{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T15:30:10Z","timestamp":1769009410095,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T00:00:00Z","timestamp":1668556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["EXPL\/BAA-GR\/0663\/2021"],"award-info":[{"award-number":["EXPL\/BAA-GR\/0663\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/144994\/2019"],"award-info":[{"award-number":["SFRH\/BD\/144994\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["CEECIND\/01886\/2020"],"award-info":[{"award-number":["CEECIND\/01886\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Actinidia arguta (Siebold &amp; Zucc.) Planch. ex Miq. (kiwiberry) leaves are a source of phenolic compounds with pro-health biological effects, such as antioxidant and anti-inflammatory activities. Despite the huge number of studies reporting the composition of A. arguta leaves, no in vitro or in vivo studies explore its potential use as nutraceutical ingredient based on these activities. Therefore, this study aims to characterize the safety profile of kiwiberry leaf extracts using in vitro and in vivo approaches through the assessment of intestinal cell viability (Caco-2 and HT29-MTX), 3D intestinal permeation, and, most important, the redox markers, biochemical profile and liver and kidney function effects after the animal assays. Briefly, wistar rats were orally treated for 7 days with kiwiberry leaf extracts (50 and 75 mg\/kg bw), water (negative control), or vitamin C (positive control). The cell viability was above 90% at 1000 \u03bcg\/mL for both cells. Coumaroyl quinic acid and rutin achieved a permeation higher than 25% in the 3D intestinal model. The animal studies confirmed the extracts\u2019 ability to increase superoxide dismutase, glutathione peroxidase, and catalase content in animals\u2019 livers and kidneys while simultaneously decreasing the triglycerides content. This study highlighted the antioxidant capacity of kiwiberry leaf extracts, ensuring their efficacy and safety as a nutraceutical ingredient.<\/jats:p>","DOI":"10.3390\/ijms232214130","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T02:24:53Z","timestamp":1668565493000},"page":"14130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Insights into the 3D In Vitro Permeability and In Vivo Antioxidant Protective Effects of Kiwiberry Leaf Extract: A Step Forward to Human Nutraceutical Use"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1823-9816","authenticated-orcid":false,"given":"Ana Margarida","family":"Silva","sequence":"first","affiliation":[{"name":"REQUIMTE\/LAQV, Polytechnic of Porto-School of Engineering, Rua Dr. Ant\u00f3nio Bernardino de Almeida, 4249-015 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6186-8696","authenticated-orcid":false,"given":"Andreia","family":"Almeida","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Polytechnic of Porto-School of Engineering, Rua Dr. Ant\u00f3nio Bernardino de Almeida, 4249-015 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8264-6953","authenticated-orcid":false,"given":"Stefano","family":"Dall\u2019Acqua","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35121 Padova, Italy"}]},{"given":"Francesca","family":"Loschi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35121 Padova, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-7553","authenticated-orcid":false,"given":"Bruno","family":"Sarmento","sequence":"additional","affiliation":[{"name":"i3S, Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"INEB, Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute for Research and Advanced Training in Health Sciences and Technologies, CESPU, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1152-3398","authenticated-orcid":false,"given":"Paulo C.","family":"Costa","sequence":"additional","affiliation":[{"name":"REQUIMTE\/UCIBIO, MedTech-Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3924-776X","authenticated-orcid":false,"given":"Cristina","family":"Delerue-Matos","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Polytechnic of Porto-School of Engineering, Rua Dr. Ant\u00f3nio Bernardino de Almeida, 4249-015 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8803-0041","authenticated-orcid":false,"given":"Francisca","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Polytechnic of Porto-School of Engineering, Rua Dr. Ant\u00f3nio Bernardino de Almeida, 4249-015 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.tifs.2021.08.031","article-title":"Extraordinary composition of Actinidia arguta by-products as skin ingredients: A new challenge for cosmetic and medical skincare industries","volume":"116","author":"Silva","year":"2021","journal-title":"Trends Food Sci. Technol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109449","DOI":"10.1016\/j.foodres.2020.109449","article-title":"Bioactivity, phytochemical profile and pro-healthy properties of Actinidia arguta: A review","volume":"136","author":"Pinto","year":"2020","journal-title":"Food Res. Int."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ravipati, A.S., Zhang, L., Koyyalamudi, S.R., Jeong, S.C., Reddy, N., Bartlett, J., Smith, P.T., Shanmugam, K., M\u00fcnch, G., and Wu, M.J. (2012). Antioxidant and anti-inflammatory activities of selected Chinese medicinal plants and their relation with antioxidant content. BMC Complement. Altern. Med., 12.","DOI":"10.1186\/1472-6882-12-173"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s11130-017-0637-y","article-title":"The nutritional and health benefits of kiwiberry (Actinidia arguta)\u2014A review","volume":"72","author":"Latocha","year":"2017","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.jff.2017.01.018","article-title":"Phytochemical compounds and biological effects of Actinidia fruits","volume":"30","author":"Nowicka","year":"2017","journal-title":"J. Funct. Foods"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3109\/09637480903517788","article-title":"Antioxidant activity and chemical difference in fruit of different Actinidia sp","volume":"61","author":"Latocha","year":"2010","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100593","DOI":"10.1016\/j.scp.2021.100593","article-title":"Influence of temperature on the subcritical water extraction of Actinidia arguta leaves: A screening of pro-healthy compounds","volume":"25","author":"Silva","year":"2022","journal-title":"Sustain. Chem. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.foodchem.2018.03.113","article-title":"Hardy kiwifruit leaves (Actinidia arguta): An extraordinary source of value-added compounds for food industry","volume":"259","author":"Almeida","year":"2018","journal-title":"Food Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cbi.2014.08.012","article-title":"Modification of the properties of biological membrane and its protection against oxidation by Actinidia arguta leaf extract","volume":"222","author":"Cyboran","year":"2014","journal-title":"Chem. Biol. Interact."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Silva, A.M., Pinto, D., Fernandes, I., Freitas, V.d., C\u00e1diz-Gurrea, M.d.l.L., Costa, P., Delerue-Matos, C., and Rodrigues, F. (2021). An Insight into Kiwiberry Leaf Valorization: Phenolic Composition, Bioactivity and Health Benefits. Molecules, 26.","DOI":"10.3390\/molecules26082314"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.foodres.2018.06.029","article-title":"Hardy kiwi leaves extracted by multi-frequency multimode modulated technology: A sustainable and promising by-product for industry","volume":"112","author":"Marangi","year":"2018","journal-title":"Food Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.foodchem.2019.03.105","article-title":"Infusions and decoctions of dehydrated fruits of Actinidia arguta and Actinidia deliciosa: Bioactivity, radical scavenging activity and effects on cells viability","volume":"289","author":"Silva","year":"2019","journal-title":"Food Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tan, C., Wang, Z., Feng, X., Irfan, M., and Liu, C. (2020). Identification of bioactive compounds and antioxidant activity in leaves and fruits of Actinidia arguta accessions from northeastern China. Preprints, 2020120453.","DOI":"10.20944\/preprints202012.0453.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"104315","DOI":"10.1016\/j.jff.2020.104315","article-title":"Improving effect of Actinidia arguta leaf on hyperglycemia-induced cognitive dysfunction","volume":"76","author":"Yoo","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tifs.2015.11.008","article-title":"In vivo antioxidant activity of phenolic compounds: Facts and gaps","volume":"48","author":"Martins","year":"2016","journal-title":"Trends Food Sci. Technol."},{"key":"ref_16","first-page":"R6","article-title":"The role of dietary fiber in the bioaccessibility and bioavailability of fruit and vegetable antioxidants","volume":"76","year":"2011","journal-title":"J. Food Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1111\/j.1365-2621.2012.03067.x","article-title":"Phenolic compounds in fruits\u2013an overview","volume":"47","author":"Haminiuk","year":"2012","journal-title":"Int. J. Food Sci. Technol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Silva, A.M., Pinto, D., Moreira, M.M., Costa, P.C., Delerue-Matos, C., and Rodrigues, F. (2022). Valorization of Kiwiberry Leaves Recovered by Ultrasound-Assisted Extraction for Skin Application: A Response Surface Methodology Approach. Antioxidants, 11.","DOI":"10.3390\/antiox11040763"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1517\/17425255.2012.673586","article-title":"Cell-based in vitro models for predicting drug permeability","volume":"8","author":"Sarmento","year":"2012","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_20","unstructured":"Sarmento, B. (2016). Cell-based in vitro models for intestinal permeability studies. Concepts and Models for Drug Permeability Studies, Elsevier."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.ejpb.2012.10.003","article-title":"Establishment of a triple co-culture in vitro cell models to study intestinal absorption of peptide drugs","volume":"83","author":"Antunes","year":"2013","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1517\/17425255.4.4.395","article-title":"The Caco-2 cell monolayer: Usefulness and limitations","volume":"4","author":"Sun","year":"2008","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_23","first-page":"113","article-title":"Phenolic compound bioavailability using in vitro and in vivo models","volume":"Volume 3","author":"Campos","year":"2019","journal-title":"Bioactive Compounds"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1021\/acs.molpharmaceut.6b01165","article-title":"Usefulness of Caco-2\/HT29-MTX and Caco-2\/HT29-MTX\/Raji B coculture models to predict intestinal and colonic permeability compared to Caco-2 monoculture","volume":"14","author":"Bermejo","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1208\/s12249-018-1195-9","article-title":"Nano-lipid complex of rutin: Development, characterisation and in vivo investigation of hepatoprotective, antioxidant activity and bioavailability study in rats","volume":"19","author":"Ravi","year":"2018","journal-title":"AAPS PharmSciTech"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"112831","DOI":"10.1016\/j.biopha.2022.112831","article-title":"The Regulatory effect of chlorogenic acid on gut-brain function and its mechanism: A systematic review","volume":"149","author":"Zeng","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1039\/D0FO02629H","article-title":"Demonstrating the involvement of an active efflux mechanism in the intestinal absorption of chlorogenic acid and quinic acid using a caco-2 bidirectional permeability assay","volume":"12","author":"Spacova","year":"2021","journal-title":"Food Funct."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ijpharm.2013.10.003","article-title":"Towards the characterization of an in vitro triple co-culture intestine cell model for permeability studies","volume":"458","author":"Sarmento","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_29","first-page":"27","article-title":"Influence of cocoa flavanols and procyanidins on free radical-induced human erythrocyte hemolysis","volume":"12","author":"Zhu","year":"2005","journal-title":"Clin. Dev. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.foodchem.2009.04.076","article-title":"In vitro and in vivo antioxidant activity of Pinus koraiensis seed extract containing phenolic compounds","volume":"117","author":"Su","year":"2009","journal-title":"Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.foodchem.2007.09.030","article-title":"Antioxidant activities of the extracts from chestnut flower, leaf, skins and fruit","volume":"107","author":"Barreira","year":"2008","journal-title":"Food Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/1440-1681.13221","article-title":"Hesperidin attenuates altered redox homeostasis in an experimental hyperlipidaemic model of rat","volume":"47","author":"Kumar","year":"2020","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3621","DOI":"10.2147\/IJN.S104623","article-title":"Safety profile of solid lipid nanoparticles loaded with rosmarinic acid for oral use: In vitro and animal approaches","volume":"11","author":"Madureira","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102095","DOI":"10.1016\/j.bcab.2021.102095","article-title":"Antidiabetic and antilipidemic effect of Clerodendrum paniculatum flower ethanolic extract. An in vivo investigation in Albino Wistar rats","volume":"36","author":"Varghese","year":"2021","journal-title":"Biocatal. Agric. Biotechnol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/(SICI)1099-1573(200005)14:3<174::AID-PTR624>3.0.CO;2-O","article-title":"Antioxidant activity ofBacopa monniera in rat frontal cortex, striatum and hippocampus","volume":"14","author":"Bhattacharya","year":"2000","journal-title":"Phytother. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1093\/jexbot\/53.372.1331","article-title":"Role of superoxide dismutases (SODs) in controlling oxidative stress in plants","volume":"53","author":"Alscher","year":"2002","journal-title":"J. Exp. Bot."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/BF03260057","article-title":"Catalase enzyme mutations and their association with diseases","volume":"8","author":"Rass","year":"2004","journal-title":"Mol. Diagn. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0168-9452(85)90025-1","article-title":"Evidence for glutathione peroxidase activities in cultured plant cells","volume":"42","author":"Drotar","year":"1985","journal-title":"Plant Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1016\/j.fct.2012.08.004","article-title":"Assessment of red onion on antioxidant activity in rat","volume":"50","author":"Lee","year":"2012","journal-title":"Food Chem. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4686","DOI":"10.1002\/jsfa.9709","article-title":"Insights into the development of grapefruit nutraceutical powder by spray drying: Physical characterization, chemical composition and 3D intestinal permeability","volume":"99","author":"Sarmento","year":"2019","journal-title":"J. Sci. Food Agric."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"115090","DOI":"10.1016\/j.indcrop.2022.115090","article-title":"Eco-friendly insights on kiwiberry leaves valorization through in-vitro and in-vivo studies","volume":"184","author":"Silva","year":"2022","journal-title":"Ind. Crops Prod."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1016\/j.fct.2011.04.010","article-title":"In vitro and in vivo antioxidant activity of Symplocos cochinchinensis S. Moore leaves containing phenolic compounds","volume":"49","author":"Sunil","year":"2011","journal-title":"Food Chem. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"126618","DOI":"10.1016\/j.foodchem.2020.126618","article-title":"In vivo acute and subacute toxicities of phenolic extract from rambutan (Nephelium lappaceum) peels by oral administration","volume":"320","author":"Li","year":"2020","journal-title":"Food Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.fct.2007.03.006","article-title":"Effect of Lactarius piperatus fruiting body maturity stage on antioxidant activity measured by several biochemical assays","volume":"45","author":"Barros","year":"2007","journal-title":"Food Chem. Toxicol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14130\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:19:05Z","timestamp":1760145545000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,16]]},"references-count":44,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214130"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214130","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,16]]}}}