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The potential mechanism of Bupleurum against anxiety was predicted by network pharmacology study and molecular docking

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Abstract

Bupleurum chinense DC. (Chaihu) is a traditional Chinese medicine (TCM) used in the treatment of anxiety. But the anxiolytic mechanisms of bupleurum are still unclear. Therefore, this unknown is predicted by network pharmacology study with molecular docking in the present study. The components of bupleurum were obtained from the databases. Genes associated with components and disease were also provided by databases. Overlapping genes between components and disease were analyzed. The network of medicine-components-targets-disease was constructed, visualized, and analyzed. Protein-protein interaction (PPI), gene ontology (GO), pathway enrichment (KEGG) and molecular docking were conducted to predict the potential mechanisms of bupleurum on anxiety. A total of 9 bioactive components derived from bupleurum with 80 target genes were involved in anxiety. Neurotransmitter receptor activity, G protein-coupled amine receptor activity, regulation of blood circulation, neuroactive ligand-receptor interaction, calcium signaling pathway and salivary secretion may play significant roles in the anxiolytic of bupleurum. Molecular docking implicated that ACHE and MAOA showed high affinity for stigmasterol. Based on network pharmacology study with molecular docking, multi-component-multi-target-multi-pathway action mode of bupleurum on anxiety was elaborated. Stigmasterol might be the core bioactive component, while ACHE and MAOA might be the core target genes in the pharmacological profile of bupleurum on anxiety.

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Data availability

1. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

2. All data generated or analyzed during this study are included in this published article.

References

  • Andrade A, Brennecke A, Mallat S, Brown J, Gomez-Rivadeneira J, Czepiel N, Londrigan L (2019) Genetic associations between voltage-gated calcium channels and psychiatric disorders. Int J Mol Sci 20(14):3537

    Article  CAS  PubMed Central  Google Scholar 

  • Ashoor D, Ben Khalaf N, Marzouq M, Jarjanazi H, Chlif S, Fathallah MD (2021) A computational approach to evaluate the combined effect of SARS-CoV-2 RBD mutations and ACE2 receptor genetic variants on infectivity: the COVID-19 host-pathogen Nexus. Front Cell Infect Microbiol 11:13

    Article  CAS  Google Scholar 

  • Asthana S, Agarwal T, Singothu S, Samal A, Banerjee I, Pal K, Pramanik K, Ray SS (2015) Molecular docking and interactions of Pueraria Tuberosa with vascular endothelial growth factor receptors. Indian J Pharm Sci 77(4):439–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28(1):235–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bitsko RH, Holbrook JR, Ghandour RM, Blumberg SJ, Visser SN, Perou R, Walkup JT (2018) Epidemiology and impact of health care provider-diagnosed anxiety and depression among US children. J Dev Behav Pediatr : JDBP 39(5):395–403

    Article  PubMed  Google Scholar 

  • Borrow AP, Handa RJ (2017) Estrogen receptors modulation of anxiety-like behavior. Vitam Horm 103:27–52

    Article  CAS  PubMed  Google Scholar 

  • Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 108(38):16050–16055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brinza I, Abd-Alkhalek AM, El-Raey MA, Boiangiu RS, Eldahshan OA, Hritcu L (2020) Ameliorative effects of Rhoifolin in scopolamine-induced amnesic zebrafish () model. Antioxidants (Basel) 9(7):580

    Article  CAS  Google Scholar 

  • Campos GV, de Noronha SR, de Souza AA, Lima PM, Abreu AR, Chianca D Jr, de Menezes RC (2019) Estrogen receptor beta activation within dorsal raphe nucleus reverses anxiety-like behavior induced by food restriction in female rats. Behav Brain Res 357-358:57–64

    Article  CAS  PubMed  Google Scholar 

  • Choudhary MI, Shaikh M, Tul-Wahab A, Ur-Rahman A (2020) In silico identification of potential inhibitors of key SARS-CoV-2 3CL hydrolase (Mpro) via molecular docking, MMGBSA predictive binding energy calculations, and molecular dynamics simulation. PLoS One 15(7):e0235030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D (2014) Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55(6):791–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doncheva NT, Morris JH, Gorodkin J, Jensen LJ (2019) Cytoscape StringApp: network analysis and visualization of proteomics data. J Proteome Res 18(2):623–632

    Article  CAS  PubMed  Google Scholar 

  • Frankiensztajn LM, Elliott E, Koren O (2020) The microbiota and the hypothalamus-pituitary-adrenocortical (HPA) axis, implications for anxiety and stress disorders. Curr Opin Neurobiol 62:76–82

    Article  CAS  PubMed  Google Scholar 

  • Gao L-Q, Xu J, Chen S-D (2020) In silico screening of potential Chinese herbal medicine against COVID-19 by targeting SARS-CoV-2 3CLpro and angiotensin converting enzyme II using molecular docking. Chin J Integr Med 26(7):527–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giltay EJ, Enter D, Zitman FG, Penninx BWJH, van Pelt J, Spinhoven P, Roelofs K (2012) Salivary testosterone: associations with depression, anxiety disorders, and antidepressant use in a large cohort study. J Psychosom Res 72(3):205–213

    Article  PubMed  Google Scholar 

  • Goes FS (2015) The importance of anxiety states in bipolar disorder. Curr Psychiatry Rep 17(2):3

    Article  PubMed  Google Scholar 

  • Hek K, Direk N, Newson RS, Hofman A, Hoogendijk WJG, Mulder CL, Tiemeier H (2013) Anxiety disorders and salivary cortisol levels in older adults: a population-based study. Psychoneuroendocrinology 38(2):300–305

    Article  CAS  PubMed  Google Scholar 

  • Houghton KT, Forrest A, Awad A, Atkinson LZ, Stockton S, Harrison PJ, Geddes JR, Cipriani A (2017) Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis. BMJ Open 7(3):e013433

    Article  PubMed  PubMed Central  Google Scholar 

  • Jia Y, Zou J, Wang Y, Zhang X, Shi Y, Liang Y, Guo D, Yang M (2021) Action mechanism of Roman chamomile in the treatment of anxiety disorder based on network pharmacology. J Food Biochem 45(1):e13547

    Article  CAS  PubMed  Google Scholar 

  • Kambe J, Watcharin S, Makioka-Itaya Y, Inoue R, Watanabe G, Yamaguchi H, Nagaoka K (2020) Heat-killed Enterococcus fecalis (EC-12) supplement alters the expression of neurotransmitter receptor genes in the prefrontal cortex and alleviates anxiety-like behavior in mice. Neurosci Lett 720:134753

    Article  CAS  PubMed  Google Scholar 

  • Kanwal S, Jamil F, Ali A, Sehgal SA (2017) Comparative modeling, molecular docking, and revealing of potential binding pockets of RASSF2; a candidate Cancer gene. Interdiscip Sci 9(2):214–223

    Article  CAS  PubMed  Google Scholar 

  • Karim N, Khan I, Abdelhalim A, Halim SA, Khan A, Al-Harrasi A (2021) Stigmasterol can be new steroidal drug for neurological disorders: evidence of the GABAergic mechanism via receptor modulation. Phytomedicine 90:153646

    Article  CAS  PubMed  Google Scholar 

  • Khurana K, Bansal N (2019) Lacidipine attenuates caffeine-induced anxiety-like symptoms in mice: role of calcium-induced oxido-nitrosative stress. Pharmacol Rep 71(6):1264–1272

    Article  CAS  PubMed  Google Scholar 

  • Krushna GS, Shivaranjani VL, Umamaheswari J, Srinivasulu C, Hussain SA, Kareem MA, Reddy VD, Ali D, Lokhande KB, Swamy KV, Kodidhela LD (2017) In vivo and molecular docking studies using whole extract and phytocompounds of Aegle marmelos fruit protective effects against isoproterenol-induced myocardial infarction in rats. Biomed Pharmacother 91:880–889

    Article  CAS  PubMed  Google Scholar 

  • Lecca D, Abbracchio MP (2008) Deorphanisation of G protein-coupled receptors: a tool to provide new insights in nervous system pathophysiology and new targets for psycho-active drugs. Neurochem Int 52(3):339–351

    Article  CAS  PubMed  Google Scholar 

  • Lee B, Yun H-Y, Shim I, Lee H, Hahm D-H (2012) Bupleurum falcatum prevents depression and anxiety-like behaviors in rats exposed to repeated restraint stress. J Microbiol Biotechnol 22(3):422–430

    Article  PubMed  Google Scholar 

  • Li S, Zhang B (2013) Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med 11(2):110–120

    Article  PubMed  Google Scholar 

  • Li Z-Y, Sun H-M, Xing J, Qin X-M, Du G-H (2015) Chemical and biological comparison of raw and vinegar-baked Radix Bupleuri. J Ethnopharmacol 165:20–28

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Guo F, Wang Y, Li C, Zhang X, Li H, Diao L, Gu J, Wang W, Li D, He F (2016) BATMAN-TCM: a bioinformatics analysis tool for molecular mechANism of traditional Chinese medicine. Sci Rep 6:21146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu P-L, Song A-R, Dong C-D, Chu Q, Xu B-L, Liu J-M, Yan Z-J (2021) Network pharmacology study on the mechanism of the herb pair of prepared Rehmannia root-Chinese arborvitae kernel for anxiety disorders. Ann Palliat Med 10(3):3313–3327

    Article  PubMed  Google Scholar 

  • Lu Y, Yang J, Sun J, Lu W, Wang J-H (2020) mRNA and miRNA profiles in the nucleus accumbens are associated with psychological stress-induced susceptible and resilient mice. Pharmacol Biochem Behav 199:173062

    Article  CAS  PubMed  Google Scholar 

  • Luo T-T, Lu Y, Yan S-K, Xiao X, Rong X-L, Guo J (2020) Network pharmacology in research of Chinese medicine formula: methodology, application and prospective. Chin J Integr Med 26(1):72–80

    Article  CAS  PubMed  Google Scholar 

  • Mineur YS, Obayemi A, Wigestrand MB, Fote GM, Calarco CA, Li AM, Picciotto MR (2013) Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior. Proc Natl Acad Sci U S A 110(9):3573–3578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murrough JW, Yaqubi S, Sayed S, Charney DS (2015) Emerging drugs for the treatment of anxiety. Expert Opin Emerg Drugs 20(3):393–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nota B (2017) Gogadget: an R package for interpretation and visualization of GO enrichment results. Mol Inform 36:5–6

    Article  CAS  Google Scholar 

  • Piñero J, Bravo À, Queralt-Rosinach N, Gutiérrez-Sacristán A, Deu-Pons J, Centeno E, García-García J, Sanz F, Furlong LI (2017) DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res 45(D1):D833–D839

    Article  PubMed  CAS  Google Scholar 

  • Pinzi L, Rastelli G (2019) Molecular docking: shifting paradigms in drug discovery. Int J Mol Sci 20(18):4331

    Article  CAS  PubMed Central  Google Scholar 

  • Priya R, Sumitha R, Doss CG, Rajasekaran C, Babu S, Seenivasan R, Siva R (2015) Molecular docking and molecular dynamics to identify a novel human immunodeficiency virus inhibitor from alkaloids of Toddalia asiatica. Pharmacogn Mag 11(Suppl 3):S414–S422

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu ZK, Liu ZT, Pang JL, Wu HB, Liu X, Yang ZM, Li X, Chen JS (2021) A network pharmacology study with molecular docking to investigate the possibility of licorice against posttraumatic stress disorder. Metab Brain Dis 36(7):1763–1777

    Article  CAS  PubMed  Google Scholar 

  • Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, Xu X, Li Y, Wang Y, Yang L (2014) TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. Aust J Chem 6:13

    Google Scholar 

  • Scariot R, Tomaz CO, Calixto RD, Gerber JT, Pivetta Petinati MF, Cavalcante RC, Küchler EC, João da Costa D (2019) Association between gender, estrogen receptors genes and anxiety levels in patients undergoing orthognathic surgery. J Cranio-Maxillo-Facial Surg : Off Publ Eur Assoc Cranio-Maxillo-Facial Surg 47(8):1300–1305

    Article  Google Scholar 

  • Seidel L, Walkup JT (2006) Selective serotonin reuptake inhibitor use in the treatment of the pediatric non-obsessive-compulsive disorder anxiety disorders. J Child Adolesc Psychopharmacol 16(1–2):171–179

    Article  PubMed  Google Scholar 

  • Sklan EH, Lowenthal A, Korner M, Ritov YA, Landers DM, Rankinen T, Bouchard C, Leon AS, Rice T, Rao DC, Wilmore JH, Skinner JS, Soreq H (2004) Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in health, risk factors, exercise training, and genetics study. Proc Natl Acad Sci U S A 101(15):5512–5517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suarez-Lopez JR, Hood N, Suárez-Torres J, Gahagan S, Gunnar MR, López-Paredes D (2019) Associations of acetylcholinesterase activity with depression and anxiety symptoms among adolescents growing up near pesticide spray sites. Int J Hyg Environ Health 222(7):981–990

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Li X, Pan R, Xu Y, Wang Q, Song M (2018) Total Saikosaponins of Bupleurum yinchowense reduces depressive, anxiety-like behavior and increases synaptic proteins expression in chronic corticosterine-treated mice. BMC Complement Altern Med 18(1):117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tomasi J, Zai CC, Zai G, Herbert D, King N, Freeman N, Kennedy JL, Tiwari AK (2020) The effect of polymorphisms in startle-related genes on anxiety symptom severity. J Psychiatr Res 125:144–151

    Article  PubMed  Google Scholar 

  • Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461

    CAS  PubMed  PubMed Central  Google Scholar 

  • UniProt Consortium, T (2018) UniProt: the universal protein knowledgebase. Nucleic Acids Res 46(5):2699

    Article  CAS  Google Scholar 

  • Van Ameringen M, Mancini C, Patterson B, Bennett M (2005) An evaluation of paroxetine in generalised social anxiety disorder. Expert Opin Pharmacother 6(5):819–830

    Article  PubMed  Google Scholar 

  • Vasa RA, Mazurek MO, Mahajan R, Bennett AE, Bernal MP, Nozzolillo AA, Arnold LE, Coury DL (2016) Assessment and treatment of anxiety in youth with autism Spectrum disorders. Pediatrics 137(Suppl 2):S115–S123

    Article  PubMed  Google Scholar 

  • von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B (2003) STRING: a database of predicted functional associations between proteins. Nucleic Acids Res 31(1):258–261

    Article  CAS  Google Scholar 

  • Wang S, Wang C, Yu Z, Wu C, Peng D, Liu X, Liu Y, Yang Y, Guo P, Wei J (2018) Agarwood essential oil ameliorates restrain stress-induced anxiety and depression by inhibiting HPA Axis hyperactivity. Int J Mol Sci 19(11):3468

    Article  PubMed Central  CAS  Google Scholar 

  • Wang Y, Zhang S, Li F, Zhou Y, Zhang Y, Wang Z, Zhang R, Zhu J, Ren Y, Tan Y, Qin C, Li Y, Li X, Chen Y, Zhu F (2020) Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Res 48(D1):D1031–D1041

    CAS  PubMed  Google Scholar 

  • Watkins LR, Orlandi C (2020) Orphan G protein coupled receptors in affective disorders. Genes (Basel) 11(6):694

    Article  CAS  Google Scholar 

  • White SW, Simmons GL, Gotham KO, Conner CM, Smith IC, Beck KB, Mazefsky CA (2018) Psychosocial treatments targeting anxiety and depression in adolescents and adults on the autism Spectrum: review of the latest research and recommended future directions. Curr Psychiatry Rep 20(10):82

    Article  PubMed  PubMed Central  Google Scholar 

  • Wolgensinger L (2015) Cognitive behavioral group therapy for anxiety: recent developments. Dialogues Clin Neurosci 17(3):347–351

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie F, Xie M, Yang Y, Zhang M, Xu X, Liu N, Xiao W, Gu J (2020) Assessing the anti-inflammatory mechanism of Reduning injection by network pharmacology. Biomed Res Int 2020:6134098

    PubMed  PubMed Central  Google Scholar 

  • Xiong T-W, Wu Q, Liu J, Liu B, Xu Y-Y, Wang L-N, Zhang C-C, Zhang W, Shi J-S (2020) Research progress of effect of anxiolytic traditional Chinese medicines and formulas on neurotransmitters. Zhongguo Zhong Yao Za Zhi 45(1):14–19

    PubMed  Google Scholar 

  • Xue R, Fang Z, Zhang M, Yi Z, Wen C, Shi T (2013) TCMID: traditional Chinese medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res 41(Database issue):D1089–D1095

    CAS  PubMed  Google Scholar 

  • Yang F, Dong X, Yin X, Wang W, You L, Ni J (2017) A review of traditional uses, botany, Phytochemistry, pharmacology, and toxicology. Biomed Res Int 2017:7597596

    PubMed  PubMed Central  Google Scholar 

  • Yuanyuan J, Junyan Z, Cuola D, Jingjing C, Yuhui S, Dan X, Wei D, Yongsheng Z (2018) Memantine attenuated alcohol withdrawal-induced anxiety-like behaviors through down-regulating NR1-CaMKII-ERK signaling pathway. Neurosci Lett 686:133–139

    Article  PubMed  CAS  Google Scholar 

  • Zamponi GW, Striessnig J, Koschak A, Dolphin AC (2015) The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 67(4):821–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang JD, Wiemann S (2009) KEGGgraph: a graph approach to KEGG PATHWAY in R and bioconductor. Bioinformatics 25(11):1470–1471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Zhang S, Hu M, Chen Y, Wang W, Zhang K, Kuang H, Wang Q (2020) An integrative metabolomics and network pharmacology method for exploring the effect and mechanism of Radix Bupleuri and Radix Paeoniae Alba on anti-depression. J Pharm Biomed Anal 189:113435

    Article  CAS  PubMed  Google Scholar 

  • Zhu S, Noviello CM, Teng J, Walsh RM, Kim JJ, Hibbs RE (2018) Structure of a human synaptic GABA receptor. Nature 559(7712):67–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziegler C, Domschke K (2018) Epigenetic signature of MAOA and MAOB genes in mental disorders. J Neural Transm (Vienna) 125(11):1581–1588

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by National Key Clinical Specialty Construction Project (Clinical Pharmacy) and High Level Clinical Key Specialty (Clinical Pharmacy) in Guangdong Province. In addition, the study was also supported by funding of Guangdong province hospital association (No.2021YXQN08).

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  1. Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China

    Han-Biao Wu, Yu-Gang Xiao, Ji-Sheng Chen & Zhi-Kun Qiu

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  1. Han-Biao Wu
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  2. Yu-Gang Xiao
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All authors contributed to the study conception and design. Han-Biao Wu, Yu-Gang Xiao and Zhi-Kun Qiu designed the experimental methods. Han-Biao Wu, Yu-Gang Xiao, Ji-Sheng Chen and Zhi-Kun Qiu collected and analyzed the data. Han-Biao Wu and Zhi-Kun Qiu wrote the initial draft of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zhi-Kun Qiu.

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Wu, HB., Xiao, YG., Chen, JS. et al. The potential mechanism of Bupleurum against anxiety was predicted by network pharmacology study and molecular docking. Metab Brain Dis 37, 1609–1639 (2022). https://doi.org/10.1007/s11011-022-00970-1

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