{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T17:54:56Z","timestamp":1781373296723,"version":"3.54.1"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"New Giza University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Anchusa<\/jats:italic>\n                    species have traditionally been used to treat arthritis, gout, rheumatism, and skin wounds. Cisplatin (Cis) is a widely used chemotherapy drug associated with serious adverse effects. The study aimed to evaluate the potential synergistic anticancer effects of\n                    <jats:italic>Anchusa azurea<\/jats:italic>\n                    methanol extract (AAME) in combination with cisplatin against bone, skin, and oral cancer cell lines. This study involved a comprehensive metabolomic profiling of AAME, alongside cytotoxicity assays, cell cycle analysis, autophagy assessment, and evaluation of IL-17 and TNF-\u03b1 pathway-related protein expression. AAME inhibited the proliferation of MG63 and HNO97 cancer cells while sparing HSF normal cells. AAME and Cis displayed synergistic effects (combination index\u2009&lt;\u20091), especially in HNO97 cells. Treatments led to a synergistic decrease in TNF-\u03b1, p\/t-JNK, IL-17, pNF\u03baB\/tNF\u03baB, TRAF6, pMAPK\/tMAPK ratios, and AP1 expression, also increased Casp3 and Casp8 levels, cell cycle arrest, and enhanced autophagy. The TPC and TFC of AAME are 5.46 mgGAE\/gE and 0.13 mgRE\/gE respectively, reflecting on its radical scavenging activity (EC50 209.67\n                    <jats:italic>\u00b5<\/jats:italic>\n                    g\/mL). HRLC-MS\/MS leading to the annotation of 50 metabolites, including phenolics and flavonoid derivatives, notably with a prevalence of rosmarinic acid, quercetin, and kaempferol. In network pharmacology, the 90 genes are common between AAME constituents and oral cancer.\n                    <jats:italic>A. azurea<\/jats:italic>\n                    enhances cisplatin\u2019s anticancer effects by modulating IL-17, TNF-\u03b1, and apoptotic pathways, offering a promising adjuvant therapeutic strategy. Further in vivo investigations are warranted to validate the observed in vitro synergistic anticancer effects of\n                    <jats:italic>A. azurea<\/jats:italic>\n                    in combination with Cis.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-56489-3","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T16:44:20Z","timestamp":1781369060000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anchusa azurea enhances cisplatin efficacy in oral and bone cancers through IL-17 and TNF-\u03b1 pathway modulation: a metabolomic and network pharmacology approach"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7934-5030","authenticated-orcid":false,"given":"Sally A.","family":"Fahim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaadin E.","family":"El-Haddad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehab I.","family":"Moustafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimaa O.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Sharaky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nouran H.","family":"El Sherazy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliaa A.","family":"Elsherbiny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashrakat Y.","family":"Nabawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Elwakil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba Alah","family":"Esam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Emad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menatallah","family":"Abdelrahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Ayman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hind A. H.","family":"Soliman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman M.","family":"El-Deeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr M.","family":"Saadeldeen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"56489_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.5530\/amdhs.2019.3.10","volume":"2","author":"FHS Hussain","year":"2019","unstructured":"Hussain, F. H. S., Ahamad, J. & Shafiq Osw, P. A Comprehensive review on pharmacognostical and pharmacological characters of Anchusa azurea. Advances in Medical. Dent. Health Sci. 2, 33\u201337. https:\/\/doi.org\/10.5530\/amdhs.2019.3.10 (2019).","journal-title":"Dent. Health Sci."},{"key":"56489_CR2","doi-asserted-by":"publisher","first-page":"4280","DOI":"10.1039\/c9fo00582j","volume":"10","author":"J Ceramella","year":"2019","unstructured":"Ceramella, J. et al. Anchusa azurea Mill. (Boraginaceae) aerial parts methanol extract interfering with cytoskeleton organization induces programmed cancer cells death. Food Funct. 10, 4280\u20134290. https:\/\/doi.org\/10.1039\/c9fo00582j (2019).","journal-title":"Food Funct."},{"key":"56489_CR3","first-page":"64","volume":"3","author":"O Safa","year":"2013","unstructured":"Safa, O. et al. An ethnobotanical survey on hormozgan province, Iran. Avicenna J. Phytomed. 3, 64\u201381 (2013).","journal-title":"Avicenna J. Phytomed"},{"key":"56489_CR4","doi-asserted-by":"publisher","first-page":"106384","DOI":"10.1016\/J.JDDST.2024.106384","volume":"102","author":"NM Sheta","year":"2024","unstructured":"Sheta, N. M. et al. Xanthone-loaded niosomes as innovative potential delivery platform: Formulation, characterization, and cytotoxic effect on human cancer cell lines. J. Drug Deliv Sci. Technol. 102, 106384. https:\/\/doi.org\/10.1016\/J.JDDST.2024.106384 (2024).","journal-title":"J. Drug Deliv Sci. Technol."},{"key":"56489_CR5","unstructured":"Esmail Al-Snafi, A. & Esmail Al-snafi, A. The pharmacology of Anchusa Italica and Anchusa strigosa. A review Medicinal plants with antifungal activity View project Medicinal plant with gastrointestinal effects View (project The pharmacology of anchusa italica and anchusa strigosa. A review, 2014)."},{"key":"56489_CR6","doi-asserted-by":"publisher","first-page":"112887","DOI":"10.1016\/j.jep.2020.112887","volume":"257","author":"S Wang","year":"2020","unstructured":"Wang, S. et al. Total flavonoids from Anchusa italica Retz. Improve cardiac function and attenuate cardiac remodeling post myocardial infarction in mice. J. Ethnopharmacol. 257, 112887. https:\/\/doi.org\/10.1016\/j.jep.2020.112887 (2020).","journal-title":"J. Ethnopharmacol."},{"key":"56489_CR7","unstructured":"Suleymanb, A. K. U. H. et al. Investigation on Anti-Inflammatory and Antiulcer Activities of Anchusa azurea Extracts and their Major Constituent Rosmarinic Acid (Zeitschrift f{\\~A}$1\/4$r Naturforschung C, 2014)."},{"key":"56489_CR8","doi-asserted-by":"publisher","first-page":"416","DOI":"10.3390\/molecules27020416","volume":"27","author":"M Khomsi","year":"2022","unstructured":"Khomsi, M. et al. Antimicrobial and antioxidant properties of total polyphenols of Anchusa italica Retz. Molecules 27, 416. https:\/\/doi.org\/10.3390\/molecules27020416 (2022).","journal-title":"Molecules"},{"key":"56489_CR9","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/CAAC.21834","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74, 229\u2013263. https:\/\/doi.org\/10.3322\/CAAC.21834 (2024).\u00a0","journal-title":"CA Cancer J. Clin."},{"key":"56489_CR10","doi-asserted-by":"publisher","DOI":"10.3322\/caac.70048","author":"H Rumgay","year":"2025","unstructured":"Rumgay, H. et al. Global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2022. Ca https:\/\/doi.org\/10.3322\/caac.70048 (2025).","journal-title":"Ca"},{"key":"56489_CR11","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1007\/s12672-025-02208-9","volume":"16","author":"VK Morya","year":"2025","unstructured":"Morya, V. K., Magar, A. G., Park, S. H. & Noh, K. C. Systemic strategies for osteosarcoma: advances and future directions. Discover Oncology. 16 1367 https:\/\/doi.org\/10.1007\/S12672-025-02208-9 (2025).","journal-title":"Discover Oncology"},{"key":"56489_CR12","doi-asserted-by":"publisher","first-page":"986","DOI":"10.3390\/cells12070986","volume":"12","author":"A Gieleci\u0144ska","year":"2023","unstructured":"Gieleci\u0144ska, A. et al. Substances of natural origin in medicine: Plants vs. Cancer Cells. 12, 986. https:\/\/doi.org\/10.3390\/cells12070986 (2023).","journal-title":"Cancer Cells"},{"key":"56489_CR13","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s41420-024-02278-8","volume":"11","author":"N Chandimali","year":"2025","unstructured":"Chandimali, N. et al. Free radicals and their impact on health and antioxidant defenses: a review. Cell. Death Discov. 11, 19. https:\/\/doi.org\/10.1038\/s41420-024-02278-8 (2025).","journal-title":"Cell. Death Discov"},{"key":"56489_CR14","unstructured":"Madhulaxmi, M. et al. Role of cisplatin in oral squamous cell carcinoma-A review (2017)."},{"key":"56489_CR15","doi-asserted-by":"publisher","first-page":"331","DOI":"10.3389\/FONC.2020.00331\/FULL","volume":"10","author":"M Fanelli","year":"2020","unstructured":"Fanelli, M. et al. Cisplatin resistance in osteosarcoma: in vitro validation of candidate DNA Repair-related therapeutic targets and drugs for tailored treatments. Front. Oncol. 10, 331. https:\/\/doi.org\/10.3389\/FONC.2020.00331\/FULL (2020).","journal-title":"Front. Oncol."},{"key":"56489_CR16","doi-asserted-by":"publisher","first-page":"6645","DOI":"10.1039\/C8DT00838H","volume":"47","author":"R Oun","year":"2018","unstructured":"Oun, R., Moussa, Y. E. & Wheate, N. J. The side effects of platinum-based chemotherapy drugs: A review for chemists. Dalton Trans. 47, 6645\u20136653. https:\/\/doi.org\/10.1039\/C8DT00838H (2018).","journal-title":"Dalton Trans."},{"key":"56489_CR17","doi-asserted-by":"publisher","unstructured":"Balasubramanian, B. et al. Citation: naeem, a molecules natural products as anticancer agents: current status and future perspectives. (2022). https:\/\/doi.org\/10.3390\/molecules27238367","DOI":"10.3390\/molecules27238367"},{"key":"56489_CR18","doi-asserted-by":"publisher","first-page":"2480","DOI":"10.3390\/molecules27082480","volume":"27","author":"HA El Gizawy","year":"2022","unstructured":"El Gizawy, H. A. et al. In vitro cytotoxic activity and phytochemical characterization (UPLC\/T-TOF-MS\/MS) of the watermelon (Citrullus lanatus) rind extract. Molecules 27, 2480 https:\/\/doi.org\/10.3390\/MOLECULES27082480 (2022).","journal-title":"Molecules"},{"key":"56489_CR19","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.3390\/MOLECULES28031022","volume":"28","author":"J Wu","year":"2023","unstructured":"Wu, J., Li, Y., He, Q. & Yang, X. Exploration of the use of natural compounds in combination with chemotherapy drugs for tumor treatment. Molecules 28, 1022. https:\/\/doi.org\/10.3390\/MOLECULES28031022 (2023).","journal-title":"Molecules"},{"key":"56489_CR20","doi-asserted-by":"publisher","unstructured":"Heydari, M. et al. Editorial: Clinical safety of natural products, an evidence-based approach. (2022). https:\/\/doi.org\/10.3389\/fphar.2022.960556","DOI":"10.3389\/fphar.2022.960556"},{"key":"56489_CR21","doi-asserted-by":"publisher","DOI":"10.20517\/CDR.2025.107","author":"K Sandu","year":"2025","unstructured":"Sandu, K. et al. Cisplatin resistance in head and neck squamous cell carcinoma is linked to DNA damage response and cell cycle arrest transcriptomics rather than poor drug uptake. Cancer Drug Resist. https:\/\/doi.org\/10.20517\/CDR.2025.107 (2025).","journal-title":"Cancer Drug Resist."},{"key":"56489_CR22","doi-asserted-by":"publisher","unstructured":"Neisi, E. & Hasanvandi, S. Synthesis of a Novel Polymer- Iron (\u0399\u0399\u0399) Complex and Study of Its Anticancer Properties on A375 Melanoma Cell Line. (2023). https:\/\/doi.org\/10.20944\/PREPRINTS202308.2171.V1","DOI":"10.20944\/PREPRINTS202308.2171.V1"},{"key":"56489_CR23","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.3390\/MOLECULES26061666","volume":"26","author":"X Gao","year":"2021","unstructured":"Gao, X. et al. Berberine and cisplatin exhibit synergistic anticancer effects on osteosarcoma MG-63 cells by inhibiting the MAPK pathway. Molecules 26, 1666. https:\/\/doi.org\/10.3390\/MOLECULES26061666 (2021).","journal-title":"Molecules"},{"key":"56489_CR24","doi-asserted-by":"publisher","first-page":"e1984","DOI":"10.21769\/BIOPROTOC.1984","volume":"6","author":"EA Orellana","year":"2016","unstructured":"Orellana, E. A. & Kasinski, A. L. Sulforhodamine B (SRB) Assay in Cell Culture to Investigate Cell Proliferation. Bio Protoc. 6, e1984. https:\/\/doi.org\/10.21769\/BIOPROTOC.1984 (2016).","journal-title":"Bio Protoc."},{"key":"56489_CR25","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","volume":"70","author":"TC Chou","year":"2010","unstructured":"Chou, T. C. Drug combination studies and their synergy quantification using the chou-talalay method. Cancer Res. 70, 440\u2013446. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-1947 (2010).","journal-title":"Cancer Res."},{"key":"56489_CR26","doi-asserted-by":"publisher","first-page":"D1202","DOI":"10.1093\/NAR\/GKV951","volume":"44","author":"S Kim","year":"2016","unstructured":"Kim, S. et al. PubChem substance and compound databases. Nucleic Acids Res. 44, D1202\u2013D1213. https:\/\/doi.org\/10.1093\/NAR\/GKV951 (2016).","journal-title":"Nucleic Acids Res."},{"key":"56489_CR27","doi-asserted-by":"publisher","first-page":"W32","DOI":"10.1093\/NAR\/GKU293","volume":"42","author":"D Gfeller","year":"2014","unstructured":"Gfeller, D. et al. SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Res. 42, W32\u2013W38. https:\/\/doi.org\/10.1093\/NAR\/GKU293 (2014).","journal-title":"Nucleic Acids Res."},{"key":"56489_CR28","doi-asserted-by":"publisher","DOI":"10.1093\/DATABASE\/BAQ020","author":"M Safran","year":"2010","unstructured":"Safran, M. et al. GeneCards Version 3: the human gene integrator. Database 2010. https:\/\/doi.org\/10.1093\/DATABASE\/BAQ020 (2010).","journal-title":"Database 2010"},{"key":"56489_CR29","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1021\/ACS.JPROTEOME.8B00702","volume":"18","author":"NT Doncheva","year":"2019","unstructured":"Doncheva, N. T., Morris, J. H., Gorodkin, J. & Jensen, L. J. Cytoscape StringApp: network analysis and visualization of proteomics data. J. Proteome Res. 18, 623\u2013632. https:\/\/doi.org\/10.1021\/ACS.JPROTEOME.8B00702 (2019).","journal-title":"J. Proteome Res."},{"key":"56489_CR30","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0184129","author":"L Chen","year":"2017","unstructured":"Chen, L. et al. Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways. PLoS One. https:\/\/doi.org\/10.1371\/JOURNAL.PONE.0184129 (2017).","journal-title":"PLoS One"},{"key":"56489_CR31","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/NAR\/GKAC1000","volume":"51","author":"D Szklarczyk","year":"2023","unstructured":"Szklarczyk, D. et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51, D638\u2013D646. https:\/\/doi.org\/10.1093\/NAR\/GKAC1000 (2023).","journal-title":"Nucleic Acids Res."},{"key":"56489_CR32","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1590\/S1517-83822007000200034","volume":"38","author":"C Valgas","year":"2007","unstructured":"Valgas, C., De Souza, S. M., Sm\u00e2nia, E. F. A. & Sm\u00e2nia, A. Screening methods to determine antibacterial activity of natural products. Brazilian J. Microbiol. 38, 369\u2013380. https:\/\/doi.org\/10.1590\/S1517-83822007000200034 (2007).","journal-title":"Brazilian J. Microbiol."},{"key":"56489_CR33","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1080\/10412905.2000.9699509","volume":"12","author":"SG Griffin","year":"2000","unstructured":"Griffin, S. G., Markham, J. L. & Leach, D. N. An agar dilution method for the determination of the minimum inhibitory concentration of essential oils. J. Essent. Oil Res. 12, 249\u2013255. https:\/\/doi.org\/10.1080\/10412905.2000.9699509 (2000).","journal-title":"J. Essent. Oil Res."},{"key":"56489_CR34","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1590\/S1517-83822000000400003","volume":"31","author":"GGF Nascimento","year":"2000","unstructured":"Nascimento, G. G. F., Locatelli, J., Freitas, P. C. & Silva, G. L. Antibacterial activity of plant extracts and phytochemicals on antibiotic-resistant bacteria. Brazilian J. Microbiol. 31, 247\u2013256. https:\/\/doi.org\/10.1590\/S1517-83822000000400003 (2000).","journal-title":"Brazilian J. Microbiol."},{"key":"56489_CR35","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1002\/ptr.1488","volume":"18","author":"F Odabasoglu","year":"2004","unstructured":"Odabasoglu, F. et al. Comparison of antioxidant activity and phenolic content of three lichen species. Phytother. Res. 18, 938\u2013941. https:\/\/doi.org\/10.1002\/ptr.1488 (2004).","journal-title":"Phytother. Res."},{"key":"56489_CR36","first-page":"1086","volume":"46","author":"T Bahorun","year":"1996","unstructured":"Bahorun, T. et al. Oxygen species scavenging activity of phenolic extracts from hawthorn fresh plant organs and pharmaceutical preparations. Arzneimittelforschung 46, 1086\u20131089 (1996).","journal-title":"Arzneimittelforschung"},{"key":"56489_CR37","unstructured":"ICH Q8 (R2. ) Pharmaceutical development - Scientific guideline | European Medicines Agency (EMA). (Accessed 01 May 2026). https:\/\/www.ema.europa.eu\/en\/ich-q8-r2-pharmaceutical-development-scientific-guideline"},{"key":"56489_CR38","first-page":"133","volume":"4","author":"F Naghibi","year":"2009","unstructured":"Naghibi, F. et al. Cytotoxic activities of selected medicinal plants from Iran and phytochemical evaluation of the most potent extract. Res. Pharm. Sci. 4, 133 (2009).","journal-title":"Res. Pharm. Sci."},{"key":"56489_CR39","doi-asserted-by":"publisher","first-page":"e37894","DOI":"10.1016\/J.HELIYON.2024.E37894","volume":"10","author":"X Zhang","year":"2024","unstructured":"Zhang, X. et al. Review on effects and mechanisms of plant-derived natural products against breast cancer bone metastasis. Heliyon 10, e37894. https:\/\/doi.org\/10.1016\/J.HELIYON.2024.E37894 (2024).","journal-title":"Heliyon"},{"key":"56489_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.envres.2023.116432","author":"HS Budi","year":"2023","unstructured":"Budi, H. S. & Farhood, B. Tumor microenvironment remodeling in oral cancer: Application of plant derived-natural products and nanomaterials. Environ. Res. https:\/\/doi.org\/10.1016\/j.envres.2023.116432 (2023).","journal-title":"Environ. Res."},{"key":"56489_CR41","doi-asserted-by":"publisher","unstructured":"Dasari, S. et al. Pharmacological effects of cisplatin combination with natural products in cancer chemotherapy. (2022). https:\/\/doi.org\/10.3390\/ijms23031532","DOI":"10.3390\/ijms23031532"},{"key":"56489_CR42","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/J.IJOM.2025.01.002","volume":"54","author":"A Jain","year":"2025","unstructured":"Jain, A. et al. TNF-\u03b1 polymorphism in oral cancer and oral potentially malignant disorders: meta-analysis and investigation as a potential tool to determine individual susceptibility and the prognosis. Int. J. Oral Maxillofac. Surg. 54, 494\u2013505. https:\/\/doi.org\/10.1016\/J.IJOM.2025.01.002 (2025).","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"56489_CR43","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.3390\/CANCERS15061841","volume":"15","author":"G Brierly","year":"2023","unstructured":"Brierly, G. et al. Tumour necrosis factor alpha (TNF-\u03b1) and oral squamous cell carcinoma. Cancers (Basel). 15, 1841. https:\/\/doi.org\/10.3390\/CANCERS15061841 (2023).","journal-title":"Cancers (Basel)"},{"key":"56489_CR44","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/J.DRUDIS.2006.06.002","volume":"11","author":"AT Paul","year":"2006","unstructured":"Paul, A. T., Gohil, V. M. & Bhutani, K. K. Modulating TNF-\u03b1 signaling with natural products. Drug Discov Today. 11, 725\u2013732. https:\/\/doi.org\/10.1016\/J.DRUDIS.2006.06.002 (2006).","journal-title":"Drug Discov Today"},{"key":"56489_CR45","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1128\/CVI.13.3.319-328.2006","volume":"13","author":"MP Nair","year":"2006","unstructured":"Nair, M. P. et al. The flavonoid quercetin inhibits proinflammatory cytokine (Tumor Necrosis Factor Alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-\u03ba\u03b2 system. Clin. Vaccine Immunol. 13, 319. https:\/\/doi.org\/10.1128\/CVI.13.3.319-328.2006 (2006).","journal-title":"Clin. Vaccine Immunol."},{"key":"56489_CR46","doi-asserted-by":"publisher","first-page":"104077","DOI":"10.1016\/J.MICPATH.2020.104077","volume":"142","author":"X Zhu","year":"2020","unstructured":"Zhu, X. et al. Alpha-linolenic acid protects against lipopolysaccharide-induced acute lung injury through anti-inflammatory and anti-oxidative pathways. Microb. Pathog. 142, 104077. https:\/\/doi.org\/10.1016\/J.MICPATH.2020.104077 (2020).","journal-title":"Microb. Pathog"},{"key":"56489_CR47","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.canlet.2009.06.033","volume":"288","author":"DO Moon","year":"2010","unstructured":"Moon, D. O. et al. Rosmarinic acid sensitizes cell death through suppression of TNF-\u03b1-induced NF-\u03baB activation and ROS generation in human leukemia U937 cells. Cancer Lett. 288, 183\u2013191. https:\/\/doi.org\/10.1016\/j.canlet.2009.06.033 (2010).","journal-title":"Cancer Lett."},{"key":"56489_CR48","doi-asserted-by":"publisher","first-page":"1479505","DOI":"10.3389\/FIMMU.2024.1479505\/XML\/NLM","volume":"15","author":"X Zhang","year":"2024","unstructured":"Zhang, X. et al. The role of interleukin-17 in inflammation-related cancers. Front. Immunol. 15, 1479505. https:\/\/doi.org\/10.3389\/FIMMU.2024.1479505\/XML\/NLM (2024).","journal-title":"Front. Immunol."},{"key":"56489_CR49","doi-asserted-by":"publisher","first-page":"9874","DOI":"10.3390\/IJMS24129874","volume":"24","author":"N Ladjevac","year":"2023","unstructured":"Ladjevac, N. et al. The role of IL-17 in the pathogenesis of oral squamous cell carcinoma. Int. J. Mol. Sci. 24, 9874. https:\/\/doi.org\/10.3390\/IJMS24129874 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"56489_CR50","doi-asserted-by":"publisher","first-page":"109032","DOI":"10.1016\/J.INTIMP.2022.109032","volume":"110","author":"L Zhong","year":"2022","unstructured":"Zhong, L. et al. The immunoregulatory effects of natural products on psoriasis via its action on Th17 cells versus regulatory T cells balance. Int. Immunopharmacol. 110, 109032. https:\/\/doi.org\/10.1016\/J.INTIMP.2022.109032 (2022).","journal-title":"Int. Immunopharmacol."},{"key":"56489_CR51","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3390\/NU16010002","volume":"16","author":"EK Konstantinou","year":"2023","unstructured":"Konstantinou, E. K. et al. Molecular pathways of rosmarinic acid anticancer activity in triple-negative breast cancer cells. Literature Rev. Nutrients 2024. 16, 2. https:\/\/doi.org\/10.3390\/NU16010002 (2023).","journal-title":"Literature Rev. Nutrients 2024"},{"key":"56489_CR52","doi-asserted-by":"publisher","first-page":"283","DOI":"10.31557\/APJCP.2023.24.1.283","volume":"24","author":"HK Son","year":"2023","unstructured":"Son, H. K. & Kim, D. Quercetin induces cell cycle arrest and apoptosis in YD10B and YD38 oral squamous cell carcinoma cells. Asian Pac. J. Cancer Prev. 24, 283\u2013289. https:\/\/doi.org\/10.31557\/APJCP.2023.24.1.283 (2023).","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"56489_CR53","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/934207","author":"N Wang","year":"2015","unstructured":"Wang, N. & Feng, Y. Elaborating the role of natural products-induced autophagy in cancer treatment: achievements and artifacts in the state of the art. Biomed. Res. Int. https:\/\/doi.org\/10.1155\/2015\/934207 (2015).","journal-title":"Biomed. Res. Int."},{"key":"56489_CR54","doi-asserted-by":"publisher","first-page":"6859","DOI":"10.3892\/MMR.2018.8686\/DOWNLOAD","volume":"17","author":"J Chen","year":"2018","unstructured":"Chen, J. et al. Inhibition of autophagy promotes cisplatin-induced apoptotic cell death through Atg5 and Beclin 1 in A549 human lung cancer cells. Mol. Med. Rep. 17, 6859\u20136865. https:\/\/doi.org\/10.3892\/MMR.2018.8686\/DOWNLOAD (2018).","journal-title":"Mol. Med. Rep."},{"key":"56489_CR55","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.2147\/DDDT.S126464","volume":"11","author":"JF Lin","year":"2017","unstructured":"Lin, J. F. et al. Cisplatin induces protective autophagy through activation of BECN1 in human bladder cancer cells. Drug Des. Devel Ther. 11, 1517. https:\/\/doi.org\/10.2147\/DDDT.S126464 (2017).","journal-title":"Drug Des. Devel Ther."},{"key":"56489_CR56","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41419-024-06975-1","volume":"15","author":"SY Oh","year":"2024","unstructured":"Oh, S. Y. et al. Chromatin remodeling-driven autophagy activation induces cisplatin resistance in oral squamous cell carcinoma. Cell. Death Disease 2024. 15, 8. https:\/\/doi.org\/10.1038\/s41419-024-06975-1 (2024).","journal-title":"Cell. Death Disease 2024"},{"key":"56489_CR57","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.ctrv.2003.07.007","volume":"30","author":"J\u00c1 Fresno Vara","year":"2004","unstructured":"Fresno Vara, J. \u00c1. et al. P13K\/Akt signalling pathway and cancer. Cancer Treat. Rev. 30, 193\u2013204 (2004). https:\/\/doi.org\/10.1016\/J.CTRV.2003.07.007\/ASSET\/A5595073-9F5F-4EAF-B1A2-EFEA0990851A\/MAIN.ASSETS\/GR1.SML","journal-title":"Cancer Treat. Rev."},{"key":"56489_CR58","first-page":"4700","volume":"11","author":"V Remadevi","year":"2021","unstructured":"Remadevi, V., Muraleedharan, P. & Sreeja, S. FOXO1: a pivotal pioneer factor in oral squamous cell carcinoma. Am. J. Cancer Res. 11, 4700 (2021).","journal-title":"Am. J. Cancer Res."},{"key":"56489_CR59","doi-asserted-by":"publisher","first-page":"116634","DOI":"10.1016\/J.BCP.2024.116634","volume":"230","author":"A Kotwal","year":"2024","unstructured":"Kotwal, A., Goldner, W. S. & Bennett, R. G. Role of relaxin signaling in cancer: a review. Biochem. Pharmacol. 230, 116634. https:\/\/doi.org\/10.1016\/J.BCP.2024.116634 (2024).","journal-title":"Biochem. Pharmacol."},{"key":"56489_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/S41467-020-16616-8","author":"HY Choi","year":"2020","unstructured":"Choi, H. Y. et al. Targeting signalling pathways and the immune microenvironment of cancer stem cells \u2014 a clinical update. Nat. Commun. https:\/\/doi.org\/10.1038\/S41467-020-16616-8 (2020).","journal-title":"Nat. Commun."},{"key":"56489_CR61","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1023\/A:1014479702575\/METRICS","volume":"22","author":"RK Furse","year":"2002","unstructured":"Furse, R. K., Rossetti, R. G., Seiler, C. M. & Zurier, R. B. Oral administration of gammalinolenic acid, an unsaturated fatty acid with anti-inflammatory properties, modulates interleukin-1\u03b2 production by human monocytes. J. Clin. Immunol. 22, 83\u201391. https:\/\/doi.org\/10.1023\/A:1014479702575\/METRICS (2002).","journal-title":"J. Clin. Immunol."},{"key":"56489_CR62","doi-asserted-by":"publisher","first-page":"24","DOI":"10.2174\/1871523020666211201162917","volume":"21","author":"N Boussoualim","year":"2021","unstructured":"Boussoualim, N. et al. In vitro anti-hemolytic effect, in vivo anti-inflammatory and in vitro anti-oxidant activity of Anchusa azurea Mill. Antiinflamm Antiallergy Agents Med. Chem. 21, 24\u201333. https:\/\/doi.org\/10.2174\/1871523020666211201162917 (2021).","journal-title":"Antiinflamm Antiallergy Agents Med. Chem."},{"key":"56489_CR63","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.3390\/microorganisms8121851","volume":"8","author":"M Hamidian","year":"2020","unstructured":"Hamidian, M. et al. Analysis of complete genome sequence of Acinetobacter baumannii strain ATCC 19606 reveals novel mobile genetic elements and novel prophage. Microorganisms 8 1851 https:\/\/doi.org\/10.3390\/MICROORGANISMS8121851 (2020).","journal-title":"Microorganisms"},{"key":"56489_CR64","doi-asserted-by":"publisher","first-page":"502","DOI":"10.3923\/pjbs.2019.502.509","volume":"22","author":"AE El-Haddad","year":"2019","unstructured":"El-Haddad, A. E., Saadeldeen, A. M. & El-Emam, S. Z. Anti-angiogenic activity of major phenolics in tamarind assessed with molecular docking study on VEGF kinase proteins. Pak. J. Biol. Sci. 22, 502\u2013509 (2019).","journal-title":"Pak. J. Biol. Sci."},{"key":"56489_CR65","unstructured":"(PDF)In Vivo free radical scavenging, antihemolytic activity and antibacterial effects of Anchusa azurea extracts. (Accessed 01 May 2026). https:\/\/www.researchgate.net\/publication\/283855905_In_Vivo_Free_Radical_Scavenging_Antihemolytic_Activity_and_Antibacterial_Effects_of_Anchusa_Azurea_Extracts"},{"key":"56489_CR66","doi-asserted-by":"publisher","first-page":"2480","DOI":"10.3390\/molecules27082480","volume":"27","author":"HA El Gizawy","year":"2022","unstructured":"El Gizawy, H. A. et al. In vitro cytotoxic activity and phytochemical characterization (UPLC\/T-TOF-MS\/MS) of the watermelon (Citrullus lanatus) rind extract. Molecules 27, 2480 (2022).","journal-title":"Molecules"},{"key":"56489_CR67","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.3390\/ph16101379","volume":"16","author":"R Mounir","year":"2023","unstructured":"Mounir, R. et al. Unlocking the power of onion peel extracts: antimicrobial and anti-inflammatory effects improve wound healing through repressing notch-1\/NLRP3\/caspase-1 signaling. Pharmaceuticals 16, 1379 (2023).","journal-title":"Pharmaceuticals"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-56489-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-56489-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-56489-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T16:57:34Z","timestamp":1781369854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-56489-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,13]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["56489"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-56489-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,13]]},"assertion":[{"value":"23 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18366"}}