{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:22:46Z","timestamp":1792606966187,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Depressive disorder is a common mental disorder characterized by depressed mood and loss of interest or pleasure. As the Herbal medicines are mainly used as complementary and alternative therapy for depression. This study aimed at exploring antidepressant activity of Huang-lian Jie-du Decoction (HLJDD), and evaluating active components and potential depression-associated targets. HLJDD was administered on chronic unpredictable mild stress-induced (CUMS) depressive mice. Behavior evaluation was performed through force swimming test (FST), novelty-suppressed feeding test (NSF), and open field test (OFT). Active components of HLJDD, potential targets, and metabolic pathways involved in depression were explored through systemic biology-based network pharmacology assay, molecular docking and metabonomics. FST assay showed that CUMS mice administered with HLJDD had significantly shorter immobility time compared with control mice. Further, HLJDD alleviated feeding latency of CUMS mice in NSFand increased moving distance and duration in OFT. In the following network pharmacology assay, thirty-eight active compounds in HLJDD were identified based on drug-like characteristics, and pharmacokinetics and pharmacodynamics profiles. Moreover, forty-eight molecular targets and ten biochemical pathways were uncovered through molecular docking and metabonomics. GRIN2B, DRD, PRKCA, HTR, MAOA, SLC6A4, GRIN2A, and CACNA1A are implicated in inhibition of depressive symptoms through modulating tryptophan metabolism, serotonergic and dopaminergic synaptic activities, cAMP signaling pathway, and calcium signaling pathway. Further network pharmacology-based analysis showed a correlation between HLJDD and tryptophan metabolism. A total of thirty-seven active compounds, seventy-six targets, and sixteen biochemical pathways were involved in tryptophan metabolism. These findings show that HLJDD acts on potential targets such as SLC6A4, HTR, INS, MAO, CAT, and FoxO, PI3K\/Akt, calcium, HIF-1, and mTOR signaling pathways, and modulates serotoninergic and dopaminergic synaptic functions. In addition, metabonomics showed that tryptophan metabolism is the primary target for HLJDD in CUMS mice. The findings of the study show that HLJDD exhibited antidepressant effects. SLC6A4 and MAOA in tryptophan metabolism were modulated by berberine, baicalein, tetrahydroberberine, candicine and may be the main antidepressant targets for HLJDD.<\/jats:p>","DOI":"10.3389\/fphar.2021.619288","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T09:17:55Z","timestamp":1614849475000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":67,"title":["Analysis of Antidepressant Activity of Huang-Lian Jie-Du Decoction Through Network Pharmacology and Metabolomics"],"prefix":"10.3389","volume":"12","author":[{"given":"Shu-Yue","family":"Qu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Heng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Yu","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Yuan","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai-jia","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeng-Ying","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nian-Yun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi-Chun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-Xu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e46921","DOI":"10.1371\/journal.pone.0046921","article-title":"Abnormal hippocampal BDNF and miR-16 expression is associated with depression-like behaviors induced by stress during early life","volume":"7","author":"Bai","year":"2012","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3206","DOI":"10.1021\/jm101459g","article-title":"Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder","volume":"54","author":"Bang-Andersen","year":"2011","journal-title":"J. Med. Chem"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1080\/14656566.2016.1254188","article-title":"Adjunctive brexpiprazole for the treatment of major depressive disorder","volume":"17","author":"Beyer","year":"2016","journal-title":"Expet Opin. Pharmacother"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7977","DOI":"10.1073\/pnas.1337088100","article-title":"Systematic discovery of multicomponent therapeutics","volume":"100","author":"Borisy","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"B5","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1055\/s-2001-15180","article-title":"Serotonin, norepinephrine and dopamine involvement in the antidepressant action of hypericum perforatum","volume":"34","author":"Calapai","year":"2001","journal-title":"Pharmacopsychiatry"},{"key":"B6","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1159\/000371865","article-title":"New classification of selective serotonin reuptake inhibitor withdrawal","volume":"84","author":"Chouinard","year":"2015","journal-title":"Psychother. Psychosom"},{"key":"B7","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1176\/appi.focus.16407","article-title":"Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis","volume":"16","author":"Cipriani","year":"2018","journal-title":"Focus"},{"key":"B8","doi-asserted-by":"publisher","first-page":"6707850","DOI":"10.1155\/2018\/6707850","article-title":"A new strategy to uncover the anticancer mechanism of Chinese compound formula by integrating systems pharmacology and bioinformatics","volume":"2018","author":"Dai","year":"2018","journal-title":"Evid Based Complement Alternat Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.neubiorev.2005.03.017","article-title":"Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test","volume":"29","author":"Dulawa","year":"2005","journal-title":"Neurosci. Biobehav. Rev"},{"key":"B10","doi-asserted-by":"publisher","first-page":"123","DOI":"10.4088\/jcp.v64n0204","article-title":"Can long-term treatment with antidepressant drugs worsen the course of depression?","volume":"64","author":"Fava","year":"2003","journal-title":"J. Clin. Psychiatr"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1056\/NEJM195412162512504","article-title":"Mental depression in hypertensive patients treated for long periods with large doses of reserpine","volume":"251","author":"Freis","year":"1954","journal-title":"N. Engl. J. Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"347","DOI":"10.3389\/fphar.2020.00347","article-title":"Network pharmacology-based dissection of the anti-diabetic mechanism of Lobelia chinensis","volume":"11","author":"Ge","year":"2020","journal-title":"Front. Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.3390\/molecules22081386","article-title":"Effects of refined xiaoyaosan on depressive-like behaviors in rats with chronic unpredictable mild stress through neurosteroids, their synthesis and metabolic enzymes","volume":"22","author":"Guo","year":"2017","journal-title":"Molecules"},{"key":"B14","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/S0944-7113(00)80027-6","article-title":"Pharmacodynamic study of Hypericum perforatum L","volume":"7","author":"Jakovljevic","year":"2000","journal-title":"Phytomedicine"},{"key":"B15","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/sj.mp.4001920","article-title":"Serotonergic vulnerability and depression: assumptions, experimental evidence and implications","volume":"12","author":"Jans","year":"2007","journal-title":"Mol. Psychiatr"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1002\/ptr.4938","article-title":"Anti-depressant effects of aqueous extract from Acanthopanax senticosus in mice","volume":"27","author":"Jin","year":"2013","journal-title":"Phytother Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e12696","DOI":"10.1111\/cpr.12696","article-title":"Mechanisms of Panax ginseng action as an antidepressant","volume":"52","author":"Jin","year":"2019","journal-title":"Cell Prolif"},{"key":"B18","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/nrd1609","article-title":"Multicomponent therapeutics for networked systems","volume":"4","author":"Keith","year":"2005","journal-title":"Nat. Rev. Drug Discov"},{"key":"B19","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1055\/s-0030-1248553","article-title":"Metabolic syndrome in patients with depressive disorder\u2013features of comorbidity","volume":"23","author":"Kozumplik","year":"2011","journal-title":"Psychiatr. Danub"},{"key":"B20","doi-asserted-by":"publisher","first-page":"379","DOI":"10.4196\/kjpp.2012.16.6.379","article-title":"Effect of berberine on depression- and anxiety-like behaviors and activation of the noradrenergic system induced by development of morphine dependence in rats","volume":"16","author":"Lee","year":"2012","journal-title":"Korean J. Physiol. Pharmacl"},{"key":"B21","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.jad.2014.08.027","article-title":"Herbal medicine for hospitalized patients with severe depressive episode: a retrospective controlled study","volume":"170","author":"Liu","year":"2015","journal-title":"J. Affect. Disord"},{"key":"B22","doi-asserted-by":"publisher","first-page":"W609","DOI":"10.1093\/nar\/gkq300","article-title":"PharmMapper server: a web server for potential drug target identification using pharmacophore mapping approach","volume":"38","author":"Liu","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"113549","DOI":"10.1016\/j.jep.2020.113549","article-title":"Integrating hippocampal metabonomics and network pharmacology deciphers the antidepressant mechanisms of Xiaoyaosan","volume":"268","author":"Liu","year":"2020","journal-title":"J. Ethnopharmacol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"8340192","DOI":"10.1155\/2019\/8340192","article-title":"Modified huang-lian-jie-du decoction ameliorates A","volume":"2019","author":"Liu","year":"2019","journal-title":"Oxid. Med. Cell Longev"},{"key":"B25","doi-asserted-by":"publisher","first-page":"21146","DOI":"10.1038\/srep21146","article-title":"BATMAN-TCM: a bioinformatics analysis tool for molecular mechANism of traditional Chinese medicine","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep"},{"key":"B26","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1590\/s1413-86702010000100020","article-title":"Novel pharmaceutical molecules against emerging resistant gram-positive cocci","volume":"14","author":"Manfredi","year":"2010","journal-title":"Braz. J. Infect. Dis"},{"key":"B27","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.neuroscience.2014.01.006","article-title":"Modulation of oxidative stress and Ca(2+) mobilization through TRPM2 channels in rat dorsal root ganglion neuron by Hypericum perforatum","volume":"263","author":"Naziroglu","year":"2014","journal-title":"Neuroscience"},{"key":"B28","doi-asserted-by":"publisher","first-page":"151","DOI":"10.2147\/NDT.S38318","article-title":"Orengedoku-to augmentation in cases showing partial response to yokukan-san treatment: a case report and literature review of the evidence for use of these Kamp herbal formulae","volume":"9","author":"Okamoto","year":"2013","journal-title":"Neuropsychiatric Dis. Treat"},{"key":"B29","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s00441-018-2978-8","article-title":"Monoaminergic system and depression","volume":"377","author":"Perez-Caballero","year":"2019","journal-title":"Cell Tissue Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"201","DOI":"10.4103\/0253-7176.106011","article-title":"Depression - the global crisis","volume":"34","author":"Reddy","year":"2012","journal-title":"Indian J. Psychol. Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1159\/000077365","article-title":"Altered 5-HT2A and 5-HT4 postsynaptic receptors and their intracellular signalling systems IP3 and cAMP in brains from depressed violent suicide victims","volume":"49","author":"Rosel","year":"2004","journal-title":"Neuropsychobiology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: a database of systems pharmacology for drug discovery from herbal medicines","volume":"6","author":"Ru","year":"2014","journal-title":"J. Cheminf"},{"key":"B33","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1472-6882-6-23","article-title":"Effect of three different cultivars of Lepidium meyenii (Maca) on learning and depression in ovariectomized mice","volume":"6","author":"Rubio","year":"2006","journal-title":"BMC Compl. Alternative Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1248\/yakushi1947.120.6_559","article-title":"[The mechanism of alteration of monoamine metabolism in brain regions in marble burying behavior-isolated housing mice and effect of oren-gedoku-to on this alteration]","volume":"120","author":"Sasaki","year":"2000","journal-title":"Yakugaku Zasshi"},{"key":"B35","doi-asserted-by":"publisher","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 (Berlin)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1042\/BST20051037","article-title":"Insulin and cognitive function in humans: experimental data and therapeutic considerations","volume":"33","author":"Strachan","year":"2005","journal-title":"Biochem. Soc. Trans"},{"key":"B50","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"Autodockvina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.pscychresns.2010.10.009","article-title":"The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS","volume":"191","author":"Valentine","year":"2011","journal-title":"Psychiatr. Res"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.3389\/fphar.2019.01288","article-title":"Intermodule coupling analysis of huang-lian-jie-du decoction on stroke","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Pharmacol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jep.2013.06.035","article-title":"Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia\/reperfusion via MAPK-mTOR signaling pathway","volume":"149","author":"Wang","year":"2013","journal-title":"J. Ethnopharmacol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"668","DOI":"10.3389\/fphar.2018.00668","article-title":"A computational systems pharmacology approach to investigate molecular mechanisms of herbal formula tian-ma-gou-teng-yin for treatment of Alzheimer\u2019s disease","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Pharmacol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.psychres.2017.09.045","article-title":"Themolecular aspects of oxidative & nitrosative stress and the tryptophan catabolites pathway (TRYCATs) as potential causes of depression","volume":"262","author":"Wigner","year":"2018","journal-title":"Psychiatry Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e52331","DOI":"10.1371\/journal.pone.0052331","article-title":"Chronic unpredictable stress decreases expression of brain-derived neurotrophic factor (BDNF) in mouse ovaries: relationship to oocytes developmental potential","volume":"7","author":"Wu","year":"2012","journal-title":"PLoS One"},{"key":"B42","doi-asserted-by":"publisher","first-page":"112827","DOI":"10.1016\/j.jep.2020.112827","article-title":"Rapid action of mechanism investigation of Yixin Ningshen tablet in treating depression by combinatorial use of systems biology and bioinformatics tools","volume":"257","author":"Wu","year":"2020","journal-title":"J. Ethnopharmacol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"291","DOI":"10.3233\/JAD-140414","article-title":"The Ido inhibitor coptisine ameliorates cognitive impairment in a mouse model of Alzheimer's disease","volume":"43","author":"Yu","year":"2015","journal-title":"J Alzheimers Dis"},{"key":"B44","doi-asserted-by":"publisher","first-page":"565784","DOI":"10.1155\/2014\/565784","article-title":"Effect of huanglian jiedu decoction on thoracic aorta gene expression in spontaneous hypertensive rats","volume":"2014","author":"Yue","year":"2014","journal-title":"Evid Based Complement Alternat Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1016\/j.fitote.2010.01.004","article-title":"Comparative pharmacokinetics of baicalin in plasma after oral administration of Huang-Lian-Jie-Du-Tang or pure baicalin in MCAO and sham-operated rats","volume":"81","author":"Zeng","year":"2010","journal-title":"Fitoterapia"},{"key":"B46","doi-asserted-by":"publisher","first-page":"30951","DOI":"10.1038\/srep30951","article-title":"Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety\/depression","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci. Rep"},{"key":"B47","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fphar.2019.00123","article-title":"Network pharmacology databases for traditional Chinese medicine: review and assessment","volume":"10","author":"Zhang","year":"2019","journal-title":"Front. Pharmacol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1097\/GME.0000000000001558","article-title":"The effects of a new, improved Chinese medicine, Gengnianchun formula granules, on hot flushes, depression, anxiety, and sleep in Chinese peri- and postmenopausal women: a randomized placebo-controlled trial","volume":"27","author":"Zhang","year":"2020","journal-title":"Menopause"},{"key":"B49","doi-asserted-by":"publisher","first-page":"112832","DOI":"10.1016\/j.jep.2020.112832","article-title":"Antidepressant metabonomics study of Danzhi Xiaoyao powder on rat model of chronic unpredictable mild stress(CUMS)","author":"Zhu","year":"2020","journal-title":"J. Ethnopharmacol"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.619288\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T09:17:58Z","timestamp":1614849478000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.619288\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,4]]},"references-count":51,"alternative-id":["10.3389\/fphar.2021.619288"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.619288","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,4]]},"article-number":"619288"}}