A network pharmacology for exploring the pharmacological mechanism of the herbal formula Xiaoyao pills on insomnia

doi:10.5246/jcps.2024.02.014

Abstract

Abstract:

The study aimed to investigate the potential mechanism of the Xiaoyao pills (XYP) for treating insomnia using network pharmacology. The researchers employed several analytical methods and databases to predict and screen the active components and targets of XYP, as well as potential targets related to insomnia. Comparative analysis was then conducted to identify overlapping genes between the active component targets and insomnia-related targets. The researchers constructed networks of the active component-target and target pathways using Cytoscape software and the STRING database. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID database. The findings revealed 161 active components present in XYP and identified 76 potential targets associated with these active components. Furthermore, 36 overlapping genes were identified as both active component targets and targets related to insomnia treatment. The network pharmacology analysis highlighted the potential significance of radix bupleuri, Chinese angelica, and liquorice in the treatment of insomnia. The proposed mechanism of XYP in treating insomnia involved 10 core targets: TNF, IL1B, CASP3, TP53, HSP90AA1, PPARG, SLC6A4, ESR1, GSK3B, and AChE. The treatment of insomnia using XYP was found to primarily affect seven enriched GO terms and six related pathways. Notably, XYP targeted TNF, IL1B, CASP3, TP53, HSP90AA1, PPARG, SLC6A4, ESR1, GSK3B, and AChE, while participating in pathways such as neuroactive ligand-receptor interaction, pathways in cancer, and calcium signaling pathway. These findings provided valuable insights into the potential molecular targets and pathways through which XYP might exert its therapeutic effects in treating insomnia.

Key words: Xiaoyao pills, Insomnia, Network pharmacology, Core targets

Supporting:

Dan Wang. A network pharmacology for exploring the pharmacological mechanism of the herbal formula Xiaoyao pills on insomnia[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(2): 169-177.

Figures/Tables 7

Table 1. The number of components in XYP with OB ≥ 30% and DL index ≥ 0.18.

Table 2. Top 10 ingredients based on the network of ingredients by MCC using Cytoscape 3.8.2.

References 26

[1]	Pin Arboledas, G.; Soto Insuga, V.; Jurado Luque, M.J.; Fernandez Gomariz, C.; Hidalgo Vicario, I.; Lluch Rosello, A.; Rodríguez Hernández, P.J.; Madrid, J.A. Insomnio en niños y adolescentes. documento de consenso. Anales De Pediatría. 2017, 86, 165.e1–165.e11.
[2]	Li, J.M.; Mu, Z.N.; Xie, J.; Ma, T.T.; Zhang, Y.; Qi, X.H.; Teng, J. Effectiveness and safety of Chinese herbal medicine Xiaoyao San for the treatment of insomnia. Medicine. 2019, 98, e16481.
[3]	Zhao, H.B.; Jiang, Y.M.; Li, X.J.; Liu, Y.Y.; Bai, X.H.; Li, N.; Chen, J.X.; Liu, Q.; Yan, Z.Y.; Zhao, F.Z. Xiao Yao San improves the anxiety-like behaviors of rats induced by chronic immobilization stress: the involvement of the JNK signaling pathway in the hippocampus. Biol. Pharm. Bull. 2017, 40, 187–194.
[4]	Jiao, H.Y.; Fan, Y.L.; Gong, A.M.; Li, T.; Fu, X.; Yan, Z.Y. Xiaoyaosan ameliorates CUMS-induced depressive-like and anorexia behaviors in mice via necroptosis related cellular senescence in hypothalamus. J. Ethnopharmacol. 2023, 318, 116938.
[5]	Du, H.G.; Ming, L.; Chen, S.J.; Li, C.D. Xiaoyao pill for treatment of functional dyspepsia in perimenopausal women with depression. World J. Gastroenterol. 2014, 20, 16739–16744.
[6]	Fang, T.T.; Liu, L.Q.; Liu, W.J. Network pharmacology-based strategy for predicting therapy targets of Tripterygium wilfordii on acute myeloid leukemia. Medicine. 2020, 99, e23546.
[7]	Huan,Y.; Wang, J.; Fu, H.; Yang, M.; Qu, M.; Fang, Z.E. Discussion on the potential target and mechanism of Dachaihu Decoction in treating hyperlipidemia based on network pharmacology. J. Chin. Pharm. Sci. 2023, 32, 446–459.
[8]	Wu, D.Y.; Wang, X.D.; Chai, J.M.; Li, Q.Q.; Li, Y.; Bi, M.; Gui, W.W.; Cao, H.M. Study on the mechanism of Danggui Buxue decoction in the treatment of diabetic retinopathy based on network pharmacology and experiment. J. Chin. Pharm. Sci. 2023, 32, 527–538.
[9]	Jing, L.L.; Zhu, X.X.; Lv, Z.P.; Sun, X.G. Effect of Xiaoyaosan on major depressive disorder. Chin. Med. 2015, 10, 18.
[10]	Liu, W.D.; Zhao, M. Clinical evaluation of modified Xiaoyao pill on the treatment of oral lichen planus patients with anxiety or depression. Shanghai J. Stomatol. 2019, 28, 312–316.
[11]	Jin, X.; Jiang, M.L.; Gong, D.D.; Chen, Y.H.; Fan, Y. Efficacy and safety of Xiaoyao formula as an adjuvant treatment for post-stroke depression: a meta-analysis. EXPLORE-NY. 2018, 14, 224–229.
[12]	Lu, J.D.; Fu, L.J.; Qin, G.Z.; Shi, P.L.; Fu, W.J. The regulatory effect of Xiaoyao San on glucocorticoid receptors under the condition of chronic stress. Cell Mol. Biol. 2018, 64, 103–109.
[13]	Yang, H.R.; Liu, L.N.; Fei, G.; Yan, J.; Chen, Q.L.; Wei-Ting, L.; Qiao, F. Effect of Xiaoyao San on OVX combined with CUS anxiety and depression model rats based on hippocampal microglia M1 polarization. China J. Chin. Mater. Med. 2020, 45, 4964–4970.
[14]	Chen, C.C.; Yin, Q.C.; Tian, J.S.; Gao, X.X.; Qin, X.M.; Du, G.H.; Zhou, Y.Z. Studies on the potential link between antidepressant effect of Xiaoyao San and its pharmacological activity of hepatoprotection based on multi-platform metabolomics. J. Ethnopharmacol. 2020, 249, 112432.
[15]	Li, Y.J.; Wei, D.D.; Zhang, M.H.; Yue, T.T.; Du, H.M.; Liu, Q.; Gan, S.H.; Liu, H.B.; Dong, Y.J.; Qiao, X.Y.; Zhang, Y.C.; Yang, L.P. Xiaoyao Pill improves the Affective Dysregulation of Sleep-deprived Female Mice by inhibiting Brain Injury and regulating the Content of Monoamine Neurotransmitter. Curr. Pharm. Biotechnol. 2022, 23, 1080–1093.
[16]	Fang, Y.; Shi, B.Y.; Liu, X.B.; Luo, J.E.; Rao, Z.L.; Liu, R.; Zeng, N. Xiaoyao pills attenuate inflammation and nerve injury induced by lipopolysaccharide in hippocampal neurons in vitro. Neural Plast. 2020, 2020, 1–12.
[17]	Guo, R.; Qin, W.S.; Zhang, S.Y.; Zhang, S.L. Effects of modified Xiaoyao San on TLR4/NF-κB pathway in hippocampal microglia of LPS-induced depression model rats. Chin. J. Appl. Physiol. 2020, 36, 354–357.
[18]	Wang, M.M.; Bi, Y.M.; Zeng, S.M.; Liu, Y.; Shao, M.; Liu, K.; Deng, Y.J.; Wen, G.; Sun, X.G.; Zeng, P.; Jing, L.L.; Lv, Z.P. Modified Xiaoyao San ameliorates depressive-like behaviors by triggering autophagosome formation to alleviate neuronal apoptosis. Biomed. Pharmacother. 2019, 111, 1057–1065.
[19]	Shi, B.Y.; Rao, Z.L.; Luo, J.; Liu, X.B.; Fang, Y.; Cao, H.J.; Zeng, N. Protective effect and mechanism of Xiaoyao San on lipopolysaccharide-induced hippocampal neurons injury. China J. Chin. Mater. Med. 2019, 44, 781–786.
[20]	Liu, C.Z.; Ying, Z.H.; Li, Z.F.; Zhang, L.; Li, X.; Gong, W.B.; Sun, J.; Fan, X.J.; Yang, K.; Wang, X.C.; Wei, S.; Dong, N. Danzhi Xiaoyao Powder promotes neuronal regeneration by downregulating Notch signaling pathway in the treatment of generalized anxiety disorder. Front Pharmacol. 2021, 12, 772576.
[21]	Chen, G.A.; Feng, P.M.; Wang, S.F.; Ding, X.P.; Xiong, J.Y.; Wu, J.H.; Wang, L.H.; Chen, W.; Chen, G.X.; Han, M.; Zou, T.; Li, L.; Du, H.B. An herbal formulation of Jiawei Xiaoyao for the treatment of functional dyspepsia: a multicenter, randomized, placebo-controlled, clinical trial. Clin. Transl. Gastroenterol. 2020, 11, e00241.
[22]	Ren, X.J.; Wang, Q.Q.; Zhang, X.P.; Wang, G.Y.; Liu, T.; Deng, N.; Yan, D.Q. Establishment of a rat model with ageing insomnia induced by D-galactosef and para-chlorophenylalanine. Exp. Ther. Med. 2020, 20, 3228–3236.
[23]	Qiu, Y.Y.; Mao, Z.J.; Ruan, Y.P.; Zhang, X. Exploration of the anti-insomnia mechanism of Ganoderma by central-peripheral multi-level interaction network analysis. BMC Microbiol. 2021, 21, 296.
[24]	Pahal, S.; Gupta, A.; Choudhary, P.; Chaudhary, A.; Singh, S. Network pharmacological evaluation of Withania somnifera bioactive phytochemicals for identifying novel potential inhibitors against neurodegenerative disorder. J. Biomol. Struct. Dyn. 2022, 40, 10887–10898.
[25]	Costemale-Lacoste, J.F.; Colle, R.; Martin, S.; El Asmar, K.; Loeb, E.; Feve, B.; Verstuyft, C.; Trabado, S.; Ferreri, F.; Haffen, E.; Polosan, M.; Becquemont, L.; Corruble, E. Glycogen synthase kinase-3β genetic polymorphisms and insomnia in depressed patients: a prospective study. J. Affect. Disord. 2018, 240, 230–236.
[26]	Liao, Y.L.; Bae, H.J.; Park, J.H.; Zhang, J.B.; Koo, B.; Lim, M.K.; Han, E.H.; Lee, S.H.; Jung, S.Y.; Lew, J.H.; Ryu, J.H. Aster glehni extract ameliorates scopolamine-induced cognitive impairment in mice. J. Med. Food. 2019, 22, 685–695.