{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:22:21Z","timestamp":1790605341769,"version":"4.1.0"},"reference-count":88,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Shanxi Leading Talent Team Building Program","award":["202204051002010"],"award-info":[{"award-number":["202204051002010"]}]},{"name":"Shanxi Provincial Science and Technology Department Centralized Guided Local Projects","award":["YDZJSX2021C026"],"award-info":[{"award-number":["YDZJSX2021C026"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81870354"],"award-info":[{"award-number":["81870354"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Youth Fund of the Second Hospital of Shanxi Medical University","award":["202002-5"],"award-info":[{"award-number":["202002-5"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Lipids Health Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Atherosclerosis (AS) is a persistent inflammatory condition triggered and exacerbated by several factors including lipid accumulation, endothelial dysfunction and macrophages infiltration. Nobiletin (NOB) has been reported to alleviate atherosclerosis; however, the underlying mechanism remains incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study involved comprehensive bioinformatic analysis, including multidatabase target prediction; GO and KEGG enrichment analyses for function and pathway exploration; DeepSite and AutoDock for drug binding site prediction; and CIBERSORT for immune cell involvement. In addition, target intervention was verified via cell scratch assays, oil red O staining, ELISA, flow cytometry, qRT\u2012PCR and Western blotting. In addition, by establishing a mouse model of AS, it was demonstrated that NOB attenuated lipid accumulation and the extent of atherosclerotic lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>(1) Altogether, 141 potentially targetable genes were identified through which NOB could intervene in atherosclerosis. (2) Lipid and atherosclerosis, fluid shear stress and atherosclerosis may be the dominant pathways and potential mechanisms. (3) ALB, AKT1, CASP3 and 7 other genes were identified as the top 10 target genes. (4) Six genes, including PPARG, MMP9, SRC and 3 other genes, were related to the M0 fraction. (5) CD36 and PPARG were upregulated in atherosclerosis samples compared to the normal control. (6) By inhibiting lipid uptake in RAW264.7 cells, NOB prevents the formation of foam cell. (7) In RAW264.7 cells, the inhibitory effect of oxidized low-density lipoprotein on foam cells formation and lipid accumulation was closely associated with the PPARG signaling pathway. (8) In vivo validation showed that NOB significantly attenuated intra-arterial lipid accumulation and macrophage infiltration and reduced CD36 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG\/CD36 pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12944-024-02049-5","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T08:01:27Z","timestamp":1710144087000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG\/CD36 pathway"],"prefix":"10.1186","volume":"23","author":[{"given":"Heng","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiujing","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyi","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoping","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honglin","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,11]]},"reference":[{"key":"2049_CR1","doi-asserted-by":"publisher","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","volume":"76","author":"GA Roth","year":"2020","unstructured":"Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, et al. Global Burden of cardiovascular diseases and risk factors, 1990\u20132019: update from the GBD 2019 study. J Am Coll Cardiol. 2020;76:2982\u20133021.","journal-title":"J Am Coll Cardiol"},{"key":"2049_CR2","doi-asserted-by":"publisher","first-page":"e1332","DOI":"10.1016\/S2214-109X(19)30318-3","volume":"7","author":"World Health Organization cardiovascular disease","year":"2019","unstructured":"World Health Organization cardiovascular disease. Risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health. 2019;7:e1332\u201345.","journal-title":"Lancet Glob Health"},{"key":"2049_CR3","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1016\/j.cell.2022.04.004","volume":"185","author":"JLM Bjorkegren","year":"2022","unstructured":"Bjorkegren JLM, Lusis AJ. Atherosclerosis: recent developments. Cell. 2022;185:1630\u201345.","journal-title":"Cell"},{"key":"2049_CR4","doi-asserted-by":"crossref","unstructured":"Jebari-Benslaiman S, Galicia-Garcia U, Larrea-Sebal A, Olaetxea JR, Alloza I, Vandenbroeck K, Benito-Vicente A, Martin C. Pathophysiology of atherosclerosis. Int J Mol Sci 2022, 23.","DOI":"10.3390\/ijms23063346"},{"key":"2049_CR5","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1007\/s12272-019-01116-1","volume":"42","author":"JG Park","year":"2019","unstructured":"Park JG, Oh GT. Current pharmacotherapies for atherosclerotic cardiovascular diseases. Arch Pharm Res. 2019;42:206\u201323.","journal-title":"Arch Pharm Res"},{"key":"2049_CR6","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1161\/CIRCRESAHA.118.312782","volume":"124","author":"NC Ward","year":"2019","unstructured":"Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res. 2019;124:328\u201350.","journal-title":"Circ Res"},{"key":"2049_CR7","doi-asserted-by":"crossref","unstructured":"Susser LI, Rayner KJ. Through the layers: how macrophages drive atherosclerosis across the vessel wall. J Clin Invest 2022, 132.","DOI":"10.1172\/JCI157011"},{"key":"2049_CR8","doi-asserted-by":"crossref","unstructured":"Poznyak AV, Wu WK, Melnichenko AA, Wetzker R, Sukhorukov V, Markin AM, Khotina VA, Orekhov AN. Signaling pathways and key genes involved in regulation of foam cell formation in atherosclerosis. Cells 2020, 9.","DOI":"10.3390\/cells9030584"},{"key":"2049_CR9","doi-asserted-by":"crossref","unstructured":"Fernandez-Gallego N, Castillo-Gonzalez R, Mendez-Barbero N, Lopez-Sanz C, Obeso D, Villasenor A, Escribese MM, Lopez-Melgar B, Salamanca J, Benedicto-Buendia A et al. The impact of type 2 immunity and allergic diseases in atherosclerosis. Allergy 2022.","DOI":"10.22541\/au.165173768.80156257\/v1"},{"key":"2049_CR10","doi-asserted-by":"crossref","unstructured":"Abifadel M, Boileau C. Genetic and molecular architecture of familial hypercholesterolemia. J Intern Med 2022.","DOI":"10.1111\/joim.13577"},{"key":"2049_CR11","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s41590-018-0113-3","volume":"19","author":"GJ Koelwyn","year":"2018","unstructured":"Koelwyn GJ, Corr EM, Erbay E, Moore KJ. Regulation of macrophage immunometabolism in atherosclerosis. Nat Immunol. 2018;19:526\u201337.","journal-title":"Nat Immunol"},{"key":"2049_CR12","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/s41569-019-0265-3","volume":"17","author":"T Kuznetsova","year":"2020","unstructured":"Kuznetsova T, Prange KHM, Glass CK, de Winther MPJ. Transcriptional and epigenetic regulation of macrophages in atherosclerosis. Nat Rev Cardiol. 2020;17:216\u201328.","journal-title":"Nat Rev Cardiol"},{"key":"2049_CR13","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.trsl.2017.10.004","volume":"191","author":"C Li","year":"2018","unstructured":"Li C, Xu MM, Wang K, Adler AJ, Vella AT, Zhou B. Macrophage polarization and meta-inflammation. Transl Res. 2018;191:29\u201344.","journal-title":"Transl Res"},{"key":"2049_CR14","doi-asserted-by":"crossref","unstructured":"Wu Z, Liao F, Luo G, Qian Y, He X, Xu W, Ding S, Pu J. NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage Pyroptosis via the NF-kappaB\/NLRP3 Inflammasome Pathway. Oxid Med Cell Longev 2021, 2021:5217572.","DOI":"10.1155\/2021\/5217572"},{"key":"2049_CR15","first-page":"82","volume":"16","author":"T Wang","year":"2022","unstructured":"Wang T, Dong Y, Yao L, Lu F, Wen C, Wan Z, Fan L, Li Z, Bu T, Wei M, et al. Adoptive transfer of metabolically reprogrammed macrophages for atherosclerosis treatment in diabetic ApoE (-\/-) mice. Bioact Mater. 2022;16:82\u201394.","journal-title":"Bioact Mater"},{"key":"2049_CR16","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.1021\/acsnano.6b07842","volume":"11","author":"R Qiao","year":"2017","unstructured":"Qiao R, Qiao H, Zhang Y, Wang Y, Chi C, Tian J, Zhang L, Cao F, Gao M. Molecular imaging of vulnerable atherosclerotic plaques in vivo with osteopontin-specific upconversion nanoprobes. ACS Nano. 2017;11:1816\u201325.","journal-title":"ACS Nano"},{"key":"2049_CR17","doi-asserted-by":"publisher","first-page":"3313","DOI":"10.1002\/jcb.23257","volume":"112","author":"KH Lam","year":"2011","unstructured":"Lam KH, Alex D, Lam IK, Tsui SK, Yang ZF, Lee SM. Nobiletin, a polymethoxylated flavonoid from citrus, shows anti-angiogenic activity in a zebrafish in vivo model and HUVEC in vitro model. J Cell Biochem. 2011;112:3313\u201321.","journal-title":"J Cell Biochem"},{"key":"2049_CR18","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1758-2946-6-13","volume":"6","author":"J Ru","year":"2014","unstructured":"Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014;6:13.","journal-title":"J Cheminform"},{"key":"2049_CR19","doi-asserted-by":"publisher","first-page":"963662","DOI":"10.3389\/fnut.2022.963662","volume":"9","author":"Q Chen","year":"2022","unstructured":"Chen Q, Gu Y, Tan C, Sundararajan B, Li Z, Wang D, Zhou Z. Comparative effects of five polymethoxyflavones purified from Citrus tangerina on inflammation and cancer. Front Nutr. 2022;9:963662.","journal-title":"Front Nutr"},{"key":"2049_CR20","doi-asserted-by":"crossref","unstructured":"Wang HH, Sun YN, Qu TQ, Sang XQ, Zhou LM, Li YX, Ren FZ. Nobiletin prevents D-Galactose-Induced C2C12 cell aging by improving mitochondrial function. Int J Mol Sci 2022, 23.","DOI":"10.3390\/ijms231911963"},{"key":"2049_CR21","doi-asserted-by":"publisher","first-page":"3923","DOI":"10.1038\/s41467-019-11926-y","volume":"10","author":"K Nohara","year":"2019","unstructured":"Nohara K, Mallampalli V, Nemkov T, Wirianto M, Yang J, Ye Y, Sun Y, Han L, Esser KA, Mileykovskaya E, et al. Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge. Nat Commun. 2019;10:3923.","journal-title":"Nat Commun"},{"key":"2049_CR22","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/s10495-022-01721-4","volume":"27","author":"J Huang","year":"2022","unstructured":"Huang J, Chang Z, Lu Q, Chen X, Najafi M. Nobiletin as an inducer of programmed cell death in cancer: a review. Apoptosis. 2022;27:297\u2013310.","journal-title":"Apoptosis"},{"key":"2049_CR23","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.2337\/db10-0589","volume":"60","author":"EE Mulvihill","year":"2011","unstructured":"Mulvihill EE, Assini JM, Lee JK, Allister EM, Sutherland BG, Koppes JB, Sawyez CG, Edwards JY, Telford DE, Charbonneau A, et al. Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance. Diabetes. 2011;60:1446\u201357.","journal-title":"Diabetes"},{"key":"2049_CR24","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1146\/annurev-nutr-071715-050718","volume":"36","author":"EE Mulvihill","year":"2016","unstructured":"Mulvihill EE, Burke AC, Huff MW. Citrus flavonoids as regulators of Lipoprotein Metabolism and Atherosclerosis. Annu Rev Nutr. 2016;36:275\u201399.","journal-title":"Annu Rev Nutr"},{"key":"2049_CR25","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1194\/jlr.M087387","volume":"59","author":"AC Burke","year":"2018","unstructured":"Burke AC, Sutherland BG, Telford DE, Morrow MR, Sawyez CG, Edwards JY, Drangova M, Huff MW. Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr(-\/-) mice. J Lipid Res. 2018;59:1714\u201328.","journal-title":"J Lipid Res"},{"key":"2049_CR26","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nchembio.118","volume":"4","author":"AL Hopkins","year":"2008","unstructured":"Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4:682\u201390.","journal-title":"Nat Chem Biol"},{"key":"2049_CR27","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1039\/C5NP00005J","volume":"32","author":"M Kibble","year":"2015","unstructured":"Kibble M, Saarinen N, Tang J, Wennerberg K, Makela S, Aittokallio T. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Nat Prod Rep. 2015;32:1249\u201366.","journal-title":"Nat Prod Rep"},{"key":"2049_CR28","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.tips.2021.11.004","volume":"43","author":"C Nogales","year":"2022","unstructured":"Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI, Schmidt H. Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci. 2022;43:136\u201350.","journal-title":"Trends Pharmacol Sci"},{"key":"2049_CR29","doi-asserted-by":"crossref","unstructured":"Noor F, Tahir Ul Qamar M, Ashfaq UA, Albutti A, Alwashmi ASS, Aljasir MA. Network Pharmacology Approach for Medicinal Plants: Review and Assessment. Pharmaceuticals (Basel) 2022, 15.","DOI":"10.3390\/ph15050572"},{"key":"2049_CR30","doi-asserted-by":"publisher","first-page":"W356","DOI":"10.1093\/nar\/gkx374","volume":"45","author":"X Wang","year":"2017","unstructured":"Wang X, Shen Y, Wang S, Li S, Zhang W, Liu X, Lai L, Pei J, Li H. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017;45:W356\u201360.","journal-title":"Nucleic Acids Res"},{"key":"2049_CR31","doi-asserted-by":"crossref","unstructured":"Safran M, Rosen N, Twik M, BarShir R, Stein TI, Dahary D, Fishilevich S, Lancet D. The GeneCards Suite. In Practical Guide to Life Science Databases Edited by Abugessaisa I, Kasukawa T. Singapore: Springer Nature Singapore; 2021: 27\u201356.","DOI":"10.1007\/978-981-16-5812-9_2"},{"key":"2049_CR32","doi-asserted-by":"publisher","first-page":"D1038","DOI":"10.1093\/nar\/gky1151","volume":"47","author":"JS Amberger","year":"2019","unstructured":"Amberger JS, Bocchini CA, Scott AF, Hamosh A. OMIM.org: leveraging knowledge across phenotype-gene relationships. Nucleic Acids Res. 2019;47:D1038\u201343.","journal-title":"Nucleic Acids Res"},{"key":"2049_CR33","first-page":"D845","volume":"48","author":"J Pinero","year":"2020","unstructured":"Pinero J, Ramirez-Anguita JM, Sauch-Pitarch J, Ronzano F, Centeno E, Sanz F, Furlong LI. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 2020;48:D845\u201355.","journal-title":"Nucleic Acids Res"},{"key":"2049_CR34","doi-asserted-by":"crossref","unstructured":"Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, Imamichi T, Chang W. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res 2022.","DOI":"10.1093\/nar\/gkac194"},{"key":"2049_CR35","doi-asserted-by":"publisher","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","volume":"49","author":"D Szklarczyk","year":"2021","unstructured":"Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, Doncheva NT, Legeay M, Fang T, Bork P, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets. Nucleic Acids Res. 2021;49:D605\u201312.","journal-title":"Nucleic Acids Res"},{"key":"2049_CR36","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498\u2013504.","journal-title":"Genome Res"},{"key":"2049_CR37","doi-asserted-by":"publisher","first-page":"38731","DOI":"10.1074\/jbc.M005460200","volume":"275","author":"AA Bhattacharya","year":"2000","unstructured":"Bhattacharya AA, Curry S, Franks NP. Binding of the general anesthetics propofol and halothane to human serum albumin. High resolution crystal structures. J Biol Chem. 2000;275:38731\u20138.","journal-title":"J Biol Chem"},{"key":"2049_CR38","doi-asserted-by":"publisher","first-page":"5297","DOI":"10.1038\/s41467-021-25512-8","volume":"12","author":"L Quambusch","year":"2021","unstructured":"Quambusch L, Depta L, Landel I, Lubeck M, Kirschner T, Nabert J, Uhlenbrock N, Weisner J, Kostka M, Levy LM, et al. Cellular model system to dissect the isoform-selectivity of akt inhibitors. Nat Commun. 2021;12:5297.","journal-title":"Nat Commun"},{"key":"2049_CR39","doi-asserted-by":"publisher","first-page":"4421","DOI":"10.1021\/acs.jmedchem.8b00096","volume":"61","author":"E Nuti","year":"2018","unstructured":"Nuti E, Cuffaro D, Bernardini E, Camodeca C, Panelli L, Chaves S, Ciccone L, Tepshi L, Vera L, Orlandini E, et al. Development of Thioaryl-based Matrix Metalloproteinase-12 inhibitors with alternative zinc-binding groups: synthesis, Potentiometric, NMR, and Crystallographic studies. J Med Chem. 2018;61:4421\u201335.","journal-title":"J Med Chem"},{"key":"2049_CR40","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/s43018-022-00351-8","volume":"3","author":"C To","year":"2022","unstructured":"To C, Beyett TS, Jang J, Feng WW, Bahcall M, Haikala HM, Shin BH, Heppner DE, Rana JK, Leeper BA, et al. An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer. Nat Cancer. 2022;3:402\u201317.","journal-title":"Nat Cancer"},{"key":"2049_CR41","doi-asserted-by":"publisher","first-page":"5184","DOI":"10.1021\/jm020970s","volume":"46","author":"G Lange","year":"2003","unstructured":"Lange G, Lesuisse D, Deprez P, Schoot B, Loenze P, B\u00e9nard D, Marquette J-P, Broto P, Sarubbi E, Mandine E. Requirements for specific binding of Low Affinity inhibitor fragments to the SH2 domain of pp60Src are identical to those for High Affinity binding of full length inhibitors. J Med Chem. 2003;46:5184\u201395.","journal-title":"J Med Chem"},{"key":"2049_CR42","doi-asserted-by":"publisher","first-page":"11022","DOI":"10.1021\/bi0109111","volume":"40","author":"FF Vajdos","year":"2001","unstructured":"Vajdos FF, Ultsch M, Schaffer ML, Deshayes KD, Liu J, Skelton NJ, de Vos AM. Crystal structure of human insulin-like growth Factor-1: detergent binding inhibits binding protein interactions. Biochemistry. 2001;40:11022\u20139.","journal-title":"Biochemistry"},{"key":"2049_CR43","doi-asserted-by":"publisher","first-page":"e202112919","DOI":"10.1002\/anie.202112919","volume":"61","author":"TR Stachowski","year":"2022","unstructured":"Stachowski TR, Vanarotti M, Seetharaman J, Lopez K, Fischer M. Water networks repopulate protein-ligand interfaces with temperature. Angew Chem Int Ed Engl. 2022;61:e202112919.","journal-title":"Angew Chem Int Ed Engl"},{"key":"2049_CR44","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1248\/bpb.b21-00232","volume":"44","author":"A Honda","year":"2021","unstructured":"Honda A, Kamata S, Satta C, Machida Y, Uchii K, Terasawa K, Nemoto A, Oyama T, Ishii I. Structural basis for anti-non-alcoholic fatty liver Disease and Diabetic Dyslipidemia Drug Saroglitazar as a PPAR \u03b1\/\u03b3 dual agonist. Biol Pharm Bull. 2021;44:1210\u20139.","journal-title":"Biol Pharm Bull"},{"key":"2049_CR45","doi-asserted-by":"crossref","unstructured":"Min J, Nwachukwu JC, Min CK, Njeri JW, Srinivasan S, Rangarajan ES, Nettles CC, Sanabria Guillen V, Ziegler Y, Yan S et al. Dual-mechanism estrogen receptor inhibitors. Proc Natl Acad Sci U S A 2021, 118.","DOI":"10.1073\/pnas.2101657118"},{"key":"2049_CR46","doi-asserted-by":"publisher","first-page":"3036","DOI":"10.1093\/bioinformatics\/btx350","volume":"33","author":"J Jimenez","year":"2017","unstructured":"Jimenez J, Doerr S, Martinez-Rosell G, Rose AS, De Fabritiis G. DeepSite: protein-binding site predictor using 3D-convolutional neural networks. Bioinformatics. 2017;33:3036\u201342.","journal-title":"Bioinformatics"},{"key":"2049_CR47","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","volume":"61","author":"J Eberhardt","year":"2021","unstructured":"Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock Vina 1.2.0: new docking methods, expanded force field, and Python Bindings. J Chem Inf Model. 2021;61:3891\u20138.","journal-title":"J Chem Inf Model"},{"key":"2049_CR48","doi-asserted-by":"publisher","first-page":"W530","DOI":"10.1093\/nar\/gkab294","volume":"49","author":"MF Adasme","year":"2021","unstructured":"Adasme MF, Linnemann KL, Bolz SN, Kaiser F, Salentin S, Haupt VJ, Schroeder M. PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA. Nucleic Acids Res. 2021;49:W530\u20134.","journal-title":"Nucleic Acids Res"},{"key":"2049_CR49","unstructured":"Schrodinger LLC. The PyMOL Molecular Graphics System, Version 1.8. 2015."},{"key":"2049_CR50","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s12038-013-9310-2","volume":"38","author":"H Ayari","year":"2013","unstructured":"Ayari H, Bricca G. Identification of two genes potentially associated in iron-heme homeostasis in human carotid plaque using microarray analysis. J Biosci. 2013;38:311\u20135.","journal-title":"J Biosci"},{"key":"2049_CR51","doi-asserted-by":"publisher","first-page":"D991","DOI":"10.1093\/nar\/gks1193","volume":"41","author":"T Barrett","year":"2013","unstructured":"Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, et al. NCBI GEO: archive for functional genomics data sets\u2013update. Nucleic Acids Res. 2013;41:D991\u2013995.","journal-title":"Nucleic Acids Res"},{"key":"2049_CR52","doi-asserted-by":"publisher","first-page":"166533","DOI":"10.1016\/j.bbadis.2022.166533","volume":"1868","author":"Y Duan","year":"2022","unstructured":"Duan Y, Zhang X, Zhang X, Lin J, Shu X, Man W, Jiang M, Zhang Y, Wu D, Zhao Z, Sun D. Inhibition of macrophage-derived foam cells by Adipsin attenuates progression of atherosclerosis. Biochim Biophys Acta Mol Basis Dis. 2022;1868:166533.","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"2049_CR53","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/S0092-8674(00)81575-5","volume":"93","author":"P Tontonoz","year":"1998","unstructured":"Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte\/macrophage differentiation and uptake of oxidized LDL. Cell. 1998;93:241\u201352.","journal-title":"Cell"},{"key":"2049_CR54","doi-asserted-by":"crossref","unstructured":"Chen Y, Zhang J, Cui W, Silverstein RL. CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate. J Exp Med 2022, 219.","DOI":"10.1084\/jem.20211314"},{"key":"2049_CR55","doi-asserted-by":"publisher","first-page":"4261","DOI":"10.1111\/jcmm.15087","volume":"24","author":"Y Chen","year":"2020","unstructured":"Chen Y, Waqar AB, Nishijima K, Ning B, Kitajima S, Matsuhisa F, Chen L, Liu E, Koike T, Yu Y, et al. Macrophage-derived MMP-9 enhances the progression of atherosclerotic lesions and vascular calcification in transgenic rabbits. J Cell Mol Med. 2020;24:4261\u201374.","journal-title":"J Cell Mol Med"},{"key":"2049_CR56","doi-asserted-by":"publisher","first-page":"512926","DOI":"10.1155\/2012\/512926","volume":"2012","author":"SE Byeon","year":"2012","unstructured":"Byeon SE, Yi YS, Oh J, Yoo BC, Hong S, Cho JY. The role of src kinase in macrophage-mediated inflammatory responses. Mediators Inflamm. 2012;2012:512926.","journal-title":"Mediators Inflamm"},{"key":"2049_CR57","doi-asserted-by":"crossref","unstructured":"Trizzino M, Zucco A, Deliard S, Wang F, Barbieri E, Veglia F, Gabrilovich D, Gardini A. EGR1 is a gatekeeper of inflammatory enhancers in human macrophages. Sci Adv 2021, 7.","DOI":"10.1126\/sciadv.aaz8836"},{"key":"2049_CR58","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.jaci.2022.03.028","volume":"150","author":"A Adachi","year":"2022","unstructured":"Adachi A, Honda T, Egawa G, Kanameishi S, Takimoto R, Miyake T, Hossain MR, Komine M, Ohtsuki M, Gunzer M, et al. Estradiol suppresses psoriatic inflammation in mice by regulating neutrophil and macrophage functions. J Allergy Clin Immunol. 2022;150:909\u2013919e908.","journal-title":"J Allergy Clin Immunol"},{"key":"2049_CR59","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1056\/NEJMp2033115","volume":"384","author":"GH Gibbons","year":"2021","unstructured":"Gibbons GH, Seidman CE, Topol EJ. Conquering atherosclerotic Cardiovascular Disease \u2014 50 years of Progress. N Engl J Med. 2021;384:785\u20138.","journal-title":"N Engl J Med"},{"key":"2049_CR60","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1161\/CIR.0000000000000580","volume":"138","author":"AS Volgman","year":"2018","unstructured":"Volgman AS, Palaniappan LS, Aggarwal NT, Gupta M, Khandelwal A, Krishnan AV, Lichtman JH, Mehta LS, Patel HN, Shah KS, et al. Atherosclerotic Cardiovascular Disease in South asians in the United States: epidemiology, risk factors, and treatments: A Scientific Statement from the American Heart Association. Circulation. 2018;138:e1\u2013e34.","journal-title":"Circulation"},{"key":"2049_CR61","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.cca.2013.06.006","volume":"424","author":"XH Yu","year":"2013","unstructured":"Yu XH, Fu YC, Zhang DW, Yin K, Tang CK. Foam cells in atherosclerosis. Clin Chim Acta. 2013;424:245\u201352.","journal-title":"Clin Chim Acta"},{"key":"2049_CR62","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1161\/CIRCULATIONAHA.121.054285","volume":"145","author":"C Li","year":"2022","unstructured":"Li C, Qu L, Matz AJ, Murphy PA, Liu Y, Manichaikul AW, Aguiar D, Rich SS, Herrington DM, Vu D, et al. AtheroSpectrum reveals Novel Macrophage Foam Cell Gene signatures Associated with Atherosclerotic Cardiovascular Disease Risk. Circulation. 2022;145:206\u201318.","journal-title":"Circulation"},{"key":"2049_CR63","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1093\/cvr\/cvy079","volume":"114","author":"Z Ding","year":"2018","unstructured":"Ding Z, Liu S, Wang X, Theus S, Deng X, Fan Y, Zhou S, Mehta JL. PCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages. Cardiovasc Res. 2018;114:1145\u201353.","journal-title":"Cardiovasc Res"},{"key":"2049_CR64","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.freeradbiomed.2019.02.021","volume":"136","author":"M Yang","year":"2019","unstructured":"Yang M, Silverstein RL. CD36 signaling in vascular redox stress. Free Radic Biol Med. 2019;136:159\u201371.","journal-title":"Free Radic Biol Med"},{"key":"2049_CR65","doi-asserted-by":"publisher","first-page":"865367","DOI":"10.3389\/fcvm.2022.865367","volume":"9","author":"A von Ehr","year":"2022","unstructured":"von Ehr A, Bode C, Hilgendorf I. Macrophages in Atheromatous Plaque Developmental stages. Front Cardiovasc Med. 2022;9:865367.","journal-title":"Front Cardiovasc Med"},{"key":"2049_CR66","doi-asserted-by":"publisher","first-page":"1864","DOI":"10.1093\/eurheartj\/ehab920","volume":"43","author":"A Edsfeldt","year":"2022","unstructured":"Edsfeldt A, Swart M, Singh P, Dib L, Sun J, Cole JE, Park I, Al-Sharify D, Persson A, Nitulescu M, et al. Interferon regulatory factor-5-dependent CD11c\u2009+\u2009macrophages contribute to the formation of rupture\u2013prone atherosclerotic plaques. Eur Heart J. 2022;43:1864\u201377.","journal-title":"Eur Heart J"},{"key":"2049_CR67","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/s41596-021-00665-4","volume":"17","author":"X Huang","year":"2022","unstructured":"Huang X, Liu C, Kong N, Xiao Y, Yurdagul A Jr., Tabas I, Tao W. Synthesis of siRNA nanoparticles to silence plaque-destabilizing gene in atherosclerotic lesional macrophages. Nat Protoc. 2022;17:748\u201380.","journal-title":"Nat Protoc"},{"key":"2049_CR68","doi-asserted-by":"crossref","unstructured":"Tang J, Lobatto ME, Hassing L, van der Staay S, van Rijs SM, Calcagno C, Braza MS, Baxter S, Fay F, Sanchez-Gaytan BL et al. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Sci Adv 2015, 1.","DOI":"10.1126\/sciadv.1400223"},{"key":"2049_CR69","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.phrs.2018.07.012","volume":"135","author":"L Qiao","year":"2018","unstructured":"Qiao L, Chen W. Atheroprotective effects and molecular targets of bioactive compounds from traditional Chinese medicine. Pharmacol Res. 2018;135:212\u201329.","journal-title":"Pharmacol Res"},{"key":"2049_CR70","doi-asserted-by":"publisher","first-page":"115749","DOI":"10.1016\/j.jep.2022.115749","volume":"301","author":"W Zhi","year":"2023","unstructured":"Zhi W, Liu Y, Wang X, Zhang H. Recent advances of traditional Chinese medicine for the prevention and treatment of atherosclerosis. J Ethnopharmacol. 2023;301:115749.","journal-title":"J Ethnopharmacol"},{"key":"2049_CR71","doi-asserted-by":"crossref","unstructured":"Goh JXH, Tan LT, Goh JK, Chan KG, Pusparajah P, Lee LH, Goh BH. Nobiletin and derivatives: functional compounds from Citrus Fruit Peel for Colon cancer chemoprevention. Cancers (Basel) 2019, 11.","DOI":"10.3390\/cancers11060867"},{"key":"2049_CR72","doi-asserted-by":"crossref","unstructured":"Nakajima A, Ohizumi Y. Potential Benefits of Nobiletin, A Citrus Flavonoid, against Alzheimer\u2019s Disease and Parkinson\u2019s Disease. Int J Mol Sci 2019, 20.","DOI":"10.3390\/ijms20143380"},{"key":"2049_CR73","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.atherosclerosis.2004.07.034","volume":"178","author":"SC Whitman","year":"2005","unstructured":"Whitman SC, Kurowska EM, Manthey JA, Daugherty A. Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class a scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis. 2005;178:25\u201332.","journal-title":"Atherosclerosis"},{"key":"2049_CR74","doi-asserted-by":"publisher","first-page":"e21849","DOI":"10.1016\/j.heliyon.2023.e21849","volume":"9","author":"F Ebrahimi","year":"2023","unstructured":"Ebrahimi F, Ghazimoradi MM, Fatima G, Bahramsoltani R. Citrus flavonoids and adhesion molecules: potential role in the management of atherosclerosis. Heliyon. 2023;9:e21849.","journal-title":"Heliyon"},{"key":"2049_CR75","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1038\/s41569-021-00569-6","volume":"18","author":"D Montaigne","year":"2021","unstructured":"Montaigne D, Butruille L, Staels B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol. 2021;18:809\u201323.","journal-title":"Nat Rev Cardiol"},{"key":"2049_CR76","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1016\/j.ejmech.2019.01.067","volume":"166","author":"AZ Mirza","year":"2019","unstructured":"Mirza AZ, Althagafi II, Shamshad H. Role of PPAR receptor in different diseases and their ligands: physiological importance and clinical implications. Eur J Med Chem. 2019;166:502\u201313.","journal-title":"Eur J Med Chem"},{"key":"2049_CR77","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S1097-2765(01)00164-2","volume":"7","author":"A Chawla","year":"2001","unstructured":"Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7:161\u201371.","journal-title":"Mol Cell"},{"key":"2049_CR78","doi-asserted-by":"crossref","unstructured":"Marechal L, Laviolette M, Rodrigue-Way A, Sow B, Brochu M, Caron V, Tremblay A. The CD36-PPARgamma pathway in metabolic disorders. Int J Mol Sci 2018, 19.","DOI":"10.3390\/ijms19051529"},{"key":"2049_CR79","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1093\/eurheartj\/ehz667","volume":"41","author":"S Oppi","year":"2020","unstructured":"Oppi S, Nusser-Stein S, Blyszczuk P, Wang X, Jomard A, Marzolla V, Yang K, Velagapudi S, Ward LJ, Yuan XM, et al. Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARgamma signature. Eur Heart J. 2020;41:995\u20131005.","journal-title":"Eur Heart J"},{"key":"2049_CR80","doi-asserted-by":"publisher","first-page":"115733","DOI":"10.1016\/j.taap.2021.115733","volume":"431","author":"J-L Zhuang","year":"2021","unstructured":"Zhuang J-L, Liu Y-Y, Li Z-Z, Zhuang Q-Z, Tang W-Z, Xiong Y, Huang X-Z. Amentoflavone prevents ox-LDL-induced lipid accumulation by suppressing the PPAR\u03b3\/CD36 signal pathway. Toxicol Appl Pharmcol. 2021;431:115733.","journal-title":"Toxicol Appl Pharmcol"},{"key":"2049_CR81","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1021\/acs.chemrestox.2c00043","volume":"35","author":"Q Ren","year":"2022","unstructured":"Ren Q, Xie X, Zhao C, Wen Q, Pan R, Du Y. 2,2\u2032,4,4\u2032-Tetrabromodiphenyl ether (PBDE 47) selectively stimulates proatherogenic PPAR\u03b3 signatures in human THP-1 macrophages to contribute to Foam cell formation. Chem Res Toxicol. 2022;35:1023\u201335.","journal-title":"Chem Res Toxicol"},{"key":"2049_CR82","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1093\/cvr\/cvaa319","volume":"118","author":"H Shu","year":"2022","unstructured":"Shu H, Peng Y, Hang W, Nie J, Zhou N, Wang DW. The role of CD36 in cardiovascular disease. Cardiovasc Res. 2022;118:115\u201329.","journal-title":"Cardiovasc Res"},{"key":"2049_CR83","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/S0092-8674(00)81574-3","volume":"93","author":"L Nagy","year":"1998","unstructured":"Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998;93:229\u201340.","journal-title":"Cell"},{"key":"2049_CR84","doi-asserted-by":"crossref","unstructured":"Van der Vorst EPC, Biessen EAL. Unwrapped and uNCORked: PPAR-gamma repression in atherosclerosis. Eur Heart J 2019.","DOI":"10.1093\/eurheartj\/ehz770"},{"key":"2049_CR85","doi-asserted-by":"publisher","first-page":"750078","DOI":"10.3389\/fphar.2021.750078","volume":"12","author":"Z Gao","year":"2021","unstructured":"Gao Z, Xu X, Li Y, Sun K, Yang M, Zhang Q, Wang S, Lin Y, Lou L, Wu A, et al. Mechanistic insight into PPARgamma and Tregs in atherosclerotic Immune inflammation. Front Pharmacol. 2021;12:750078.","journal-title":"Front Pharmacol"},{"key":"2049_CR86","doi-asserted-by":"publisher","first-page":"105639","DOI":"10.1016\/j.phrs.2021.105639","volume":"169","author":"S Zheng","year":"2021","unstructured":"Zheng S, Huang H, Li Y, Wang Y, Zheng Y, Liang J, Zhang S, Liu M, Fang Z. Yin-xing-tong-mai decoction attenuates atherosclerosis via activating PPARgamma-LXRalpha-ABCA1\/ABCG1 pathway. Pharmacol Res. 2021;169:105639.","journal-title":"Pharmacol Res"},{"key":"2049_CR87","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.atherosclerosis.2021.02.013","volume":"323","author":"J Wang","year":"2021","unstructured":"Wang J, Xu X, Li P, Zhang B, Zhang J. HDAC3 protects against atherosclerosis through inhibition of inflammation via the microRNA-19b\/PPARgamma\/NF-kappaB axis. Atherosclerosis. 2021;323:1\u201312.","journal-title":"Atherosclerosis"},{"key":"2049_CR88","doi-asserted-by":"crossref","unstructured":"Cheng WL, Zhang Q, Li B, Cao JL, Jiao L, Chao SP, Lu Z, Zhao F. PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPARgamma Expression. Oxid Med Cell Longev 2021, 2021:6957900.","DOI":"10.1155\/2021\/6957900"}],"container-title":["Lipids in Health and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12944-024-02049-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12944-024-02049-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12944-024-02049-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T11:08:42Z","timestamp":1710414522000},"score":1,"resource":{"primary":{"URL":"https:\/\/lipidworld.biomedcentral.com\/articles\/10.1186\/s12944-024-02049-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,11]]},"references-count":88,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["2049"],"URL":"https:\/\/doi.org\/10.1186\/s12944-024-02049-5","relation":{},"ISSN":["1476-511X"],"issn-type":[{"value":"1476-511X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,11]]},"assertion":[{"value":"1 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal experiments were conducted in compliance with the National Institutes of Health guidelines and were approved by the Ethics Committee of the Second Hospital of Shanxi Medical University (No: DW2023047).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All the authors approved the final manuscript and its submission to this journal.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no known competing financial interests or personal relationships that may have influenced the work reported in this paper.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"76"}}