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A range of innovative therapeutic approaches is currently under investigation, such as stem cell-based therapies, gene-editing platforms such as CRISPR, and immunotherapies directed at pathogenic proteins. Moreover, phytochemicals such as \u03b2-caryophyllene and xanthohumol have demonstrated significant neuroprotective potential in preclinical models. These natural agents exert multifaceted effects by modulating neuroinflammatory pathways, oxidative stress responses, and aberrant protein aggregation\u2014pathological mechanisms that are central to the development and progression of neurodegenerative disorders. Recent investigations have increasingly emphasized the optimization of the pharmacokinetic properties of \u03b2-caryophyllene and xanthohumol through the development of advanced drug-delivery systems, including polymer- and lipid-based nano- and microscale carriers. Such advancements not only enhance the bioavailability and therapeutic potential of these phytochemicals but also underscore their growing relevance as natural candidates in the development of future interventions for neurodegenerative disorders.<\/jats:p>","DOI":"10.3390\/molecules30183702","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T14:23:50Z","timestamp":1757600630000},"page":"3702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Advancing Brain Health Naturally: \u03b2-Caryophyllene and Xanthohumol as Neuroprotective Agents"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1282-7868","authenticated-orcid":false,"given":"Stanislava","family":"Ivanova","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoya","family":"Dzhakova","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9840-6890","authenticated-orcid":false,"given":"Velislava","family":"Todorova","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8594-1712","authenticated-orcid":false,"given":"Radka","family":"Boyuklieva","sequence":"additional","affiliation":[{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2333-9879","authenticated-orcid":false,"given":"Plamen","family":"Simeonov","sequence":"additional","affiliation":[{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9158-6208","authenticated-orcid":false,"given":"Plamen","family":"Katsarov","sequence":"additional","affiliation":[{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lamptey, R.N.L., Chaulagain, B., Trivedi, R., Gothwal, A., Layek, B., and Singh, J. (2022). A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics. IJMS, 23.","DOI":"10.3390\/ijms23031851"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/B978-0-12-802395-2.00021-3","article-title":"Concepts and Classification of Neurodegenerative Diseases","volume":"Volume 145","author":"Kovacs","year":"2018","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_3","first-page":"97","article-title":"Pathophysiology and Classification of Neurodegenerative Diseases","volume":"15","author":"Relja","year":"2004","journal-title":"EJIFCC"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington Disease","volume":"1","author":"Bates","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1093\/brain\/awab111","article-title":"The Role of Noradrenaline in Cognition and Cognitive Disorders","volume":"144","author":"Holland","year":"2021","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/mds.24996","article-title":"Identifying Prodromal Parkinson\u2019s Disease: Pre-Motor Disorders in Parkinson\u2019s Disease","volume":"27","author":"Postuma","year":"2012","journal-title":"Mov. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e268","DOI":"10.1212\/WNL.0000000000005828","article-title":"Diffuse Lewy Body Disease Manifesting as Corticobasal Syndrome: A Rare Form of Lewy Body Disease","volume":"91","author":"Kasanuki","year":"2018","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/bs.irn.2019.10.014","article-title":"Corticobasal Degeneration","volume":"Volume 149","author":"Saranza","year":"2019","journal-title":"International Review of Neurobiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"574","DOI":"10.2174\/1871527320666210903101841","article-title":"Neurodegenerative Disorders and the Current State, Pathophysiology, andManagement of Parkinson\u2019s Disease","volume":"21","author":"Rahul","year":"2022","journal-title":"CNSNDDT"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6476","DOI":"10.1007\/s12035-023-03502-9","article-title":"Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders","volume":"60","author":"Gupta","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chopade, P., Chopade, N., Zhao, Z., Mitragotri, S., Liao, R., and Chandran Suja, V. (2023). Alzheimer\u2019s and Parkinson\u2019s Disease Therapies in the Clinic. Bioeng. Transl. Med., 8.","DOI":"10.1002\/btm2.10367"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s42452-024-05811-7","article-title":"Some Promising Medicinal Plants Used in Alzheimer\u2019s Disease: An Ethnopharmacological Perspective","volume":"6","author":"Bordoloi","year":"2024","journal-title":"Discov. Appl. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/s11064-023-04046-z","article-title":"Natural Phenolic Compounds with Neuroprotective Effects","volume":"49","author":"Tavan","year":"2024","journal-title":"Neurochem. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.neuroscience.2014.08.043","article-title":"de \u03b2-Caryophyllene Protects the C6 Glioma Cells against Glutamate-Induced Excitotoxicity through the Nrf2 Pathway","volume":"279","author":"Assis","year":"2014","journal-title":"Neuroscience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cbi.2016.11.015","article-title":"The Cannabinoid Beta-Caryophyllene (BCP) Induces Neuritogenesis in PC12 Cells by a Cannabinoid-Receptor-Independent Mechanism","volume":"261","author":"Santos","year":"2017","journal-title":"Chem.-Biol. Interact."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.intimp.2017.07.009","article-title":"Trans-Caryophyllene Inhibits Amyloid \u03b2 (A\u03b2) Oligomer-Induced Neuroinflammation in BV-2 Microglial Cells","volume":"51","author":"Hu","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.biopha.2018.03.168","article-title":"\u03b2-Caryophyllene (BCP) Ameliorates MPP+ Induced Cytotoxicity","volume":"103","author":"Wang","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.bcp.2018.12.001","article-title":"Promising Neuroprotective Effects of \u03b2-Caryophyllene against LPS-Induced Oligodendrocyte Toxicity: A Mechanistic Study","volume":"159","author":"Askari","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.lfs.2018.12.059","article-title":"The Protective Effects of \u03b2-Caryophyllene on LPS-Induced Primary Microglia M1\/M2 Imbalance: A Mechanistic Evaluation","volume":"219","author":"Askari","year":"2019","journal-title":"Life Sci."},{"key":"ref_20","first-page":"25","article-title":"Anti-Inflammatory and Neuroprotective Activity of Viphyllin a Standardized Extract of \u03b2-Caryophyllene from Black Pepper (Piper nigrum L.) and Its Associated Mechanisms in Mouse Macrophage Cells and Human Neuroblastoma SH-SY5Y Cells","volume":"7","author":"Gouthamchandra","year":"2024","journal-title":"Fortune J. Health Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Huang, Q., Wang, S., Liao, Z., Jin, H., Huang, S., Hong, X., Liu, Y., Pang, J., and Shen, Q. (2022). The Food Additive \u03b2-Caryophyllene Exerts Its Neuroprotective Effects Through the JAK2-STAT3-BACE1 Pathway. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.814432"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Anbaraki, A., Dindar, Z., Mousavi-Jarrahi, Z., Ghasemi, A., Moeini, Z., Evini, M., Saboury, A.A., and Seyedarabi, A. (2024). The Novel Anti-Fibrillary Effects of Volatile Compounds \u03b1-Asarone and \u03b2-Caryophyllene on Tau Protein: Towards Promising Therapeutic Agents for Alzheimer\u2019s Disease. Int. J. Biol. Macromol., 271.","DOI":"10.1016\/j.ijbiomac.2024.132401"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rathod, S.S., and Agrawal, Y.O. (2025). \u03b2-Caryophyllene (CB2 Agonist) Mitigates Rotenone-Induced Neurotoxicity and Apoptosis in SH-SY5Y Neuroblastoma Cells via Modulation of GSK-3\u03b2\/NRF2\/HO-1 Axis. Naunyn-Schmiedeberg\u2019s Arch. Pharmacol., 1\u201321.","DOI":"10.1007\/s00210-025-04281-x"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.biopha.2017.04.092","article-title":"\u03b2-Caryophyllene Ameliorates the Development of Experimental Autoimmune Encephalomyelitis in C57BL\/6 Mice","volume":"91","author":"Fontes","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1934578X20962229","DOI":"10.1177\/1934578X20962229","article-title":"Anxiety Therapeutic Interventions of \u03b2-Caryophyllene: A Laboratory-Based Study","volume":"15","author":"Machado","year":"2020","journal-title":"Nat. Product. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000362689","article-title":"\u03b2-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP\/PS1 Mice through CB2 Receptor Activation and the PPAR\u03b3 Pathway","volume":"94","author":"Cheng","year":"2014","journal-title":"Pharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11010-016-2733-y","article-title":"\u03b2-Caryophyllene, a Phytocannabinoid Attenuates Oxidative Stress, Neuroinflammation, Glial Activation, and Salvages Dopaminergic Neurons in a Rat Model of Parkinson Disease","volume":"418","author":"Ojha","year":"2016","journal-title":"Mol. Cell Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Viveros-Paredes, J.M., Gonz\u00e1lez-Casta\u00f1eda, R.E., Gertsch, J., Chaparro-Huerta, V., L\u00f3pez-Roa, R.I., V\u00e1zquez-Valls, E., Beas-Zarate, C., Camins-Espuny, A., and Flores-Soto, M.E. (2017). Neuroprotective Effects of \u03b2-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson\u2019s Disease Induced by MPTP. Pharmaceuticals, 10.","DOI":"10.3390\/ph10030060"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Alberti, T.B., Barbosa, W.L.R., Vieira, J.L.F., Raposo, N.R.B., and Dutra, R.C. (2017). (\u2212)-\u03b2-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040691"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lou, J., Teng, Z., Zhang, L., Yang, J., Ma, L., Wang, F., Tian, X., An, R., Yang, M., and Zhang, Q. (2017). \u03b2-Caryophyllene\/Hydroxypropyl-\u03b2-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the Cannabinoid Receptor Type 2-Mediated Pathway. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00002"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27","DOI":"10.7324\/JAPS.2019.90704","article-title":"\u03b2-Caryophyllene Causes Remyelination and Modifies Cytokines Expression in C57BL\/6 Mice with Experimental Autoimmune Encephalomyelitis","volume":"9","author":"Mesquita","year":"2019","journal-title":"J. App Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"963","DOI":"10.2174\/1871527320666210202121103","article-title":"Beta-Caryophyllene, a CB2R Selective Agonist, Protects Against Cognitive Impairment Caused by Neuro-Inflammation and Not in Dementia Due to Ageing Induced by Mitochondrial Dysfunction","volume":"20","author":"Kanojia","year":"2021","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"135534","DOI":"10.1016\/j.neulet.2020.135534","article-title":"\u03b2-Caryophyllene Exerts Protective Antioxidant Effects through the Activation of NQO1 in the MPTP Model of Parkinson\u2019s Disease","volume":"742","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Askari, V.R., Baradaran Rahimi, V., and Shafiee-Nick, R. (2023). Low Doses of \u03b2-Caryophyllene Reduced Clinical and Paraclinical Parameters of an Autoimmune Animal Model of Multiple Sclerosis: Investigating the Role of CB2 Receptors in Inflammation by Lymphocytes and Microglial. Brain Sci., 13.","DOI":"10.3390\/brainsci13071092"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"105906","DOI":"10.1016\/j.parkreldis.2023.105906","article-title":"\u03b2-Caryophyllene Decreases Neuroinflammation and Exerts Neuroprotection of Dopaminergic Neurons in a Model of Hemiparkinsonism through Inhibition of the NLRP3 Inflammasome","volume":"117","year":"2023","journal-title":"Park. Relat. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.nrl.2022.11.004","article-title":"Beta-Caryophyllene Inhibits the Permeability of the Blood\u2013Brain Barrier in MPTP-Induced Parkinsonism","volume":"40","year":"2025","journal-title":"Neurolog\u00eda"},{"key":"ref_37","first-page":"31","article-title":"Beta-Caryophyllene, An Anti-Inflammatory Natural Compound, Improves Cognition","volume":"3","author":"Bell","year":"2021","journal-title":"J. Food Nutr. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.phytochem.2004.04.025","article-title":"Xanthohumol and Related Prenylflavonoids from Hops and Beer: To Your Good Health!","volume":"65","author":"Stevens","year":"2004","journal-title":"Phytochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kundu, P., Holden, S., Paraiso, I.L., Sudhakar, R., McQuesten, C., Choi, J., Miranda, C.L., Maier, C.S., Bobe, G., and Stevens, J.F. (2022). ApoE Isoform-Dependent Effects of Xanthohumol on High Fat Diet-Induced Cognitive Impairments and Hippocampal Metabolic Pathways. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.954980"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e29922","DOI":"10.1590\/fst.29922","article-title":"Effect of Hop Mixture Containing Xanthohumol on Sleep Enhancement in a Mouse Model and ROS Scavenging Effect in Oxidative Stress-Induced HT22 Cells","volume":"42","author":"Min","year":"2022","journal-title":"Food Sci. Technol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1021\/acs.jnatprod.1c00505","article-title":"Neuroregenerative Potential of Prenyl- and Pyranochalcones: A Structure\u2013Activity Study","volume":"84","author":"Urmann","year":"2021","journal-title":"J. Nat. Prod."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbr.2014.08.045","article-title":"Xanthohumol Improved Cognitive Flexibility in Young Mice","volume":"275","author":"Zamzow","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/mnfr.201100554","article-title":"Pharmacokinetics of Xanthohumol and Metabolites in Rats after Oral and Intravenous Administration","volume":"56","author":"Legette","year":"2012","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1021\/cb200492h","article-title":"Xanthohumol Impairs Autophagosome Maturation through Direct Inhibition of Valosin-Containing Protein","volume":"7","author":"Sasazawa","year":"2012","journal-title":"ACS Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1021\/jf505075n","article-title":"Xanthohumol, a Polyphenol Chalcone Present in Hops, Activating Nrf2 Enzymes To Confer Protection against Oxidative Damage in PC12 Cells","volume":"63","author":"Yao","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.phymed.2018.03.009","article-title":"Molecular Modeling and in Vitro Approaches towards Cholinesterase Inhibitory Effect of Some Natural Xanthohumol, Naringenin, and Acyl Phloroglucinol Derivatives","volume":"42","author":"Orhan","year":"2018","journal-title":"Phytomedicine"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Huang, X., Wang, J., Chen, X., Liu, P., Wang, S., Song, F., Zhang, Z., Zhu, F., Huang, X., and Liu, J. (2018). The Prenylflavonoid Xanthohumol Reduces Alzheimer-Like Changes and Modulates Multiple Pathogenic Molecular Pathways in the Neuro2a\/APPswe Cell Model of AD. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00199"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7865","DOI":"10.1039\/C9FO02133G","article-title":"Xanthohumol Inhibits Tau Protein Aggregation and Protects Cells against Tau Aggregates","volume":"10","author":"Zhang","year":"2019","journal-title":"Food Funct."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1021\/acschemneuro.9b00171","article-title":"Xanthohumol Analogues as Potent Nrf2 Activators against Oxidative Stress Mediated Damages of PC12 Cells","volume":"10","author":"Bai","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1093\/ijnp\/pyz052","article-title":"Naturally Derived Polyphenols Protect Against Corticosterone-Induced Changes in Primary Cortical Neurons","volume":"22","author":"Donoso","year":"2019","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1021\/acschemneuro.1c00130","article-title":"Modulation of Adenosine Receptors by Hops and Xanthohumol in Cell Cultures","volume":"12","author":"Alonso","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Molteni, L., Bruzzone, C., Ami, D., De Luigi, A., Colombo, L., Moretti, L., Natalello, A., Palmioli, A., and Airoldi, C. (2025). Xanthohumol Destabilizes the Structure of Amyloid-\u03b2 (A\u03b2) Oligomers and Promotes the Formation of High-Molecular-Weight Amorphous Aggregates. Int. J. Biol. Macromol., 319.","DOI":"10.1016\/j.ijbiomac.2025.145720"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Tejero, A., Le\u00f3n-Navarro, D.A., and Mart\u00edn, M. (2024). Effect of Xanthohumol, a Bioactive Natural Compound from Hops, on Adenosine Pathway in Rat C6 Glioma and Human SH-SY5Y Neuroblastoma Cell Lines. Nutrients, 16.","DOI":"10.3390\/nu16111792"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1021\/jf204909p","article-title":"Neuroprotective Effects of Xanthohumol, a Prenylated Flavonoid from Hops (Humulus lupulus), in Ischemic Stroke of Rats","volume":"60","author":"Yen","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.jnutbio.2017.07.011","article-title":"Protective Effect of Xanthohumol against Age-Related Brain Damage","volume":"49","author":"Paredes","year":"2017","journal-title":"J. Nutr. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1007\/s11033-019-05128-4","article-title":"Xanthohumol Protects Neuron from Cerebral Ischemia Injury in Experimental Stroke","volume":"47","author":"Jiao","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"104629","DOI":"10.1016\/j.neuint.2019.104629","article-title":"Xanthohumol, an Active Constituent from Hope, Affords Protection against Kainic Acid-Induced Excitotoxicity in Rats","volume":"133","author":"Wang","year":"2020","journal-title":"Neurochem. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3135","DOI":"10.1007\/s11064-021-03396-w","article-title":"Xanthohumol Attenuates Lipopolysaccharide-Induced Depressive Like Behavior in Mice: Involvement of NF-\u03baB\/Nrf2 Signaling Pathways","volume":"46","author":"Rahman","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1093\/jpp\/rgab052","article-title":"Xanthohumol Ameliorates Memory Impairment and Reduces the Deposition of \u03b2-Amyloid in APP\/PS1 Mice via Regulating the mTOR\/LC3II and Bax\/Bcl-2 Signalling Pathways","volume":"73","author":"Sun","year":"2021","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Liu, W., He, K., Wu, D., Zhou, L., Li, G., Lin, Z., Yang, X., Liu, J., and Pui Man Hoi, M. (2022). Natural Dietary Compound Xanthohumol Regulates the Gut Microbiota and Its Metabolic Profile in a Mouse Model of Alzheimer\u2019s Disease. Molecules, 27.","DOI":"10.3390\/molecules27041281"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s00213-023-06355-1","article-title":"Xanthohumol Improves Cognitive Impairment by Regulating miRNA-532-3p\/Mpped1 in Ovariectomized Mice","volume":"240","author":"Liu","year":"2023","journal-title":"Psychopharmacology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s11418-022-01642-1","article-title":"Humulus lupulus L. Extract and Its Active Constituent Xanthohumol Attenuate Oxidative Stress and Nerve Injury Induced by Iron Overload via Activating AKT\/GSK3\u03b2 and Nrf2\/NQO1 Pathways","volume":"77","author":"Ting","year":"2023","journal-title":"J. Nat. Med."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Hu, F.-F., Pan, S.-Y., Chu, J.-Y., Liu, J.-J., Duan, T.-T., Luo, Y., Zhou, W., Wang, Z.-M., Liu, W., and Zeng, Y. (2024). Xanthohumol Protects Against Neuronal Excitotoxicity and Mitochondrial Dysfunction in APP\/PS1 Mice: An Omics-Based Study. Nutrients, 16.","DOI":"10.3390\/nu16213754"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Liu, W., Chen, X., Zhao, J., Yang, C., Huang, G., Zhang, Z., and Liu, J. (2024). Protective Signature of Xanthohumol on Cognitive Function of APP\/PS1 Mice: A Urine Metabolomics Approach by Age. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1423060"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"111316","DOI":"10.1016\/j.brainresbull.2025.111316","article-title":"Preventive Effects of Xanthohumol in APP\/PS1 Mice Based on Multi-Omics Atlas","volume":"224","author":"Liu","year":"2025","journal-title":"Brain Res. Bull."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"106792","DOI":"10.1016\/j.jddst.2025.106792","article-title":"Quality by Design Endorsed Fabrication of Xanthohumol Loaded Solid Nanostructured Lipid Carrier Based Powder for Effective Treatment of Alzheimer\u2019s Disease in Rats","volume":"107","author":"Khandale","year":"2025","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"836","DOI":"10.2174\/1567205016666190827123222","article-title":"Amyloid-\u03b2 Aggregation Inhibitory and Neuroprotective Effects of Xanthohumol and Its Derivatives for Alzheimer\u2019s Diseases","volume":"16","author":"Wang","year":"2019","journal-title":"CAR"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e087955","DOI":"10.1002\/alz.087955","article-title":"Xanthohumol Loaded Self-Nano Emulsifying Drug Delivery System: Harnessing Neuroprotective Effects in Alzheimer\u2019s Disease Management","volume":"20","author":"Bashir","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"106385","DOI":"10.1016\/j.jddst.2024.106385","article-title":"Formulation and Optimization of Xanthohumol Loaded Solid Dispersion for Effective Treatment of Parkinson\u2019s Disease in Rats: In Vitro and in Vivo Assessment","volume":"102","author":"Alam","year":"2024","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Ghazwani, M., Hani, U., Alqarni, M.H., and Alam, A. (2023). Beta Caryophyllene-Loaded Nanostructured Lipid Carriers for Topical Management of Skin Disorders: Statistical Optimization, In Vitro and Dermatokinetic Evaluation. Gels, 9.","DOI":"10.3390\/gels9070550"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"M\u00f6dinger, Y., Knaub, K., Dharsono, T., Wacker, R., Meyrat, R., Land, M.H., Petraglia, A.L., and Sch\u00f6n, C. (2022). Enhanced Oral Bioavailability of \u03b2-Caryophyllene in Healthy Subjects Using the VESIsorb\u00ae Formulation Technology, a Novel Self-Emulsifying Drug Delivery System (SEDDS). Molecules, 27.","DOI":"10.3390\/molecules27092860"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Di Sotto, A., Paolicelli, P., Nardoni, M., Abete, L., Garzoli, S., Di Giacomo, S., Mazzanti, G., Casadei, M.A., and Petralito, S. (2018). SPC Liposomes as Possible Delivery Systems for Improving Bioavailability of the Natural Sesquiterpene \u03b2-Caryophyllene: Lamellarity and Drug-Loading as Key Features for a Rational Drug Delivery Design. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10040274"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"24045","DOI":"10.1021\/acsomega.0c03456","article-title":"Preparation and Characterization of Liposomal \u03b2-Caryophyllene (Rephyll) by Nanofiber Weaving Technology and Its Effects on Delayed Onset Muscle Soreness (DOMS) in Humans: A Randomized, Double-Blinded, Crossover-Designed, and Placebo-Controlled Study","volume":"5","author":"Amalraj","year":"2020","journal-title":"ACS Omega"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1007\/s11064-020-03037-8","article-title":"\u03b2-Caryophyllene Liposomes Attenuate Neurovascular Unit Damage After Subarachnoid Hemorrhage in Rats","volume":"45","author":"Wang","year":"2020","journal-title":"Neurochem. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"105318","DOI":"10.1016\/j.ejps.2020.105318","article-title":"Healing Activity of Hydrogel Containing Nanoemulsified \u03b2-Caryophyllene","volume":"148","author":"Bidone","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Alharthi, S., Ziora, Z.M., Mustafa, G., Chaubey, P., El Kirdasy, A.F., and Alotaibi, G. (2023). \u03b2-Caryophyllene-Loaded Microemulsion-Based Topical Hydrogel: A Promising Carrier to Enhance the Analgesic and Anti-Inflammatory Outcomes. Gels, 9.","DOI":"10.3390\/gels9080634"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.indcrop.2017.10.025","article-title":"Microemulsions Containing Copaifera Multijuga Hayne Oil-Resin: Challenges to Achieve an Efficient System for \u03b2-Caryophyllene Delivery","volume":"111","author":"Pessoa","year":"2018","journal-title":"Ind. Crops Prod."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.ejpb.2023.08.020","article-title":"Co-Delivery of Beta-Caryophyllene and Indomethacin in the Oily Core of Nanoemulsions Potentiates the Anti-Inflammatory Effect in LPS-Stimulated Macrophage Model","volume":"191","author":"Weimer","year":"2023","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"111805","DOI":"10.1016\/j.lwt.2021.111805","article-title":"Formulation and Characterization of \u03b2-Caryophellene-Loaded Lipid Nanocarriers with Different Carrier Lipids for Food Processing Applications","volume":"149","author":"Lee","year":"2021","journal-title":"LWT"},{"key":"ref_80","first-page":"36","article-title":"Design and Characterization of Stable \u03b2-Caryophyllene-Loaded Nanoemulsions: A Rational HLB-Based Approach for Enhanced Volatility Control and Sustained Release","volume":"2025","author":"Baranda","year":"2025","journal-title":"Beilstein Arch."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"9080","DOI":"10.1021\/acsomega.7b01438","article-title":"Methyl-\u03b2-Cyclodextrin Inclusion Complex with \u03b2-Caryophyllene: Preparation, Characterization, and Improvement of Pharmacological Activities","volume":"2","author":"Santos","year":"2017","journal-title":"ACS Omega"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ijpharm.2013.04.013","article-title":"Physicochemical Characterization and Pharmacokinetics Evaluation of \u03b2-Caryophyllene\/\u03b2-Cyclodextrin Inclusion Complex","volume":"450","author":"Liu","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_83","first-page":"1","article-title":"pH-Sensitive Niosomal Nanoencapsulation of Beta- Caryophyllene and Its Novel Pathway in Triple Negative Breast Cancer","volume":"15","year":"2025","journal-title":"Biointerface Res. Appl. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"113345","DOI":"10.1016\/j.indcrop.2021.113345","article-title":"Development of Enhanced Drug Delivery Vehicles for Three Cannabis-Based Terpenes Using Poly(Lactic-Co-Glycolic Acid) Based Nanoparticles","volume":"164","year":"2021","journal-title":"Ind. Crops Prod."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"14447","DOI":"10.1021\/acsapm.4c02496","article-title":"Amoebicidal Potential of \u03b2-Caryophyllene-Loaded Polymeric Nanoparticles","volume":"6","author":"Porto","year":"2024","journal-title":"ACS Appl. Polym. Mater."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s11051-023-05668-8","article-title":"\u03b2-Caryophyllene Cationic Nanoemulsion for Intranasal Delivery and Treatment of Epilepsy: Development and in Vivo Evaluation of Anticonvulsant Activity","volume":"25","author":"Nogueira","year":"2023","journal-title":"J. Nanopart Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"106401","DOI":"10.1016\/j.ejps.2023.106401","article-title":"Investigation of \u03b2-Caryophyllene as Terpene Penetration Enhancer: Role of Stratum Corneum Retention","volume":"183","author":"Tang","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3390\/biophysica3030033","article-title":"Beta-Caryophyllene Induces Significant Changes in the Lipid Bilayer at Room and Physiological Temperatures: ATR-FTIR Spectroscopy Studies","volume":"3","author":"Yakimov","year":"2023","journal-title":"Biophysica"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"111824","DOI":"10.1016\/j.msec.2020.111824","article-title":"\u03b2-Caryophyllene Nanoparticles Design and Development: Controlled Drug Delivery of Cannabinoid CB2 Agonist as a Strategic Tool towards Neurodegeneration","volume":"121","author":"Alberti","year":"2021","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"D\u0142ugosz, A., B\u0142aszak, B., Czarnecki, D., and Szulc, J. (2025). Mechanism of Action and Therapeutic Potential of Xanthohumol in Prevention of Selected Neurodegenerative Diseases. Molecules, 30.","DOI":"10.3390\/molecules30030694"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Christaki, S., Spanidi, E., Panagiotidou, E., Athanasopoulou, S., Kyriakoudi, A., Mourtzinos, I., and Gardikis, K. (2023). Cyclodextrins for the Delivery of Bioactive Compounds from Natural Sources: Medicinal, Food and Cosmetics Applications. Pharmaceuticals, 16.","DOI":"10.3390\/ph16091274"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1055\/a-1013-1276","article-title":"Development and Characterization of the Neuroregenerative Xanthohumol C\/Hydroxypropyl-\u03b2-Cyclodextrin Complex Suitable for Parenteral Administration","volume":"85","author":"Kirchinger","year":"2019","journal-title":"Planta Medica"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Oledzka, E. (2024). Xanthohumol\u2014A Miracle Molecule with Biological Activities: A Review of Biodegradable Polymeric Carriers and Naturally Derived Compounds for Its Delivery. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063398"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"153233","DOI":"10.1016\/j.phymed.2020.153233","article-title":"Micellar Solubilization Enhances the Anti-Inflammatory Effect of Xanthohumol","volume":"71","author":"Khayyal","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Ronka, S., Kowalczyk, A., Baczy\u0144ska, D., and \u017bo\u0142nierczyk, A.K. (2023). Pluronics-Based Drug Delivery Systems for Flavonoids Anticancer Treatment. Gels, 9.","DOI":"10.3390\/gels9020143"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1016\/S0142-9612(00)00115-0","article-title":"The Manufacturing Techniques of Various Drug Loaded Biodegradable Poly(Lactide-Co-Glycolide) (PLGA) Devices","volume":"21","author":"Jain","year":"2000","journal-title":"Biomaterials"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Fonseca, M., Macedo, A.S., Lima, S.A.C., Reis, S., Soares, R., and Fonte, P. (2021). Evaluation of the Antitumour and Antiproliferative Effect of Xanthohumol-Loaded PLGA Nanoparticles on Melanoma. Materials, 14.","DOI":"10.3390\/ma14216421"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Ghosh, A.K., Thapa, R., Hariani, H.N., Volyanyuk, M., Ogle, S.D., Orloff, K.A., Ankireddy, S., Lai, K., \u017diniauskait\u0117, A., and Stubbs, E.B. (2021). Poly(Lactic-Co-Glycolic Acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13091362"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Hanmantrao, M., Chaterjee, S., Kumar, R., Vishwas, S., Harish, V., Porwal, O., Alrouji, M., Alomeir, O., Alhajlah, S., and Gulati, M. (2022). Development of Guar Gum-Pectin-Based Colon Targeted Solid Self-Nanoemulsifying Drug Delivery System of Xanthohumol. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112384"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Harish, V., Tewari, D., Mohd, S., Govindaiah, P., Babu, M.R., Kumar, R., Gulati, M., Gowthamarajan, K., Madhunapantula, S.V., and Chellappan, D.K. (2022). Quality by Design Based Formulation of Xanthohumol Loaded Solid Lipid Nanoparticles with Improved Bioavailability and Anticancer Effect against PC-3 Cells. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112403"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"145453","DOI":"10.1016\/j.foodchem.2025.145453","article-title":"Xanthohumol in Liposomal Form in the Presence of Cyclodextrins: Drug Delivery and Stability Analysis","volume":"492","author":"Buczek","year":"2025","journal-title":"Food Chem."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Paul, W., and Sharma, C.P. (2020). Inorganic Nanoparticles for Targeted Drug Delivery. Biointegration of Medical Implant Materials, Elsevier.","DOI":"10.1016\/B978-0-08-102680-9.00013-5"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"103487","DOI":"10.1016\/j.jpet.2025.103487","article-title":"Preparation and Characterization of Xanthohumol-Incorporated Sub-5 Ultrafine Iron Oxide Nanoparticles: Investigation of Their Effects on Multiple Myeloma Cell Growth (Abstract ID: 190025)","volume":"392","author":"Matthews","year":"2025","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Cauda, V., and Canavese, G. (2020). Mesoporous Materials for Drug Delivery and Theranostics. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12111108"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Krajnovi\u0107, T., Panteli\u0107, N.\u0110., Wolf, K., Eichhorn, T., Maksimovi\u0107-Ivani\u0107, D., Mijatovi\u0107, S., Wessjohann, L.A., and Kalu\u0111erovi\u0107, G.N. (2022). Anticancer Potential of Xanthohumol and Isoxanthohumol Loaded into SBA-15 Mesoporous Silica Particles against B16F10 Melanoma Cells. Materials, 15.","DOI":"10.3390\/ma15145028"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"He, X.-H., Galaj, E., Bi, G.-H., He, Y., Hempel, B., Wang, Y.-L., Gardner, E.L., and Xi, Z.-X. (2021). \u03b2-Caryophyllene, an FDA-Approved Food Additive, Inhibits Methamphetamine-Taking and Methamphetamine-Seeking Behaviors Possibly via CB2 and Non-CB2 Receptor Mechanisms. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.722476"},{"key":"ref_107","unstructured":"(2025, January 08). Clinicaltrials.Gov, Available online: https:\/\/clinicaltrials.gov\/."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/18\/3702\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:44:04Z","timestamp":1760035444000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/18\/3702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,11]]},"references-count":107,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["molecules30183702"],"URL":"https:\/\/doi.org\/10.3390\/molecules30183702","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,11]]}}}