{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T05:03:16Z","timestamp":1785474196782,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2016,10,21]],"date-time":"2016-10-21T00:00:00Z","timestamp":1477008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In this study, a hydroalcoholic chestnut shell extract was characterized and tested on six different human cell lines. Gallic, ellagic, and syringic acids were the most abundant non-condensed compounds in the chestnut extract, as determined by high performance liquid chromatography (HPLC). Tannins were mainly represented by condensed monomeric units of epigallocatechin and catechin\/epicatechin. After 48 h of treatment, only the human hepatoblastoma HepG2 cells reached an inhibition corresponding to IC50 with an increase of apoptosis and mitochondrial depolarization. The cytokinome evaluation before and after treatment revealed that the vascular endothelial growth factor (VEGF) and the tumor necrosis factor (TNF)-\u03b1 decreased after the treatment, suggesting a potential anti-angiogenic and anti-inflammatory effect of this extract. Moreover, the metabolome evaluation by 1H-NMR evidenced that the polyphenols extracted from chestnut shell (PECS) treatment affected the levels of some amino acids and other metabolites. Overall, these data highlight the effects of biomolecules on cell proliferation, apoptosis, cell cycle and mitochondrial depolarization, and on cytokinomics and metabolomics profiles.<\/jats:p>","DOI":"10.3390\/molecules21101411","type":"journal-article","created":{"date-parts":[[2016,10,21]],"date-time":"2016-10-21T10:15:16Z","timestamp":1477044916000},"page":"1411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Potential Anticancer Effects of Polyphenols from Chestnut Shell Extracts: Modulation of Cell Growth, and Cytokinomic and Metabolomic Profiles"],"prefix":"10.3390","volume":"21","author":[{"given":"Angela","family":"Sorice","sequence":"first","affiliation":[{"name":"CROM, Istituto Nazionale Tumori \u201cFondazione G. 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Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/ajcn\/79.5.727","article-title":"Polyphenols: Food sources and bioavailability","volume":"79","author":"Manach","year":"2004","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"270","DOI":"10.4161\/oxim.2.5.9498","article-title":"Plant polyphenols as dietary antioxidants in human health and disease","volume":"2","author":"Pandey","year":"2009","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/978-1-4419-7347-4_4","article-title":"Plant phenolics in the prevention and treatment of cancer","volume":"698","author":"Wahle","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.2174\/18715206113139990301","article-title":"The role of phenolic compounds in the fight against cancer\u2014A review","volume":"13","author":"Carocho","year":"2013","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.eti.2015.04.001","article-title":"Bioremediation potential of natural polyphenol rich green wastes: A review of current research and recommendations for future directions","volume":"4","author":"Kuppusamya","year":"2015","journal-title":"Environ. Technol. Innov."},{"key":"ref_7","unstructured":"FAOSTAT, Food and Agriculture Organization of the United States. Available online: http:\/\/faostat.fao.org\/."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1080\/01496395.2013.838264","article-title":"Effect of the Extraction Technique and Operational Conditions on the Recovery of Bioactive Compounds from Chestnut (Castanea sativa) Bur and Shell","volume":"49","author":"Freire","year":"2014","journal-title":"Sep. Sci. Technol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.indcrop.2008.03.003","article-title":"Antioxidant activity and phenolic content of chestnut (Castanea sativa) shell and eucalyptus (Eucalyptus globulus) bark extracts","volume":"28","author":"Fontenla","year":"2008","journal-title":"Ind. Crops Prod."},{"key":"ref_10","first-page":"855","article-title":"Chestnut burs as a source of natural antioxidants","volume":"17","author":"Freire","year":"2009","journal-title":"Chem. Eng. Trans."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.indcrop.2011.06.022","article-title":"Response surface optimization of antioxidants extraction from chestnut (Castanea sativa) bur","volume":"35","author":"Freire","year":"2012","journal-title":"Ind. Crops Prod."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1002\/jsfa.4016","article-title":"Composition of European chestnut (Castanea sativa Mill.) and association with health effects: Fresh and processed products","volume":"90","author":"Bennett","year":"2010","journal-title":"J. Sci. Food Agric."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.foodchem.2007.09.030","article-title":"Antioxidant activities of the extracts from chestnut flore, leaf, skins and fruit","volume":"107","author":"Barreira","year":"2008","journal-title":"Food Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1007\/s00107-015-0936-7","article-title":"Antioxidant activity of phenolic extracts from chestnut fruit and forest industries residues","volume":"73","author":"Freire","year":"2015","journal-title":"Eur. J. Wood Wood Prod."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0960-8524(02)00167-0","article-title":"Transformation of vegetable waste into value added products: (A) the upgrading concept; practical implementations","volume":"87","author":"Laufenberg","year":"2003","journal-title":"Bioresour. Technol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1146\/annurev.phyto.40.032602.130045","article-title":"Phytochemical based strategies for nematode control","volume":"40","author":"Chitwood","year":"2002","journal-title":"Annu. Rev. Phytopathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.copbio.2011.08.007","article-title":"Polyphenols as antimicrobial agents","volume":"23","author":"Daglia","year":"2012","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1016\/j.phytochem.2007.09.014","article-title":"Nutraceuticals: Facts and fiction","volume":"68","year":"2007","journal-title":"Phytochemistry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/mnfr.200700326","article-title":"Cancer chemoprevention and chemotherapy: Dietary polyphenols and signaling pathways","volume":"52","author":"Ramos","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1002\/jcb.25302","article-title":"Neuroprotective Effects of Castanea sativa Mill. Bark Extract in Human Neuroblastoma Cells Subjected to Oxidative Stress","volume":"117","author":"Brizi","year":"2016","journal-title":"J. Cell Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.fct.2013.11.026","article-title":"Cytotoxic effects of procyanidins from Castanea mollissima Bl. Shell on human hepatoma G2 cells in vitro","volume":"64","author":"Zhang","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"185","DOI":"10.4162\/nrp.2011.5.3.185","article-title":"Chestnut extract induces apoptosis in AGS human gastric cancer cells","volume":"5","author":"Lee","year":"2011","journal-title":"Nutr. Res. Pract."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cbi.2014.09.021","article-title":"Autophagic cell death of human hepatoma G2 cells mediated by procyanidins from Castanea mollissima Bl. Shell-induced reactive oxygen species generation","volume":"5","author":"Duan","year":"2014","journal-title":"Chem. Biol. Interact."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s00226-012-0513-8","article-title":"MALDI-TOF, HPLC-ESI-TOF and 13C-NMR characterization of chestnut (Castanea sativa) shell tannins for wood adhesives","volume":"47","author":"Pizzi","year":"2013","journal-title":"Wood Sci. Technol."},{"key":"ref_25","first-page":"69","article-title":"Cellular plasticity of trans- and dedifferentiation markers in human hepatoma cells in vitro and in vivo","volume":"35","author":"Jabari","year":"2009","journal-title":"Int. J. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s11130-009-0147-7","article-title":"Sugars Profiles of Different Chestnut (Castanea sativa Mill.) and Almond (Prunus dulcis) Cultivars by HPLC-RI","volume":"65","author":"Barreira","year":"2010","journal-title":"Plant Food Hum. Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.cej.2011.09.059","article-title":"Membrane concentration of antioxidants from Castanea sativa leaves aqueous Extracts","volume":"175","author":"Moure","year":"2011","journal-title":"Chem. Eng. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.cej.2012.06.122","article-title":"Optimization of antioxidants\u2014Extraction from Castanea sativa leaves","volume":"203","author":"Couto","year":"2012","journal-title":"Chem. Eng. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3109\/03639045.2013.850712","article-title":"Characterization of an antioxidant surfactant-free topical formulation containing Castanea sativa leaf extract","volume":"41","author":"Almeida","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.indcrop.2008.07.004","article-title":"Evaluation of potential applications for chestnut (Castanea sativa) shell and eucalyptus (Eucalyptus globulus) bark Extracts","volume":"29","author":"Santos","year":"2009","journal-title":"Ind. Crops Prod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3177","DOI":"10.1016\/j.fct.2010.08.018","article-title":"Antioxidant effects of the chestnut (Castanea crenata) inner shell extract in t-BHP-treated HepG2 cells, and CCl4- and high-fat diet-treated mice","volume":"48","author":"Noh","year":"2010","journal-title":"Food Chem. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/S0367-326X(00)00185-4","article-title":"Antibacterial and allelopathicactivity of extract from Castanea sativa leaves","volume":"71","author":"Basile","year":"2000","journal-title":"Fitoterapia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1021\/jf049341c","article-title":"Castanea sativa mill Leaves as new sources of natural antioxidant: An electronic spin resonance study","volume":"53","author":"Calliste","year":"2005","journal-title":"J. Agric. Food Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jphotobiol.2008.02.001","article-title":"Protective effect of Castanea sativa and Quercus robur leaf extracts against oxygen and nitrogen reactive species","volume":"91","author":"Almeida","year":"2008","journal-title":"J. Photochem. Photobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.cherd.2010.11.003","article-title":"Temperature and solvent effects on polyphenol extraction process from chestnut tree wood","volume":"89","author":"Gironi","year":"2011","journal-title":"Chem. Eng. Res. Des."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.foodchem.2010.08.068","article-title":"Antioxidative effects of phenolic extracts from chestnut leaves, catkins and spiny burs in streptozotocin-treated rat pancreatic \u03b2-cells","volume":"125","author":"Mujic","year":"2011","journal-title":"Food Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1081\/FRI-200040606","article-title":"Extraction of polyphenolics from plant material for functional foods\u2014Engineering and technology","volume":"21","author":"Shi","year":"2005","journal-title":"Food Rev. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1016\/j.chroma.2011.02.059","article-title":"Influence of extraction methods on stability of flavonoids","volume":"1218","author":"Biesaga","year":"2011","journal-title":"J. Chromatogr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: A review of programmed cell death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6365","DOI":"10.3390\/molecules16086365","article-title":"Effects of Lipoic Acid, Caffeic Acid and a Synthesized Lipoyl-Caffeic Conjugate on Human Hepatoma Cell Lines","volume":"16","author":"Guerriero","year":"2011","journal-title":"Molecules"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8644","DOI":"10.3390\/molecules19068644","article-title":"Potential anti-inflammatory effects of oil polyphenols from pomegranate (Punicagranatum L.) on breast cancer cell lines","volume":"19","author":"Costantini","year":"2014","journal-title":"Molecules"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"204975","DOI":"10.1155\/2015\/204975","article-title":"Anti-inflammatory effects of a methanol extract from the marine sponge Geodiacydonium on the human breast cancer MCF-7 cell line","volume":"2015","author":"Costantini","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"166","DOI":"10.6026\/97320630005166","article-title":"Human Cytokinome: A new challenge for systems biology","volume":"5","author":"Costantini","year":"2010","journal-title":"Bioinformation"},{"key":"ref_44","first-page":"99","article-title":"Serumcytokinelevels in patients with hepatocellular carcinoma","volume":"21","author":"Capone","year":"2010","journal-title":"Eur. Cytom. Netw."},{"key":"ref_45","first-page":"209","article-title":"Serum VEGF level is associated with the outcome of patients with hepatocellular carcinoma: A meta-analysis","volume":"2","author":"Zhan","year":"2013","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.2174\/092986710793176339","article-title":"The dual role of tumor necrosis factor (TNF) in cancer biology","volume":"17","author":"Bertazza","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"90","DOI":"10.4062\/biomolther.2014.080","article-title":"Anti-Inflammatory Effects of Water Chestnut Extract on Cytokine Responses via Nuclear. Factor-\u03baB-signaling Pathway","volume":"23","author":"Kim","year":"2015","journal-title":"Biomol. Ther. (Seoul)"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"281","DOI":"10.4331\/wjbc.v6.i4.281","article-title":"Targeting amino acid metabolism in cancer growth and anti-tumor immune response","volume":"6","author":"Ananieva","year":"2015","journal-title":"World Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1089\/omi.2010.0121","article-title":"Metabolic signatures in apoptotic human cancer cell lines","volume":"15","author":"Halama","year":"2011","journal-title":"Omics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1085\/jgp.8.6.519","article-title":"The metabolism of tumors in the body","volume":"8","author":"Warburg","year":"1927","journal-title":"J. Gen. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1097\/MCO.0b013e32833a5577","article-title":"Glucose metabolism in cancer cells","volume":"13","author":"Annibaldi","year":"2010","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_52","first-page":"2489","article-title":"Cancer metabolism: Current perspectives and future directions","volume":"3","author":"Ricci","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"144","DOI":"10.5344\/ajev.1965.16.3.144","article-title":"Colourimetry of total phenolics with phosphomolybdic\u2013phospholungistic acid reagents","volume":"16","author":"Singleton","year":"1965","journal-title":"Am. J. Enol. Vitic."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8033","DOI":"10.1021\/jf0612171","article-title":"Polyphenolic profiles and antioxidant activities of heartnut (Juglan sailanthifolia Var. cordiformis) and Persian walnut (Juglans regia L.)","volume":"54","author":"Li","year":"2006","journal-title":"J. Agric. Food Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/nar\/gkv380","article-title":"MetaboAnalyst 3.0\u2014Making metabolomics more meaningful","volume":"43","author":"Xia","year":"2015","journal-title":"Nucl. Acids Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"W127","DOI":"10.1093\/nar\/gks374","article-title":"MetaboAnalyst 2.0\u2014A comprehensive server for metabolomic data analysis","volume":"40","author":"Xia","year":"2012","journal-title":"Nucleic Acids Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/10\/1411\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:33:41Z","timestamp":1760211221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/10\/1411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,21]]},"references-count":56,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2016,10]]}},"alternative-id":["molecules21101411"],"URL":"https:\/\/doi.org\/10.3390\/molecules21101411","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,21]]}}}