{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:55:04Z","timestamp":1785426904004,"version":"3.56.0"},"reference-count":76,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GRRC program of Gyeonggi Province","award":["GRRC-Ajou2023-B01"],"award-info":[{"award-number":["GRRC-Ajou2023-B01"]}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2025-02314060"],"award-info":[{"award-number":["RS-2025-02314060"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RS-2025-02314060"],"award-info":[{"award-number":["RS-2025-02314060"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Sleep disorders, particularly insomnia, represent a major public health concern, while currently available hypnotic drugs are often limited by adverse effects and poor long-term tolerability. Methods: In this study, we investigated the sleep-promoting effects of a mixture of Hypericum perforatum L. and Melissa officinalis L. extract (HME) and its underlying mechanisms in male ICR and C57BL\/6 mice. In a pentobarbital-induced sleep model in mice, sleep onset latency and total sleep time were measured. Pharmacological studies using various antagonists and agonists were conducted to elucidate receptor-mediated mechanisms. Immunohistochemical and immunofluorescence analyses were performed to assess neuronal activity, and cortical mRNA expression was evaluated by quantitative analysis. HPLC analysis was used to identify the major constituents of HME, and their pharmacological profiles were functionally evaluated. Results: HME significantly reduced sleep onset latency and prolonged total sleep time. These hypnotic effects were shown to be mediated through adenosine and melatonin receptor signaling pathways. Immunohistochemical and immunofluorescence analyses showed that HME suppressed neuronal activity in wake-promoting cholinergic and orexinergic neurons of the basal forebrain and lateral hypothalamus, while enhancing activation of sleep-promoting GABAergic neurons in the ventrolateral preoptic nucleus. At the molecular level, HME increased cortical mRNA expression levels of adenosine A1 receptor, adenosine A2A receptor, melatonin receptor 1, and melatonin receptor 2. From the HPLC analysis, rosmarinic acid and hyperoside were identified as the major constituents of HME. Functional evaluation of these compounds revealed complementary pharmacological profiles, with hyperoside primarily acting through adenosine receptors and rosmarinic acid engaging both adenosine and melatonin receptor pathways. Conclusions: These findings suggest that HME enhances both sleep initiation and maintenance through adenosine and melatonin receptor signaling pathways, thereby supporting its potential as a multitarget therapeutic agent for improving sleep quality.<\/jats:p>","DOI":"10.3390\/nu18111666","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T16:06:08Z","timestamp":1779465968000},"page":"1666","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypnotic Effects of Hypericum perforatum L. and Melissa officinalis L. Through Adenosine and Melatonin Receptors"],"prefix":"10.3390","volume":"18","author":[{"given":"Hye Jin","family":"Jee","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk Jin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Ryeong","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"R&D Division, Maeil Health Nutrition Co., Ltd., Pyeongtaek 17714, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoung-Su","family":"Park","sequence":"additional","affiliation":[{"name":"R&D Division, Maeil Health Nutrition Co., Ltd., Pyeongtaek 17714, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Jeong","family":"See","sequence":"additional","affiliation":[{"name":"R&D Division, Maeil Health Nutrition Co., Ltd., Pyeongtaek 17714, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7078-2077","authenticated-orcid":false,"given":"Yi-Sook","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"},{"name":"Research Institute of Pharmaceutical Sciences and Technology, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e91355","DOI":"10.7554\/eLife.91355","article-title":"Homeostatic control of deep sleep and molecular correlates of sleep pressure in Drosophila","volume":"12","author":"Chowdhury","year":"2023","journal-title":"eLife"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.2147\/NSS.S34842","article-title":"Sleep disturbance in mental health problems and neurodegenerative disease","volume":"5","author":"Anderson","year":"2013","journal-title":"Nat. Sci. Sleep"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1126\/science.aah4968","article-title":"Mechanisms linking circadian clocks, sleep, and neurodegeneration","volume":"354","author":"Musiek","year":"2016","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"151","DOI":"10.2147\/NSS.S134864","article-title":"Short- and long-term health consequences of sleep disruption","volume":"9","author":"Medic","year":"2017","journal-title":"Nat. Sci. Sleep"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e70089","DOI":"10.1111\/jsr.70089","article-title":"The Prevalence of Insomnia Disorder in the General Population: A Meta-Analysis","volume":"34","author":"Weinreich","year":"2025","journal-title":"J. Sleep Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Benge, E., Pavlova, M., and Javaheri, S. (2024). Sleep health challenges among women: Insomnia across the lifespan. Front. Sleep, 3.","DOI":"10.3389\/frsle.2024.1322761"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.jpainsymman.2014.03.001","article-title":"Benzodiazepines","volume":"47","author":"Howard","year":"2014","journal-title":"J. Pain Symptom Manag."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1007\/s13311-012-0148-3","article-title":"Insomnia pharmacotherapy","volume":"9","author":"Roehrs","year":"2012","journal-title":"Neurotherapeutics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1136\/bmj.38623.768588.47","article-title":"Sedative hypnotics in older people with insomnia: Meta-analysis of risks and benefits","volume":"331","author":"Glass","year":"2005","journal-title":"BMJ"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nrd2464","article-title":"Emerging anti-insomnia drugs: Tackling sleeplessness and the quality of wake time","volume":"7","author":"Wafford","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.conb.2017.03.021","article-title":"Wake-sleep circuitry: An overview","volume":"44","author":"Saper","year":"2017","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.neuron.2017.01.014","article-title":"Neural Circuitry of Wakefulness and Sleep","volume":"93","author":"Scammell","year":"2017","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2174\/157015908787386050","article-title":"Neurophysiology of sleep and wakefulness: Basic science and clinical implications","volume":"6","author":"Schwartz","year":"2008","journal-title":"Curr. Neuropharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1378\/chest.14-1617","article-title":"The pathophysiology of insomnia","volume":"147","author":"Levenson","year":"2015","journal-title":"Chest"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.smrv.2009.04.002","article-title":"The hyperarousal model of insomnia: A review of the concept and its evidence","volume":"14","author":"Riemann","year":"2010","journal-title":"Sleep Med. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e255","DOI":"10.5001\/omj.2021.56","article-title":"The Effects of Valerian on Sleep Quality, Depression, and State Anxiety in Hemodialysis Patients: A Randomized, Double-blind, Crossover Clinical Trial","volume":"36","author":"Tammadon","year":"2021","journal-title":"Oman Med. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/S0924-977X(99)00032-2","article-title":"Hypericum for depression: An update of the clinical evidence","volume":"9","author":"Stevinson","year":"1999","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lacroix, M.M., de Lavill\u00e9on, G., Lefort, J., El Kanbi, K., Bagur, S., Laventure, S., Dauvilliers, Y., Peyron, C., and Benchenane, K. (2018). Improved sleep scoring in mice reveals human-like stages. bioRxiv, 489005.","DOI":"10.1101\/489005"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lazarus, M., Hayashi, Y., Honjoh, S., Vogt, K.E., Eban-Rothschild, A., Liu, Q., and Sakurai, T. (2020). Editorial: The Gating and Maintenance of Sleep and Wake: New Circuits and Insights. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00773"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s44323-024-00013-1","article-title":"Melatonin\u2019s role in the timing of sleep onset is conserved in nocturnal mice","volume":"1","author":"Kim","year":"2024","journal-title":"npj Biol. Timing Sleep"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1136\/bmj.313.7052.253","article-title":"St John\u2019s wort for depression\u2014An overview and meta-analysis of randomised clinical trials","volume":"313","author":"Linde","year":"1996","journal-title":"BMJ"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.jad.2016.12.048","article-title":"Clinical use of Hypericum perforatum (St John\u2019s wort) in depression: A meta-analysis","volume":"210","author":"Ng","year":"2017","journal-title":"J. Affect. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s10354-015-0372-7","article-title":"The mechanisms of action of St. John\u2019s wort: An update","volume":"165","author":"Schmidt","year":"2015","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1211\/0022357991772862","article-title":"Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat","volume":"51","author":"Calapai","year":"1999","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/S0091-3057(02)00777-3","article-title":"Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm)","volume":"72","author":"Kennedy","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3233\/s12349-010-0045-4","article-title":"Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances","volume":"4","author":"Cases","year":"2011","journal-title":"Mediterr. J. Nutr. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1002\/ptr.2712","article-title":"Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity","volume":"23","author":"Awad","year":"2009","journal-title":"Phytother. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Araj-Khodaei, M., Noorbala, A.A., Yarani, R., Emadi, F., Emaratkar, E., Faghihzadeh, S., Parsian, Z., Alijaniha, F., Kamalinejad, M., and Naseri, M. (2020). A double-blind, randomized pilot study for comparison of Melissa officinalis L. and Lavandula angustifolia Mill. with Fluoxetine for the treatment of depression. BMC Complement. Med. Ther., 20.","DOI":"10.1186\/s12906-020-03003-5"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6690","DOI":"10.1002\/ptr.7252","article-title":"The effects of lemon balm (Melissa officinalis L.) on depression and anxiety in clinical trials: A systematic review and meta-analysis","volume":"35","author":"Ghazizadeh","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bano, A., Hepsomali, P., Rabbani, F., Farooq, U., Kanwal, A., Saleem, A., Bugti, A.A., Khan, A.A., Khalid, Z., and Bugti, M. (2023). The possible \u201ccalming effect\u201d of subchronic supplementation of a standardised phospholipid carrier-based Melissa officinalis L. extract in healthy adults with emotional distress and poor sleep conditions: Results from a prospective, randomised, double-blinded, placebo-controlled clinical trial. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1250560"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1007\/s11064-010-0312-2","article-title":"Effects of Melissa officinalis L. (lemon balm) extract on neurogenesis associated with serum corticosterone and GABA in the mouse dentate gyrus","volume":"36","author":"Yoo","year":"2011","journal-title":"Neurochem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.phymed.2010.01.012","article-title":"Effects of chronic administration of Melissa officinalis L. extract on anxiety-like reactivity and on circadian and exploratory activities in mice","volume":"17","author":"Ibarra","year":"2010","journal-title":"Phytomedicine"},{"key":"ref_33","first-page":"119","article-title":"Sleep-Time Variation for Ethanol and the Hypnotic Drugs Tribromoethanol, Urethane, Pentobarbital, and Propofol within Outbred ICR Mice","volume":"51","author":"Koizumi","year":"2002","journal-title":"Exp. Anim.\/Jpn. Assoc. Lab. Anim. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.5625\/lar.2017.33.1.8","article-title":"Comparison of commonly used ICR stocks and the characterization of Korl:ICR","volume":"33","author":"Shin","year":"2017","journal-title":"Lab. Anim. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s002130050327","article-title":"Behavioral phenotypes of inbred mouse strains: Implications and recommendations for molecular studies","volume":"132","author":"Crawley","year":"1997","journal-title":"Psychopharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1538\/expanim.58.141","article-title":"Genetic differences among C57BL\/6 substrains","volume":"58","author":"Mekada","year":"2009","journal-title":"Exp. Anim."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3264","DOI":"10.1038\/s41598-025-87428-3","article-title":"Lactiplantibacillus plantarum 22 A-3 ameliorates leaky gut in mice through its anti-inflammatory effects","volume":"15","author":"Kobayashi","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"531","DOI":"10.4062\/biomolther.2024.106","article-title":"\u03b2-Lapachone Exerts Hypnotic Effects via Adenosine A(1) Receptor in Mice","volume":"32","author":"Lee","year":"2024","journal-title":"Biomol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Qiu, R.-H., Zhu, S.-M., Zhang, Y., Xue, R., Li, S., Fan, Q.-Y., Li, J.-C., and Zhang, Y.-Z. (2026). Evaluation of Therapeutic Effects and Underlying Mechanisms of Baichuan Baile Formula in Rodent Insomnia Models. Nutrients, 18.","DOI":"10.3390\/nu18050723"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1093\/ilar\/ilab016","article-title":"Mouse Anesthesia: The Art and Science","volume":"62","author":"Navarro","year":"2021","journal-title":"Ilar J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.neuroscience.2003.08.066","article-title":"Disinhibition of ventrolateral preoptic area sleep-active neurons by adenosine: A new mechanism for sleep promotion","volume":"123","author":"Morairty","year":"2004","journal-title":"Neuroscience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4278","DOI":"10.1523\/JNEUROSCI.23-10-04278.2003","article-title":"A1 Receptor and Adenosinergic Homeostatic Regulation of Sleep-Wakefulness: Effects of Antisense to the A1 Receptor in the Cholinergic Basal Forebrain","volume":"23","author":"Thakkar","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.conb.2017.03.020","article-title":"Lateral hypothalamic circuits for sleep-wake control","volume":"44","author":"Yamashita","year":"2017","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lazarus, M., Oishi, Y., Bjorness, T.E., and Greene, R.W. (2019). Gating and the Need for Sleep: Dissociable Effects of Adenosine A(1) and A(2A) Receptors. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00740"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.sleep.2024.02.012","article-title":"Functions and mechanisms of adenosine and its receptors in sleep regulation","volume":"115","author":"Huang","year":"2024","journal-title":"Sleep Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.neuroscience.2005.05.045","article-title":"The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus","volume":"134","author":"Gallopin","year":"2005","journal-title":"Neuroscience"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.neuropharm.2018.10.022","article-title":"Enhancing endogenous adenosine A(2A) receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function","volume":"144","author":"Korkutata","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/nn1491","article-title":"Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine","volume":"8","author":"Huang","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"R1715","DOI":"10.1152\/ajpregu.00247.2005","article-title":"Effects on sleep of microdialysis of adenosine A1 and A2a receptor analogs into the lateral preoptic area of rats","volume":"289","author":"Methippara","year":"2005","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S0306-4522(01)00383-9","article-title":"An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons","volume":"107","author":"Scammell","year":"2001","journal-title":"Neuroscience"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0014-2999(98)00302-1","article-title":"Involvement of adenosine A2A receptor in sleep promotion","volume":"351","author":"Satoh","year":"1998","journal-title":"Eur. J. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/01616412.2017.1315864","article-title":"A review of sleep disorders and melatonin","volume":"39","author":"Xie","year":"2017","journal-title":"Neurol. Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"\u017be\u0142abowski, K., Pichowicz, W., Skowron, I., Szwach, J., Biedka, K., Weso\u0142owski, M., B\u0142aszczyk, K., Ziobro, O., Petrov, W., and Kukula-Koch, W. (2025). The Efficacy of Melatonergic Receptor Agonists Used in Clinical Practice in Insomnia Treatment: Melatonin, Tasimelteon, Ramelteon, Agomelatine, and Selected Herbs. Molecules, 30.","DOI":"10.3390\/molecules30183814"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1124\/pr.110.002832","article-title":"International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors","volume":"62","author":"Dubocovich","year":"2010","journal-title":"Pharmacol. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1600-079X.2005.00223.x","article-title":"N-acetyltransferase is not the rate-limiting enzyme of melatonin synthesis at night","volume":"39","author":"Liu","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e12544","DOI":"10.1111\/jpi.12544","article-title":"Sleep well. Untangling the role of melatonin MT1 and MT2 receptors in sleep","volume":"66","author":"Gobbi","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev-pharmtox-010814-124742","article-title":"MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective","volume":"56","author":"Liu","year":"2016","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1097\/00001756-200106130-00013","article-title":"Opposite changes in adenosine A1 and A2A receptor mRNA in the rat following sleep deprivation","volume":"12","author":"Basheer","year":"2001","journal-title":"NeuroReport"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1523\/JNEUROSCI.5066-06.2007","article-title":"Sleep Deprivation Increases A1 Adenosine Receptor Binding in the Human Brain: A Positron Emission Tomography Study","volume":"27","author":"Elmenhorst","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1503\/jpn.130009","article-title":"Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: A novel target in psychopharmacology","volume":"39","author":"Comai","year":"2014","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.brainres.2008.12.056","article-title":"Sleep deprivation increases A(1) adenosine receptor density in the rat brain","volume":"1258","author":"Elmenhorst","year":"2009","journal-title":"Brain Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4243","DOI":"10.1073\/pnas.1614677114","article-title":"Recovery sleep after extended wakefulness restores elevated A(1) adenosine receptor availability in the human brain","volume":"114","author":"Elmenhorst","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"112483","DOI":"10.1016\/j.biopha.2021.112483","article-title":"Involvement of the adenosine A(1) receptor in the hypnotic effect of rosmarinic acid","volume":"146","author":"Kim","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"114630","DOI":"10.1016\/j.jep.2021.114630","article-title":"Sedative-hypnotic, anxiolytic and possible side effects of Salvia limbata C. A. Mey. Extracts and the effects of phenological stage and altitude on the rosmarinic acid content","volume":"282","author":"Jahani","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1007\/s12272-012-0810-7","article-title":"In vivo sedative and gastroprotective activities of Salvia plebeia extract and its composition of polyphenols","volume":"35","author":"Nugroho","year":"2012","journal-title":"Arch. Pharm. Res."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Orzelska-G\u00f3rka, J., Dos Santos Szewczyk, K., Gawro\u0144ska-Grzywacz, M., Herbet, M., Lesniak, A., Bielenica, A., Bujalska-Zadro\u017cny, M., and Bia\u0142a, G. (2023). Procognitive, Anxiolytic, and Antidepressant-like Properties of Hyperoside and Protocatechuic Acid Corresponding with the Increase in Serum Serotonin Level after Prolonged Treatment in Mice. Pharmaceuticals, 16.","DOI":"10.3390\/ph16121691"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1002\/ptr.7478","article-title":"Hyperoside: A review on its sources, biological activities, and molecular mechanisms","volume":"36","author":"Wang","year":"2022","journal-title":"Phytother Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Shoji, K., Yuasa, T., Kitajima, Y., and Hirakawa, Y. (2026). Hyperoside-Rich Blueberry Leaf Tea Improves Sleep Continuity in Adults with Poor Sleep: A Two-Week Randomized Double-Blind Controlled Trial. Nutrients, 18.","DOI":"10.3390\/nu18030453"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"240","DOI":"10.2174\/157488711304180911095818","article-title":"Rosmarinic Acid as Potential Anti-Inflammatory Agent","volume":"13","author":"Colica","year":"2018","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"114969","DOI":"10.1016\/j.jpba.2022.114969","article-title":"Attenuation of neuroinflammation in microglia cells by extracts with high content of rosmarinic acid from in vitro cultured Melissa officinalis L. cells","volume":"220","author":"Borgonetti","year":"2022","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Zielinski, M.R., Systrom, D.M., and Rose, N.R. (2019). Fatigue, Sleep, and Autoimmune and Related Disorders. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01827"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/npp.2016.148","article-title":"Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity","volume":"42","author":"Irwin","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S1043-6618(02)00266-9","article-title":"Current St John\u2019s wort research from mode of action to clinical efficacy","volume":"47","year":"2003","journal-title":"Pharmacol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/ptr.5050","article-title":"Hypericum perforatum: Pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions","volume":"28","author":"Russo","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"114788","DOI":"10.1016\/j.jep.2021.114788","article-title":"Lemon balm (Melissa officinalis L.) essential oil and citronellal modulate anxiety-related symptoms\u2014In vitro and in vivo studies","volume":"284","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Petrisor, G., Motelica, L., Craciun, L.N., Oprea, O.C., Ficai, D., and Ficai, A. (2022). Melissa officinalis: Composition, Pharmacological Effects and Derived Release Systems\u2014A Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073591"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/11\/1666\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:18:43Z","timestamp":1780460323000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/11\/1666"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":76,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["nu18111666"],"URL":"https:\/\/doi.org\/10.3390\/nu18111666","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]}}}