{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:38:05Z","timestamp":1788381485333,"version":"build-2803163510"},"reference-count":110,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,8]],"date-time":"2024-12-08T00:00:00Z","timestamp":1733616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Walailak University Graduate Research Fund","award":["CGS-RF-2023\/04"],"award-info":[{"award-number":["CGS-RF-2023\/04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitragyna speciosa Korth. Havil (MS) has a traditional use in relieving pain, managing hypertension, treating cough, and diarrhea, and as a morphine substitute in addiction recovery. Its potential in addressing Alzheimer\u2019s disease (AD), a neurodegenerative condition with no effective treatments, is under investigation. This study aims to explore MS mechanisms in treating AD through network pharmacology, molecular docking, and in vitro studies. Using network pharmacology, we identified 19 MS components that may affect 60 AD-related targets. The compound\u2013target network highlighted significant interactions among 60 nodes and 470 edges, with an average node degree of 15.7. The KEGG enrichment analysis revealed Alzheimer\u2019s disease (hsa05010) as a relevant pathway. We connected 20 targets to tau and \u03b2-amyloid proteins through gene expression data from the AlzData database. Docking studies demonstrated high binding affinities of MS compounds like acetylursolic acid, beta-sitosterol, isomitraphylline, and speciophylline to AD-related proteins, such as AKT1, GSK3B, NF\u03baB1, and BACE1. In vitro studies showed that ethanolic (EE), distilled water (DWE), and pressurized hot water (PHWE) extracts of MS-treated 100 \u03bcM H2O2-induced SH-SY5Y cells significantly reduced oxidative damage. This research underscores the multi-component, multi-target, and multi-pathway effects of MS on AD, providing insights for future research and potential clinical applications.<\/jats:p>","DOI":"10.3390\/ijms252313201","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T04:01:37Z","timestamp":1733716897000},"page":"13201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Network Pharmacology, Molecular Docking, and In Vitro Insights into the Potential of Mitragyna speciosa for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2261-341X","authenticated-orcid":false,"given":"Rahni","family":"Hossain","sequence":"first","affiliation":[{"name":"College of Graduate Studies, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Research Excellence Center for Innovation and Health Product (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunwadee","family":"Noonong","sequence":"additional","affiliation":[{"name":"School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Research Excellence Center for Innovation and Health Product (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1325-5489","authenticated-orcid":false,"given":"Manit","family":"Nuinoon","sequence":"additional","affiliation":[{"name":"School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Research Excellence Center for Innovation and Health Product (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Hematology and Transfusion Science Research Center, Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2842-0467","authenticated-orcid":false,"given":"Hideyuki J.","family":"Majima","sequence":"additional","affiliation":[{"name":"School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Research Excellence Center for Innovation and Health Product (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komgrit","family":"Eawsakul","sequence":"additional","affiliation":[{"name":"Research Excellence Center for Innovation and Health Product (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradoldej","family":"Sompol","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4902-8923","authenticated-orcid":false,"given":"Md. Atiar","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4768-7829","authenticated-orcid":false,"given":"Jitbanjong","family":"Tangpong","sequence":"additional","affiliation":[{"name":"School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Research Excellence Center for Innovation and Health Product (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kirova, A.M., Bays, R.B., and Lagalwar, S. (2015). Working memory and executive function decline across normal aging, mild cognitive impairment, and Alzheimer\u2019s disease. BioMed Res. Int., 1.","DOI":"10.1155\/2015\/748212"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.1002\/alz.13809","article-title":"2024 Alzheimer\u2019s disease facts and figures","volume":"20","author":"Better","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e17339","DOI":"10.7717\/peerj.17339","article-title":"Alzheimer\u2019s diseases in America, Europe, and Asian regions: A global genetic variation","volume":"12","author":"Hossain","year":"2024","journal-title":"PeerJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.2174\/1570159X18666200528142429","article-title":"Recent advancements in pathogenesis, diagnostics and treatment of Alzheimer\u2019s disease","volume":"11","author":"Khan","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rostagno, A.A. (2022). Pathogenesis of Alzheimer\u2019s disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010107"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100437","DOI":"10.1016\/j.fochx.2022.100437","article-title":"Elderberry (Sambucus nigra L.) extracts promote anti-inflammatory and cellular antioxidant activity","volume":"15","author":"Ferreira","year":"2022","journal-title":"Food Chem. X"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1093\/jxb\/erv099","article-title":"ROS and RNS in plant physiology: An overview","volume":"66","year":"2015","journal-title":"J. Exp. Bot."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/oby.2002.131","article-title":"Obesity, aerobic exercise, and vascular disease: The role of oxidant stress","volume":"10","author":"Fenster","year":"2002","journal-title":"Obes. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ijpharm.2014.05.011","article-title":"Cationic solid lipid nanoparticles interfere with the activity of antioxidant enzymes in hepatocellular carcinoma cells","volume":"471","author":"Santos","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sadef, Y., Javed, T., Javed, R., Mahmood, A., Alwahibi, M.S., Elshikh, M.S., AbdelGawwa, M.R., Alhaji, J.H., and Rasheed, R.A. (2022). Nutritional status, antioxidant activity and total phenolic content of different fruits and vegetables peels. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0265566"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7006","DOI":"10.1523\/JNEUROSCI.22-16-07006.2002","article-title":"An in vitro model of Parkinson\u2019s disease: Linking mitochondrial impairment to altered \u03b1-synuclein metabolism and oxidative damage","volume":"22","author":"Sherer","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/S0891-5849(02)00967-X","article-title":"DNA damage and apoptosis in hydrogen peroxide-exposed Jurkat cells: Bolus addition versus continuous generation of H2O2","volume":"33","author":"Barbouti","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wr\u00f3blewski, M., Wr\u00f3blewska, W., and Sobiesiak, M. (2024). The Role of Selected Elements in Oxidative Stress Protection: Key to Healthy Fertility and Reproduction. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179409"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pham-Huy, L.A., He, H., and Pham-Huy, C. (2008). Free radicals, antioxidants in disease and health. Int. J. Biomed. Sci. IJBS, 4.","DOI":"10.59566\/IJBS.2008.4089"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5629","DOI":"10.1007\/s11033-021-06512-9","article-title":"Recent advances on drug development and emerging therapeutic agents for Alzheimer\u2019s disease","volume":"48","author":"Athar","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_16","first-page":"5100904","article-title":"Bioactive compounds and their derivatives: An insight into prospective phytotherapeutic approach against Alzheimer\u2019s disease","volume":"1","author":"Islam","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1248\/cpb.52.916","article-title":"Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa","volume":"52","author":"Takayama","year":"2004","journal-title":"Chem. Pharm. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hossain, R., Sultana, A., Nuinoon, M., Noonong, K., Tangpong, J., Hossain, K.H., and Rahman, M.A. (2023). A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds. Molecules, 28.","DOI":"10.20944\/preprints202309.1502.v1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.drugpo.2019.05.003","article-title":"Kratom policy: The challenge of balancing therapeutic potential with public safety","volume":"70","author":"Prozialeck","year":"2019","journal-title":"Int. J. Drug Policy"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3964","DOI":"10.3390\/molecules14103964","article-title":"Evaluation of antioxidant and antibacterial activities of aqueous, methanolic and alkaloid extracts from Mitragyna speciosa (Rubiaceae family) leaves","volume":"14","author":"Parthasarathy","year":"2009","journal-title":"Molecules"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Goh, Y.S., Karunakaran, T., Murugaiyah, V., Santhanam, R., Abu Bakar, M.H., and Ramanathan, S. (2021). Accelerated solvent extractions (ASE) of Mitragyna speciosa Korth.(Kratom) leaves: Evaluation of its cytotoxicity and antinociceptive activity. Molecules, 26.","DOI":"10.3390\/molecules26123704"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sengnon, N., Vonghirundecha, P., Chaichan, W., Juengwatanatrakul, T., Onthong, J., Kitprasong, P., Sriwiriyajan, S., Chittrakarn, S., Limsuwanchote, S., and Wungsintaweekul, J. (2023). Seasonal and geographic variation in alkaloid content of kratom (Mitragyna speciosa (Korth.) Havil.) from Thailand. Plants, 12.","DOI":"10.3390\/plants12040949"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pang, Q.Q., Kim, J.H., Kim, H.Y., Kim, J.H., and Cho, E.J. (2023). Protective Effects and Mechanisms of Pectolinarin against H2O2-Induced Oxidative Stress in SH-SY5Y Neuronal Cells. Molecules, 28.","DOI":"10.3390\/molecules28155826"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/978-1-62703-640-5_2","article-title":"Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology","volume":"1078","author":"Kovalevich","year":"2013","journal-title":"Neuronal Cell Cult. Methods Protoc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lei, P., Li, Z., Hua, Q., Song, P., Gao, L., Zhou, L., and Cai, Q. (2023). Ursolic Acid Alleviates Neuroinflammation after Intracerebral Hemorrhage by Mediating Microglial Pyroptosis via the NF-\u03baB\/NLRP3\/GSDMD Pathway. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914771"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"W257","DOI":"10.1093\/nar\/gky318","article-title":"ProTox-II: A webserver for the prediction of toxicity of chemicals","volume":"46","author":"Banerjee","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jalz.2017.08.012","article-title":"A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimer\u2019s disease","volume":"14","author":"Xu","year":"2018","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Jong Huat, T., Camats-Perna, J., Newcombe, E.A., Onraet, T., Campbell, D., Sucic, J.T., Martini, A., Forner, S., Mirzaei, M., and Poon, W. (2024). The impact of astrocytic NF-\u03baB on healthy and Alzheimer\u2019s disease brains. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-65248-1"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Primiani, C.T., Ryan, V.H., Rao, J.S., Cam, M.C., Ahn, K., Modi, H.R., and Rapoport, S.I. (2014). Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110972"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cucos, C.A., Milanesi, E., Dobre, M., Musat, I.A., Manda, G., and Cuadrado, A. (2022). Altered Blood and Brain Expression of Inflammation and Redox Genes in Alzheimer\u2019s Disease, Common to APPV717I \u00d7 TAUP301L Mice and Patients. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105799"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sun, E., Motolani, A., Campos, L., and Lu, T. (2022). The pivotal role of NF-kB in the pathogenesis and therapeutics of Alzheimer\u2019s disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23168972"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mehmood, A., Javid, S., Khan, M.F., Ahmad, K.S., and Mustafa, A. (2022). In vitro total phenolics, total flavonoids, antioxidant and antibacterial activities of selected medicinal plants using different solvent systems. BMC Chem., 16.","DOI":"10.1186\/s13065-022-00858-2"},{"key":"ref_35","first-page":"100071","article-title":"Role of plant derived alkaloids as antioxidant agents for neurodegenerative diseases","volume":"6","author":"Sirin","year":"2023","journal-title":"Health Sci. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1016\/j.foodchem.2010.12.026","article-title":"A critical review of methods for characterisation of polyphenolic compounds in fruits and vegetables","volume":"126","author":"Ignat","year":"2011","journal-title":"Food Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Limcharoen, T., Pouyfung, P., Ngamdokmai, N., Prasopthum, A., Ahmad, A.R., Wisdawati, W., Prugsakij, W., and Warinhomhoun, S. (2022). Inhibition of \u03b1-Glucosidase and Pan-creatic Lipase Properties of Mitragyna speciosa (Korth.) Havil (Kratom) Leaves. Nutrients, 14.","DOI":"10.3390\/nu14193909"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.etp.2011.02.002","article-title":"Antioxidant ability and total phenolic content of aqueous leaf extract of Stevia rebaudiana Bert","volume":"64","author":"Shukla","year":"2012","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/ptr.687","article-title":"Screening of Brazilian plant extracts for antioxidant activity by the use of DPPH free radical method","volume":"15","author":"Mensor","year":"2001","journal-title":"Phytother. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.jfca.2011.01.008","article-title":"Comparison of ABTS\/DPPH assays to measure antioxidant capacity in popular antioxidant-rich US foods","volume":"24","author":"Floegel","year":"2011","journal-title":"J. Food Compos. Anal."},{"key":"ref_41","first-page":"1934578X0900400705","article-title":"Phytochemical characterization of the leaves of Mitragyna speciosa grown in USA","volume":"4","author":"Habib","year":"2009","journal-title":"Nat. Prod. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0308-8146(00)00298-3","article-title":"Antioxidant activity of grape seed (Vitis vinifera) extracts on peroxidation models in vitro","volume":"73","author":"Jayaprakasha","year":"2001","journal-title":"Food Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.cbi.2014.10.016","article-title":"Free radicals, reactive oxygen species, oxidative stress and its classification","volume":"224","author":"Lushchak","year":"2014","journal-title":"Chem.-Biol. Interact."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.mex.2015.05.001","article-title":"Optimized enzymatic colorimetric assay for determination of hydrogen peroxide (H2O2) scavenging activity of plant extracts","volume":"2","author":"Fernando","year":"2015","journal-title":"MethodsX"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hazra, B., Biswas, S., and Mandal, N. (2008). Antioxidant and free radical scavenging activity of Spondias pinnata. BMC Complement. Altern. Med., 8.","DOI":"10.1186\/1472-6882-8-63"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"FSO272","DOI":"10.4155\/fsoa-2017-0086","article-title":"Evaluation of the free-radical scavenging and antioxidant activities of Chilauni, Schima wallichii Korth in vitro","volume":"4","author":"Lalhminghlui","year":"2018","journal-title":"Future Sci. OA"},{"key":"ref_47","first-page":"52","article-title":"In vitro antioxidant activity of coumarin compounds by DPPH, Super oxide and nitric oxide free radical scavenging methods","volume":"1","year":"2011","journal-title":"J. Adv. Pharm. Educ. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4205","DOI":"10.3892\/mmr.2016.5056","article-title":"Lycopene protects human SH-SY5Y neuroblastoma cells against hydrogen peroxide-induced death via inhibition of oxidative stress and mitochondria-associated apoptotic pathways","volume":"13","author":"Feng","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1007\/s10571-014-0073-6","article-title":"Neuroprotective effects of bikaverin on H2O2-induced oxidative stress mediated neuronal damage in SH-SY5Y cell line","volume":"34","author":"Nirmaladevi","year":"2014","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Lingappa, S., Shivakumar, M.S., Manivasagam, T., Somasundaram, S.T., and Seedevi, P. (2021). Neuroprotective effect of epalrestat on hydrogen peroxide-induced neurodegeneration in SH-SY5Y cellular model. J. Microbiol. Biotechnol., 31.","DOI":"10.4014\/jmb.2101.01002"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41582-018-0116-6","article-title":"A critical appraisal of amyloid-\u03b2-targeting therapies for Alzheimer disease","volume":"15","author":"Panza","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.molmed.2007.02.004","article-title":"A\u03b2, tau and ApoE4 in Alzheimer\u2019s disease: The axonal connection","volume":"13","author":"Adalbert","year":"2007","journal-title":"Trends Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Li, J., Du, Q., Li, N., Du, S., and Sun, Z. (2021). Alpiniae oxyphyllae Fructus and Alzheimer\u2019s disease: An update and current perspective on this traditional Chinese medicine. Biomed. Pharmacother., 135.","DOI":"10.1016\/j.biopha.2020.111167"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Andronie-Cioara, F.L., Ardelean, A.I., Nistor-Cseppento, C.D., Jurcau, A., Jurcau, M.C., Pascalau, N., and Marcu, F. (2023). Molecular mechanisms of neuroinflammation in aging and Alzheimer\u2019s disease progression. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24031869"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Zhang, P., Wei, W., Zhang, X., Wen, C., Ovatlarnporn, C., and Olatunji, O.J. (2023). Antidiabetic and antioxidant activities of Mitragyna speciosa (kratom) leaf extract in type 2 diabetic rats. Biomed. Pharmacother., 162.","DOI":"10.1016\/j.biopha.2023.114689"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Chen, L., Fei, S., and Olatunji, O.J. (2022). LC\/ESI\/TOF-MS characterization, anxiolytic and antidepressant-like effects of Mitragyna speciosa Korth extract in diabetic rats. Molecules, 27.","DOI":"10.3390\/molecules27072208"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"13291","DOI":"10.1074\/jbc.R900010200","article-title":"The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress","volume":"284","author":"Nguyen","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.bcp.2007.07.007","article-title":"Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose","volume":"74","author":"Lu","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1590\/0004-282x20160065","article-title":"Ursolic acid attenuates beta-amyloid-induced memory impairment in mice","volume":"74","author":"Liang","year":"2016","journal-title":"Arq. De Neuro-Psiquiatr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e24785","DOI":"10.1016\/j.heliyon.2024.e24785","article-title":"A network pharmacology approach to reveal the key ingredients in Scrophulariae Radix (SR) and their effects against Alzheimer\u2019s disease","volume":"10","author":"Shi","year":"2024","journal-title":"Heliyon"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S1016-8478(23)17016-6","article-title":"Inhibitory effect of ursolic acid purified from Origanum majorana L. on the acetylcholinesterase","volume":"11","author":"Chung","year":"2001","journal-title":"Mol. Cells"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Alam, M., Ali, S., Ahmed, S., Elasbali, A.M., Adnan, M., Islam, A., Hassan, M.I., and Yadav, D.K. (2021). Therapeutic potential of ursolic acid in cancer and diabetic neuropathy diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212162"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8512048","DOI":"10.1155\/2019\/8512048","article-title":"Antioxidant and anti-inflammatory mechanisms of neuroprotection by ursolic acid: Addressing brain injury, cerebral ischemia, cognition deficit, anxiety, and depression","volume":"2019","author":"Habtemariam","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.neuroscience.2013.05.022","article-title":"Substitution of membrane cholesterol with \u03b2-sitosterol promotes nonamyloidogenic cleavage of endogenous amyloid precursor protein","volume":"247","author":"Wang","year":"2013","journal-title":"Neuroscience"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"39","DOI":"10.4196\/kjpp.2020.24.1.39","article-title":"\u03b2-Sitosterol treatment attenuates cognitive deficits and prevents amyloid plaque deposition in amyloid protein precursor\/presenilin 1 mice","volume":"24","author":"Ye","year":"2020","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Ayaz, M., Junaid, M., Ullah, F., Subhan, F., Sadiq, A., Ali, G., Ovais, M., Shahid, M., Ahmad, A., and Wadood, A. (2017). Anti-Alzheimer\u2019s studies on \u03b2-sitosterol isolated from Polygonum hydropiper L.. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00697"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1016\/j.bbagen.2012.12.012","article-title":"Incorporation of \u03b2-sitosterol into the membrane increases resistance to oxidative stress and lipid peroxidation via estrogen receptor-mediated PI3K\/GSK3\u03b2 signaling","volume":"1830","author":"Shi","year":"2013","journal-title":"Biochim. Et Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1007\/s10863-011-9383-2","article-title":"\u03b2-sitosterol inhibits high cholesterol-induced platelet \u03b2-amyloid release","volume":"43","author":"Shi","year":"2011","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s10787-022-01122-8","article-title":"Exploring the possible mechanism involved in the anti-nociceptive effect of \u03b2-sitosterol: Modulation of oxidative stress, nitric oxide and IL-6","volume":"31","author":"Kaur","year":"2023","journal-title":"Inflammopharmacology"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Tan, M.A., and An, S.S.A. (2020). Neuroprotective potential of the oxindole alkaloids isomitraphylline and mitraphylline in human neuroblastoma SH-SY5Y cells. 3 Biotech, 10.","DOI":"10.1007\/s13205-020-02535-4"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Azevedo, B.C., Roxo, M., Borges, M.C., Peixoto, H., Crevelin, J.E., Bertoni, B.W., Contini, S.H.T., Lopes, A.A., Fran\u00e7a, S.C., and Pereira, A.M.S. (2019). Antioxidant activity of an aqueous leaf extract from Uncaria tomentosa and its major alkaloids mitraphylline and isomitraphylline in Caenorhabditis Elegans. Molecules, 24.","DOI":"10.3390\/molecules24183299"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.ejps.2012.07.012","article-title":"16, 17-Dihydro-17b-hydroxy isomitraphylline alkaloid as an inhibitor of DPP-IV, and its effect on incretin hormone and \u03b2-cell proliferation in diabetic rat","volume":"47","author":"Shukla","year":"2012","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_73","first-page":"512","article-title":"Unlike morphine, long-term exposure to analgesic mitragynine, 7-hydroxymitragynine, paynantheine, and speciociliatine alkaloids does not contribute to antinociceptive tolerance of \u03bc-opioid receptors","volume":"47","author":"Elahian","year":"2020","journal-title":"Res. Sq."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1007\/s11064-008-9770-1","article-title":"GSK-3\u03b2 gene expression in human postmortem brain: Regional distribution, effects of age and suicide","volume":"34","author":"Pandey","year":"2009","journal-title":"Neurochem. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/B978-0-444-63473-3.00012-5","article-title":"Oxindole alkaloids of Uncaria (Rubiaceae, subfamily cinchonoideae): A review on its structure, properties, and bioactivities","volume":"45","author":"Ahmad","year":"2015","journal-title":"Stud. Nat. Prod. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"148886","DOI":"10.1016\/j.brainres.2024.148886","article-title":"Alkaloids as drug leads in Alzheimer\u2019s treatment: Mechanistic and therapeutic insights","volume":"1834","author":"Islam","year":"2024","journal-title":"Brain Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"716","DOI":"10.3109\/13880200903271298","article-title":"Xanthine oxidase\/tyrosinase inhibiting, antioxidant, and antifungal oxindole alkaloids from Isatis Costata","volume":"48","author":"Ahmad","year":"2010","journal-title":"Pharm. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1021\/acs.jnatprod.0c00257","article-title":"The chemistry of kratom [Mitragyna speciosa]: Updated characterization data and methods to elucidate indole and oxindole alkaloids","volume":"83","author":"Raja","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.forsciint.2013.01.014","article-title":"A simple HPLC\u2013DAD method for the detection and quantification of psychotropic mitragynine in Mitragyna speciosa (ketum) and its products for the application in forensic investigation","volume":"226","author":"Parthasarathy","year":"2013","journal-title":"Forensic Sci. Int."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11419-009-0070-5","article-title":"Simultaneous analysis of mitragynine, 7-hydroxymitragynine, and other alkaloids in the psychotropic plant \u201ckratom\u201d (Mitragyna speciosa) by LC-ESI-MS","volume":"27","author":"Kawamura","year":"2009","journal-title":"Forensic Toxicol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"13","DOI":"10.5740\/jaoacint.14-110","article-title":"Identification and characterization of indole and oxindole alkaloids from leaves of Mitragyna speciosa Korth using liquid chromatography\u2013accurate QToF mass spectrometry","volume":"98","author":"Avula","year":"2015","journal-title":"J. AOAC Int."},{"key":"ref_82","unstructured":"Duke, J.A. (1992). Database of Phytochemical Constituents of GRAS Herbs and Other Economic Plants, CRC Press."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/3-540-29782-0_13","article-title":"KNApSAcK: A comprehensive species-metabolite relationship database","volume":"57","author":"Shinbo","year":"2006","journal-title":"Plant Metabolomics"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"W513","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: A webserver for the prediction of toxicity of chemicals","volume":"52","author":"Banerjee","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"baq020","DOI":"10.1093\/database\/baq020","article-title":"GeneCards Version 3: The human gene integrator","volume":"2010","author":"Safran","year":"2010","journal-title":"Database"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"D789","DOI":"10.1093\/nar\/gku1205","article-title":"OMIM. org: Online Mendelian Inheritance in Man (OMIM\u00ae), an online catalog of human genes and genetic disorders","volume":"43","author":"Amberger","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_89","first-page":"D845","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Ronzano","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_90","unstructured":"Oliveros, J.C. (2024, September 15). VENNY. An Interactive Tool for Comparing Lists with Venn Diagrams. Available online: http:\/\/bioinformatics.psb.ugent.be\/webtools\/Venn\/."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: Quality-controlled protein\u2013protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1038\/nprot.2013.092","article-title":"Large-scale gene function analysis with the PANTHER classification system","volume":"8","author":"Mi","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem substance and compound databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/978-1-4939-7000-1_26","article-title":"Protein Data Bank (PDB): The single global macromolecular structure archive","volume":"1067","author":"Burley","year":"2017","journal-title":"Protein Crystallogr. Methods Protoc."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"17","DOI":"10.56808\/3027-7922.2196","article-title":"Spectrophotometric determination of total alkaloids in some Iranian medicinal plants","volume":"32","author":"Shamsa","year":"2008","journal-title":"Thai J. Pharm. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Wang, T., Liu, C., Shu, S., Zhang, Q., and Olatunji, O.J. (2022). Therapeutic efficacy of polyphenol-rich fraction of Boesenbergia rotunda in diabetic rats: A focus on hypoglycemic, antihyperlipidemic, carbohydrate metabolism, antioxidant, anti-inflammatory and pancreato-protective activities. Front. Biosci.-Landmark, 27.","DOI":"10.31083\/j.fbl2707206"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"103541","DOI":"10.1016\/j.arabjc.2021.103541","article-title":"Total phenolic and flavonoid contents, antioxidant, antidiabetic and antiplasmodial activities of Garcinia forbesii King: A correlation study","volume":"15","author":"Wairata","year":"2022","journal-title":"Arab. J. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"112089","DOI":"10.1016\/j.indcrop.2020.112089","article-title":"Essential oils of hedgenettles (Stachys inflata, S. lavandulifolia, and S. byzantina) have antioxidant, anti-Alzheimer, antidiabetic, and anti-obesity potential: A comparative study","volume":"145","author":"Bahadori","year":"2020","journal-title":"Ind. Crops Prod."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0891-5849(98)00315-3","article-title":"Antioxidant activity applying an improved ABTS radical cation decolorization assay","volume":"26","author":"Re","year":"1999","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"112640","DOI":"10.1016\/j.jep.2020.112640","article-title":"Phytochemical investigation, in vitro and in vivo antioxidant properties of aqueous and organic extracts of toxic plant: Atractylis gummifera L.","volume":"253","author":"Bouabid","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/S0006-2952(01)00565-2","article-title":"Interaction of enkephalins with oxyradicals","volume":"61","author":"Fontana","year":"2001","journal-title":"Biochem. Pharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1093\/carcin\/10.6.1003","article-title":"Prevention of cytotoxicity and inhibition of intercellular communication by antioxidant catechins isolated from Chinese green tea","volume":"10","author":"Ruch","year":"1989","journal-title":"Carcinogenesis"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"281","DOI":"10.4103\/0253-7613.39147","article-title":"Free radical scavenging activity of gossypin and nevadensin: An in-vitro Evaluation","volume":"39","author":"Ganapaty","year":"2007","journal-title":"Indian J. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ejphar.2007.01.089","article-title":"Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells","volume":"564","author":"Zhang","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.3233\/JAD-170045","article-title":"Mouse models of Alzheimer\u2019s disease","volume":"57","author":"Villegas","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Choi, M., Jang, H.S., Son, T., Kim, D., Youn, Y., Hwang, G.B., Choi, Y.P., and Jeong, Y.H. (2023). Effect sizes of cognitive and locomotive behavior tests in the 5XFAD-J mouse model of Alzheimer\u2019s disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015064"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/13201\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:49:56Z","timestamp":1760114996000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/13201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,8]]},"references-count":110,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252313201"],"URL":"https:\/\/doi.org\/10.3390\/ijms252313201","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,8]]}}}