{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:28:13Z","timestamp":1785421693979,"version":"3.56.0"},"reference-count":75,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:00:00Z","timestamp":1780790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Thailand Science Research and Innovation Fund, Chulalongkorn University"},{"id":[{"id":"https:\/\/ror.org\/028wp3y58","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD) are the two most prevalent neurodegenerative disorders, while the therapeutic efficacy of current drugs for both diseases remains limited, with unfavourable side effects. The fruit of Areca catechu L. (AC) is recognised as a popular chewing item across China and Southeast Asia and has been used for centuries as a traditional remedy, ranging from relieving digestive issues to depression. The neuroprotective role of AC has been underscored in previous studies; however, its mechanisms of action remain unclear. The present study aimed to investigate anti-neurodegenerative mechanisms of AC for the treatment of AD and PD. An integrated approach combining untargeted metabolite profiling, network pharmacology, bioinformatics analysis, and molecular docking was utilised. Experimental validation was performed using in vitro cell-based and in vivo models. The study revealed TNF-\u03b1, IL-1\u03b2, IL-6, CASP3, MAPK3, and AKT1 as top-ranked hub targets by which AC exerts its action on AD and PD. Enrichment analyses of these genes identified significant biological and functional pathways involved in neuroinflammation, apoptosis, and AD. Experimental validation showed that AC extracts significantly downregulated hub gene expressions in the neuroinflammatory BV-2 microglia cell model and prolonged the survival of the transgenic Caenorhabditis elegans AD model. Docking analysis suggested lucidine B, oxolucidine B, solanocapsine, evodiamine, and liquiritigenin are the principal phytocompounds underlying the neuroprotective properties of AC. The findings revealed the pharmacological mechanisms of AC and highlighted its potential value as an effective, multitargeting natural agent to address challenges in AD and PD therapies.<\/jats:p>","DOI":"10.3390\/ijms27125169","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:43:46Z","timestamp":1780897426000},"page":"5169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring Mechanistic Targets of Areca catechu Against Neurodegenerative Diseases Through an Integrated Network Pharmacology, Molecular Docking, and Experimental Approaches"],"prefix":"10.3390","volume":"27","author":[{"given":"Sakawrat","family":"Janpaijit","sequence":"first","affiliation":[{"name":"College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanika","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Molecular Epidemiology, ICMR-National Institute of Malaria Research, New Delhi 110077, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9079-2219","authenticated-orcid":false,"given":"Ansella Amanda Epifani","family":"Widoyanti","sequence":"additional","affiliation":[{"name":"College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4177-2165","authenticated-orcid":false,"given":"Tewin","family":"Tencomnao","sequence":"additional","affiliation":[{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8884-3077","authenticated-orcid":false,"given":"Anchalee","family":"Prasansuklab","sequence":"additional","affiliation":[{"name":"College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102357","DOI":"10.1016\/j.arr.2024.102357","article-title":"Neurodegenerative disorders: Mechanisms of degeneration and therapeutic approaches with their clinical relevance","volume":"99","author":"Gadhave","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.2147\/IJN.S200490","article-title":"Alzheimer\u2019s disease: Pathogenesis, diagnostics, and therapeutics","volume":"14","author":"Tiwari","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/s41582-024-01034-x","article-title":"Parkinson disease therapy: Current strategies and future research priorities","volume":"20","author":"Stocchi","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1093\/procel\/pwae026","article-title":"Alzheimer\u2019s disease: Insights into pathology, molecular mechanisms, and therapy","volume":"16","author":"Zheng","year":"2025","journal-title":"Protein Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","article-title":"Parkinson disease","volume":"3","author":"Poewe","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sequeira, L., Benfeito, S., Fernandes, C., Lima, I., Peixoto, J., Alves, C., Machado, C.S., Gaspar, A., Borges, F., and Chavarria, D. (2024). Drug Development for Alzheimer\u2019s and Parkinson\u2019s Disease: Where Do We Go Now?. Pharmaceutics, 16.","DOI":"10.20944\/preprints202404.0437.v1"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.dcmed.2025.05.002","article-title":"Herbal remedies for Alzheimer\u2019s disease: Neuroprotective mechanisms and cognitive enhancement potential","volume":"8","author":"Kirubakaran","year":"2025","journal-title":"Digit. Chin. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Tong, T., Xu, A., Tan, S., Jiang, H., Liu, L., Deng, S., and Wang, H. (2024). Biological Effects and Biomedical Applications of Areca Nut and Its Extract. Pharmaceuticals, 17.","DOI":"10.3390\/ph17020228"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1002\/ptr.6665","article-title":"Areca catechu\u2014From farm to food and biomedical applications","volume":"34","author":"Salehi","year":"2020","journal-title":"Phytother. Res."},{"key":"ref_10","first-page":"4151","article-title":"A review on phytochemical and pharmacological potential of Areca catechu L. Seed","volume":"3","author":"Amudhan","year":"2012","journal-title":"Int. J. Pharm. Sci. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sun, Y., Feng, J., Hou, W., Qi, H., and Liu, Y. (2024). Comprehensive insights into areca nut: Active components and omics technologies for bioactivity evaluation and quality control. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1407212"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Yi, S., Zou, L., Li, Z., Sakao, K., Wang, Y., and Hou, D.X. (2022). In Vitro Antioxidant Activity of Areca Nut Polyphenol Extracts on RAW264.7 Cells. Foods, 11.","DOI":"10.3390\/foods11223607"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"406","DOI":"10.37360\/blacpma.21.20.4.30","article-title":"Investigation of anti-Alzheimer\u2019s activity of aqueous extract of areca nuts (Areca catechu L.): In vitro and in vivo studies","volume":"20","author":"Bozorgi","year":"2021","journal-title":"Bol. Latinoam. Caribe Plantas Med. Aromat."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pradeep, S., Prabhuswaminath, S.C., Reddy, P., Srinivasa, S.M., Shati, A.A., Alfaifi, M.Y., Eldin, I.E.S., Achar, R.R., Silina, E., and Stupin, V. (2022). Anticholinesterase activity of Areca catechu: In Vitro and in silico green synthesis approach in search for therapeutic agents against Alzheimer\u2019s disease. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1044248"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1097\/WNR.0000000000001172","article-title":"Arecoline attenuates memory impairment and demyelination in a cuprizone-induced mouse model of schizophrenia","volume":"30","author":"Xu","year":"2019","journal-title":"Neuroreport"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Janpaijit, S., Sukprasansap, M., Tencomnao, T., and Prasansuklab, A. (2024). Anti-Neuroinflammatory Potential of Areca Nut Extract and Its Bioactive Compounds in Anthracene-Induced BV-2 Microglial Cell Activation. Nutrients, 16.","DOI":"10.3390\/nu16172882"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Noor, F., Tahir Ul Qamar, M., Ashfaq, U.A., Albutti, A., Alwashmi, A.S.S., and Aljasir, M.A. (2022). Network Pharmacology Approach for Medicinal Plants: Review and Assessment. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050572"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chhotaray, S., Verma, K., Sahoo, P., and Jal, S. (2025). Network pharmacology and molecular docking analysis for elucidation of mechanism of action and molecular targets of Commiphora wightii in treatment of atherosclerosis. Advancement in Animal Handling and Generative AI for Pre-clinical Studies, CRC Press.","DOI":"10.1201\/9781003672869-7"},{"key":"ref_19","first-page":"3584","article-title":"Neuroinflammation as a Link in Parkinson\u2019s and Alzheimer\u2019s Diseases: A Systematic Review and Meta-Analysis","volume":"16","author":"Tylutka","year":"2024","journal-title":"Aging Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a risk factor for neurodegenerative disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102481","DOI":"10.1016\/j.arr.2024.102481","article-title":"Pathogenesis, diagnostics, and therapeutics for Alzheimer\u2019s disease: Breaking the memory barrier","volume":"101","author":"Kamatham","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1016\/j.parkreldis.2003.11.005","article-title":"Alpha-synuclein, Parkinson\u2019s disease, and Alzheimer\u2019s disease","volume":"10","author":"Kim","year":"2004","journal-title":"Park. Relat. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0006-8993(99)02207-6","article-title":"Plaque-associated alpha-synuclein (NACP) pathology in aged transgenic mice expressing amyloid precursor protein","volume":"853","author":"Yang","year":"2000","journal-title":"Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"648740","DOI":"10.1155\/2014\/648740","article-title":"Shared mechanisms of neurodegeneration in Alzheimer\u2019s disease and Parkinson\u2019s disease","volume":"2014","author":"Xie","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liu, P.-F., and Chang, Y.-F. (2023). The Controversial Roles of Areca Nut: Medicine or Toxin?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108996"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/s41598-017-18996-2","article-title":"Areca nut extracts mobilize calcium and release pro-inflammatory cytokines from various immune cells","volume":"8","author":"Faouzi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Al-Qahtani, A.A., Alhamlan, F.S., and Al-Qahtani, A.A. (2024). Pro-Inflammatory and Anti-Inflammatory Interleukins in Infectious Diseases: A Comprehensive Review. Trop. Med. Infect. Dis., 9.","DOI":"10.3390\/tropicalmed9010013"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kany, S., Vollrath, J.T., and Relja, B. (2019). Cytokines in Inflammatory Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20236008"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/jnr.25167","article-title":"The association of astrogliosis and microglial activation with aging and Alzheimer\u2019s disease pathology in the chimpanzee brain","volume":"101","author":"Edler","year":"2023","journal-title":"J. Neurosci. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1007\/s11064-016-2125-4","article-title":"FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models","volume":"42","author":"Ren","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/s42003-024-06615-6","article-title":"Naringenin ameliorates amyloid-\u03b2 pathology and neuroinflammation in Alzheimer\u2019s disease","volume":"7","author":"Zhu","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lee, N., Youn, K., Yoon, J.H., Lee, B., Kim, D.H., and Jun, M. (2023). The Role of Fucoxanthin as a Potent Nrf2 Activator via Akt\/GSK-3\u03b2\/Fyn Axis against Amyloid-\u03b2 Peptide-Induced Oxidative Damage. Antioxidants, 12.","DOI":"10.3390\/antiox12030629"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"379817","DOI":"10.1155\/2015\/379817","article-title":"Implication of Caspase-3 as a Common Therapeutic Target for Multineurodegenerative Disorders and Its Inhibition Using Nonpeptidyl Natural Compounds","volume":"2015","author":"Khan","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s41419-024-07014-9","article-title":"Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response","volume":"15","author":"Ruiz","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1212\/01.wnl.0000198511.09968.b3","article-title":"Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease","volume":"66","author":"Blandini","year":"2006","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1021\/jasms.4c00083","article-title":"Profiling of the Proteins Interacting with Amyloid Beta Peptides in Clinical Samples by PACTS-TPP","volume":"35","author":"Xu","year":"2024","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"105619","DOI":"10.1016\/j.jbc.2023.105619","article-title":"Akt activation ameliorates deficits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer\u2019s disease mouse model","volume":"300","author":"Kommaddi","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wawrzyniak, A., Krawczyk-Mar\u0107, I., \u017bury\u0144, A., Walocha, J., and Balawender, K. (2025). Diversity, Functional Complexity, and Translational Potential of Glial Cells in the Central Nervous System. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26189080"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s12974-021-02158-3","article-title":"Crosstalk between astrocytes and microglia results in increased degradation of \u03b1-synuclein and amyloid-\u03b2 aggregates","volume":"18","author":"Rostami","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s40035-021-00273-y","article-title":"Gram-negative bacteria and their lipopolysaccharides in Alzheimer\u2019s disease: Pathologic roles and therapeutic implications","volume":"10","author":"Kim","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1002\/mds.29432","article-title":"The Endotoxin Hypothesis of Parkinson\u2019s Disease","volume":"38","author":"Brown","year":"2023","journal-title":"Mov. Disord."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Skrzypczak-Wiercioch, A., and Sa\u0142at, K. (2022). Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use. Molecules, 27.","DOI":"10.3390\/molecules27175481"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kalyan, M., Tousif, A.H., Sonali, S., Vichitra, C., Sunanda, T., Praveenraj, S.S., Ray, B., Gorantla, V.R., Rungratanawanich, W., and Mahalakshmi, A.M. (2022). Role of Endogenous Lipopolysaccharides in Neurological Disorders. Cells, 11.","DOI":"10.3390\/cells11244038"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8899240","DOI":"10.1155\/2023\/8899240","article-title":"Flavonoids as Strong Inhibitors of MAPK3: A Computational Drug Discovery Approach","volume":"2023","author":"Taherkhani","year":"2023","journal-title":"Int. J. Anal. Chem."},{"key":"ref_45","first-page":"6683470","article-title":"Natural Anthraquinones as Promising MAPK3 Inhibitors for Complementary Cancer Therapy","volume":"2023","author":"Taherkhani","year":"2023","journal-title":"J. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s41537-024-00504-x","article-title":"Exploring the molecular targets of fingolimod and siponimod for treating the impaired cognition of schizophrenia using network pharmacology and molecular docking","volume":"10","author":"Li","year":"2024","journal-title":"Schizophrenia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1089\/vim.2020.0319","article-title":"Evodiamine Enhanced the Anti-Inflammation Effect of Clindamycin in the BEAS-2B Cells Infected with H5N1 and Pneumoniae D39 Through CREB-C\/EBP\u03b2 Signaling Pathway","volume":"34","author":"Liu","year":"2021","journal-title":"Viral Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/aps.2010.230","article-title":"Evodiamine improves congnitive abilities in SAMP8 and APP(swe)\/PS1(\u0394E9) transgenic mouse models of Alzheimer\u2019s disease","volume":"32","author":"Yuan","year":"2011","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Wang, J., Wang, C., Li, Z., Liu, X., Zhang, J., Lu, J., and Wang, D. (2018). Pharmacological Basis for the Use of Evodiamine in Alzheimer\u2019s Disease: Antioxidation and Antiapoptosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051527"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/bjp.2008.79","article-title":"Anti-inflammatory effects of liquiritigenin as a consequence of the inhibition of NF-kappaB-dependent iNOS and proinflammatory cytokines production","volume":"154","author":"Kim","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"686","DOI":"10.3892\/mmr.2021.12326","article-title":"Liquiritigenin attenuates isoprenaline-induced myocardial fibrosis in mice through the TGF-\u03b21\/Smad2 and AKT\/ERK signaling pathways","volume":"24","author":"Li","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Valenzuela-Arzeta, I.E., Soto-Rojas, L.O., Flores-Martinez, Y.M., Delgado-Minjares, K.M., Gatica-Garcia, B., Mascotte-Cruz, J.U., Nava, P., Aparicio-Trejo, O.E., Reyes-Corona, D., and Mart\u00ednez-D\u00e1vila, I.A. (2023). LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054628"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1007\/s10571-025-01600-x","article-title":"LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer\u2019s Disease Cell Models","volume":"45","author":"Shademan","year":"2025","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.bja.2022.05.036","article-title":"The drug titration paradox: More drug does not correlate with more effect in individual clinical data","volume":"129","author":"Schnider","year":"2022","journal-title":"Br. J. Anaesth."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kazemi, K., Fadl, A., Sperandio, F.F., and Leask, A. (2025). The Areca Nut and Oral Submucosal Fibrosis: A Narrative Review. Dent. J., 13.","DOI":"10.3390\/dj13080364"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.job.2024.02.005","article-title":"Areca nut-induced oral fibrosis\u2014Reassessing the biology of oral submucous fibrosis","volume":"66","author":"Sharma","year":"2024","journal-title":"J. Oral Biosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1039\/C9NP00011A","article-title":"Synergy and antagonism in natural product extracts: When 1 + 1 does not equal 2","volume":"36","author":"Caesar","year":"2019","journal-title":"Nat. Prod. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Vaou, N., Stavropoulou, E., Voidarou, C.C., Tsakris, Z., Rozos, G., Tsigalou, C., and Bezirtzoglou, E. (2022). Interactions between Medical Plant-Derived Bioactive Compounds: Focus on Antimicrobial Combination Effects. Antibiotics, 11.","DOI":"10.3390\/antibiotics11081014"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7225","DOI":"10.1038\/s41598-023-34183-y","article-title":"Transcriptomic analysis of glutamate-induced HT22 neurotoxicity as a model for screening anti-Alzheimer\u2019s drugs","volume":"13","author":"Prasansuklab","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Prasertsuksri, P., Kraokaew, P., Pranweerapaiboon, K., Sobhon, P., and Chaithirayanon, K. (2023). Neuroprotection of Andrographolide against Neurotoxin MPP(+)-Induced Apoptosis in SH-SY5Y Cells via Activating Mitophagy, Autophagy, and Antioxidant Activities. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108528"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.55730\/1300-0144.6117","article-title":"Moltkia coerulea extracts alleviate caspase-3 activity via reducing oxidative stress in LPS-induced neurotoxicity in BV-2 cells","volume":"55","author":"Altay","year":"2025","journal-title":"Turk. J. Med. Sci."},{"key":"ref_62","first-page":"43","article-title":"Current Methods for Quantifying Drug Synergism","volume":"1","author":"Ma","year":"2019","journal-title":"Proteome Bioinform."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"100110","DOI":"10.1016\/j.crphar.2022.100110","article-title":"Evaluation of synergism in drug combinations and reference models for future orientations in oncology","volume":"3","author":"Duarte","year":"2022","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2302680","DOI":"10.1155\/2021\/2302680","article-title":"A Network Pharmacology Approach to Estimate Potential Targets of the Active Ingredients of Epimedium for Alleviating Mild Cognitive Impairment and Treating Alzheimer\u2019s Disease","volume":"2021","author":"Gao","year":"2021","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e70166","DOI":"10.1002\/iid3.70166","article-title":"Identification and Exploration of Immunity-Related Genes and Natural Products for Alzheimer\u2019s Disease Based on Bioinformatics, Molecular Docking, and Molecular Dynamics","volume":"13","author":"Liang","year":"2025","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1038\/s41598-024-55013-9","article-title":"Network analysis-guided drug repurposing strategies targeting LPAR receptor in the interplay of COVID, Alzheimer\u2019s, and diabetes","volume":"14","author":"Malar","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"9569","DOI":"10.1038\/s41598-023-36687-z","article-title":"Use of network pharmacology and molecular docking to explore the mechanism of action of curcuma in the treatment of osteosarcoma","volume":"13","author":"Hu","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"8227","DOI":"10.1038\/s41598-022-12366-3","article-title":"Network pharmacology combined with GEO database identifying the mechanisms and molecular targets of Polygoni Cuspidati Rhizoma on Peri-implants","volume":"12","author":"Shan","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Chhotaray, S., Verma, K., Badgayan, N.D., Banerjee, R., and Jal, S. (2024, January 24\u201328). Identification of Hub Genes Indicating Association of Atherosclerosis with Rheumatoid Arthritis. Proceedings of the 2024 15th International Conference on Computing Communication and Networking Technologies (ICCCNT), Kamand, India.","DOI":"10.1109\/ICCCNT61001.2024.10725659"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly accurate protein structure prediction for the human proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1080\/07391102.2020.1815584","article-title":"Molecular docking, validation, dynamics simulations, and pharmacokinetic prediction of natural compounds against the SARS-CoV-2 main-protease","volume":"40","author":"Shivanika","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/nprot.2016.051","article-title":"Computational protein-ligand docking and virtual drug screening with the AutoDock suite","volume":"11","author":"Forli","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"11779322221125605","DOI":"10.1177\/11779322221125605","article-title":"Molecular Docking, Validation, Dynamics Simulations, and Pharmacokinetic Prediction of Phytochemicals Isolated From Croton dichogamus Against the HIV-1 Reverse Transcriptase","volume":"16","author":"Terefe","year":"2022","journal-title":"Bioinform. Biol. Insights"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Roomi, M.S., Culletta, G., Longo, L., Filgueira de Azevedo, W., Perricone, U., and Tutone, M. (2025). Docking in the Dark: Insights into Protein-Protein and Protein-Ligand Blind Docking. Pharmaceuticals, 18.","DOI":"10.3390\/ph18121777"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Janpaijit, S., Sillapachaiyaporn, C., Theerasri, A., Charoenkiatkul, S., Sukprasansap, M., and Tencomnao, T. (2023). Cleistocalyx nervosum var. paniala Berry Seed Protects against TNF-\u03b1-Stimulated Neuroinflammation by Inducing HO-1 and Suppressing NF-\u03baB Mechanism in BV-2 Microglial Cells. Molecules, 28.","DOI":"10.3390\/molecules28073057"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5169\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:48:05Z","timestamp":1780897685000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,7]]},"references-count":75,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125169"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125169","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,7]]}}}