{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T04:12:39Z","timestamp":1745554359168,"version":"3.40.4"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012021","name":"Iran University of Medical Sciences","doi-asserted-by":"publisher","award":["30410"],"award-info":[{"award-number":["30410"]}],"id":[{"id":"10.13039\/100012021","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Microbiol"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Inflammatory events followed by bacterial infections are related to the progression of the atherosclerosis process. The study investigated the signaling and metabolic pathways of endothelial cells (ECs), macrophages (MQs), vascular smooth muscle cells (VSMCs), and dendritic cells (DCs) after exposure to Gram-negative bacterial infections. Moreover, it aimed at cross-talking and enriching the pathways on the cellular and plaque networks.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Materials<\/jats:title>\n            <jats:p>High-throughput expression data series (<jats:italic>n<\/jats:italic> =\u20099) were selected through GEO and MAT data repositories. Upregulated differential expression genes (DEGs) were determined using R software and applied to identify the cellular signaling pathways using Enricher\/Reactome tools. Then, the cell networks were visualized using the Cytoscape software and enriched by the pathways of secretory proteins identified using Gene ontology (GO).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The important pathways of the Cytokines (Degree 4, <jats:italic>p<\/jats:italic>\u2009&lt; 6\u2009\u00d7 10<jats:sup>\u201326<\/jats:sup>), and INF (Degree 4, <jats:italic>p<\/jats:italic>\u2009&lt; 8.6 \u00d7\u200910<jats:sup>\u201331<\/jats:sup>) in ECs, Cytokines (Degree 4, <jats:italic>p<\/jats:italic>\u2009&lt; 9.35 \u00d7\u200910<jats:sup>\u20138<\/jats:sup>), and GPCR (Degree 3, <jats:italic>p<\/jats:italic>\u2009&lt; 1.45 \u00d7\u200910<jats:sup>\u20134<\/jats:sup>) in MQs, NOTCH (Degree 6, <jats:italic>p<\/jats:italic>\u2009&lt; 0.027) in VSMCs, and Cytokines (Degree 4, <jats:italic>p<\/jats:italic>\u2009&lt; 1.45 \u00d7\u200910<jats:sup>\u201317<\/jats:sup>) in DCs were found to be activated and enriched after exposure to Gram-negative bacterial infections on the cell networks. Furthermore, the Netrin- 1 (Degree 6, <jats:italic>p<\/jats:italic>\u2009&lt; 0.028), and EGFR (Degree 5, <jats:italic>p<\/jats:italic>\u2009&lt; 0.036) pathways were activated in the intimal thick\/xanthoma plaque network while the innate (Degree 9, <jats:italic>p<\/jats:italic>\u2009&lt; 8.9 \u00d7\u200910<jats:sup>\u201320<\/jats:sup>) and adaptive (Degree 7, <jats:italic>p<\/jats:italic>\u2009&lt; 4.1 \u00d7\u200910<jats:sup>\u201312<\/jats:sup>) immune systems pathways were activated in the fibrous cap atheroma plaque network.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The study revealed the signaling pathways after exposure to Gram-negative bacterial infections on the cell networks in the vessel microenvironment. Furthermore, the cell cross-talks exacerbated these pathways in cells and unstable plaques.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical Trial Number<\/jats:title>\n            <jats:p>Not applicable.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12866-025-03933-5","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T04:16:25Z","timestamp":1745468185000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gram-negative bacteria activate cellular pathways in plaque microenvironment; Systems biology approach"],"prefix":"10.1186","volume":"25","author":[{"given":"Reza","family":"Ganjali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Elahimanesh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamidreza","family":"Aghazadeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-4174","authenticated-orcid":false,"given":"Mohammad","family":"Najafi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"3933_CR1","doi-asserted-by":"publisher","first-page":"E84","DOI":"10.5888\/pcd19.220347","volume":"19","author":"F Coronado","year":"2022","unstructured":"Coronado F, Melvin SC, Bell RA, Zhao G. Global Responses to Prevent, Manage, and Control Cardiovascular Diseases. Prev Chronic Dis. 2022;19:E84.","journal-title":"Prev Chronic Dis"},{"issue":"6","key":"3933_CR2","doi-asserted-by":"publisher","first-page":"3346","DOI":"10.3390\/ijms23063346","volume":"23","author":"S Jebari-Benslaiman","year":"2022","unstructured":"Jebari-Benslaiman S, Galicia-Garc\u00eda U, Larrea-Sebal A, Olaetxea JR, Alloza I, Vandenbroeck K, et al. Pathophysiology of atherosclerosis. Int J Mol Sci. 2022;23(6):3346.","journal-title":"Int J Mol Sci"},{"key":"3933_CR3","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.841545","volume":"9","author":"MB Lorey","year":"2022","unstructured":"Lorey MB, \u00d6\u00f6rni K, Kovanen PT. Modified lipoproteins induce arterial wall inflammation during atherogenesis. Frontiers in cardiovascular medicine. 2022;9: 841545.","journal-title":"Frontiers in cardiovascular medicine"},{"issue":"43","key":"3933_CR4","doi-asserted-by":"publisher","first-page":"3195","DOI":"10.1093\/eurheartj\/ehx362","volume":"38","author":"NVK Pothineni","year":"2017","unstructured":"Pothineni NVK, Subramany S, Kuriakose K, Shirazi LF, Romeo F, Shah PK, et al. Infections, atherosclerosis, and coronary heart disease. Eur Heart J. 2017;38(43):3195\u2013201.","journal-title":"Eur Heart J"},{"key":"3933_CR5","doi-asserted-by":"publisher","first-page":"1281562","DOI":"10.1080\/20002297.2017.1281562","volume":"9","author":"JLC Mougeot","year":"2017","unstructured":"Mougeot JLC, Stevens CB, Paster BJ, Brennan MT, Lockhart PB, Mougeot FKB. Porphyromonas gingivalis is the most abundant species detected in coronary and femoral arteries. J Oral Microbiol. 2017;9:1281562.","journal-title":"J Oral Microbiol"},{"key":"3933_CR6","doi-asserted-by":"crossref","unstructured":"Aronova A, Tosato F, Naser N, Asare Y. Innate Immune Pathways in Atherosclerosis-From Signaling to Long-Term Epigenetic Reprogramming. Cells. 2023;12(19):2359.","DOI":"10.3390\/cells12192359"},{"key":"3933_CR7","doi-asserted-by":"crossref","unstructured":"Austermann J, Roth J, Barczyk-Kahlert K. The Good and the Bad: Monocytes' and Macrophages' Diverse Functions in Inflammation. Cells. 2022;11(12):1979.","DOI":"10.3390\/cells11121979"},{"issue":"1","key":"3933_CR8","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1186\/s40001-023-01301-5","volume":"28","author":"M Wang","year":"2023","unstructured":"Wang M, Feng J, Zhou D, Wang J. Bacterial lipopolysaccharide-induced endothelial activation and dysfunction: a new predictive and therapeutic paradigm for sepsis. Eur J Med Res. 2023;28(1):339.","journal-title":"Eur J Med Res"},{"issue":"11","key":"3933_CR9","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.2967\/jnumed.107.038661","volume":"48","author":"LG Spagnoli","year":"2007","unstructured":"Spagnoli LG, Bonanno E, Sangiorgi G, Mauriello A. Role of inflammation in atherosclerosis. J Nucl Med. 2007;48(11):1800\u201315.","journal-title":"J Nucl Med"},{"key":"3933_CR10","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.csbj.2022.12.028","volume":"21","author":"G Minadakis","year":"2023","unstructured":"Minadakis G, Christodoulou K, Tsouloupas G, Spyrou GM. PathIN: an integrated tool for the visualization of pathway interaction networks. Comput Struct Biotechnol J. 2023;21:378\u201387.","journal-title":"Comput Struct Biotechnol J"},{"issue":"1","key":"3933_CR11","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s12964-023-01153-w","volume":"21","author":"E Mahdinia","year":"2023","unstructured":"Mahdinia E, Shokri N, Taheri AT, Asgharzadeh S, Elahimanesh M, Najafi M. Cellular crosstalk in atherosclerotic plaque microenvironment. Cell Communication and Signaling. 2023;21(1):125.","journal-title":"Cell Communication and Signaling"},{"issue":"3","key":"3933_CR12","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.22207\/JPAM.16.3.08","volume":"16","author":"G Munusamy","year":"2022","unstructured":"Munusamy G, Shanmugam R. Bacterial Infections and Atherosclerosis\u2013A Mini Review. J Pure Appl Microbiol. 2022;16(3):1595\u2013607.","journal-title":"J Pure Appl Microbiol"},{"key":"3933_CR13","doi-asserted-by":"crossref","unstructured":"Mulhall H, Huck O, Amar S. Porphyromonas gingivalis, a Long-Range Pathogen: Systemic Impact and Therapeutic Implications. Microorganisms. 2020;8(6):869.","DOI":"10.3390\/microorganisms8060869"},{"issue":"7","key":"3933_CR14","doi-asserted-by":"publisher","first-page":"15105","DOI":"10.3390\/ijms140715105","volume":"14","author":"M Di Pietro","year":"2013","unstructured":"Di Pietro M, Filardo S, De Santis F, Sessa R. Chlamydia pneumoniae infection in atherosclerotic lesion development through oxidative stress: a brief overview. Int J Mol Sci. 2013;14(7):15105\u201320.","journal-title":"Int J Mol Sci"},{"key":"3933_CR15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.639834","volume":"12","author":"W Xiang","year":"2021","unstructured":"Xiang W, Yu N, Lei A, Li X, Tan S, Huang L, et al. Insights into host cell cytokines in Chlamydia infection. Front Immunol. 2021;12: 639834.","journal-title":"Front Immunol"},{"issue":"11","key":"3933_CR16","doi-asserted-by":"publisher","first-page":"944","DOI":"10.3390\/pathogens9110944","volume":"9","author":"F Mei","year":"2020","unstructured":"Mei F, Xie M, Huang X, Long Y, Lu X, Wang X, et al. Porphyromonas gingivalis and its systemic impact: current status. Pathogens. 2020;9(11):944.","journal-title":"Pathogens"},{"key":"3933_CR17","doi-asserted-by":"crossref","unstructured":"Jin M, Fang J, Wang J-j, Shao X, Xu S-w, Liu P-q, et al. Regulation of toll-like receptor (TLR) signaling pathways in atherosclerosis: from mechanisms to targeted therapeutics. Acta Pharmacologica Sinica. 2023;44(12):2358\u201375.","DOI":"10.1038\/s41401-023-01123-5"},{"key":"3933_CR18","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1038\/s41368-020-00096-z","volume":"12","author":"M Xie","year":"2020","unstructured":"Xie M, Tang Q, Yu S, Sun J, Mei F, Zhao J, et al. Porphyromonas gingivalis disrupts vascular endothelial homeostasis in a TLR-NF-\u03baB axis dependent manner. Int J Oral Sci. 2020;12:28.","journal-title":"Int J Oral Sci"},{"key":"3933_CR19","doi-asserted-by":"crossref","unstructured":"Susser LI, Rayner KJ. Through the layers: how macrophages drive atherosclerosis across the vessel wall. J Clin Investig. 2022;132(9):e157011.","DOI":"10.1172\/JCI157011"},{"issue":"3","key":"3933_CR20","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1002\/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H","volume":"50","author":"HT Idriss","year":"2000","unstructured":"Idriss HT, Naismith JH. TNF Alpha and the TNF Receptor Superfamily: Structure-Function Relationship(S). Microsc Res Tech. 2000;50(3):184\u201395.","journal-title":"Microsc Res Tech"},{"issue":"11","key":"3933_CR21","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1093\/cvr\/cvab046","volume":"117","author":"MO Grootaert","year":"2021","unstructured":"Grootaert MO, Bennett MR. Vascular smooth muscle cells in atherosclerosis: time for a re-assessment. Cardiovasc Res. 2021;117(11):2326\u201339.","journal-title":"Cardiovasc Res"},{"key":"3933_CR22","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/bs.apha.2016.07.002","volume":"78","author":"JT Baeten","year":"2017","unstructured":"Baeten JT, Lilly B. Notch Signaling in Vascular Smooth Muscle Cells. Adv Pharmacol. 2017;78:351\u201382.","journal-title":"Adv Pharmacol"},{"issue":"16","key":"3933_CR23","doi-asserted-by":"publisher","first-page":"12861","DOI":"10.3390\/ijms241612861","volume":"24","author":"X Huang","year":"2023","unstructured":"Huang X, Xie M, Lu X, Mei F, Song W, Liu Y, et al. The Roles of Periodontal Bacteria in Atherosclerosis. Int J Mol Sci. 2023;24(16):12861.","journal-title":"Int J Mol Sci"},{"issue":"1","key":"3933_CR24","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1038\/s41392-022-00955-7","volume":"7","author":"P Kong","year":"2022","unstructured":"Kong P, Cui Z-Y, Huang X-F, Zhang D-D, Guo R-J, Han M. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther. 2022;7(1):131.","journal-title":"Signal Transduct Target Ther"},{"key":"3933_CR25","doi-asserted-by":"publisher","first-page":"508","DOI":"10.3389\/fphys.2017.00508","volume":"8","author":"W Gao","year":"2017","unstructured":"Gao W, Xiong Y, Li Q, Yang H. Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol. 2017;8:508.","journal-title":"Front Physiol"},{"key":"3933_CR26","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.756315","volume":"9","author":"M Farooq","year":"2021","unstructured":"Farooq M, Batool M, Kim MS, Choi S. Toll-like receptors as a therapeutic target in the era of immunotherapies. Frontiers in Cell and Developmental Biology. 2021;9: 756315.","journal-title":"Frontiers in Cell and Developmental Biology"},{"issue":"12","key":"3933_CR27","doi-asserted-by":"publisher","first-page":"7231","DOI":"10.1128\/IAI.72.12.7231-7239.2004","volume":"72","author":"A Gervassi","year":"2004","unstructured":"Gervassi A, Alderson MR, Suchland R, Maisonneuve JF, Grabstein KH, Probst P. Differential Regulation of Inflammatory Cytokine Secretion by Human Dendritic Cells Upon Chlamydia Trachomatis Infection. Infect Immun. 2004;72(12):7231\u20139.","journal-title":"Infect Immun"}],"container-title":["BMC Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12866-025-03933-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12866-025-03933-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12866-025-03933-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T04:16:34Z","timestamp":1745468194000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmicrobiol.biomedcentral.com\/articles\/10.1186\/s12866-025-03933-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,24]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3933"],"URL":"https:\/\/doi.org\/10.1186\/s12866-025-03933-5","relation":{},"ISSN":["1471-2180"],"issn-type":[{"value":"1471-2180","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,24]]},"assertion":[{"value":"11 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"243"}}