{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T05:30:25Z","timestamp":1773725425271,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,2,29]],"date-time":"2020-02-29T00:00:00Z","timestamp":1582934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Environmental stress, exhaustive industrialization and the use of chemicals in our daily lives contribute to increasing incidence of cancer and other pathologies. Although the cancer treatment has revolutionized in last 2\u20133 decades, shortcomings such as (i) extremely high cost of treatment, (ii) poor availability of drugs, (iii) severe side effects and (iv) emergence of drug resistance have prioritized the need of developing alternate natural, economic and welfare (NEW) therapeutics reagents. Identification and characterization of such anti-stress NEW drugs that not only limit the growth of cancer cells but also reprogram them to perform their specific functions are highly desired. We recruited rat glioma- and human neuroblastoma-based assays to explore such activities of resveratrol, a naturally occurring stilbenoid. We demonstrate that nontoxic doses of resveratrol protect cells against a variety of stresses that are largely involved in age-related brain pathologies. These included oxidative, DNA damage, metal toxicity, heat, hypoxia, and protein aggregation stresses. Furthermore, it caused differentiation of cells to functional astrocytes and neurons as characterized by the upregulation of their specific protein markers. These findings endorse multiple bioactivities of resveratrol and encourage them to be tested for their benefits in animal models and humans.<\/jats:p>","DOI":"10.3390\/nu12030671","type":"journal-article","created":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T03:13:28Z","timestamp":1583205208000},"page":"671","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Anti-Stress, Glial- and Neuro-Differentiation Potential of Resveratrol: Characterization by Cellular, Biochemical and Imaging Assays"],"prefix":"10.3390","volume":"12","author":[{"given":"Sajal","family":"Afzal","sequence":"first","affiliation":[{"name":"DAILAB, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), National Institute of Advanced Industrial Science &amp; Technology (AIST), Tsukuba 305-8565, Japan"},{"name":"School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8577, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6296-234X","authenticated-orcid":false,"given":"Sukant","family":"Garg","sequence":"additional","affiliation":[{"name":"DAILAB, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), National Institute of Advanced Industrial Science &amp; Technology (AIST), Tsukuba 305-8565, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Divya","family":"Adiga","sequence":"additional","affiliation":[{"name":"DAILAB, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), National Institute of Advanced Industrial Science &amp; Technology (AIST), Tsukuba 305-8565, Japan"},{"name":"Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576-104, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Ishida","sequence":"additional","affiliation":[{"name":"CycloChem Co., Ltd., 7-4-5 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiji","family":"Terao","sequence":"additional","affiliation":[{"name":"CycloChem Co., Ltd., 7-4-5 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunil C.","family":"Kaul","sequence":"additional","affiliation":[{"name":"DAILAB, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), National Institute of Advanced Industrial Science &amp; Technology (AIST), Tsukuba 305-8565, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renu","family":"Wadhwa","sequence":"additional","affiliation":[{"name":"DAILAB, DBT-AIST International Center for Translational and Environmental Research (DAICENTER), National Institute of Advanced Industrial Science &amp; Technology (AIST), Tsukuba 305-8565, Japan"},{"name":"School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8577, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1124\/pr.117.013755","article-title":"Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration-Approved Drugs","volume":"69","author":"Coussens","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.tox.2017.06.012","article-title":"Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants","volume":"391","author":"Roubicek","year":"2017","journal-title":"Toxicology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E6152","DOI":"10.1073\/pnas.1804869115","article-title":"Aldehydes are the predominant forces inducing DNA damage and inhibiting DNA repair in tobacco smoke carcinogenesis","volume":"115","author":"Weng","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/jat.3749","article-title":"The use of cobalt chloride as a chemical hypoxia model","volume":"39","year":"2019","journal-title":"J. Appl. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Afzal, S., Garg, S., Ishida, Y., Terao, K., Kaul, S.C., and Wadhwa, R. (2019). Rat Glioma Cell-Based Functional Characterization of Anti-Stress and Protein Deaggregation Activities in the Marine Carotenoids, Astaxanthin and Fucoxanthin. Mar. Drugs, 17.","DOI":"10.3390\/md17030189"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fendo.2018.00343","article-title":"Inflammatory Signaling in Hypertension: Regulation of Adrenal Catecholamine Biosynthesis","volume":"9","author":"Byrne","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7545","DOI":"10.1093\/nar\/gkm1059","article-title":"DNA replication stress, genome instability and aging","volume":"35","author":"Burhans","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1515\/reveh-2016-0032","article-title":"Future of environmental research in the age of epigenomics and exposomics","volume":"32","author":"Holland","year":"2017","journal-title":"Rev. Environ. Health"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13045-019-0736-3","article-title":"Emerging therapies for small cell lung cancer","volume":"12","author":"Yang","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.18632\/oncotarget.26523","article-title":"Clinical characteristics, treatment outcomes and potential novel therapeutic options for patients with neuroendocrine carcinoma of the prostate","volume":"10","author":"Apostolidis","year":"2019","journal-title":"Oncotarget"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1002\/glia.22836","article-title":"Astrocyte development: A Guide for the Perplexed","volume":"63","author":"Molofsky","year":"2015","journal-title":"Glia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"664","DOI":"10.14336\/AD.2018.0720","article-title":"Reactive Astrocytes in Neurodegenerative Diseases","volume":"10","author":"Li","year":"2019","journal-title":"Aging Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nrneurol.2017.54","article-title":"Management of diffuse low-grade gliomas in adults-use of molecular diagnostics","volume":"13","author":"Buckner","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"22194","DOI":"10.18632\/oncotarget.25175","article-title":"Natural products: A hope for glioblastoma patients","volume":"9","author":"Vengoji","year":"2018","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1159\/000490693","article-title":"Anti-Stress and Glial Differentiation Effects of a Novel Combination of Cucurbitacin B and Withanone (CucWi-N): Experimental Evidence","volume":"25","author":"Garg","year":"2018","journal-title":"Ann. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1002\/glia.23484","article-title":"How to reprogram microglia toward beneficial functions","volume":"66","author":"Fumagalli","year":"2018","journal-title":"Glia"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Oh, J., Kim, Y., Che, L., Kim, J.B., Chang, G.E., Cheong, E., Kang, S.G., and Ha, Y. (2017). Regulation of cAMP and GSK3 signaling pathways contributes to the neuronal conversion of glioma. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178881"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00414","DOI":"10.1002\/brb3.414","article-title":"Induction of neural differentiation in rat C6 glioma cells with taxol","volume":"5","author":"Chao","year":"2015","journal-title":"Brain Behav."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/s13046-017-0642-x","article-title":"Drug repurposing for the treatment of glioblastoma multiforme","volume":"36","author":"Abbruzzese","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Garg, S., Huifu, H., Kumari, A., Sundar, D., Kaul, S.C., and Wadhwa, R. (2019). Induction of Senescence in Cancer Cells by a Novel Combination of Cucurbitacin B and Withanone: Molecular Mechanism and Therapeutic Potential. J. Gerontol. A Biol. Sci. Med. Sci.","DOI":"10.1093\/gerona\/glz077"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5276130","DOI":"10.1155\/2016\/5276130","article-title":"Role of Antioxidants and Natural Products in Inflammation","volume":"2016","author":"Arulselvan","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/j.ypmed.2011.11.011","article-title":"Age-associated chronic diseases require age-old medicine: Role of chronic inflammation","volume":"54","author":"Prasad","year":"2012","journal-title":"Prev. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrd2060","article-title":"Therapeutic potential of resveratrol: The in vivo evidence","volume":"5","author":"Baur","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1007\/s12035-017-0448-z","article-title":"Resveratrol and Brain Mitochondria: A Review","volume":"55","author":"Jardim","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2016.08.032","article-title":"Resveratrol limits diabetes-associated cognitive decline in rats by preventing oxidative stress and inflammation and modulating hippocampal structural synaptic plasticity","volume":"1650","author":"Tian","year":"2016","journal-title":"Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1111\/bph.13492","article-title":"Antioxidant effects of resveratrol in the cardiovascular system","volume":"174","author":"Xia","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/biof.1399","article-title":"Role of resveratrol in regulation of cellular defense systems against oxidative stress","volume":"44","author":"Truong","year":"2018","journal-title":"Biofactors"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4264","DOI":"10.1021\/jf104917q","article-title":"Resveratrol reduces the invasive growth and promotes the acquisition of a long-lasting differentiated phenotype in human glioblastoma cells","volume":"59","author":"Castino","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Han, Y., Jo, H., Cho, J.H., Dhanasekaran, D.N., and Song, Y.S. (2019). Resveratrol as a Tumor-Suppressive Nutraceutical Modulating Tumor Microenvironment and Malignant Behaviors of Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040925"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.yexcr.2018.06.031","article-title":"Resveratrol promotes oxidative stress to drive DLC1 mediated cellular senescence in cancer cells","volume":"370","author":"Ji","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_31","first-page":"3237","article-title":"The role of the 3D environment in hypoxia-induced drug and apoptosis resistance","volume":"31","author":"Kim","year":"2011","journal-title":"Anticancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.3892\/mmr.2014.2417","article-title":"A novel anticancer effect of resveratrol: Reversal of epithelialmesenchymal transition in prostate cancer cells","volume":"10","author":"Li","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"532","DOI":"10.4149\/neo_2016_406","article-title":"Resveratrol inhibits hypoxia-induced glioma cell migration and invasion by the p-STAT3\/miR-34a axis","volume":"63","author":"Wang","year":"2016","journal-title":"Neoplasma"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.fct.2013.05.030","article-title":"Dual role of resveratrol in modulation of genotoxicity induced by sodium arsenite via oxidative stress and apoptosis","volume":"59","author":"Chen","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"826","DOI":"10.3892\/or.2012.2151","article-title":"Resveratrol induces MMP-9 and cell migration via the p38 kinase and PI-3K pathways in HT1080 human fibrosarcoma cells","volume":"29","author":"Gweon","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Simunkova, M., Alwasel, S.H., Alhazza, I.M., Jomova, K., Kollar, V., Rusko, M., and Valko, M. (2019). Management of oxidative stress and other pathologies in Alzheimer\u2019s disease. Arch. Toxicol.","DOI":"10.1007\/s00204-019-02538-y"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6133","DOI":"10.3892\/mmr.2015.4199","article-title":"Resveratrol inhibits oligomeric Abeta-induced microglial activation via NADPH oxidase","volume":"12","author":"Yao","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1016\/S0021-9258(18)53295-6","article-title":"Identification of a novel member of mouse hsp70 family. Its association with cellular mortal phenotype","volume":"268","author":"Wadhwa","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Mirabelli, P., Coppola, L., and Salvatore, M. (2019). Cancer Cell Lines Are Useful Model Systems for Medical Research. Cancers, 11.","DOI":"10.3390\/cancers11081098"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11010-016-2917-5","article-title":"Resveratrol modulates GSH system in C6 astroglial cells through heme oxygenase 1 pathway","volume":"428","author":"Arus","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jnutbio.2016.04.003","article-title":"Resveratrol ameliorates benzo(a)pyrene-induced testicular dysfunction and apoptosis: Involvement of p38 MAPK\/ATF2\/iNOS signaling","volume":"34","author":"Banerjee","year":"2016","journal-title":"J. Nutr. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s12640-013-9439-7","article-title":"Resveratrol protects DAergic PC12 cells from high glucose-induced oxidative stress and apoptosis: Effect on p53 and GRP75 localization","volume":"25","author":"Renaud","year":"2014","journal-title":"Neurotox. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00441-014-1996-4","article-title":"Wnt signalling in neuronal differentiation and development","volume":"359","author":"Inestrosa","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nri3442","article-title":"The integration of T cell migration, differentiation and function","volume":"13","author":"Masopust","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1093\/neuonc\/nox091","article-title":"Global incidence of malignant brain and other central nervous system tumors by histology, 2003-2007","volume":"19","author":"Leece","year":"2017","journal-title":"Neuro. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1651325","DOI":"10.1155\/2017\/1651325","article-title":"Resveratrol Induces Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Neuron-Like Cells","volume":"2017","author":"Guo","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.neulet.2014.10.024","article-title":"Resveratrol-induced SIRT1 activation promotes neuronal differentiation of human bone marrow mesenchymal stem cells","volume":"584","author":"Joe","year":"2015","journal-title":"Neurosci. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/bpa.12274","article-title":"Mortalin is Expressed by Astrocytes and Decreased in the Midbrain of Parkinson\u2019s Disease Patients","volume":"26","author":"Cook","year":"2016","journal-title":"Brain Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1074\/jbc.M113.492587","article-title":"Down-regulation of mortalin exacerbates Abeta-mediated mitochondrial fragmentation and dysfunction","volume":"289","author":"Park","year":"2014","journal-title":"J. Biol. Chem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/3\/671\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:02:54Z","timestamp":1760173374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/3\/671"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,29]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["nu12030671"],"URL":"https:\/\/doi.org\/10.3390\/nu12030671","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,29]]}}}