{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T19:35:29Z","timestamp":1786649729201,"version":"build-2736575974"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:p>\n                    Alzheimer\u2019s disease (AD) is the most prevalent type of dementia, negatively affecting the overall quality of life. Targeting the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a regulator of protective genes, offers potential AD therapies. Inhibiting Kelch-like ECH-associated protein 1 (Keap1), which suppresses Nrf2, may help reduce neuronal damage.\n                    <jats:italic toggle=\"yes\">Rhizophora mucronata<\/jats:italic>\n                    , a mangrove known for its anti-inflammatory and antioxidant properties, contains rutin, which is a promising potential AD therapy. The study aimed to explore the potential of rutin, a compound from\n                    <jats:italic toggle=\"yes\">R. mucronata<\/jats:italic>\n                    leaves, to inhibit the Keap1-Nrf2. The study analyzed the metabolomic profile of\n                    <jats:italic toggle=\"yes\">R. mucronata leaves<\/jats:italic>\n                    and evaluated their compound, rutin, as AD therapeutic potential via the Keap1-Nrf2 pathway using\n                    <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                    molecular docking.\n                    <jats:italic toggle=\"yes\">R. mucronata<\/jats:italic>\n                    was extracted using 96% ethanol. Metabolomic analysis employed liquid chromatography-high resolution mass spectrometry (LC-HRMS). The\n                    <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                    simulations used BIOVIA Discovery Studio and AutoDock Tool 1.5.7 for docking rutin and donepezil with the Keap1. Docking results were evaluated based on binding energy scores and inhibition constant. HRMS identified hundreds of compounds, with quercetin and rutin as major flavonoids. Molecular docking indicated rutin and donepezil had a binding energy of \u22126.97 \u00b1 0.16 kcal\/mol and \u22127.63 \u00b1 0.04 kcal\/mol, respectively. Their amino acid interaction was similar.\n                    <jats:italic toggle=\"yes\">R. mucronata<\/jats:italic>\n                    leaf extract, particularly rutin, showed promise as an AD therapeutic agent through the Keap1-Nrf2 pathway, warranting further research.\n                  <\/jats:p>","DOI":"10.4103\/japtr.japtr_313_24","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T04:01:59Z","timestamp":1747627319000},"page":"73-79","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":7,"title":["Potential of rutin from Rhizophora mucronata leaves as a Inhibitor of Kelch-like ECH-associated protein 1\/Nuclear factor erythroid 2 related factor 2 Keap1\/Nrf2): An in silico study for Alzheimer\u2019s therapy"],"prefix":"10.4103","volume":"16","author":[{"given":"Legis Ocktaviana","family":"Saputri","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Health Sciences, Mataram University, Mataram, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Permatasari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Medicine and Health Sciences, Mataram University, Mataram, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herpan Syafii","family":"Harahap","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine and Health Sciences, Mataram University, Mataram, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohadi Muhammad","family":"Rosyidi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Faculty of Medicine and Health Sciences, Mataram University, Mataram, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arina Windri","family":"Rivarti","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Health Sciences, Mataram University, Mataram, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lale Maulin","family":"Prihatina","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Faculty of Medicine and Health Sciences, Mataram University, Mataram, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilfia","family":"Rahayu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Medicine and Health Sciences, Mataram University, Mataram, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiwin","family":"Azariani","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Medicine and Health Sciences, Mataram University, Mataram, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"R2-20260423","first-page":"107","article-title":"Poor cognitive reserve status as predictors of memory impairment among elderly","volume":"9","author":"Harahap","year":"2023","journal-title":"Malang Neurol J"},{"key":"R3-20260423","doi-asserted-by":"crossref","first-page":"472.","DOI":"10.3389\/fnins.2019.00472","article-title":"Meta-analysis of randomized controlled trials on the efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer\u2019s disease","volume":"13","author":"Li","year":"2019","journal-title":"Front Neurosci"},{"key":"R4-20260423","first-page":"100467.","article-title":"Impacts of FDA approval and Medicare restriction on antiamyloid therapies for Alzheimer\u2019s disease: Patient outcomes, healthcare costs, and drug development","volume":"20","author":"Brockmann","year":"2023","journal-title":"Lancet Reg Health Am"},{"key":"R5-20260423","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.jconrel.2024.01.047","article-title":"Alzheimer\u2019s disease current therapies, novel drug delivery systems and future directions for better disease management","volume":"367","author":"Singh","year":"2024","journal-title":"J Control Release"},{"key":"R6-20260423","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.neurobiolaging.2021.07.014","article-title":"Emerging roles of oxidative stress in brain aging and Alzheimer\u2019s disease","volume":"107","author":"Ionescu-Tucker","year":"2021","journal-title":"Neurobiol Aging"},{"key":"R7-20260423","doi-asserted-by":"crossref","first-page":"e1006593.","DOI":"10.1371\/journal.pgen.1006593","article-title":"Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer\u2019s disease","volume":"13","author":"Kerr","year":"2017","journal-title":"PLoS Genet"},{"key":"R8-20260423","doi-asserted-by":"crossref","first-page":"189","DOI":"10.46542\/pe.2023.234.189195","article-title":"Alzheimer\u2019s disease from a diabetic brain: Exploring the molecular process to determine the potential therapy target from marine sources","volume":"23","author":"Rivarti","year":"2023","journal-title":"Pharm Educ"},{"key":"R9-20260423","doi-asserted-by":"crossref","first-page":"102726.","DOI":"10.1016\/j.redox.2023.102726","article-title":"The KEAP1-NRF2 pathway: Targets for therapy and role in cancer","volume":"63","author":"Adinolfi","year":"2023","journal-title":"Redox Biol"},{"key":"R10-20260423","doi-asserted-by":"crossref","first-page":"101206.","DOI":"10.1016\/j.arr.2020.101206","article-title":"Nrf2: A dark horse in Alzheimer\u2019s disease treatment","volume":"64","author":"Osama","year":"2020","journal-title":"Ageing Res Rev"},{"key":"R11-20260423","doi-asserted-by":"crossref","first-page":"195","DOI":"10.21776\/ub.jkb.2015.028.03.6","article-title":"Combination of artemisinin and Moringa oleifera extract decreases NF-\u1d4fB expression but not iNOS expression in the brain of malaria-infected mice","volume":"28","author":"Harahap","year":"2015","journal-title":"Journal Kedokteran Brawijaya"},{"key":"R12-20260423","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.bj.2018.02.005","article-title":"Nrf2 activation attenuates the early suppression of mitochondrial respiration due to the \u03b1-synuclein overexpression","volume":"41","author":"Fu","year":"2018","journal-title":"Biomed J"},{"key":"R13-20260423","doi-asserted-by":"crossref","first-page":"12516","DOI":"10.1073\/pnas.1819541116","article-title":"NRF2\/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer\u2019s models","volume":"116","author":"Bahn","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R14-20260423","doi-asserted-by":"crossref","first-page":"3496.","DOI":"10.1038\/ncomms4496","article-title":"Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52","volume":"5","author":"Jo","year":"2014","journal-title":"Nat Commun"},{"key":"R15-20260423","doi-asserted-by":"crossref","first-page":"e13998.","DOI":"10.14814\/phy2.13998","article-title":"Effects of Nrf2 deficiency on mitochondrial oxidative stress in aged skeletal muscle","volume":"7","author":"Kitaoka","year":"2019","journal-title":"Physiol Rep"},{"key":"R16-20260423","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.neurobiolaging.2017.12.001","article-title":"Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner","volume":"63","author":"Tang","year":"2018","journal-title":"Neurobiol Aging"},{"key":"R17-20260423","doi-asserted-by":"crossref","first-page":"10149","DOI":"10.1039\/C9SC03042E","article-title":"Alleviation of symptoms of Alzheimer's disease by diminishing A\u03b2 neurotoxicity and neuroinflammation","volume":"10","author":"Yang","year":"2019","journal-title":"Chem Sci"},{"key":"R18-20260423","doi-asserted-by":"crossref","first-page":"375","DOI":"10.18280\/ijsdp.170203","article-title":"Saving mangrove forest extinction in urban areas: Will government interventions help?","volume":"17","author":"Tresiana","year":"2022","journal-title":"Int J Sustain Dev Plan"},{"key":"R19-20260423","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.33758\/mbi.v14i3.310","article-title":"Vegetation suitability in mitigating tsunami disaster in Sepi Bay, West Lombok","volume":"14","author":"Andini","year":"2019","journal-title":"MEDIA BINA ILM"},{"key":"R21-20260423","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.sajb.2022.02.036","article-title":"Physico-chemical and functional characterization of polysaccharide purified from mangrove Rhizophora mucronata leaves having potent biological activity","volume":"147","author":"Jha","year":"2022","journal-title":"South Afr J Bot"},{"key":"R22-20260423","doi-asserted-by":"crossref","first-page":"417","DOI":"10.21472\/bjbs.051018","article-title":"In vitro anti inflammatory activity of mangrove plant Rhizophora mucronata Lam. (Malpighiales: Rhizophoraceae)","volume":"5","author":"Kaur","year":"2018","journal-title":"Braz J Biol Sci"},{"key":"R23-20260423","doi-asserted-by":"crossref","first-page":"s562","DOI":"10.5530\/ijper.54.3s.155","article-title":"Protective effect of Rhizophora mucronata leaves on hepatic oxidative stress, serum cytokines and insulin resistance in type 2 diabetic rats","volume":"54","author":"Ray","year":"2020","journal-title":"Indian J Pharm Educ Res"},{"key":"R24-20260423","doi-asserted-by":"crossref","first-page":"979","DOI":"10.3390\/chemistry3030070","article-title":"Phytochemicals from Rhizophora mucronata propagules, its in vitro anti-cancer and in silico drug-likeness potential","volume":"3","author":"Yunos","year":"2021","journal-title":"Chemistry"},{"key":"R25-20260423","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.13057\/biodiv\/d220730","article-title":"Identification of pigment profiles and antioxidant activity of Rhizophora mucronata mangrove leaves origin Lembeh, North Sulawesi, Indonesia","volume":"22","author":"Rumengan","year":"2021","journal-title":"Biodiversitas J Biol Divers"},{"key":"R26-20260423","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1007\/s11033-021-06145-y","article-title":"Rutin improves glutamate uptake and inhibits glutamate excitotoxicity in rat brain slices","volume":"48","author":"Ferreira","year":"2021","journal-title":"Mol Biol Rep"},{"key":"R27-20260423","doi-asserted-by":"crossref","first-page":"106163.","DOI":"10.1016\/j.phrs.2022.106163","article-title":"Rutin ameliorates inflammation and improves metabolic function: A comprehensive analysis of scientific literature","volume":"178","author":"Muvhulawa","year":"2022","journal-title":"Pharmacol Res"},{"key":"R28-20260423","doi-asserted-by":"crossref","first-page":"119878.","DOI":"10.1016\/j.lfs.2021.119878","article-title":"Rutin prevents cardiac oxidative stress and inflammation induced by bisphenol A and dibutyl phthalate exposure via NRF-2\/NF-\u03baB pathway","volume":"284","author":"Oluranti","year":"2021","journal-title":"Life Sci"},{"key":"R29-20260423","doi-asserted-by":"crossref","first-page":"271","DOI":"10.31764\/jau.v10i3.16596","article-title":"Determination of total flavonoid content of extract and fractions of mangrove leaves (Avicennia marina)","volume":"10","author":"Annas","year":"2023","journal-title":"Jurnal Aggrotek UMMAT"},{"key":"R30-20260423","doi-asserted-by":"crossref","first-page":"17876.","DOI":"10.1038\/s41598-021-95769-y","article-title":"Effect of particle size on phytochemical composition and antioxidant properties of Sargassum cristaefolium ethanol extract","volume":"11","author":"Prasedya","year":"2021","journal-title":"Sci Rep"},{"key":"R31-20260423","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1007\/s43994-023-00031-y","article-title":"Impact of different solvents on extraction yield, phenolic composition, in vitro antioxidant and antibacterial activities of deseeded Opuntia stricta fruit","volume":"9","author":"El Mannoubi","year":"2023","journal-title":"J Umm Al Qura Univ Appl Sci"},{"key":"R32-20260423","doi-asserted-by":"crossref","first-page":"106646.","DOI":"10.1016\/j.ultsonch.2023.106646","article-title":"A comprehensive review of ultrasonic assisted extraction (UAE) for bioactive components: Principles, advantages, equipment, and combined technologies","volume":"101","author":"Shen","year":"2023","journal-title":"Ultrason Sonochem"},{"key":"R33-20260423","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3233\/BPL-200098","article-title":"Flavonoids as an intervention for Alzheimer\u2019s disease: Progress and hurdles towards defining a mechanism of action","volume":"6","author":"Hole","year":"2021","journal-title":"Brain Plast"},{"key":"R34-20260423","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.bbrc.2017.07.151","article-title":"Quercetin ameliorates learning and memory via the Nrf2-ARE signaling pathway in d-galactose-induced neurotoxicity in mice","volume":"491","author":"Dong","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"R35-20260423","doi-asserted-by":"crossref","first-page":"918.","DOI":"10.3390\/molecules27030918","article-title":"In silico analysis of metabolites from Peruvian native plants as potential therapeutics against Alzheimer\u2019s disease","volume":"27","author":"Goyzueta-Mamani","year":"2022","journal-title":"Molecules"},{"key":"R36-20260423","doi-asserted-by":"crossref","first-page":"549.","DOI":"10.3390\/biom13030549","article-title":"The role of the transcription factor Nrf2 in Alzheimer\u2019s disease: Therapeutic opportunities","volume":"13","author":"De Plano","year":"2023","journal-title":"Biomolecules"},{"key":"R37-20260423","doi-asserted-by":"crossref","first-page":"700","DOI":"10.22146\/jfps.5485","article-title":"Potential activity of caryophyllene derivatives as xanthine oxidase inhibitor: An in silico quantitative structure-activity relationship analysis","volume":"3","author":"Setiawansyah","year":"2022","journal-title":"J Food Pharm Sci"},{"key":"R38-20260423","doi-asserted-by":"crossref","first-page":"143","DOI":"10.22270\/jddt.v10i2.3923","article-title":"Pharmacophore and molecular docking-based virtual screening of B-cell lymphoma 2 (BCL 2) inhibitor from zinc natural database as anti-small cell lung cancer","volume":"10","author":"Muttaqin","year":"2020","journal-title":"J Drug Deliv Ther"},{"key":"R39-20260423","doi-asserted-by":"crossref","first-page":"73","DOI":"10.29244\/cb.9.2.3","article-title":"In silico analysis of active compounds of avocado fruit (Persea americana Mill.) as tyrosinase enzyme inhibitors","volume":"9","author":"Puspita","year":"2022","journal-title":"Curr Biochem"},{"key":"R40-20260423","doi-asserted-by":"crossref","first-page":"101707.","DOI":"10.1016\/j.jksus.2021.101707","article-title":"Molecular docking and dynamics studies on propolis sulabiroin-a as a potential inhibitor of SARS-CoV-2","volume":"34","author":"Fatriansyah","year":"2022","journal-title":"J King Saud Univ Sci"},{"key":"R42-20260423","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3233\/ADR-210061","article-title":"Neuroprotective effects of cholinesterase inhibitors: Current scenario in therapies for Alzheimer\u2019s disease and future perspectives","volume":"6","author":"Moreira","year":"2022","journal-title":"J Alzheimers Dis Rep"},{"key":"R43-20260423","first-page":"1","article-title":"Molecular docking, validation, dynamics simulations, and pharmacokinetic prediction of natural compounds against the SARS-CoV-2 main-protease","volume":"9","author":"Shivanika","year":"2020","journal-title":"J Biomol Struct Dyn"},{"key":"R44-20260423","doi-asserted-by":"crossref","first-page":"e12029.","DOI":"10.1371\/journal.pone.0012029","article-title":"Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing","volume":"5","author":"Patil","year":"2010","journal-title":"PLoS One"},{"key":"R45-20260423","doi-asserted-by":"crossref","first-page":"100706.","DOI":"10.1016\/j.imu.2021.100706","article-title":"Physicochemical, spectral, molecular docking and ADMET studies of bisphenol analogues; a computational approach","volume":"25","author":"Uzzaman","year":"2021","journal-title":"Inform Med Unlocked"},{"key":"R46-20260423","doi-asserted-by":"crossref","first-page":"4147.","DOI":"10.3390\/molecules26144147","article-title":"In silico prediction, molecular docking and dynamics studies of steroidal alkaloids of Holarrhena pubescens wall. Ex G. Don to guanylyl cyclase C: Implications in designing of novel antidiarrheal therapeutic strategies","volume":"26","author":"Gupta","year":"2021","journal-title":"Molecules"},{"key":"R47-20260423","doi-asserted-by":"crossref","first-page":"9124.","DOI":"10.3390\/ijms22179124","article-title":"Exploring the binding mechanism of PF-07321332 SARS-CoV-2 protease inhibitor through molecular dynamics and binding free energy simulations","volume":"22","author":"Ahmad","year":"2021","journal-title":"Int J Mol Sci"},{"key":"R48-20260423","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1039\/C7MD00381A","article-title":"A systematic analysis of atomic protein-ligand interactions in the PDB","volume":"8","author":"Ferreira de Freitas","year":"2017","journal-title":"Med Chem Comm"}],"container-title":["Journal of Advanced Pharmaceutical Technology &amp; Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/JAPTR.JAPTR_313_24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T18:57:45Z","timestamp":1786647465000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/JAPTR.JAPTR_313_24"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":45,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.4103\/japtr.japtr_313_24","relation":{},"ISSN":["2231-4040","0976-2094"],"issn-type":[{"value":"2231-4040","type":"print"},{"value":"0976-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]},"assertion":[{"value":"2024-09-28","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-21","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}