{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:57:55Z","timestamp":1791496675883,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,5]],"date-time":"2018-11-05T00:00:00Z","timestamp":1541376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science &amp; Technology Programs from Hainan Province of China","award":["ZDKJ2016004"],"award-info":[{"award-number":["ZDKJ2016004"]}]},{"name":"the Central Organization Department Plan of the Leading Talents Project of Science and Technology Innovation","award":["99950534"],"award-info":[{"award-number":["99950534"]}]},{"name":"the Mmajor Science and Technology Innovation Project of Chinese Academy Medical Sciences","award":["2016-I2M-2-003"],"award-info":[{"award-number":["2016-I2M-2-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In our previous investigation, we found that agarwood essential oil (AEO) has a sedative-hypnotic effect. Sedative-hypnotic drugs usually have an anxiolytic effect, where concomitant anxiety and depression are a common comorbidity. Therefore, this study further investigated the anxiolytic and antidepressant effects of AEO using a series of animal behavior tests on a restraint stress-induced mice model. The elevated plus maze (EPM) test, the light dark exploration (LDE) test, and the open field (OF) test demonstrated that AEO has a significant anxiolytic effect. Simultaneously, the tail suspension (TS) test and the forced swimming (FS) test illuminated that AEO has an antidepressant effect with the immobility time decreased. Stress can cause cytokine and nitric oxide (NO) elevation, and further lead to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. AEO was shown to dose-dependently inhibit the levels of cytokines, including interleukin 1\u03b1 (IL-1\u03b1), IL-1\u03b2, and IL-6 in serum, significantly decrease the mRNA level of neural nitric oxide synthase (nNOS) in the cerebral cortex and hippocampus, and inhibit the nNOS protein level in the hippocampus. Concomitant measurements of the HPA axis upstream regulator corticotropin releasing factor (CRF) and its receptor CRFR found that AEO significantly decreases the gene expression of CRF, and significantly inhibits the gene transcription and protein expression of CRFR in the cerebral cortex and hippocampus. Additionally, AEO dose-dependently reduces the concentrations of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) downstream of the HPA axis, as measured by ELISA kits. These results together demonstrate that AEO exerts anxiolytic and antidepressant effects which are related to the inhibition of CRF and hyperactivity of the HPA axis.<\/jats:p>","DOI":"10.3390\/ijms19113468","type":"journal-article","created":{"date-parts":[[2018,11,5]],"date-time":"2018-11-05T10:43:45Z","timestamp":1541414625000},"page":"3468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Agarwood Essential Oil Ameliorates Restrain Stress-Induced Anxiety and Depression by Inhibiting HPA Axis Hyperactivity"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6931-4006","authenticated-orcid":false,"given":"Shuai","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"},{"name":"Ministry of Education &amp; National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"},{"name":"Pharmacology and Toxicology Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Hainan Provincial Key Laboratory of Resources Conservation and Development of Southern Medicine, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"},{"name":"Key Laboratory of State Administration of Traditional Chinese Medicine for Agarwood Sustainable Utilization, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangxin","family":"Yu","sequence":"additional","affiliation":[{"name":"Hainan Provincial Key Laboratory of Resources Conservation and Development of Southern Medicine, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"},{"name":"Key Laboratory of State Administration of Traditional Chinese Medicine for Agarwood Sustainable Utilization, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2898-370X","authenticated-orcid":false,"given":"Chongming","family":"Wu","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deqian","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Hainan Medical College, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmin","family":"Liu","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Hainan Provincial Key Laboratory of Resources Conservation and Development of Southern Medicine, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"},{"name":"Key Laboratory of State Administration of Traditional Chinese Medicine for Agarwood Sustainable Utilization, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Yang","sequence":"additional","affiliation":[{"name":"Hainan Provincial Key Laboratory of Resources Conservation and Development of Southern Medicine, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"},{"name":"Key Laboratory of State Administration of Traditional Chinese Medicine for Agarwood Sustainable Utilization, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Guo","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhe","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"},{"name":"Ministry of Education &amp; National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"},{"name":"Pharmacology and Toxicology Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing 100193, China"},{"name":"Hainan Provincial Key Laboratory of Resources Conservation and Development of Southern Medicine, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"},{"name":"Key Laboratory of State Administration of Traditional Chinese Medicine for Agarwood Sustainable Utilization, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,5]]},"reference":[{"key":"ref_1","unstructured":"CITES (2004, January 2). Amendments to appendices I and II of CITES. Proceedings of the Thirteenth Meeting of the Conference of the Parties, Bangkok, Thailand."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.jep.2016.06.055","article-title":"Aquilaria spp. (agarwood) as source of health beneficial compounds: A review of traditional use, phytochemistry and pharmacology","volume":"189","author":"Hashim","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Korinek, M., Wagh, V.D., Lo, I.W., Hsu, Y.M., Hsu, H.Y., Hwang, T.L., Wu, Y.C., Cheng, Y.B., Chen, B.H., and Chang, F.R. (2016). Antiallergic Phorbol Ester from the Seeds of Aquilaria malaccensis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17030398"},{"key":"ref_4","unstructured":"National Pharmacopoeia Committee (2015). Pharmacopoeia of the People\u2019s Republic of China, Chinese Medical Science and Technology Press. [1st ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11808","DOI":"10.3390\/molecules200711808","article-title":"The Anticancer, antioxidant and antimicrobial properties of the sesquiterpene \u03b2-caryophyllene from the essential oil of Aquilaria crassna","volume":"20","author":"Dahham","year":"2015","journal-title":"Molecules"},{"key":"ref_6","first-page":"548","article-title":"Comparative study on antiinflammatory of agarwood leaves and resion","volume":"31","author":"Lin","year":"2013","journal-title":"Chin. Arch. Tradit. Chin. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1078\/094471102321621322","article-title":"Anti-inflammatory activity of linalool and linalyl acetate constituents of essential oils","volume":"9","author":"Peana","year":"2002","journal-title":"Phytomedicine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"360","DOI":"10.2174\/1573409911309030012","article-title":"Molecular docking and ADME studies of natural compounds of Agarwood oil for topical anti-inflammatory activity","volume":"9","author":"Yadav","year":"2013","journal-title":"Curr. Comput.-Aided Drug Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.phytochem.2011.11.017","article-title":"2-(2-phenylethyl)chromones from Chinese eaglewood","volume":"76","author":"Yang","year":"2012","journal-title":"Phytochemistry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3571","DOI":"10.1016\/j.bmc.2006.01.023","article-title":"New sesquiterpene from Vietnamese agarwood and its induction effect on brain-derived neurotrophic factor mRNA expression in vitro","volume":"14","author":"Ueda","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e12365","DOI":"10.1111\/jfbc.12365","article-title":"Neuritogenic and neuroprotective constituents from Aquilaria crassna leaves","volume":"41","author":"Supasuteekul","year":"2017","journal-title":"J. Food Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1080\/10286020.2012.704910","article-title":"Two new sesquiterpene derivatives from Chinese eaglewood","volume":"14","author":"Yang","year":"2012","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1021\/np3006925","article-title":"Antidepressant abietane diterpenoids from Chinese eaglewood","volume":"76","author":"Yang","year":"2013","journal-title":"J. Nat. Prod."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wang, S., Wang, C., Peng, D., Liu, X., Wu, C., Guo, P., and Wei, J. (2017). Agarwood essential oil displays sedative-hypnotic effects through the GABAergic system. Molecules, 22.","DOI":"10.3390\/molecules22122190"},{"key":"ref_15","first-page":"1082","article-title":"Effect of agarwood produced by whole-tree agarwood-inducing technique on hypnotic and spontaneous activity inhibition of mice","volume":"43","author":"Wang","year":"2016","journal-title":"J. Int. Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s11418-007-0177-0","article-title":"Sedative effects of vapor inhalation of agarwood oil and spikenard extract and identification of their active components","volume":"62","author":"Takemoto","year":"2008","journal-title":"J. Nat. Med."},{"key":"ref_17","unstructured":"Guo, J., Wang, W., Fang, H., Liu, Q., and Zhang, W. (2002). Agarofuan Derivatives, Their Preparation, Pharmaceutical Composition Containing Them and Their Use as Medicine. (6,486,201), U.S. Patent."},{"key":"ref_18","first-page":"125","article-title":"The synthensis and centrol nervous system activity of agarofuran","volume":"13","author":"Liu","year":"2003","journal-title":"Chin. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/nrd4075","article-title":"50 years of hurdles and hope in anxiolytic drug discovery","volume":"12","author":"Griebel","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.euroneuro.2011.07.018","article-title":"The size and burden of mental disorders and other disorders of the brain in Europe 2010","volume":"21","author":"Wittchen","year":"2011","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/S1734-1140(13)71527-5","article-title":"Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems","volume":"65","author":"Gadek","year":"2013","journal-title":"Pharmacol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.tips.2016.09.004","article-title":"The CRF system as a therapeutic target for neuropsychiatric disorders","volume":"37","author":"Sanders","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6340","DOI":"10.1523\/JNEUROSCI.15-10-06340.1995","article-title":"Localization of novel corticotropin-releasing factor receptor (CRF,) mRNA expression to specific subcortical nuclei in rat brain comparison with CRF, receptor mRNA expression","volume":"15","author":"Chalmers","year":"1995","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"295","DOI":"10.31887\/DCNS.2015.17.3\/mbourin","article-title":"Animal models for screening anxiolytic-like drugs: A perspective","volume":"17","author":"Bourin","year":"2015","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0014-2999(03)01274-3","article-title":"The mouse light\/dark box test","volume":"463","author":"Bourin","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.neuropharm.2016.10.026","article-title":"Environmental enrichment protects against stress-induced anxiety: Role of glucocorticoid receptor, ERK, and CREB signaling in the basolateral amygdala","volume":"113","author":"Novaes","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/0896-6273(91)90374-9","article-title":"Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase","volume":"7","author":"Bredt","year":"1991","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.bbr.2015.02.010","article-title":"Anxiolytic-like effects of restraint during the dark cycle in adolescent mice","volume":"284","author":"Ota","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.1999.79.1.1","article-title":"Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: Actions and mechanisms of action","volume":"79","author":"Turnbull","year":"1999","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.bbi.2017.01.011","article-title":"The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis","volume":"64","author":"Marsland","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/1440-1681.12826","article-title":"The changes in, and relationship between, plasma nitric oxide and corticotropin-releasing hormone in patients with major depressive disorder","volume":"45","author":"Lu","year":"2017","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.neubiorev.2005.02.002","article-title":"Pleiotropic contributions of nitric oxide to aggressive behavior","volume":"30","author":"Nelson","year":"2006","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1016\/S1734-1140(12)70935-0","article-title":"Effect of repeated restraint on homotypic stress-induced nitric oxide synthases expression in brain structures regulating HPA axis","volume":"64","author":"Gadek","year":"2012","journal-title":"Pharmacol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.bbr.2012.07.037","article-title":"The differential role of NOS inhibitors on stress-induced anxiety and neuroendocrine alterations in the rat","volume":"235","author":"Joung","year":"2012","journal-title":"Behav. Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"135","DOI":"10.2174\/187152706776359682","article-title":"Neuropeptides in psychiatric diseases: An overview with a particular focus on depression and anxiety disorders","volume":"5","author":"Belzung","year":"2006","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1038\/nrn.2016.94","article-title":"Region-specific roles of the corticotropin-releasing factor-urocortin system in stress","volume":"17","author":"Henckens","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3086","DOI":"10.3390\/molecules18033086","article-title":"Whole-tree agarwood-inducing technique: An efficient novel technique for producing high-quality agarwood in cultivated Aquilaria sinensis trees","volume":"18","author":"Liu","year":"2013","journal-title":"Molecules"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0165-0270(85)90031-7","article-title":"Validation of open: Closed arm entries in an elevated plus-maze as a measure of anxiety in the rat","volume":"14","author":"Pellow","year":"1985","journal-title":"J. Neurosci. Methods"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/0091-3057(80)90067-2","article-title":"Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines","volume":"13","author":"Crawley","year":"1980","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9277","DOI":"10.1021\/acs.jafc.5b04141","article-title":"Lotus leaf alkaloid extract displays sedative-hypnotic and anxiolytic effects through GABAA Receptor","volume":"63","author":"Yan","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.lfs.2017.02.010","article-title":"Protective effects of linalool against amyloid \u03b2-induced cognitive deficits and damages in mice","volume":"174","author":"Xu","year":"2017","journal-title":"Life Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/BF00428203","article-title":"The tail suspension test: A new method for screening antidepressants in mice","volume":"85","author":"Steru","year":"1985","journal-title":"Psychopharmacology"},{"key":"ref_43","first-page":"327","article-title":"Behavioral despair in mice: A primary screening test for antidepressants","volume":"229","author":"Porsolt","year":"1977","journal-title":"Arch. Int. Pharmacodyn. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.3109\/13880209.2014.986688","article-title":"Chrysin inhibits foam cell formation through promoting cholesterol efflux from RAW264.7 macrophages","volume":"53","author":"Wang","year":"2015","journal-title":"Pharm. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1126\/science.aad5177","article-title":"In vivo gene editing in dystrophic mouse muscle and muscle stem cells","volume":"351","author":"Tabebordbar","year":"2016","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/ncb3282","article-title":"Human keratinocytes have two interconvertible modes of proliferation","volume":"18","author":"Roshan","year":"2016","journal-title":"Nat. Cell Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3468\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:27:59Z","timestamp":1760196479000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,5]]},"references-count":46,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["ijms19113468"],"URL":"https:\/\/doi.org\/10.3390\/ijms19113468","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,5]]}}}