{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:55:11Z","timestamp":1790823311746,"version":"4.1.0"},"reference-count":74,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Startup Foundation for Doctors of North Sichuan Medical College","award":["CBY23-QDA11"],"award-info":[{"award-number":["CBY23-QDA11"]}]},{"name":"Key Research and Development Projects of the Sichuan Provincial Department of Science and Technology","award":["2020YFS0528"],"award-info":[{"award-number":["2020YFS0528"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Atherosclerosis (AS) is a major global contributor to cardiovascular diseases and associated mortality. The traditional treatment primarily relies on statins; however, these drugs are often linked to side effects such as liver dysfunction and muscle impairment. Recent studies have highlighted the potential protective properties of saponin compounds derived from traditional herbal sources, such as notoginsenoside R1 (NGR1) and saikosaponin B2 (SSB2), in combating atherosclerosis. However, the comprehensive effects of these compounds against atherosclerosis and their underlying mechanisms remain inadequately understood. Firstly, we employed network pharmacology analysis to identify 113 common targets, including mTOR and CASP3, for NGR1, SSB2, and atherosclerosis from databases such as TCMSP. We constructed a protein-protein interaction (PPI) network and performed GO and KEGG enrichment analyses, whcih revealed key signaling pathways involved in PI3K\/Akt, inflammation, and autophagy. The atherosclerosis model was established using ApoE<jats:sup>-\/-<\/jats:sup> mice fed with a \u201cWestern diet\u201d followed by treatment with NGR1, SSB2, or NS combination. Histological examinations, including hematoxylin-eosin (HE) staining, oil red O (ORO) staining, and CD68 immunofluorescence, were conducted to evaluate the pathological conditions of the aortic root, liver and kidneys in ApoE<jats:sup>-\/-<\/jats:sup> mice. Our findings demonstrate that the NS combination improves lipid levels, lipid transport, and unstable plaque formation in ApoE<jats:sup>-\/-<\/jats:sup> mice without adverse effects on liver or kidney function. Finally, oxidized low-density lipoprotein (ox-LDL) was used to culture RAW264.7 macrophages to establish an <jats:italic>in vitro<\/jats:italic> foam cell model. The effects of NS combination on lipid uptake, inflammatory response, apoptosis, the PI3K\/Akt\/mTOR signaling pathway, and autophagy were evaluated using methods such as CCK-8 assay, Oil Red O staining, immunofluorescence analysis, flow cytometry, RT-PCR, and Western blot analysis. The results indicated that NS combination promoted autophagy by inhibiting the PI3K\/Akt\/mTOR pathway. This significantly alleviated inflammation, reduced apoptosis, and decreasing lipid accumulation, thereby improving the pathological progression of atherosclerosis. Collectively, this study demonstrates, for the first time, that the NS combination synergistically activates macrophage autophagy by suppressing the PI3K\/AKT\/mTOR pathway, thereby attenuating lipid accumulation, inflammation, and apoptosis in atherosclerotic models.<\/jats:p>","DOI":"10.1371\/journal.pone.0326687","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T17:27:27Z","timestamp":1751045247000},"page":"e0326687","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Synergistic effects of notoginsenoside R1 and saikosaponin B2 in atherosclerosis: A novel approach targeting PI3K\/AKT\/mTOR pathway and macrophage autophagy"],"prefix":"10.1371","volume":"20","author":[{"given":"Yihua","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9916-742X","authenticated-orcid":true,"given":"Chunyang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"issue":"8","key":"pone.0326687.ref001","doi-asserted-by":"crossref","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association","volume":"143","author":"SS Virani","year":"2021","journal-title":"Circulation"},{"key":"pone.0326687.ref002","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/1741-7015-11-117","article-title":"Immunity, atherosclerosis and cardiovascular disease","volume":"11","author":"J Frosteg\u00e5rd","year":"2013","journal-title":"BMC Med"},{"key":"pone.0326687.ref003","volume-title":"Global health estimates 2020: Deaths by cause, age, sex, by country and by region, 2000\u20132019","year":"2020"},{"issue":"9","key":"pone.0326687.ref004","doi-asserted-by":"crossref","first-page":"4695","DOI":"10.3390\/ijms23094695","article-title":"Cardiovascular Diseases-A Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies","volume":"23","author":"\u0141 Bu\u0142dak","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"7855","key":"pone.0326687.ref005","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/s41586-021-03392-8","article-title":"The changing landscape of atherosclerosis","volume":"592","author":"P Libby","year":"2021","journal-title":"Nature"},{"issue":"11","key":"pone.0326687.ref006","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.tem.2018.04.007","article-title":"Atherosclerosis Is an Epigenetic Disease","volume":"29","author":"S Xu","year":"2018","journal-title":"Trends Endocrinol Metab"},{"issue":"6","key":"pone.0326687.ref007","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1002\/ptr.6991","article-title":"Effects of phytochemicals on macrophage cholesterol efflux capacity: Impact on atherosclerosis","volume":"35","author":"S Soltani","year":"2021","journal-title":"Phytother Res"},{"key":"pone.0326687.ref008","doi-asserted-by":"crossref","first-page":"121565","DOI":"10.1016\/j.carbpol.2023.121565","article-title":"Structural elucidation of an active polysaccharide from Radix Puerariae lobatae and its protection against acute alcoholic liver disease","volume":"325","author":"W Cao","year":"2024","journal-title":"Carbohydr Polym"},{"issue":"11","key":"pone.0326687.ref009","article-title":"Rutosides for prevention of post-thrombotic syndrome","volume":"11","author":"JR Morling","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"issue":"23","key":"pone.0326687.ref010","doi-asserted-by":"crossref","first-page":"4998","DOI":"10.3390\/nu14234998","article-title":"Advances in the Bioactivities of Phytochemical Saponins in the Prevention and Treatment of Atherosclerosis","volume":"14","author":"H Luo","year":"2022","journal-title":"Nutrients"},{"key":"pone.0326687.ref011","doi-asserted-by":"crossref","first-page":"551","DOI":"10.2147\/DDDT.S240511","article-title":"Focus on Notoginsenoside R1 in Metabolism and Prevention Against Human Diseases","volume":"14","author":"H Liu","year":"2020","journal-title":"Drug Des Devel Ther"},{"issue":"6","key":"pone.0326687.ref012","article-title":"Notoginsenoside R1 attenuates atherosclerotic lesions in ApoE deficient mouse model","volume":"9","author":"C Jia","year":"2014","journal-title":"PLoS One"},{"key":"pone.0326687.ref013","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.2147\/DDDT.S451565","article-title":"Notoginsenoside R1 Ameliorate High-Fat-Diet and Vitamin D3-Induced Atherosclerosis via Alleviating Inflammatory Response, Inhibiting Endothelial Dysfunction, and Regulating Gut Microbiota","volume":"18","author":"L Ma","year":"2024","journal-title":"Drug Des Devel Ther"},{"issue":"1","key":"pone.0326687.ref014","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s11418-023-01753-3","article-title":"Highly sensitive indirect competitive enzyme-linked immunosorbent assay based on a monoclonal antibody against saikosaponin b2 for quality control of Kampo medicines containing Bupleuri radix","volume":"78","author":"A Ochi","year":"2024","journal-title":"J Nat Med"},{"issue":"9","key":"pone.0326687.ref015","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1248\/bpb1978.8.718","article-title":"Structural transformation of saikosaponins by gastric juice and intestinal flora","volume":"8","author":"K Shimizu","year":"1985","journal-title":"J Pharmacobiodyn"},{"issue":"1","key":"pone.0326687.ref016","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1007\/s10753-018-0898-0","article-title":"Saikosaponin B2 Suppresses Inflammatory Responses Through IKK\/I\u03baB\u03b1\/NF-\u03baB Signaling Inactivation in LPS-Induced RAW 264.7 Macrophages","volume":"42","author":"J-S Shin","year":"2019","journal-title":"Inflammation"},{"key":"pone.0326687.ref017","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jpba.2016.01.010","article-title":"HepG2 cells biospecific extraction and HPLC-ESI-MS analysis for screening potential antiatherosclerotic active components in Bupeuri radix","volume":"121","author":"S Liu","year":"2016","journal-title":"J Pharm Biomed Anal"},{"issue":"1","key":"pone.0326687.ref018","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41572-019-0106-z","article-title":"Atherosclerosis","volume":"5","author":"P Libby","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"pone.0326687.ref019","doi-asserted-by":"crossref","first-page":"845942","DOI":"10.3389\/fcvm.2022.845942","article-title":"Foam Cells in Atherosclerosis: Novel Insights Into Its Origins, Consequences, and Molecular Mechanisms","volume":"9","author":"Y Gui","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"pone.0326687.ref020","doi-asserted-by":"crossref","first-page":"111440","DOI":"10.1016\/j.ecoenv.2020.111440","article-title":"Atmospheric fine particulate matter exposure exacerbates atherosclerosis in apolipoprotein E knockout mice by inhibiting autophagy in macrophages via the PI3K\/Akt\/mTOR signaling pathway","volume":"208","author":"Q Wan","year":"2021","journal-title":"Ecotoxicol Environ Saf"},{"issue":"14","key":"pone.0326687.ref021","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1161\/CIRCULATIONAHA.116.024503","article-title":"Retinol-Binding Protein-Dependent Cholesterol Uptake Regulates Macrophage Foam Cell Formation and Promotes Atherosclerosis","volume":"135","author":"Y Liu","year":"2017","journal-title":"Circulation"},{"issue":"4","key":"pone.0326687.ref022","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1080\/15548627.2020.1741202","article-title":"The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis","volume":"17","author":"S Pi","year":"2021","journal-title":"Autophagy"},{"issue":"6","key":"pone.0326687.ref023","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/ATVBAHA.116.308916","article-title":"microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis","volume":"37","author":"M Ouimet","year":"2017","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"5","key":"pone.0326687.ref024","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.cmet.2011.04.004","article-title":"Autophagy in the cellular energetic balance","volume":"13","author":"R Singh","year":"2011","journal-title":"Cell Metab"},{"key":"pone.0326687.ref025","doi-asserted-by":"crossref","first-page":"15750","DOI":"10.1038\/ncomms15750","article-title":"Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis","volume":"8","author":"I Sergin","year":"2017","journal-title":"Nat Commun"},{"key":"pone.0326687.ref026","volume-title":"Guide for the Care and Use of Laboratory Animals","year":"2011"},{"issue":"4","key":"pone.0326687.ref027","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/0091-3057(94)00331-9","article-title":"Behavioral effects of vehicles: DMSO, ethanol, Tween-20, Tween-80, and emulphor-620","volume":"50","author":"CA Castro","year":"1995","journal-title":"Pharmacol Biochem Behav"},{"issue":"8","key":"pone.0326687.ref028","first-page":"1581","article-title":"Acute toxicity of various solvents in the mouse and rat. LD50 of ethanol, diethylacetamide, dimethylformamide, dimethylsulfoxide, glycerine, N-methylpyrrolidone, polyethylene glycol 400, 1,2-propanediol and Tween 20","volume":"26","author":"W Bartsch","year":"1976","journal-title":"Arzneimittel-Forschung"},{"issue":"1","key":"pone.0326687.ref029","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1080\/13880209.2024.2318349","article-title":"Notoginsenoside R1 improves intestinal microvascular functioning in sepsis by targeting Drp1-mediated mitochondrial quality imbalance","volume":"62","author":"D Hou","year":"2024","journal-title":"Pharm Biol"},{"issue":"2","key":"pone.0326687.ref030","first-page":"1943","article-title":"Antitumor effects of saikosaponin b2 on breast cancer cell proliferation and migration","volume":"20","author":"Q Ma","year":"2019","journal-title":"Mol Med Rep"},{"key":"pone.0326687.ref031","volume-title":"AVMA Guidelines for the Euthanasia of Animals: 2020 Edition","author":"S Leary","year":"2020"},{"issue":"1","key":"pone.0326687.ref032","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1186\/s12933-024-02507-5","article-title":"ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-\/- mice","volume":"23","author":"M Svecla","year":"2024","journal-title":"Cardiovasc Diabetol"},{"key":"pone.0326687.ref033","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"A Daina","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pone.0326687.ref034","article-title":"ETCM: an encyclopaedia of traditional Chinese medicine","volume":"47","author":"H-Y Xu","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pone.0326687.ref035","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: a database of systems pharmacology for drug discovery from herbal medicines","volume":"6","author":"J Ru","year":"2014","journal-title":"J Cheminform"},{"key":"pone.0326687.ref036","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkaa1063","article-title":"HERB: a high-throughput experiment- and reference-guided database of traditional Chinese medicine","volume":"49","author":"S Fang","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"pone.0326687.ref037","doi-asserted-by":"crossref","DOI":"10.1093\/database\/baq020","article-title":"GeneCards Version 3: the human gene integrator","volume":"2010","author":"M Safran","year":"2010","journal-title":"Database (Oxford)"},{"issue":"4","key":"pone.0326687.ref038","doi-asserted-by":"crossref","DOI":"10.1002\/wsbm.1417","article-title":"PharmGKB: A worldwide resource for pharmacogenomic information","volume":"10","author":"JM Barbarino","year":"2018","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"pone.0326687.ref039","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gku1205","article-title":"OMIM.org: Online Mendelian Inheritance in Man (OMIM\u00ae), an online catalog of human genes and genetic disorders","volume":"43","author":"JS Amberger","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pone.0326687.ref040","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"D Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pone.0326687.ref041","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"G Yu","year":"2012","journal-title":"OMICS"},{"issue":"23","key":"pone.0326687.ref042","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/j.jacc.2009.09.009","article-title":"Inflammation in atherosclerosis: from pathophysiology to practice","volume":"54","author":"P Libby","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"pone.0326687.ref043","doi-asserted-by":"crossref","first-page":"719313","DOI":"10.3389\/fphar.2021.719313","article-title":"Notoginsenoside R1 Reverses Abnormal Autophagy in Hippocampal Neurons of Mice With Sleep Deprivation Through Melatonin Receptor 1A","volume":"12","author":"Y Cao","year":"2021","journal-title":"Front Pharmacol"},{"issue":"5","key":"pone.0326687.ref044","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1161\/CIRCULATIONAHA.122.059062","article-title":"Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling","volume":"147","author":"A Canfr\u00e1n-Duque","year":"2023","journal-title":"Circulation"},{"key":"pone.0326687.ref045","doi-asserted-by":"crossref","first-page":"155227","DOI":"10.1016\/j.phymed.2023.155227","article-title":"Essential oil from Fructus Alpinia zerumbet ameliorates atherosclerosis by activating PPAR\u03b3-LXR\u03b1-ABCA1\/G1 signaling pathway","volume":"123","author":"S-Q Wang","year":"2024","journal-title":"Phytomedicine"},{"issue":"7","key":"pone.0326687.ref046","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1161\/CIRCULATIONAHA.112.000588","article-title":"Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice","volume":"127","author":"OM Khan","year":"2013","journal-title":"Circulation"},{"issue":"12","key":"pone.0326687.ref047","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1161\/ATVBAHA.108.179697","article-title":"Oxidized low-density lipoprotein and atherosclerosis","volume":"30","author":"D Steinberg","year":"2010","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"12","key":"pone.0326687.ref048","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.acvd.2016.04.002","article-title":"Inflammation in atherosclerosis","volume":"109","author":"S Taleb","year":"2016","journal-title":"Arch Cardiovasc Dis"},{"issue":"3","key":"pone.0326687.ref049","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1002\/jcp.25930","article-title":"NLRP3 inflammasome: Its regulation and involvement in atherosclerosis","volume":"233","author":"Z Hoseini","year":"2018","journal-title":"J Cell Physiol"},{"issue":"5","key":"pone.0326687.ref050","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s41569-023-00957-0","article-title":"Programmed death of macrophages in atherosclerosis: mechanisms and therapeutic targets","volume":"21","author":"GRY De Meyer","year":"2024","journal-title":"Nat Rev Cardiol"},{"issue":"1","key":"pone.0326687.ref051","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nri2675","article-title":"Macrophage death and defective inflammation resolution in atherosclerosis","volume":"10","author":"I Tabas","year":"2010","journal-title":"Nat Rev Immunol"},{"issue":"4","key":"pone.0326687.ref052","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.cmet.2012.01.022","article-title":"Macrophage autophagy plays a protective role in advanced atherosclerosis","volume":"15","author":"X Liao","year":"2012","journal-title":"Cell Metab"},{"issue":"3","key":"pone.0326687.ref053","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1152\/physrev.00026.2020","article-title":"Regulation and metabolic functions of mTORC1 and mTORC2","volume":"101","author":"A Szwed","year":"2021","journal-title":"Physiol Rev"},{"key":"pone.0326687.ref054","doi-asserted-by":"crossref","first-page":"113629","DOI":"10.1016\/j.intimp.2024.113629","article-title":"Taoren Honghua Decoction alleviates atherosclerosis by inducing autophagy and inhibiting the PI3K-AKT signaling pathway to regulate cholesterol efflux and inflammatory responses","volume":"144","author":"X Chang","year":"2025","journal-title":"Int Immunopharmacol"},{"issue":"12","key":"pone.0326687.ref055","doi-asserted-by":"crossref","first-page":"6778","DOI":"10.3390\/ijms25126778","article-title":"Pivotal Role of mTOR in Non-Skin Manifestations of Psoriasis","volume":"25","author":"K Joo","year":"2024","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0326687.ref056","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s42255-024-00984-2","article-title":"Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk","volume":"6","author":"X Zhang","year":"2024","journal-title":"Nat Metab"},{"key":"pone.0326687.ref057","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.yjmcc.2023.10.011","article-title":"Mechanistic target of rapamycin in regulating macrophage function in inflammatory cardiovascular diseases","volume":"186","author":"MC Mangione","year":"2024","journal-title":"J Mol Cell Cardiol"},{"issue":"3","key":"pone.0326687.ref058","first-page":"2798","article-title":"MicroRNA\u2011155 promotes ox\u2011LDL\u2011induced autophagy in human umbilical vein endothelial cells by targeting the PI3K\/Akt\/mTOR pathway","volume":"18","author":"S Yin","year":"2018","journal-title":"Mol Med Rep"},{"issue":"23","key":"pone.0326687.ref059","doi-asserted-by":"crossref","first-page":"6093","DOI":"10.3390\/ijms20236093","article-title":"Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells","volume":"20","author":"H Cao","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pone.0326687.ref060","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3389\/fphar.2019.00603","article-title":"Shen-Yuan-Dan Capsule Attenuates Atherosclerosis and Foam Cell Formation by Enhancing Autophagy and Inhibiting the PI3K\/Akt\/mTORC1 Signaling Pathway","volume":"10","author":"M Zhou","year":"2019","journal-title":"Front Pharmacol"},{"issue":"6","key":"pone.0326687.ref061","article-title":"Upconversion nanoparticle-mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage-derived foam cells via ROS generation","volume":"8","author":"XB Han","year":"2017","journal-title":"Cell Death Dis"},{"issue":"6","key":"pone.0326687.ref062","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.bbalip.2013.03.007","article-title":"Autophagy in obesity and atherosclerosis: Interrelationships between cholesterol homeostasis, lipoprotein metabolism and autophagy in macrophages and other systems","volume":"1831","author":"M Ouimet","year":"2013","journal-title":"Biochim Biophys Acta"},{"issue":"12","key":"pone.0326687.ref063","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1016\/j.biocel.2004.05.009","article-title":"LC3 conjugation system in mammalian autophagy","volume":"36","author":"I Tanida","year":"2004","journal-title":"Int J Biochem Cell Biol"},{"issue":"6","key":"pone.0326687.ref064","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/s41418-021-00912-x","article-title":"The caspase-6-p62 axis modulates p62 droplets based autophagy in a dominant-negative manner","volume":"29","author":"E Valionyte","year":"2022","journal-title":"Cell Death Differ"},{"issue":"4","key":"pone.0326687.ref065","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/ncb0411-342","article-title":"Lysosome positioning coordinates mTORC1 activity and autophagy","volume":"13","author":"C Po\u00fcs","year":"2011","journal-title":"Nat Cell Biol"},{"key":"pone.0326687.ref066","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.mam.2006.08.005","article-title":"Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy","volume":"27","author":"E-L Eskelinen","year":"2006","journal-title":"Mol Aspects Med"},{"issue":"12","key":"pone.0326687.ref067","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.4161\/15548627.2014.981787","article-title":"Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury","volume":"10","author":"C Sarkar","year":"2014","journal-title":"Autophagy"},{"key":"pone.0326687.ref068","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.phymed.2018.01.005","article-title":"Early LC3 lipidation induced by d-limonene does not rely on mTOR inhibition, ERK activation and ROS production and it is associated with reduced clonogenic capacity of SH-SY5Y neuroblastoma cells","volume":"40","author":"L Berliocchi","year":"2018","journal-title":"Phytomedicine"},{"issue":"2","key":"pone.0326687.ref069","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"M Laplante","year":"2012","journal-title":"Cell"},{"issue":"6","key":"pone.0326687.ref070","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1073\/pnas.79.6.1889","article-title":"3-Methyladenine: specific inhibitor of autophagic\/lysosomal protein degradation in isolated rat hepatocytes","volume":"79","author":"PO Seglen","year":"1982","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pone.0326687.ref071","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.cmet.2011.03.023","article-title":"Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase","volume":"13","author":"M Ouimet","year":"2011","journal-title":"Cell Metab"},{"issue":"4","key":"pone.0326687.ref072","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.cmet.2012.02.011","article-title":"Autophagy links inflammasomes to atherosclerotic progression","volume":"15","author":"B Razani","year":"2012","journal-title":"Cell Metab"},{"key":"pone.0326687.ref073","doi-asserted-by":"crossref","first-page":"6141902","DOI":"10.1155\/2018\/6141902","article-title":"Emerging Role of mTOR Signaling-Related miRNAs in Cardiovascular Diseases","volume":"2018","author":"A Samidurai","year":"2018","journal-title":"Oxid Med Cell Longev"},{"issue":"1","key":"pone.0326687.ref074","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.ijcard.2014.09.035","article-title":"mTOR mediates the cross-talk of macrophage polarization and autophagy in atherosclerosis","volume":"177","author":"F Tian","year":"2014","journal-title":"Int J Cardiol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0326687","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T17:27:44Z","timestamp":1751045264000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0326687"}},"subtitle":[],"editor":[{"given":"Riyaz Ahmad","family":"Rather","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,27]]},"references-count":74,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0326687","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,27]]}}}