{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T02:08:36Z","timestamp":1783649316581,"version":"3.55.0"},"reference-count":65,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T00:00:00Z","timestamp":1673913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science Foundation Ireland under the Frontiers for the Future Programme","award":["#20\/FFP-P\/8649"],"award-info":[{"award-number":["#20\/FFP-P\/8649"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Neuroinflammation is a hallmark of traumatic brain injury (TBI)\u2019s acute and chronic phases. Despite the medical and scientific advances in recent years, there is still no effective treatment that mitigates the oxidative and inflammatory damage that affects neurons and glial cells. Therefore, searching for compounds with a broader spectrum of action that can regulate various inflammatory signaling pathways is of clinical interest. In this study, we determined not only the in vitro antioxidant capacity of apple pomace phenolics, namely, phlorizin and its metabolite, phloretin, but we also hypothesize that the use of these bioactive molecules may have potential use in TBI. We explored the antioxidant effects of both compounds in vitro (DPPH, iron-reducing capacity (IRC), and Folin\u2013Ciocalteu reducing capacity (FCRC)), and using network pharmacology, we investigated the proteins involved in their protective effects in TBI. Our results showed that the antioxidant properties of phloretin were superior to those of phlorizin in the DPPH (12.95 vs. 3.52 mg ascorbic acid equivalent (AAE)\/L), FCRC (86.73 vs. 73.69 mg gallic acid equivalent (GAE)\/L), and iron-reducing capacity (1.15 vs. 0.88 mg GAE\/L) assays. Next, we examined the molecular signature of both compounds and found 11 proteins in common to be regulated by them and involved in TBI. Meta-analysis and GO functional enrichment demonstrated their implication in matrix metalloproteinases, p53 signaling, and cell secretion\/transport. Using MCODE and Pearson\u2019s correlation analysis, a subcluster was generated. We identified ESR1 (estrogen receptor alpha) as a critical cellular hub being regulated by both compounds and with potential therapeutic use in TBI. In conclusion, our study suggests that because of their vast antioxidant effects, probably acting on estrogen receptors, phloretin and phlorizin may be repurposed for TBI treatment due to their ease of obtaining and low cost.<\/jats:p>","DOI":"10.3390\/molecules28030919","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T03:41:52Z","timestamp":1673926912000},"page":"919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Comparison of Antioxidant Capacity and Network Pharmacology of Phloretin and Phlorizin against Neuroinflammation in Traumatic Brain Injury"],"prefix":"10.3390","volume":"28","author":[{"given":"Kubra Kizil","family":"Ongay","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science and Engineering, University of Limerick, V94 T9PX Limerick, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-1597","authenticated-orcid":false,"given":"Daniel","family":"Granato","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science and Engineering, University of Limerick, V94 T9PX Limerick, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George E.","family":"Barreto","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science and Engineering, University of Limerick, V94 T9PX Limerick, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"895852","DOI":"10.3389\/fpsyt.2022.895852","article-title":"Neurological Symptoms and Their Associations with Inflammatory Biomarkers in the Chronic Phase Following Traumatic Brain Injuries","volume":"13","author":"Li","year":"2022","journal-title":"Front. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"577619","DOI":"10.1016\/j.jneuroim.2021.577619","article-title":"Multipotential and systemic effects of traumatic brain injury","volume":"357","author":"Sabet","year":"2021","journal-title":"J. Neuroimmunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1089\/neu.2015.4126","article-title":"Epidemiology of Traumatic Brain Injury in Europe: A Living Systematic Review","volume":"38","author":"Brazinova","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1089\/neu.2021.0062","article-title":"Epidemiology of Chronic Effects of Traumatic Brain Injury","volume":"38","author":"Pugh","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/ije\/dyn189","article-title":"Patient outcome after traumatic brain injury in high-, middle- and low-income countries: Analysis of data on 8927 patients in 46 countries","volume":"38","author":"Roberts","year":"2009","journal-title":"Int. J. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1177\/0963689717714102","article-title":"Traumatic Brain Injury: Current Treatment Strategies and Future Endeavors","volume":"26","author":"Galgano","year":"2017","journal-title":"Cell Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.mcna.2019.11.001","article-title":"Traumatic Brain Injury: An Overview of Epidemiology, Pathophysiology, and Medical Management","volume":"104","author":"Capizzi","year":"2020","journal-title":"Med. Clin. N. Am."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"van Erp, I.A.M., Michailidou, I., van Essen, T.A., van der Jagt, M., Moojen, W., Peul, W.C., Baas, F., and Fluiter, K. (2022). Tackling Neuroinflammation After Traumatic Brain Injury: Complement Inhibition as a Therapy for Secondary Injury. Neurotherapeutics, 1\u201320.","DOI":"10.1007\/s13311-022-01306-8"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Hui, Y., Zhao, H., Shi, L., and Zhang, H. (2022). Traumatic Brain Injury-Mediated Neuroinflammation and Neurological Deficits are Improved by 8-Methoxypsoralen Through Modulating PPARgamma\/NF-kappaB Pathway. Neurochem. Res., 1\u201316.","DOI":"10.1007\/s11064-022-03788-6"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JAD-191150","article-title":"Inflammation in Traumatic Brain Injury","volume":"74","author":"Postolache","year":"2020","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.expneurol.2015.05.024","article-title":"Treatment of traumatic brain injury with anti-inflammatory drugs","volume":"275","author":"Bergold","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1515\/revneuro-2015-0032","article-title":"Molecular mechanisms of estrogen for neuroprotection in spinal cord injury and traumatic brain injury","volume":"27","author":"Chakrabarti","year":"2016","journal-title":"Rev. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1001\/jama.298.12.1429","article-title":"Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: A systematic review","volume":"298","author":"Schneider","year":"2007","journal-title":"JAMA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1089\/neu.2018.6349","article-title":"Prevalence of Anterior Pituitary Dysfunction Twelve Months or More following Traumatic Brain Injury in Adults: A Systematic Review and Meta-Analysis","volume":"37","author":"Emelifeonwu","year":"2020","journal-title":"J. Neurotrauma"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"641","DOI":"10.2174\/1570159X14666160309123554","article-title":"Neuroprotection by Estrogen and Progesterone in Traumatic Brain Injury and Spinal Cord Injury","volume":"14","author":"Brotfain","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1590\/S0004-27302009000800003","article-title":"Hypogonadism after traumatic brain injury","volume":"53","author":"Hohl","year":"2009","journal-title":"Arq. Bras. de Endocrinol. Metabol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.expneurol.2019.01.017","article-title":"Experimental traumatic brain injury results in estrous cycle disruption, neurobehavioral deficits, and impaired GSK3beta\/beta-catenin signaling in female rats","volume":"315","author":"Fortress","year":"2019","journal-title":"Exp. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"108721","DOI":"10.1016\/j.intimp.2022.108721","article-title":"Identification of HMGCR, PPGARG and prohibitin as potential druggable targets of dihydrotestosterone for treatment against traumatic brain injury using system pharmacology","volume":"108","author":"McGovern","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2018.06.007","article-title":"Neuroactive steroids, neurosteroidogenesis and sex","volume":"176","author":"Giatti","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.pneurobio.2016.06.002","article-title":"Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions","volume":"144","author":"Barreto","year":"2016","journal-title":"Prog. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3039","DOI":"10.1111\/j.1460-9568.2007.05563.x","article-title":"Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: Role of its metabolites, oestradiol and dihydrotestosterone","volume":"25","author":"Barreto","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Barreto, G., McGovern, A., and Garcia-Segura, L. (2021). Role of Neuroglobin in the Neuroprotective Actions of Estradiol and Estrogenic Compounds. Cells, 10.","DOI":"10.3390\/cells10081907"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100787","DOI":"10.1016\/j.yfrne.2019.100787","article-title":"Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences","volume":"55","author":"Azcoitia","year":"2019","journal-title":"Front. Neuroendocr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e12776","DOI":"10.1111\/jne.12776","article-title":"Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds","volume":"32","author":"Echeverria","year":"2020","journal-title":"J. Neuroendocr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8651","DOI":"10.1007\/s12035-018-1008-x","article-title":"The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury","volume":"55","author":"Arevalo","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5010","DOI":"10.1210\/en.2009-0352","article-title":"Selective Estrogen Receptor Modulators Decrease Reactive Astrogliosis in the Injured Brain: Effects of Aging and Prolonged Depletion of Ovarian Hormones","volume":"150","author":"Barreto","year":"2009","journal-title":"Endocrinology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.intimp.2015.05.046","article-title":"The brain cytokine levels are modulated by estrogen following traumatic brain injury: Which estrogen receptor serves as modulator?","volume":"28","author":"Khaksari","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s12975-017-0588-5","article-title":"Effects of Female Sex Steroids Administration on Pathophysiologic Mechanisms in Traumatic Brain Injury","volume":"9","author":"Khaksari","year":"2018","journal-title":"Transl. Stroke Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"K\u00f6vesdi, E., Szab\u00f3-Meleg, E., and Abrah\u00e1m, I.M. (2020). The Role of Estradiol in Traumatic Brain Injury: Mechanism and Treatment Potential. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010011"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113155","DOI":"10.1016\/j.biopha.2022.113155","article-title":"Exploration of novel ligands to target C-C Motif Chemokine Receptor 2 (CCR2) as a promising pharmacological treatment against traumatic brain injury","volume":"151","author":"Sachdev","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113304","DOI":"10.1016\/j.biopha.2022.113304","article-title":"Role of statins in regulating molecular pathways following traumatic brain injury: A system pharmacology study","volume":"153","author":"Mahmoudi","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"276","DOI":"10.3389\/fchem.2018.00276","article-title":"Extracts of Physalis peruviana Protect Astrocytic Cells Under Oxidative Stress With Rotenone","volume":"6","author":"Robles","year":"2018","journal-title":"Front. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/biof.1516","article-title":"Medicinal plants in traumatic brain injury: Neuroprotective mechanisms revisited","volume":"45","author":"Keshavarzi","year":"2019","journal-title":"Biofactors"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112770","DOI":"10.1016\/j.biopha.2022.112770","article-title":"Identification of difluorinated curcumin molecular targets linked to traumatic brain injury pathophysiology","volume":"148","author":"Sahebkar","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1080\/1028415X.2016.1236174","article-title":"Supplements, nutrition, and alternative therapies for the treatment of traumatic brain injury","volume":"21","author":"Logsdon","year":"2018","journal-title":"Nutr. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4180","DOI":"10.2174\/1381612823666170316142803","article-title":"Medicinal Plants as Protective Strategies Against Parkinson\u2019s Disease","volume":"23","author":"Mazo","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1179\/1476830511Y.0000000028","article-title":"Effects of natural antioxidants in neurodegenerative disease","volume":"15","author":"Albarracin","year":"2012","journal-title":"Nutr. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.2174\/1570159X19666210225145957","article-title":"Novel Synthetic and Natural Therapies for Traumatic Brain Injury","volume":"19","author":"Battaglini","year":"2021","journal-title":"Curr. Neuropharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s00894-018-3632-9","article-title":"Probing the antioxidant potential of phloretin and phlorizin through a computational investigation","volume":"24","author":"Mendes","year":"2018","journal-title":"J. Mol. Model."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zielinska, D., Laparra-Llopis, J.M., Zielinski, H., Szawara-Nowak, D., and Gim\u00e9nez-Bastida, J.A. (2019). Role of Apple Phytochemicals, Phloretin and Phloridzin, in Modulating Processes Related to Intestinal Inflammation. Nutrients, 11.","DOI":"10.3390\/nu11051173"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1002\/biof.1358","article-title":"Neuroprotective effects of phloretin and its glycosylated derivative on rotenone-induced toxicity in human SH-SY5Y neuronal-like cells","volume":"43","author":"Barreca","year":"2017","journal-title":"Biofactors"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Park, S., and Park, S.-K. (2022). Anti-Oxidant and Anti-Aging Effects of Phlorizin Are Mediated by DAF-16-Induced Stress Response and Autophagy in Caenorhabditis elegans. Antioxidants, 11.","DOI":"10.3390\/antiox11101996"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"118869","DOI":"10.1016\/j.lfs.2020.118869","article-title":"Phloretin and phloridzin guard against cisplatin-induced nephrotoxicity in mice through inhibiting oxidative stress and inflammation","volume":"266","author":"Un","year":"2021","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.biopha.2017.04.066","article-title":"Immunomodulatory activities of phlorizin metabolites in lipopolysaccharide-stimulated RAW264.7 cells","volume":"91","author":"Zhao","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Xie, L., Deng, Z., Zhang, J., Dong, H., Wang, W., Xing, B., and Liu, X. (2022). Comparison of Flavonoid O-Glycoside, C-Glycoside and Their Aglycones on Antioxidant Capacity and Metabolism during In Vitro Digestion and In Vivo. Foods, 11.","DOI":"10.3390\/foods11060882"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xiao, Z., He, L., Hou, X., Wei, J., Ma, X., Gao, Z., Yuan, Y., Xiao, J., Li, P., and Yue, T. (2021). Relationships between Structure and Antioxidant Capacity and Activity of Glycosylated Flavonols. Foods, 10.","DOI":"10.3390\/foods10040849"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1093\/jn\/131.12.3227","article-title":"Bioavailability of Phloretin and Phloridzin in Rats","volume":"131","author":"Crespy","year":"2001","journal-title":"J. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"148079","DOI":"10.1016\/j.brainres.2022.148079","article-title":"Membrane estrogen receptor ERalpha activation improves tau clearance via autophagy induction in a tauopathy cell model","volume":"1795","author":"Costa","year":"2022","journal-title":"Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.3233\/JAD-200486","article-title":"Estrogen Receptor \u03b1 Agonist is Beneficial for Young Female Rats Against Chronic Unpredicted Mild Stress-Induced Depressive Behavior and Cognitive Deficits","volume":"77","author":"Qu","year":"2020","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e12961","DOI":"10.1111\/acel.12961","article-title":"Estrogen receptor \u03b1 promotes Cav1.2 ubiquitination and degradation in neuronal cells and in APP\/PS1 mice","volume":"18","author":"Lai","year":"2019","journal-title":"Aging Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.mcn.2017.05.004","article-title":"Inhibition of miR-181a protects female mice from transient focal cerebral ischemia by targeting astrocyte estrogen receptor-\u03b1","volume":"82","author":"Stary","year":"2017","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.neurobiolaging.2016.01.002","article-title":"Estrogen receptors alpha mediates postischemic inflammation in chronically estrogen-deprived mice","volume":"40","author":"Cordeau","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3097","DOI":"10.1097\/CCM.0b013e3181bc7986","article-title":"Premarin stimulates estrogen receptor-\u03b1 to protect against traumatic brain injury in male rats","volume":"37","author":"Chen","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.neuint.2010.11.006","article-title":"17Beta-estradiol attenuates programmed cell death in cortical pericontusional zone following traumatic brain injury via upregulation of ERalpha and inhibition of caspase-3 activation","volume":"58","author":"Li","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.mcn.2011.07.004","article-title":"17Beta-estradiol differentially protects cortical pericontusional zone from programmed cell death after traumatic cerebral contusion at distinct stages via non-genomic and genomic pathways","volume":"48","author":"Bao","year":"2011","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3171\/2013.4.JNS121636","article-title":"Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury","volume":"119","author":"Asl","year":"2013","journal-title":"J. Neurosurg."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1210\/ME.2015-1124","article-title":"17\u03b2-Estradiol Ameliorates Tight Junction Disruption via Repression of MMP Transcription","volume":"29","author":"Na","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S0169-328X(99)00155-2","article-title":"The tumor-suppressor gene, p53, is induced in injured brain regions following experimental traumatic brain injury","volume":"71","author":"Napieralski","year":"1999","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Raz, L., Zhang, Q.-G., Han, D., Dong, Y., De Sevilla, L., and Brann, D.W. (2011). Acetylation of the Pro-Apoptotic Factor, p53 in the Hippocampus following Cerebral Ischemia and Modulation by Estrogen. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027039"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1021\/tx970170y","article-title":"Detection of Weak Estrogenic Flavonoids Using a Recombinant Yeast Strain and a Modified MCF7 Cell Proliferation Assay","volume":"11","author":"Breinholt","year":"1998","journal-title":"Chem. Res. Toxicol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.fct.2019.04.008","article-title":"Food flavonoid ligand structure\/estrogen receptor-\u03b1 affinity\u2014Toxicity or food functionality?","volume":"129","author":"Ye","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"109090","DOI":"10.1016\/j.foodres.2020.109090","article-title":"A new analytical concept based on chemistry and toxicology for herbal extracts analysis: From phenolic composition to bioactivity","volume":"132","author":"Santos","year":"2020","journal-title":"Food Res. Int."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"132284","DOI":"10.1016\/j.foodchem.2022.132284","article-title":"From the forest to the plate\u2014Hemicelluloses, galactoglucomannan, glucuronoxylan, and phenolic-rich extracts from unconventional sources as functional food ingredients","volume":"381","author":"Granato","year":"2022","journal-title":"Food Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/3\/919\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:07:57Z","timestamp":1760119677000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/3\/919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,17]]},"references-count":65,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["molecules28030919"],"URL":"https:\/\/doi.org\/10.3390\/molecules28030919","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,17]]}}}