUVECs, whereas KPNA2 overexpression exerted the opposite effects. p65 and interferon regulatory factor 3 (IRF3), the transcription factors known to regulate the transcription of pro-inflammatory genes, interacted with KPNA2, and their nuclear translocations were blocked following KPNA2 silencing. Furthermore, we found that KPNA2 protein level was decreased by E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7), which was downregulated in the atherosclerotic mice. FBXW7 overexpression induced ubiquitination with subsequent proteasomal degradation of KPNA2. Meanwhile, the effects of KPNA2 deficiency on atherosclerotic lesions were further confirmed by in vivo experiments. Taken together, our study indicates that KPNA2 downregulation, regulated by FBXW7, may alleviate endothelial dysfunction and related inflammation in the progression of AS by suppressing the nuclear translocation of p65 and IRF3.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2024
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IF 2.5
Menglong Gao,Lishun Dong,Yulong Yang,Jinjin Yan,Yuning Liang,Xiaolin Ma,Min Zhou,Hongfei Wu,Yarong Liu,Min Dai
Atherosclerosis (AS) is the underlying cause of many severe vascular diseases and is primarily characterized by abnormal lipid metabolism. Paeonol (Pae), a bioactive compound derived from Paeonia Suffruticosa Andr., is recognized for its significant role in reducing lipid accumulation. Our research objective is to explore the link between lipid buildup in foam cells originating from macrophages and the process of ferroptosis, and explore the effect and mechanism of Pae on inhibiting AS by regulating ferroptosis. In our animal model, ApoE-deficient mice, which were provided with a high-fat regimen to provoke atherosclerosis, were administered Pae. The treatment was benchmarked against simvastatin and ferrostatin-1. The results showed that Pae significantly reduced aortic ferroptosis and lipid accumulation in the mice. In vitro experiments further demonstrated that Pae could decrease lipid accumulation in foam cells induced by oxidized low-density lipoprotein (LDL) and challenged with the ferroptosis inducer erastin. Crucially, the protective effect of Pae against lipid accumulation was dependent on the SIRT1/NRF2/GPX4 pathway, as SIRT1 knockdown abolished this effect. Our findings suggest that Pae may offer a novel therapeutic approach for AS by inhibiting lipid accumulation through the suppression of ferroptosis, mediated by the SIRT1/NRF2/GPX4 pathway. Such knowledge has the potential to inform the creation of novel therapeutic strategies aimed at regulating ferroptosis within the context of atherosclerosis.
研究领域:
心血管疾病
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
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IF 10.383
Runze Zhao,Xiaoyue Ning,Mengqi Wang,Huanhuan Wang,Guang Xing,Li Wang,Chengzhi Lu,Ao Yu,Yongjian Wang
Nanoprodrugs with responsive release properties integrate the advantages of stimuli-responsive prodrugs and nanotechnology. They would provide ultimate opportunity in fighting atherosclerosis. In this study, we synthesized a redox-responsive nanoprodrug of simvastatin (TPTS) by conjugating α-tocopherol polyethylene glycol derivative to the pharmacophore of simvastatin with a thioketal linker. TPTS formed nanoparticles and released parent simvastatin in the presence of hydrogen peroxide. Moreover, by taking advantage of the self-assembly behavior of TPTS, we developed a fibronectin-targeted delivery system (TPTS/C/T) to codelivery simvastatin prodrug and ticagrelor. In vitro and in vivo experiments indicated that TPTS and TPTS/C/T had good stability, which could reduce off-target leakage of drugs. They greatly inhibited the M1-type polarization of macrophages; reduced intracellular reactive oxygen species level and inflammatory cytokine; and TNF-α, MCP-1, and IL-1β were secreted by macrophage cells, thus providing enhanced anti-inflammatory and antioxidant effects compared with free simvastatin. TPTS/C/T realized targeted drug release to plaques and synergistic therapeutic effects of simvastatin and ticagrelor on atherosclerosis treatment in an ApoE–/– mouse model, resulting in excellent atherosclerosis therapeutic efficacy and a promising biosafety profile. Therefore, this study provides a new method for manufacturing statin nanodrugs and a new design idea for related responsive drug release nanosystems for atherosclerosis.
研究领域:
药学
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纳米技术
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心血管疾病
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药物递送系统
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Heng Ye,Gang Wang,Xuchao Wang,Lin Wang,Wei Ni,Linjian Chen,Yifan Zhu,Longshan Zhao,Zhili Xiong,Yan Wang,Cuilian Dai,Binbin Liu
Ethnopharmacological relevance Dyslipidemia is the leading risk factor of atherosclerosis (AS). Adipose tissue macrophages (ATMs) can regulate postprandial cholesterol levels via uptake and hydrolyzation of lipids and regulation of macrophage cholesterol efflux (MCE). San-wei-tan-xiang (SWTX) capsule , a Traditional Chinese medicine , exerts clinical benefits in patients with atherosclerotic cardiovascular diseases . Aim of the study This work is aimed to evaluate the chemical ingredients and mechanisms of SWTX in anti-AS. Materials and methods The chemical ingredients of SWTX identified by liquid chromatography coupled with tandem mass spectrometry were used for network pharmacological analysis. The atheroprotective function of SWTX was evaluated in ApoE −/− mice fed a cholesterol-enriched diet. Results The chemical ingredients identified in SWTX were predicated to be important for lipid metabolism and AS. Animals studies suggested that SWTX effectively attenuated the atherosclerotic plaque growth, elevated postprandial HDL cholesterol levels, elevated the proportion of Tim4 and CD36-expressed ATMs, and upregulated the uptake of lipid and lysosomal activity in ATMs. SWTX-induced elevation of postprandial HDL cholesterol levels was dependent on increased lysosomal activity, since chloroquine , an inhibitor of lysosomal function, blocked the effect of SWTX. Lastly, some predicated bioactive compounds in SWTX can elevate lysosomal activity in vitro . Conclusion SWTX could attenuate atherosclerotic plaque formation by elevating lysosomal activity and enhancing MCE in ATMs.
研究领域:
药理学
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心血管疾病
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传统中药
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代谢
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免疫学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2024
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IF 8.3
Jinjin Yu,Yajing Ma,Xinya Zhang,Siqi Wang,Lili Zhou,Xinyao Liu,Lingli Li,Lingyi Liu,Huixin Song,Yuzhi Luo,Sha Wen,Weifeng Li,Xiaofeng Niu
Natural products have been widely recognized in clinical treatment because of their low toxicity and high activity. It is worth paying attention to modifying the biopolymer into nanostructures to give natural active ingredients additional targeting effects. In this study, based on the multifunctional modification of β-cyclodextrin (β-CD), a nanoplatform encapsulating the unstable drug (−)-epicatechin gallate (ECG) was designed to deliver to atherosclerotic plaques. Acetalization cyclodextrin (PH-CD), which responds to low-pH environments, and hyaluronic acid cyclodextrin, which targets the CD44 receptor on macrophage membranes, were synthesized from β-CD and hyaluronic acid using acetalization and transesterification, respectively. The resulting dual-carrier nanoparticles (Double-NPs) loaded with ECG were prepared using a solvent evaporation method. The Double-NPs effectively scavenged reactive oxygen species, promoted macrophage migration, inhibited macrophage apoptosis, and suppressed abnormal proliferation and migration of vascular smooth muscle cells. Furthermore, the Double-NPs actively accumulated in atherosclerotic plaques in ApoE–/– mice fed with a high-fat diet, leading to a reduced plaque area, inflammatory infiltration, and plaque instability. Our findings demonstrate that the newly developed ECG nanopreparation represents an effective and safe nanotherapy for diseases such as atherosclerosis.
研究领域:
药学
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纳米技术
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心血管疾病
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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
World Journal of Traditional Chinese Medicine
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2025
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IF 3.2
Zhang Hui-Wen,Wang Jian-Ye,Liu Yan-Yan,Tian Jing-Min,Park Jinbong,Wang Huan-Yun,Xu Ying-Qi
Background: Atherosclerosis (AS) serves as the primary pathological foundation for numerous cardiovascular diseases, such as thromboembolic conditions, coronary artery disease, and ischemic cardiac-cerebral vascular disorders. Sanzi San, a traditional Chinese medicinal formulation with a long-standing clinical reputation for efficacy against AS, has not yet had its pharmacological mechanisms fully elucidated. Objective: Our objective is to investigate the impact of Sanzi San on AS in ApoE −/− mice models and elucidate the pharmacological mechanism via an integrated approach of serum pharmacochemistry, network pharmacology, and pharmacokinetic analysis. Materials and Methods: The chemical constituents in Sanzi San and serum were identified using high-performance liquid chromatography-quadrupole/Orbitrap high-resolution mass spectrometry (HPLC-Q/Orbitrap HRMS). A network pharmacology approach, including protein–protein interaction (PPI) and gene ontology enrichment analyses, was then used to investigate the connection between these components and their anti-atherosclerotic activity. Finally, ultra-HPLC-tandem mass spectrometry was used to determine the formula’s pharmacokinetic parameters following oral administration. Results: Through a comparison of serum samples from control and treated groups, 41 prototype compounds originating from Sanzi San were identified. These constituents were classified into three major groups – terpenes, iridoids, and phenolic acids – and were regarded as the potential bioactive components due to their absorption into the bloodstream. Network pharmacology analysis indicated that Sanzi San directly influences blood vessels by regulating their diameter to achieve therapeutic effects. Furthermore, Sanzi San demonstrated therapeutic potential by specifically targeting natural killer (NK) cells within plaque tissue and adventitial cells in the aorta. In vivo validation in ApoE −/− mice showed that Sanzi San improved aortic lesions and regulated body weight. Pharmacokinetic studies also revealed that seven major components of Sanzi San were present in plasma, confirming its pharmacological effects on AS. Conclusion: This study provides evidence of Sanzi San’s clinical efficacy in treating AS. The integrated strategy combining serum pharmacochemistry, network pharmacology, and pharmacokinetics offers a powerful approach for uncovering the key pharmacological mechanisms of herbal formulations.
研究领域:
药理学
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心血管医学
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中医学
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系统生物学
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质谱分析
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药代动力学
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产品关联
DOI
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2023
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IF 13.6
Bingwei Yang,Zhishuai Ye,Xiangyu Zhu,Rongchong Huang,Erqun Song,Yang Song
Further investigations are required to prove that polychlorinated biphenyls (PCBs) exposure is a cardiovascular disease risk factor. Unlike previous studies that attributed the atherogenic effect of PCBs to aryl hydrocarbon receptor activation, we illustrated a new mechanism involved in the redox reactivity of PCBs. We discover the redox reactivity of quinone moiety is the primary factor for PCB29-pQ-induced proinflammatory response, which highly depends on the status of caveolin 1 (CAV1) phosphorylation. PCB29-pQ-mediated CAV1 phosphorylation disrupts endothelial nitric oxide synthase, toll-like receptor 4, and reduces interleukin-1 receptor-associated kinase 1 binding with CAV1. Phosphorylated proteomics analysis indicated that PCB29-pQ treatment significantly enriched phosphorylated peptides in protein binding functions, inflammation, and apoptosis signaling. Meanwhile, apolipoprotein E knockout (ApoE -/- ) mice exposed to PCB29-pQ had increased atherosclerotic plaques compared to the vehicle group, while this effect was significantly reduced in ApoE -/- /CAV1 -/- double knockout mice . Thus, we hypothesis CAV1 is a platform for proinflammatory cascades induced by PCB29-pQ on atherosclerotic processes. Together, these findings confirm that the redox activity of PCB metabolite plays a role in the etiology of atherosclerosis.
研究领域:
心血管疾病
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毒理学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Yifu Lyu,Xiuyi Yang,Lei Yang,Jinyu Dai,Huanyu Qin,Yunuo Zhou,Yunan Huang,Yanmei Wang,Di Wu,Qindai Shuai,Qilong Li,Xiaofei Xin,Lifang Yin
Lipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway. We then adopted a three-round screening strategy to optimize the formulation with both high potency and selectivity to deliver siRNA-HIF-1α (siHIF1α) and silibinin (SLB) payloads to hepatocytes. The optimized SLB/siHIF1α-LNPs mediates great siRNA delivery and transfection of hepatocytes. In high fat diet (HFD)- and carbon tetrachloride (CCl 4 )-induced mouse models of MASLD, SLB/siHIF1α-LNPs enabled the silencing of hypoxia inducible factor-1α (HIF-1α), a therapeutic target primarily expressed by hepatocytes, leading to significantly reduced inflammation and liver fibrosis synergized with SLB. Moreover, it is demonstrated the hepatocyte-targeting delivery of SLB/siHIF1α-LNPs has the potential to restore the immune homeostasis by modulating the population of Tregs and cytotoxic T cells in spleen. This proof-of-concept study enable siRNA and small molecule co-delivery to hepatocytes through intrinsic variation of targeting receptors for MASLD therapy.
研究领域:
药学
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分子生物学
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肝病学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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