{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:49:16Z","timestamp":1789469356856,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2020,8,16]],"date-time":"2020-08-16T00:00:00Z","timestamp":1597536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["CB254600"],"award-info":[{"award-number":["CB254600"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["CB286653"],"award-info":[{"award-number":["CB286653"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]},{"name":"SEP-CONACYT-ANUIES-ECOS Francia","award":["296636"],"award-info":[{"award-number":["296636"]}]},{"name":"Proyectos insignia IPN","award":["IPN-2015"],"award-info":[{"award-number":["IPN-2015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>N-(2\u2032-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a VPA derivative designed to be a histone deacetylase (HDAC) inhibitor. HO-AAVPA has better antiproliferative effect than VPA in cancer cell lines. Therefore, in this work, the inhibitory effect of HO-AAVPA on HDAC1, HDAC6, and HDAC8 was determined by in silico and in vitro enzymatic assay. Furthermore, its antiproliferative effect on the cervical cancer cell line (SiHa) and the translocation of HMGB1 and ROS production were evaluated. The results showed that HO-AAVPA inhibits HDAC1, which could be related with HMGB1 translocation from the nucleus to the cytoplasm due to HDAC1 being involved in the deacetylation of HMGB1. Furthermore, an increase in ROS production was observed after the treatment with HO-AAVPA, which also could contribute to HMGB1 translocation. Therefore, the results suggest that one of the possible antiproliferative mechanisms of HO-AAVPA is by HDAC1 inhibition which entails HMGB1 translocation and ROS increased levels that could trigger the cell apoptosis.<\/jats:p>","DOI":"10.3390\/ijms21165873","type":"journal-article","created":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T04:35:51Z","timestamp":1597638951000},"page":"5873","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["N-(2\u2032-Hydroxyphenyl)-2-Propylpentanamide (HO-AAVPA) Inhibits HDAC1 and Increases the Translocation of HMGB1 Levels in Human Cervical Cancer Cells"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8903-3834","authenticated-orcid":false,"given":"Yudibeth","family":"Sixto-L\u00f3pez","sequence":"first","affiliation":[{"name":"Laboratorio de Dise\u00f1o y Desarrollo de Nuevos F\u00e1rmacos e Innovaci\u00f3n Biotecnol\u00f3gica), Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n s\/n, Casco de Santo Tom\u00e1s, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0012-580X","authenticated-orcid":false,"given":"Martha Cecilia","family":"Rosales-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratorio de Biof\u00edsica y Biocat\u00e1lisis, Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n s\/n, Casco de Santo Tom\u00e1s, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5273-3167","authenticated-orcid":false,"given":"Arturo","family":"Contis-Montes de Oca","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioqu\u00edmica, Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n s\/n, Casco de Santo Tom\u00e1s, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia Guadalupe","family":"Fragoso-Morales","sequence":"additional","affiliation":[{"name":"Laboratorio de Biof\u00edsica y Biocat\u00e1lisis, Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n s\/n, Casco de Santo Tom\u00e1s, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2471-9875","authenticated-orcid":false,"given":"Jessica Elena","family":"Mendieta-Wejebe","sequence":"additional","affiliation":[{"name":"Laboratorio de Biof\u00edsica y Biocat\u00e1lisis, Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n s\/n, Casco de Santo Tom\u00e1s, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"Correa-Basurto","sequence":"additional","affiliation":[{"name":"Laboratorio de Biof\u00edsica y Biocat\u00e1lisis, Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n s\/n, Casco de Santo Tom\u00e1s, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Abarca-Rojano","sequence":"additional","affiliation":[{"name":"Laboratorio de Respiraci\u00f3n Celular, Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n s\/n, Casco de Santo Tom\u00e1s, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Correa-Basurto","sequence":"additional","affiliation":[{"name":"Laboratorio de Dise\u00f1o y Desarrollo de Nuevos F\u00e1rmacos e Innovaci\u00f3n Biotecnol\u00f3gica), Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n s\/n, Casco de Santo Tom\u00e1s, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,16]]},"reference":[{"key":"ref_1","unstructured":"(2020, June 15). Cervical Cancer. Available online: https:\/\/www.who.int\/westernpacific\/health-topics\/cervical-cancer."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1080\/14756366.2016.1210138","article-title":"N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells","volume":"31","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_3","unstructured":"(2020, June 15). Cancer Today. Available online: http:\/\/gco.iarc.fr\/today\/home."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6779","DOI":"10.1128\/JVI.02443-08","article-title":"Human papillomavirus type 16 (HPV-16) virus-like particle L1-specific CD8+ cytotoxic T lymphocytes (CTLs) are equally effective as E7-specific CD8+ CTLs in killing autologous HPV-16-positive tumor cells in cervical cancer patients: Implications for L1 dendritic cell-based therapeutic vaccines","volume":"83","author":"Bellone","year":"2009","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"469","DOI":"10.4103\/0973-1482.137937","article-title":"Epigenetic therapy of cancer with histone deacetylase inhibitors","volume":"10","author":"Lakshmaiah","year":"2014","journal-title":"J. Cancer Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"a018713","DOI":"10.1101\/cshperspect.a018713","article-title":"Erasers of histone acetylation: The histone deacetylase enzymes","volume":"6","author":"Seto","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1002\/ijc.25170","article-title":"Histone deacetylase inhibitor-induced sensitization to TNFalpha\/TRAIL-mediated apoptosis in cervical carcinoma cells is dependent on HPV oncogene expression","volume":"127","author":"Darvas","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4807","DOI":"10.1038\/sj.onc.1207620","article-title":"HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway","volume":"23","author":"Finzer","year":"2004","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"75526","DOI":"10.18632\/oncotarget.12263","article-title":"Extrachromosomal HPV-16 LCR transcriptional activation by HDACi opposed by cellular differentiation and DNA integration","volume":"7","author":"Bojilova","year":"2016","journal-title":"Oncotarget"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Anantharaju, P.G., Reddy, D.B., Padukudru, M.A., Chitturi, C.M.K., Vimalambike, M.G., and Madhunapantula, S.V. (2017). Induction of colon and cervical cancer cell death by cinnamic acid derivatives is mediated through the inhibition of histone deacetylases (HDAC). PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186208"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4046","DOI":"10.1158\/1078-0432.CCR-13-0495","article-title":"HMGB1 in cancer: Good, bad, or both?","volume":"19","author":"Kang","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"342","DOI":"10.3109\/08916934.2012.750302","article-title":"During apoptosis HMGB1 is translocated into apoptotic cell-derived membranous vesicles","volume":"46","author":"Schiller","year":"2013","journal-title":"Autoimmunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1089\/ars.2010.3356","article-title":"High-mobility group box 1, oxidative stress, and disease","volume":"14","author":"Tang","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1080\/08916930902831522","article-title":"The translocation of HMGB1 during cell activation and cell death","volume":"42","author":"Gauley","year":"2009","journal-title":"Autoimmunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4032","DOI":"10.1111\/febs.13746","article-title":"How do tumor cells respond to HDAC inhibition?","volume":"283","author":"Newbold","year":"2016","journal-title":"FEBS J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.1158\/1535-7163.MCT-08-0385","article-title":"Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824\/fludarabine antileukemic interactions","volume":"7","author":"Rosato","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zou, J.Y., and Crews, F.T. (2014). Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087915"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"115033","DOI":"10.1016\/j.taap.2020.115033","article-title":"Anti-epileptic activity, toxicity and teratogenicity in CD1 mice of a novel valproic acid arylamide derivative, N-(2-hydroxyphenyl)-2-propylpentanamide","volume":"399","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.jpba.2018.09.010","article-title":"Pharmacokinetics and tissue distribution of N-(2-hydroxyphenyl)-2-propylpentanamide in wistar rats and its binding properties to human serum albumin","volume":"162","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/0272-0590(88)90112-1","article-title":"Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats","volume":"11","author":"Binkerd","year":"1988","journal-title":"Fundam. Appl. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1158\/0008-5472.CAN-03-0799","article-title":"Histone deacetylase is a target of valproic acid-mediated cellular differentiation","volume":"64","author":"Gurvich","year":"2004","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nchembio.2134","article-title":"Histone deacetylase 6 structure and molecular basis of catalysis and inhibition","volume":"12","author":"Hai","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1750-1326-8-7","article-title":"HDAC6 as a target for neurodegenerative diseases: What makes it different from the other HDACs?","volume":"8","author":"Zwick","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1007\/s12094-016-1494-0","article-title":"Valproic acid inhibits the angiogenic potential of cervical cancer cells via HIF-1\u03b1\/VEGF signals","volume":"18","author":"Zhao","year":"2016","journal-title":"Clin. Transl. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"33368","DOI":"10.18632\/oncotarget.26077","article-title":"N-(2\u2032-Hydroxyphenyl)-2-propylpentanamide (OH-VPA), a histone deacetylase inhibitor, induces the release of nuclear HMGB1 and modifies ROS levels in HeLa cells","volume":"9","year":"2018","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5967","DOI":"10.1523\/JNEUROSCI.0110-07.2007","article-title":"Epigenetic modulation of seizure-induced neurogenesis and cognitive decline","volume":"27","author":"Jessberger","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1021\/jm401837e","article-title":"Mutagenesis studies of the 14 \u00c5 internal cavity of histone deacetylase 1: Insights toward the acetate-escape hypothesis and selective inhibitor design","volume":"57","author":"Wambua","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3409","DOI":"10.1021\/jm0498497","article-title":"On the function of the 14 A long internal cavity of histone deacetylase-like protein: Implications for the design of histone deacetylase inhibitors","volume":"47","author":"Wang","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.sbi.2011.08.004","article-title":"Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes","volume":"21","author":"Lombardi","year":"2011","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"39888","DOI":"10.1074\/jbc.M110.128348","article-title":"High mobility group box 1 release from hepatocytes during ischemia and reperfusion injury is mediated by decreased histone deacetylase activity","volume":"285","author":"Evankovich","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wawruszak, A., Luszczki, J.J., Kalafut, J., Okla, K., Halasa, M., Rivero-Muller, A., and Stepulak, A. (2019). Additive pharmacological interaction between cisplatin (CDDP) and histone deacetylase inhibitors (HDIs) in MDA-MB-231 triple negative breast cancer (TNBC) cells with altered notch1 activity\u2014An isobolographic analysis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153663"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1093\/emboj\/20.24.6969","article-title":"Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells","volume":"20","author":"Minucci","year":"2001","journal-title":"EMBO J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1677\/joe.1.06970","article-title":"Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells","volume":"191","author":"Catalano","year":"2006","journal-title":"J. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5299","DOI":"10.1038\/onc.2010.261","article-title":"HMGB1 release and redox regulates autophagy and apoptosis in cancer cells","volume":"29","author":"Tang","year":"2010","journal-title":"Oncogene"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Filippova, M., Filippov, V., Williams, V.M., Zhang, K., Kokoza, A., Bashkirova, S., and Duerksen-Hughes, P. (2014). Cellular levels of oxidative stress affect the response of cervical cancer cells to chemotherapeutic agents. Biomed. Res. Int., 574659.","DOI":"10.1155\/2014\/574659"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2253","DOI":"10.1038\/cddis.2016.105","article-title":"ROS homeostasis and metabolism: A dangerous liason in cancer cells","volume":"7","author":"Panieri","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1089\/ars.2013.5179","article-title":"Redox modulation of HMGB1-related signaling","volume":"20","author":"Janko","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_39","unstructured":"Dennington, R., Keith, T., and Milliam, J. (2020, August 03). Gauss View, Version 5. Available online: https:\/\/gaussian.com\/gaussview6\/."},{"key":"ref_40","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Vreven, T., Kudin, K.N., and Burant, J.C. (2020, June 20). Gaussian 03, Revision C.02. Available online: https:\/\/www.scienceopen.com\/document?vid=c6dcfe99-1f71-437a-b4ed-ab662a8383f3."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1016\/0040-4020(80)80168-2","article-title":"Iterative partial equalization of orbital electronegativity\u2014A rapid access to atomic charges","volume":"36","author":"Gasteiger","year":"1980","journal-title":"Tetrahedron"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1007\/s12010-014-0976-1","article-title":"Exploring the potential binding sites of some known HDAC inhibitors on some HDAC8 conformers by docking studies","volume":"173","year":"2014","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4701","DOI":"10.1080\/07391102.2018.1557560","article-title":"Structural and energetic basis for the inhibitory selectivity of both catalytic domains of dimeric HDAC6","volume":"37","author":"Bello","year":"2019","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/jcc.540050204","article-title":"An approach to computing electrostatic charges for molecules","volume":"5","author":"Singh","year":"1984","journal-title":"J. Comput. Chem."},{"key":"ref_46","unstructured":"(2020, June 15). Dassault Syst\u00e8mes BIOVIA. Available online: https:\/\/www.3dsbiovia.com\/products\/collaborative-science\/biovia-discovery-studio\/."},{"key":"ref_47","unstructured":"Delano, W.L. (2020, August 03). The PyMOL Molecular Graphics System. Available online: https:\/\/pymol.org\/2\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/16\/5873\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:01:37Z","timestamp":1760176897000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/16\/5873"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,16]]},"references-count":47,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21165873"],"URL":"https:\/\/doi.org\/10.3390\/ijms21165873","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,16]]}}}