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      Astragaloside IV protects endothelial progenitor cells from the damage of ox-LDL via the LOX-1/NLRP3 inflammasome pathway

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          Abstract

          Purpose: Functional impairment of endothelial progenitor cells (EPCs) is frequently observed in patients with diabetic vascular complications. Astragaloside IV (ASV) has a significant protective effect against vascular endothelial dysfunction. Thus, this study aimed to investigate the role of ASV on oxidized low-density lipoprotein (ox-LDL)-induced EPCs dysfunction and its potential mechanisms.

          Methods: EPCs were isolated from the peripheral blood of mice and treated with different concentration of ASV (10, 20, 40, 60, 80, 100 and 200 µM). ox-LDL was served as a stimulus for cell model. The proliferation and migration, and improved tube formation ability of EPCs were determined. Reactive oxygen species (ROS) production and the levels of inflammatory cytokines, including interleukin 1β (IL-1β), IL-6, IL-10 and tumor necrosis factor (TNF-α) were measured. The expression oflectin-like oxidized LDL receptor (LOX-1) andNod-like receptor nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3) inflammasome were detected by Western blot analysis.

          Results: We found ASV treatment alleviated ox-LDL-induced cellular dysfunction, as evidenced by promoted proliferation and migration, and improved tube formation ability. Besides, ASV treatment significantly suppressed ox-LDL-induced ROS production and the levels of inflammatory cytokines. ASV inhibited ox-LDL-induced expression of LOX-1 in a concentration-dependent manner. Overexpression of LOX-1 in EPCs triggered NLRP3inflammasome activation, while inhibition of LOX-1 or treatment with ASV suppressed ox-LDL-induced NLRP3 inflammasome activation. Furthermore, overexpression of LOX-1 in ox-LDL-induced EPCs furtherly impaired cellular function, which could be ameliorated by ASV treatment.

          Conclusion: Our study showed that ASV may protect EPCs against ox-LDL-induced dysfunction via LOX-1/NLRP3 pathway.

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          Most cited references 33

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          Research review on the pharmacological effects of astragaloside IV.

          Astragalus membranaceus Bunge has been used to treat numerous diseases for thousands of years. As the main active substance of Astragalus membranaceus Bunge, astragaloside IV (AS-IV) also demonstrates the potent protective effect on focal cerebral ischemia/reperfusion, cardiovascular disease, pulmonary disease, liver fibrosis, and diabetic nephropathy. Based on studies published during the past several decades, the current state of AS-IV research and the pharmacological effects are detailed, elucidated, and summarized. This review systematically summarizes the pharmacological effects, metabolism mechanism, and the toxicity of AS-IV. AS-IV has multiple pharmacologic effects, including anti-inflammatory, antifibrotic, antioxidative stress, anti-asthma, antidiabetes, immunoregulation, and cardioprotective effect via numerous signaling pathways. According to the existing studies and clinical practices, AS-IV possesses potential for broad application in many diseases.
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            Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction.

            1. Recent studies have revealed an association between coronary risk factors and both the number and function of bone marrow-derived endothelial progenitor cells (EPC). We investigated the effect of oxidized low-density lipoprotein (ox-LDL) on the senescence of EPC, leading to cellular dysfunction. 2. Endothelial progenitor cells were isolated from human peripheral blood and characterized. The exposure of cultured EPC to ox-LDL (10 microg/mL) significantly accelerated the rate of senescence compared with control during 20 days in culture as determined by acidic beta-galactosidase staining. Oxidized LDL-induced EPC senescence was significantly inhibited by pretreatment with either lectin-like ox-LDL receptor-1 (LOX-1) antibody (Ab) or atorvastatin (P < 0.01). 3. Because cellular senescence is critically influenced by telomerase, which elongates telomeres, we measured telomerase activity using a polymerase chain reaction-ELISA-based assay. Oxidized LDL significantly diminished telomerase activity to approximately 50%, an effect that was significantly abolished by pretreatment with either LOX-1 Ab or atorvastatin (P < 0.01). 4. We examined whether ox-LDL-induced EPC senescence translates into EPC dysfunction. An MTS assay disclosed an inhibitory effect of ox-LDL on EPC proliferation. In a Matrigel assay, EPC treated with ox-LDL were less likely to participate in network formation compared with controls. 5. In conclusions, ox-LDL accelerates the onset of EPC senescence, which may be related to telomerase inactivation. Oxidized LDL-induced EPC senescence leads to the impairment of proliferative capacity and network formation.
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              Oxidized low-density lipoprotein induces secretion of interleukin-1β by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation.

              Oxidized low-density lipoprotein (ox-LDL) is a critical mediator of atherogenesis. Macrophage uptake of ox-LDL and their subsequent development into foam cells is the principal event in atherosclerosis. Interleukin-1β (IL-1β), a prototypic multifunctional cytokine involved in inflammation, has an important effect on the pathogenesis and progression of atherosclerosis. Here we show that the phagocytosis of ox-LDL can induce human macrophages to secrete IL-1β by activating the NLRP3 inflammasome, and we further show that the activation of the NLRP3 inflammasome is dependent on the generation of reactive oxygen species and is related to the cathepsin B pathway. Furthermore, ox-LDL can upregulate the expression of the pro-IL-1β protein, thus priming IL-1β secretion. Therefore, our results suggest that the role of ox-LDL in atherosclerosis-related inflammation may involve the activation of the NLRP3 inflammasome. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                29 July 2019
                2019
                : 13
                : 2579-2589
                Affiliations
                [1 ] Department of Lung Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250011, People’s Republic of China
                [2 ] Postdoctoral Station, Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250355, People’s Republic of China
                [3 ] Department of Traditional Chinese Medicine, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences , Jinan, Shandong 250062, People’s Republic of China
                [4 ] Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250011, People’s Republic of China
                [5 ] Academic Department, China Association of Chinese Medicine , Beijing 100029, People’s Republic of China
                [6 ] Preventive Treatment Department, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Jinan, Shandong 250001, People’s Republic of China
                Author notes
                Correspondence: Weibin QianDepartment of Lung Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Cultural Road No. 42, Jinan City, Shandong province250011, People’s Republic of ChinaTel +86 1 366 881 6868Email doctorqwb1@ 123456126.com
                Xinrui CaiShandong Academy of Occupational Health and Occupational Medicine, Shandong Academy of Medical Sciences , Yuxing Road No. 17, Jinan City, Shandong province250062, People’s Republic of ChinaTel +86 1 325 666 8165Email doctorcai@ 123456163.com
                [*]

                These authors contributed equally to this work

                Article
                207774
                10.2147/DDDT.S207774
                6677131
                © 2019 Qian et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, Tables: 1, References: 42, Pages: 11
                Categories
                Original Research

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