{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T18:05:04Z","timestamp":1770919504018,"version":"3.50.1"},"reference-count":61,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T00:00:00Z","timestamp":1603238400000},"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 a Tecnologia","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-029369 and UID\/NEU\/04539\/2019."],"award-info":[{"award-number":["POCI-01-0145-FEDER-029369 and UID\/NEU\/04539\/2019."]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Experimental evidence highlights nuclear factor (erythroid-derived 2)-like 2 (Nrf2) as a molecular target in Alzheimer\u2019s disease (AD). The well-known effect of electrophilic cysteine-reactive skin allergens on Nrf2-activation led to the hypothesis that these compounds could have a therapeutic role in AD. This was further supported by the neuroprotective activity of the skin allergen dimethyl fumarate (DMF), demonstrated in in vivo models of neurodegenerative diseases. We evaluated the effect of the cysteine-reactive allergens 1,4-phenylenediamine (PPD) and methyl heptine carbonate (MHC) on (1) neuronal redox imbalance and calcium dyshomeostasis using N2a wild-type (N2a-wt) and human APP-overexpressing neuronal cells (wild-type, N2a-APPwt) and (2) on neuroinflammation, using microglia BV-2 cells exposed to LPS (lipopolysaccharide). Phthalic anhydride (PA, mainly lysine-reactive), was used as a negative control. DMF, PPD and MHC increased Hmox1 gene and HMOX1 protein levels in N2a-APPwt cells suggesting Nrf2-dependent antioxidant activity. MHC, but also PA, rescued N2a-APPwt mitochondrial membrane potential and calcium levels in a Nrf2-independent pathway. All the chemicals showed anti-inflammatory activity by decreasing iNOS protein in microglia. This work highlights the potential neuroprotective and anti-inflammatory role of the selected skin allergens in in vitro models of AD, and supports further studies envisaging the validation of the results using in vivo AD models.<\/jats:p>","DOI":"10.3390\/ijms21207791","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T10:14:22Z","timestamp":1603275262000},"page":"7791","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Calcium Modulation, Anti-Oxidant and Anti-Inflammatory Effect of Skin Allergens Targeting the Nrf2 Signaling Pathway in Alzheimer\u2019s Disease Cellular Models"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-0376","authenticated-orcid":false,"given":"Ana","family":"Silva","sequence":"first","affiliation":[{"name":"Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Marta","family":"Pereira","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3391-543X","authenticated-orcid":false,"given":"Myl\u00e8ne A.","family":"Carrascal","sequence":"additional","affiliation":[{"name":"Tecnimede Group, 2710-089 Sintra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3705-673X","authenticated-orcid":false,"given":"Gon\u00e7alo","family":"Brites","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-3124","authenticated-orcid":false,"given":"Bruno","family":"Neves","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences and Institute for Biomedicine (iBiMED), University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2727-512X","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Moreira","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Rosa","family":"Resende","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"University of Coimbra, Institute for Interdisciplinary Research (IIIUC), 3030-789 Coimbra, Portugal"}]},{"given":"Maria Manuel","family":"Silva","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Armanda E.","family":"Santos","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Cl\u00e1udia","family":"Pereira","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9846-6754","authenticated-orcid":false,"given":"Maria Teresa","family":"Cruz","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1159\/000439568","article-title":"Early Life Epidemiology of Alzheimer\u2019s Disease\u2014A Critical Review","volume":"45","author":"Seifan","year":"2015","journal-title":"Neuroepidemiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"903","DOI":"10.2174\/156720501209151019111448","article-title":"Socio-economic Aspects of Alzheimer\u2019s Disease","volume":"12","year":"2015","journal-title":"Curr. Alzheimer Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dong, Y., Li, X., Cheng, J., and Hou, L. (2019). Drug Development for Alzheimer\u2019s Disease: Microglia Induced Neuroinflammation as a Target?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030558"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/nen.0b013e31802d6da9","article-title":"Expression of Nrf2 in Neurodegenerative Diseases","volume":"66","author":"Ramsey","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/j.freeradbiomed.2008.09.001","article-title":"Nrf2-induced antioxidant protection: A promising target to counteract ROS-mediated damage in neurodegenerative disease?","volume":"45","author":"Witte","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.freeradbiomed.2015.06.037","article-title":"Applications of the Keap1\u2013Nrf2 system for gene and cell therapy","volume":"88","author":"Kanninen","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1016\/j.bbadis.2015.03.015","article-title":"Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer\u2019s disease","volume":"1852","author":"Mota","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/toxsci\/kfp228","article-title":"The Nrf2-Keap1-ARE Toxicity Pathway as a Cellular Sensor for Skin Sensitizers\u2014Functional Relevance and a Hypothesis on Innate Reactions to Skin Sensitizers","volume":"113","author":"Natsch","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11632","DOI":"10.1016\/S0021-9258(18)99004-6","article-title":"The Antioxidant Responsive Element. Activation by oxidative stress and identification of the DNA consensus sequence required for funtional activity","volume":"266","author":"Rushmore","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.tibs.2014.02.002","article-title":"The Nrf2 regulatory network provides an interface between redox and intermediary metabolism","volume":"39","author":"Hayes","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.abb.2016.10.010","article-title":"Keap1 as the redox sensor of the antioxidant response","volume":"617","author":"Sihvola","year":"2017","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xu, Z., Zhang, F., Sun, F., Gu, K., Dong, S., and He, D. (2015). Dimethyl fumarate for multiple sclerosis. Cochrane Database Syst. Rev., CD011076.","DOI":"10.1002\/14651858.CD011076.pub2"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3389\/fneur.2018.00005","article-title":"Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis","volume":"9","author":"Mills","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1093\/brain\/awq386","article-title":"Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway","volume":"134","author":"Linker","year":"2011","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.bbr.2016.04.012","article-title":"Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats","volume":"308","author":"Majkutewicz","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_16","first-page":"446","article-title":"Dimethyl fumarate mitigates optic neuritis","volume":"25","author":"Zyla","year":"2019","journal-title":"Mol. Vis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/iid3.262","article-title":"Dimethyl fumarate abrogates dust mite-induced allergic asthma by altering dendritic cell function","volume":"7","author":"Jaiswal","year":"2019","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1002\/jat.2868","article-title":"A dataset on 145 chemicals tested in alternative assays for skin sensitization undergoing prevalidation","volume":"33","author":"Natsch","year":"2013","journal-title":"J. Appl. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1093\/toxsci\/kfn204","article-title":"Filling the concept with data: Integrating data from different in vitro and in silico assays on skin sensitizers to explore the battery approach for animal-free skin sensitization testing","volume":"107","author":"Natsch","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_20","first-page":"211","article-title":"Integrating non-animal test information into an adaptive testing strategy\u2014skin sensitization proof of concept case","volume":"28","author":"Jaworska","year":"2011","journal-title":"ALTEX-Altern. Anim. Exp."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/DER.0000000000000003","article-title":"Categorization of Chemicals According to Their Relative Human Skin Sensitizing Potency","volume":"25","author":"Basketter","year":"2014","journal-title":"Dermatitis"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1089\/ars.2015.6549","article-title":"Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson\u2019s Disease","volume":"25","author":"Scannevin","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.redox.2017.10.010","article-title":"Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy","volume":"14","author":"Cuadrado","year":"2018","journal-title":"Redox Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nitti, M., Piras, S., Brondolo, L., Marinari, U.M., Pronzato, M.A., and Furfaro, A.L. (2018). Heme Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce Neurodegeneration?. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082260"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.pneurobio.2018.06.008","article-title":"The sinister face of heme oxygenase-1 in brain aging and disease","volume":"172","author":"Schipper","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3966","DOI":"10.1016\/j.febslet.2009.10.036","article-title":"Correlation of mRNA and protein in complex biological samples","volume":"583","author":"Maier","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.mcn.2008.06.007","article-title":"Functional interference between glycogen synthase kinase-3 beta and the transcription factor Nrf2 in protection against kainate-induced hippocampal celldeath","volume":"39","author":"Rojo","year":"2008","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14841","DOI":"10.1074\/jbc.M513737200","article-title":"Glycogen Synthase Kinase-3\u03b2 Inhibits the Xenobiotic and Antioxidant Cell Response by Direct Phosphorylation and Nuclear Exclusion of the Transcription Factor Nrf2","volume":"281","author":"Salazar","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1021\/tx800115g","article-title":"Structure\u2212Activity Relationships of Methoxychalcones as Inducers of Heme Oxygenase-1","volume":"21","author":"Sawle","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1021\/acs.jmedchem.5b01091","article-title":"Inhibiting the Inflammasome: A Chemical Perspective","volume":"59","author":"Baldwin","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.cotox.2016.09.004","article-title":"NRF2 in neurodegenerative diseases","volume":"1","author":"Cuadrado","year":"2016","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1046\/j.1471-4159.1999.0721030.x","article-title":"Altered Calcium Homeostasis and Mitochondrial Dysfunction in Cortical Synaptic Compartments of Presenilin-1 Mutant Mice","volume":"72","author":"Begley","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1523\/JNEUROSCI.12-02-00376.1992","article-title":"Beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity","volume":"12","author":"Mattson","year":"1992","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1089\/ars.2010.3287","article-title":"Amyloid beta-peptide oligomers stimulate RyRmediated Ca2+ release inducing mitochondrial fragmentation in hippocampal neurons and prevent RyR-mediated dendritic spine remodeling produced by BDNF","volume":"14","author":"Adasme","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.neurobiolaging.2014.09.006","article-title":"Abeta and NMDAR activation cause mitochondrial dysfunction involving ER calcium release","volume":"36","author":"Ferreira","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.cell.2008.05.048","article-title":"A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer\u2019s disease risk","volume":"133","author":"Lambert","year":"2008","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3410","DOI":"10.1073\/pnas.0507313103","article-title":"AMPA receptor downscaling at the onset of Alzheimer\u2019s disease pathology in double knockin mice","volume":"103","author":"Chang","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"ra89","DOI":"10.1126\/scisignal.aaf1371","article-title":"Familial Alzheimer\u2019s disease-associated presenilin 1 mutants promote gamma-secretase cleavage of STIM1 to impair store-operated Ca2+ entry","volume":"9","author":"Tong","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e33052","DOI":"10.7554\/eLife.33052","article-title":"Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans","volume":"7","author":"Sarasija","year":"2018","journal-title":"eLife"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1172\/JCI66407","article-title":"Familial Alzheimer\u2019s disease\u2013associated presenilin-1 alters cerebellar activity and calcium homeostasis","volume":"124","author":"Hagel","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_41","first-page":"1","article-title":"A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease","volume":"9","author":"Bonilla","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4106","DOI":"10.1038\/emboj.2012.202","article-title":"Upregulated function of mitochondria-associated ER membranes in Alzheimer disease","volume":"31","author":"Castillo","year":"2012","journal-title":"EMBO J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-11813-6","article-title":"Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer\u2019s disease","volume":"10","author":"Jadiya","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.brainres.2004.07.084","article-title":"Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors","volume":"1025","author":"Bernhardi","year":"2004","journal-title":"Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.neuron.2011.07.001","article-title":"Nitration of Tyrosine 10 Critically Enhances Amyloid \u03b2 Aggregation and Plaque Formation","volume":"71","author":"Kummer","year":"2011","journal-title":"Neuron"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s11064-019-02719-2","article-title":"Chronic sleep restriction induces Abeta accumulation by disrupting the balance of Abeta production and clearance in rats","volume":"44","author":"Zhao","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JAD-191317","article-title":"Activation of Inflammation is Associated with Amyloid-\u03b2 Accumulation Induced by Chronic Sleep Restriction in Rats","volume":"74","author":"Liu","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1742-2094-7-30","article-title":"Dimethyl fumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation","volume":"7","author":"Wilms","year":"2010","journal-title":"J. Neuroinflamm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jneuroim.2016.08.006","article-title":"Dimethyl fumarate alters microglia phenotype and protects neurons against proinflammatory toxic microenvironments","volume":"299","author":"Peng","year":"2016","journal-title":"J. Neuroimmunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eaaw2938","DOI":"10.1126\/sciimmunol.aaw2938","article-title":"A key role for IL-13 signaling via the type 2 IL-4 receptor in experimental atopic dermatitis","volume":"5","author":"Bitton","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_51","first-page":"756357","article-title":"A review: Inflammatory process in Alzheimer\u2019s disease, role of cytokines","volume":"2012","year":"2012","journal-title":"Sci. World J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.4049\/jimmunol.1202246","article-title":"IL-4 in the brain: A cytokine to remember","volume":"189","author":"Gadani","year":"2012","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1021\/ci500467k","article-title":"iLOGP: A Simple, Robust, and Efficient Description of n-Octanol\/Water Partition Coefficient for Drug Design Using the GB\/SA Approach","volume":"54","author":"Daina","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1021\/js9804011","article-title":"Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption","volume":"88","author":"Clark","year":"1999","journal-title":"J. Pharm. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/jm970666c","article-title":"Can We Learn to Distinguish between \u201cDrug-like\u201d and \u201cNondrug-like\u201d Molecules?","volume":"41","author":"Walters","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.brainres.2012.06.025","article-title":"Dopamine induces apoptosis in APPswe-expressing Neuro2A cells following Pepstatin-sensitive proteolysis of APP in acid compartments","volume":"1471","author":"Cagnin","year":"2012","journal-title":"Brain Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5421","DOI":"10.1046\/j.1432-1327.2000.01606.x","article-title":"Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity","volume":"267","author":"Wilson","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1021\/tx300472d","article-title":"Development of an in Vitro Dendritic Cell-Based Test for Skin Sensitizer Identification","volume":"26","author":"Neves","year":"2013","journal-title":"Chem. Res. Toxicol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/20\/7791\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:25:23Z","timestamp":1760178323000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/20\/7791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,21]]},"references-count":61,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ijms21207791"],"URL":"https:\/\/doi.org\/10.3390\/ijms21207791","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,21]]}}}