{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:37:12Z","timestamp":1786624632226,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,13]]},"group-title":"In Review","reference-count":46,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,9]]},"abstract":"<title>Abstract<\/title>\n                <p>While protein fibrillation represents a critical challenge in therapeutic insulin delivery, the structural determinants and immunological consequences of insulin-derived fibrils (IDFs) formed in the presence of phenolic preservatives remain poorly characterized. This study investigated the structural characteristics of IDFs formed with (IDF (+)) and without (IDF (-)) phenolic preservatives and elucidated their differential immunomodulatory mechanisms in bone marrow-derived macrophages (BMDMs). IDF structural properties were characterized using Thioflavin T fluorescence and nanoparticle tracking analysis (Spectradyne nCS1\u2122). BMDMs were treated with IDF (+), IDF (-), or m-cresol. Cytotoxicity, reactive oxygen species (ROS) production, MIP-1\u03b1 levels, and expression of signaling pathways were quantified. Structural analysis revealed similar aggregation states between IDF (+) and IDF (-). However, IDF (+) induced greater cytotoxicity and ROS production than IDF (-), which produced minimal ROS. Both fibrils increased MIP-1\u03b1 levels. Additionally, IDF (-) upregulated NRF2 whereas m-cresol downregulated STAT6. Together, these results suggest distinct mechanisms of macrophage activation and suggest that protein aggregates can induce macrophage responses directly. Insulin fibrils activate macrophage inflammatory pathways through ROS-independent mechanisms. Phenolic preservatives enhance fibril cytotoxicity and likely ROS production while differentially modulating inflammatory signaling. These findings suggest that strategies to attenuate the effects of IDFs in insulin infusion therapy may increase longevity and biocompatibility of these devices.<\/p>","DOI":"10.21203\/rs.3.rs-9986402\/v1","type":"posted-content","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:13:16Z","timestamp":1786623196000},"source":"Crossref","is-referenced-by-count":0,"title":["Immunomodulatory Effects of Insulin-Derived Fibrils from Infusion Pumps: Role of Phenolic Preservatives in Macrophage Activation"],"prefix":"10.21203","author":[{"given":"Priscila Silva","family":"Cunegundes","sequence":"first","affiliation":[{"name":"Wayne State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congxiao","family":"Cheng","sequence":"additional","affiliation":[{"name":"Wayne State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Wisman","sequence":"additional","affiliation":[{"name":"Wayne State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L.","family":"Menkes","sequence":"additional","affiliation":[{"name":"Oakland University William Beaumont School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Klueh","sequence":"additional","affiliation":[{"name":"Wayne State University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3390\/diabetology6100110","article-title":"Development and Content Validation of the Insulin Pump Infusion Sets Satisfaction Scale (IPISS): A Self-Reported Questionnaire for Patients with Type 1 Diabetes and Caregivers","volume":"6","author":"Monte M","year":"2025","unstructured":"Del Monte, M. et al. Development and Content Validation of the Insulin Pump Infusion Sets Satisfaction Scale (IPISS): A Self-Reported Questionnaire for Patients with Type 1 Diabetes and Caregivers. Diabetology 6, 110 (2025).","journal-title":"Diabetology"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.pcd.2007.07.005","article-title":"International survey of insulin pump users: Impact of continuous subcutaneous insulin infusion therapy on glucose control and quality of life","volume":"1","author":"Hammond P","year":"2007","unstructured":"Hammond, P., Liebl, A. & Grunder, S. International survey of insulin pump users: Impact of continuous subcutaneous insulin infusion therapy on glucose control and quality of life. Prim. Care Diabetes. 1, 143\u2013146 (2007).","journal-title":"Prim. Care Diabetes"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"20406223251381573","DOI":"10.1177\/20406223251381573","article-title":"Short- and long-term complications of insulin pump therapy in children and adolescents with type 1 diabetes: a multicenter cross-sectional study from Saudi Arabia","volume":"16","author":"Bakkar A","year":"2025","unstructured":"Bakkar, A. et al. Short- and long-term complications of insulin pump therapy in children and adolescents with type 1 diabetes: a multicenter cross-sectional study from Saudi Arabia. Ther. Adv. Chronic Dis. 16, 20406223251381573 (2025).","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref4","author":"Nguyen KT","year":"2022","unstructured":"Nguyen, K. T. et al. Improving the Patient Experience With Longer Wear Infusion Sets Symposium Report. J. Diabetes Sci. Technol. 16, 775\u2013782 (2022)."},{"key":"ref5","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1177\/19322968211033868","article-title":"Insulin Derived Fibrils Induce Cytotoxicity in vitro and Trigger Inflammation in Murine Models","volume":"17","author":"Lewis BE","year":"2023","unstructured":"Lewis, B. E. et al. Insulin Derived Fibrils Induce Cytotoxicity in vitro and Trigger Inflammation in Murine Models. J. Diabetes Sci. Technol. 17, 163\u2013171 (2023).","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref6","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1177\/193229681200600210","article-title":"Insulin fibrillation and protein design: topological resistance of single-chain analogs to thermal degradation with application to a pump reservoir","volume":"6","author":"Phillips NB","year":"2012","unstructured":"Phillips, N. B., Whittaker, J., Ismail-Beigi, F. & Weiss, M. A. Insulin fibrillation and protein design: topological resistance of single-chain analogs to thermal degradation with application to a pump reservoir. J. Diabetes Sci. Technol. 6, 277\u2013288 (2012).","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref7","author":"Ivanova MI","year":"2009","unstructured":"Ivanova, M. I., Sievers, S. A., Sawaya, M. R., Wall, J. S. & Eisenberg, D. Molecular basis for insulin fibril assembly. Proc. Natl. Acad. Sci. 106, 18990\u201318995 (2009)."},{"key":"ref8","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1016\/j.bpj.2009.09.042","article-title":"Molecular modeling of the misfolded insulin subunit and amyloid fibril","volume":"97","author":"Choi JH","year":"2009","unstructured":"Choi, J. H., May, B. C. H., Wille, H. & Cohen, F. E. Molecular modeling of the misfolded insulin subunit and amyloid fibril. Biophys. J. 97, 3187\u20133195 (2009).","journal-title":"Biophys. J."},{"key":"ref9","doi-asserted-by":"crossref","first-page":"112","DOI":"10.4161\/pri.2.3.7488","article-title":"Amyloid fibrils: abnormal protein assembly","volume":"2","author":"Rambaran RN","year":"2008","unstructured":"Rambaran, R. N. & Serpell, L. C. Amyloid fibrils: abnormal protein assembly. Prion 2, 112\u2013117 (2008).","journal-title":"Prion"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"174","DOI":"10.4103\/2230-8210.146879","article-title":"Insulin-derived amyloidosis","volume":"19","author":"Gupta Y","year":"2015","unstructured":"Gupta, Y., Singla, G. & Singla, R. Insulin-derived amyloidosis. Indian J. Endocrinol. Metab. 19, 174\u2013177 (2015).","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref11","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40780-019-0151-5","article-title":"Investigation of factors that cause insulin precipitation and\/or amyloid formation in insulin formulations","volume":"5","author":"Ohno Y","year":"2019","unstructured":"Ohno, Y. et al. Investigation of factors that cause insulin precipitation and\/or amyloid formation in insulin formulations. J. Pharm. Health Care Sci. 5, 22 (2019).","journal-title":"J. Pharm. Health Care Sci."},{"key":"ref12","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.3390\/diagnostics13142415","article-title":"Localized Insulin-Derived Amyloidosis in Diabetes Mellitus Type 1 Patient: A Case Report","volume":"13","author":"Hrudka J","year":"2023","unstructured":"Hrudka, J., Sticov\u00e1, E., Krbcov\u00e1, M. & Schwarzmannov\u00e1, K. Localized Insulin-Derived Amyloidosis in Diabetes Mellitus Type 1 Patient: A Case Report. Diagnostics 13, 2415 (2023).","journal-title":"Diagnostics"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1177\/193229681200600209","article-title":"Intrinsic fibrillation of fast-acting insulin analogs","volume":"6","author":"Woods RJ","year":"2012","unstructured":"Woods, R. J., Alarc\u00f3n, J., McVey, E. & Pettis, R. J. Intrinsic fibrillation of fast-acting insulin analogs. J. Diabetes Sci. Technol. 6, 265\u2013276 (2012).","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref14","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.3390\/ijms18122551","article-title":"Insights into Insulin Fibril Assembly at Physiological and Acidic pH and Related Amyloid Intrinsic Fluorescence","volume":"18","author":"Iannuzzi C","year":"2017","unstructured":"Iannuzzi, C., Borriello, M., Portaccio, M., Irace, G. & Sirangelo, I. Insights into Insulin Fibril Assembly at Physiological and Acidic pH and Related Amyloid Intrinsic Fluorescence. Int. J. Mol. Sci. 18, 2551 (2017).","journal-title":"Int. J. Mol. Sci."},{"key":"ref15","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1080\/07388551.2024.2387167","article-title":"Insulin fibrillation under physicochemical parameters of bioprocessing and intervention by peptides and surface-active agents","volume":"45","author":"Panda C","year":"2025","unstructured":"Panda, C., Kumar, S., Gupta, S. & Pandey, L. M. Insulin fibrillation under physicochemical parameters of bioprocessing and intervention by peptides and surface-active agents. Crit. Rev. Biotechnol. 45, 643\u2013664 (2025).","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1177\/19322968251334663","article-title":"Optimizing Duration of Usage of Insulin Infusion Sets: A Response","volume":"19","author":"Kwa T","year":"2025","unstructured":"Kwa, T. et al. Optimizing Duration of Usage of Insulin Infusion Sets: A Response. J. Diabetes Sci. Technol. 19, 1161\u20131162 (2025).","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref17","doi-asserted-by":"crossref","first-page":"e1801451","DOI":"10.1002\/adhm.201801451","article-title":"Macrophage and Fibroblast Interactions in Biomaterial-Mediated Fibrosis","volume":"8","author":"Witherel CE","year":"2019","unstructured":"Witherel, C. E., Abebayehu, D., Barker, T. H. & Spiller, K. L. Macrophage and Fibroblast Interactions in Biomaterial-Mediated Fibrosis. Adv. Healthc. Mater. 8, e1801451 (2019).","journal-title":"Adv. Healthc. Mater."},{"key":"ref18","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.actbio.2021.03.038","article-title":"Macrophage phenotypes in tissue repair and the foreign body response: Implications for biomaterial-based regenerative medicine strategies","volume":"133","author":"Martin KE","year":"2021","unstructured":"Martin, K. E. & Garc\u00eda, A. J. Macrophage phenotypes in tissue repair and the foreign body response: Implications for biomaterial-based regenerative medicine strategies. Acta Biomater. 133, 4\u201316 (2021).","journal-title":"Acta Biomater."},{"key":"ref19","author":"Ni Y","year":"2023","unstructured":"Ni, Y. et al. Macrophages modulate stiffness-related foreign body responses through plasma membrane deformation. Proc. Natl. Acad. Sci. 120, e2213837120 (2023)."},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1007\/s13346-021-01070-w","article-title":"A pharmacological approach assessing the role of mast cells in insulin infusion site inflammation","volume":"12","author":"Kesserwan S","year":"2022","unstructured":"Kesserwan, S., Mao, L., Sharafieh, R., Kreutzer, D. L. & Klueh, U. A pharmacological approach assessing the role of mast cells in insulin infusion site inflammation. Drug Deliv Transl Res. 12, 1711\u20131718 (2022).","journal-title":"Drug Deliv Transl Res."},{"key":"ref21","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1002\/jbm.a.37097","article-title":"Advancing continuous subcutaneous insulin infusion in vivo: New insights into tissue challenges","volume":"109","author":"Kesserwan S","year":"2021","unstructured":"Kesserwan, S. et al. Advancing continuous subcutaneous insulin infusion in vivo: New insights into tissue challenges. J. Biomed. Mater. Res. A. 109, 1065\u20131079 (2021).","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.3390\/biomedicines11082258","article-title":"Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation","volume":"11","author":"Kesserwan S","year":"2023","unstructured":"Kesserwan, S., Sadagurski, M., Mao, L. & Klueh, U. Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation. Biomedicines 11, 2258 (2023).","journal-title":"Biomedicines"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3390\/antiox10020313","article-title":"Functions of ROS in Macrophages and Antimicrobial Immunity","volume":"10","author":"Herb M","year":"2021","unstructured":"Herb, M. & Schramm, M. Functions of ROS in Macrophages and Antimicrobial Immunity. Antioxid. Basel Switz. 10, 313 (2021).","journal-title":"Antioxid. Basel Switz."},{"key":"ref24","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1164\/rccm.2206007","article-title":"Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling","volume":"166","author":"Forman HJ","year":"2002","unstructured":"Forman, H. J. & Torres, M. Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am. J. Respir Crit. Care Med. 166, S4\u20138 (2002).","journal-title":"Am. J. Respir Crit. Care Med."},{"key":"ref25","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1021\/acsptsci.1c00047","article-title":"Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia","volume":"4","author":"Mulka A","year":"2021","unstructured":"Mulka, A. et al. Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia. ACS Pharmacol. Transl Sci. 4, 1161\u20131174 (2021).","journal-title":"ACS Pharmacol. Transl Sci."},{"key":"ref26","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.toxrep.2014.11.019","article-title":"Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release","volume":"2","author":"Weber C","year":"2015","unstructured":"Weber, C., Kammerer, D., Streit, B. & Licht, A. H. Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release. Toxicol. Rep. 2, 194\u2013202 (2015).","journal-title":"Toxicol. Rep."},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1007\/s00726-009-0339-3","article-title":"Generation of reactive oxygen species by beta amyloid fibrils and oligomers involves different intra\/extracellular pathways","volume":"38","author":"Cenini G","year":"2010","unstructured":"Cenini, G. et al. Generation of reactive oxygen species by beta amyloid fibrils and oligomers involves different intra\/extracellular pathways. Amino Acids. 38, 1101\u20131106 (2010).","journal-title":"Amino Acids"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"12052","DOI":"10.1074\/jbc.M113.525212","article-title":"\u03b2-Amyloid Fibrils in Alzheimer Disease Are Not Inert When Bound to Copper Ions but Can Degrade Hydrogen Peroxide and Generate Reactive Oxygen Species","volume":"289","author":"Mayes J","year":"2014","unstructured":"Mayes, J. et al. \u03b2-Amyloid Fibrils in Alzheimer Disease Are Not Inert When Bound to Copper Ions but Can Degrade Hydrogen Peroxide and Generate Reactive Oxygen Species. J. Biol. Chem. 289, 12052\u201312062 (2014).","journal-title":"J. Biol. Chem."},{"key":"ref29","doi-asserted-by":"crossref","first-page":"734229","DOI":"10.3389\/fimmu.2021.734229","article-title":"Reactive Oxygen Species in Macrophages: Sources and Targets","volume":"12","author":"Canton M","year":"2021","unstructured":"Canton, M. et al. Reactive Oxygen Species in Macrophages: Sources and Targets. Front. Immunol. 12, 734229 (2021).","journal-title":"Front. Immunol."},{"key":"ref30","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1161\/CIRCRESAHA.117.311401","article-title":"Reactive Oxygen Species in Metabolic and Inflammatory Signaling","volume":"122","author":"Forrester SJ","year":"2018","unstructured":"Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q. & Griendling, K. K. Reactive Oxygen Species in Metabolic and Inflammatory Signaling. Circ. Res. 122, 877\u2013902 (2018).","journal-title":"Circ. Res."},{"key":"ref31","doi-asserted-by":"crossref","first-page":"714370","DOI":"10.3389\/fcell.2021.714370","article-title":"Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man","volume":"9","author":"Sinenko SA","year":"2021","unstructured":"Sinenko, S. A., Starkova, T. Y., Kuzmin, A. A. & Tomilin, A. N. Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man. Front. Cell. Dev. Biol. 9, 714370 (2021).","journal-title":"Front. Cell. Dev. Biol."},{"key":"ref32","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/978-94-007-7696-8_27","volume-title":"General Methods in Biomarker Research and their Applications","author":"Bhavsar I","year":"2015","unstructured":"Bhavsar, I., Miller, C. S. & Al-Sabbagh, M. Macrophage Inflammatory Protein-1 Alpha (MIP-1 alpha)\/CCL3: As a Biomarker. in General Methods in Biomarker Research and their Applications (eds (eds Preedy, V. R. & Patel, V. B.) 223\u2013249 (Springer Netherlands, Dordrecht, doi:10.1007\/978-94-007-7696-8_27. (2015)."},{"key":"ref33","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1748-717X-6-86","article-title":"The interaction between different types of activated RAW 264.7 cells and macrophage inflammatory protein-1 alpha","volume":"6","author":"He Z","year":"2011","unstructured":"He, Z. et al. The interaction between different types of activated RAW 264.7 cells and macrophage inflammatory protein-1 alpha. Radiat. Oncol. 6, 86 (2011).","journal-title":"Radiat. Oncol."},{"key":"ref34","doi-asserted-by":"crossref","first-page":"11624","DOI":"10.1038\/ncomms11624","article-title":"Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription","volume":"7","author":"Kobayashi EH","year":"2016","unstructured":"Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016).","journal-title":"Nat. Commun."},{"key":"ref35","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.intimp.2019.03.023","article-title":"Nrf2 exerts mixed inflammation and glucose metabolism regulatory effects on murine RAW264.7 macrophages","volume":"71","author":"Ding L","year":"2019","unstructured":"Ding, L. et al. Nrf2 exerts mixed inflammation and glucose metabolism regulatory effects on murine RAW264.7 macrophages. Int. Immunopharmacol. 71, 198\u2013204 (2019).","journal-title":"Int. Immunopharmacol."},{"key":"ref36","doi-asserted-by":"crossref","first-page":"17020","DOI":"10.1074\/jbc.M114.563114","article-title":"Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation","volume":"289","author":"Zhao C","year":"2014","unstructured":"Zhao, C., Gillette, D. D., Li, X., Zhang, Z. & Wen, H. Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation. J. Biol. Chem. 289, 17020\u201317029 (2014).","journal-title":"J. Biol. Chem."},{"key":"ref37","author":"Lee YJ","year":"2022","unstructured":"Lee, Y. J., Kim, K., Kim, M., Ahn, Y. H. & Kang, J. L. Inhibition of STAT6 Activation by AS1517499 Inhibits Expression and Activity of PPAR\u03b3 in Macrophages to Resolve Acute Inflammation in Mice. Biomolecules 12, 447 (2022)."},{"key":"ref38","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.4049\/jimmunol.1700808","article-title":"STAT6 and Furin Are Successive Triggers for the Production of TGF-\u03b2 by T Cells","volume":"201","author":"Li Y","year":"2018","unstructured":"Li, Y. et al. STAT6 and Furin Are Successive Triggers for the Production of TGF-\u03b2 by T Cells. J. Immunol. 201, 2612\u20132623 (2018).","journal-title":"J. Immunol."},{"key":"ref39","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s00018-009-0193-1","article-title":"Biological activity of phenolic lipids","volume":"67","author":"Stasiuk M","year":"2010","unstructured":"Stasiuk, M. & Kozubek, A. Biological activity of phenolic lipids. Cell. Mol. Life Sci. CMLS. 67, 841\u2013860 (2010).","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"105699","DOI":"10.1039\/C6RA20337J","article-title":"m-Cresol affects the lipid bilayer in membrane models and living neurons","volume":"6","author":"Paiva TO","year":"2016","unstructured":"Paiva, T. O. et al. m-Cresol affects the lipid bilayer in membrane models and living neurons. RSC Adv. 6, 105699\u2013105712 (2016).","journal-title":"RSC Adv."},{"key":"ref41","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.toxrep.2014.11.019","article-title":"Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release","volume":"2","author":"Weber C","year":"2015","unstructured":"Weber, C., Kammerer, D., Streit, B. & Licht, A. H. Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release. Toxicol. Rep. 2, 194\u2013202 (2015).","journal-title":"Toxicol. Rep."},{"key":"ref42","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s42003-024-05903-5","article-title":"Phenolic compounds induce ferroptosis-like death by promoting hydroxyl radical generation in the Fenton reaction","volume":"7","author":"Sui X","year":"2024","unstructured":"Sui, X. et al. Phenolic compounds induce ferroptosis-like death by promoting hydroxyl radical generation in the Fenton reaction. Commun. Biol. 7, 199 (2024).","journal-title":"Commun. Biol."},{"key":"ref43","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","article-title":"Ferroptosis: molecular mechanisms and health implications","volume":"31","author":"Tang D","year":"2021","unstructured":"Tang, D., Chen, X., Kang, R. & Kroemer, G. Ferroptosis: molecular mechanisms and health implications. Cell. Res. 31, 107\u2013125 (2021).","journal-title":"Cell. Res."},{"key":"ref44","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1177\/193229681200600209","article-title":"Intrinsic fibrillation of fast-acting insulin analogs","volume":"6","author":"Woods RJ","year":"2012","unstructured":"Woods, R. J., Alarc\u00f3n, J., McVey, E. & Pettis, R. J. Intrinsic fibrillation of fast-acting insulin analogs. J. Diabetes Sci. Technol. 6, 265\u2013276 (2012).","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref45","author":"Weischenfeldt J","year":"2008","unstructured":"Weischenfeldt, J. & Porse, B. Bone Marrow-Derived Macrophages (BMM): Isolation and Applications. CSH Protoc. pdb.prot5080 (2008). (2008)."},{"key":"ref46","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak KJ","year":"2001","unstructured":"Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods San Diego Calif. 25, 402\u2013408 (2001).","journal-title":"Methods San Diego Calif."}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9986402\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9986402\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:13:25Z","timestamp":1786623205000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9986402\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":46,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-9986402\/v1","relation":{},"subject":[],"published":{"date-parts":[[2026,8,13]]},"subtype":"preprint"}}