Deciphering the mechanism of Liu Wei Di Huang Wan in treating premature ovarian failure: a comprehensive exploration through network pharmacology and molecular docking analysis

doi:10.5246/jcps.2024.09.060

Abstract

Abstract:

Premature ovarian failure (POF) is a prevalent gynecological disorder with significant implications for the physical and mental well-being of affected individuals. Liu Wei Di Huang Wan (LWDHW), a Chinese herbal compound, has demonstrated efficacy in alleviating the effects of POF. However, the underlying mechanism of action of LWDHW remains unclear. This study aimed to elucidate the potential molecular mechanism of LWDHW in treating POF using network pharmacology and molecular docking techniques. The active ingredients of LWDHW were initially screened through the TCMSP platform. At the same time, the relevant target genes associated with POF were identified using databases such as Disgenet, TTD, Drugbank, GeneCards, OMIM, and PharmGKB. Data analysis was conducted using the R language, Cytoscape, and STRING to construct and analyze the traditional Chinese medicine (TCM) regulatory network and protein-protein interaction (PPI) network maps. Subsequently, GO and KEGG enrichment analyses were performed using the R language. Finally, molecular docking was carried out between the protein receptors of the core genes and the corresponding small-molecule ligands. The study revealed 49 components and 189 predicted targets (after de-duplication) of LWDHW, along with 4524 targets (after de-duplication) associated with POF. Through comparative analysis, 163 potential genes were identified as common targets of LWDHW and POF, participating in biological processes such as response to chemical substances, molecular function regulation, and signaling receptor binding. Key biological pathways implicated included the MAPK signaling pathway, IL-17 signaling pathway, and HIF-1 signaling pathway, among others. Molecular docking results demonstrated a robust binding ability between the core genes of LWDHW and their corresponding ingredients. In conclusion, this comprehensive analysis provided insights into the potential molecular mechanisms of LWDHW in treating POF. The identified common targets and associated pathways contributed to our understanding of how LWDHW exerted its therapeutic effects, paving the way for further research and clinical applications. It is worth noting that future studies with experimental validation and clinical trials are essential to confirm these findings and establish the safety and efficacy of LWDHW in the treatment of POF.

Key words: Network pharmacology, Liu Wei Di Huang Wan, Premature ovarian failure, Molecular docking

Supporting:

Ping Shang, Lin Liu, Yi Fang. Deciphering the mechanism of Liu Wei Di Huang Wan in treating premature ovarian failure: a comprehensive exploration through network pharmacology and molecular docking analysis[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(9): 805-818.

Figures/Tables 11

Table 1. The main active components of LWDHW.

Table 2. The specific meaning of the abbreviated compound-target interaction network diagram of LWDHW.

Table 3. The binding energies of eight key targets and their interacting compounds.

References 37

[1]	Lim, Y.M.; Jeong, K.; Lee, S.R.; Chung, H.W.; Lee, W. Association between premature ovarian insufficiency, early menopause, socioeconomic status in a nationally representative sample from Korea. Maturitas. 2019, 121, 22–27.
[2]	Qin, Y.Y.; Jiao, X.; Simpson, J.L.; Chen, Z.J. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum. Reprod. Update. 2015, 21, 787–808.
[3]	Chen, Z.J. Reproductive endocrinology. Beijing: People’s Health Publishing House. 2016.
[4]	Shi, G.L.; Lei, Z.Y. New advances in the etiology and treatment of premature ovarian failure. Med. Inf. 2011, 24, 5597–5598.
[5]	Kalantari, H.; Madani, T.; Zari Moradi, S.; Mansouri, Z.; Almadani, N.; Gourabi, H.; Mohseni Meybodi, A. Cytogenetic analysis of 179 Iranian women with premature ovarian failure. Gynecol. Endocrinol. 2013, 29, 588–591.
[6]	Zhang, H.J.; Fan, C.L.; Wei, S.B. Current status of Chinese and Western medicine treatment for premature ovarian failure due to abnormal immune function. Clin. J. Tradit. Chin. Med. 2018, 30, 1006–1010.
[7]	Zhang, Y.; Liu, Y.; Wang, H. Exploration of Professor Wang Peijuan’s experience in treating early-onset ovarian insufficiency using the method of tonifying the kidney and activating blood. Inn. Mong. Tradit. Chin. Med. 2020, 39, 70–72.
[8]	Zhang, M.M.; Song, K.K.; Liu, J.Y. Exploration of Huang Guangying’s idea of combining Chinese and Western medicine in the treatment of early-onset ovarian insufficiency. Chin. J. Int. Tradit. Chin. West. Med. 2019, 39, 621–623.
[9]	Zhao, J.; Liu, J.J. Professor Liu Jingjun's clinical experience on ovarian insufficiency . World Abstr. Latest Med. Inf. 2018, 18, 214–215.
[10]	Liu, X.L.; Wu, Z.C.; Dai, H. Clinical effect observation of Liu Wei Di Huang Wan in the treatment of premature ovarian failure. J. Pract. Gynecol. Endocrinol. (Electronic version). 2019, 6, 72–73.
[11]	Du, J.M. Clinical observation of hormone combined with Liu Wei Di Huang Wan on replacement therapy for premature ovarian failure. Shenzhen J. Int. Med. 2016, 26, 51–53.
[12]	Huang, C.S.; He, S.D.; Guan, Y.C. Effects of cuscuta flavonoids and quercetin on ovarian function in rats with premature ovarian failure induced by Cuscuta polysaccharide. Chin. J. Clin. Pharm. 2020, 36, 667–670.
[13]	Elkady, M.A.; Shalaby, S.; Fathi, F.; El-Mandouh, S. Effects of quercetin and rosuvastatin each alone or in combination on cyclophosphamide-induced premature ovarian failure in female albino mice. Hum. Exp. Toxicol. 2019, 38, 1283–1295.
[14]	Zhao, Y.M.; Zhang, J.K.; Cai, Z.B. Advances in clinical research of Akt inhibitors. Chin. Mod. Appl. Pharm. 2017, 34, 625–630.
[15]	Wang, Q.; Yu, W.N.; Chen, X.Y.; Peng, X.D.; Jeon, S.M.; Birnbaum, M.J.; Guzman, G.; Hay, N. Spontaneous hepatocellular carcinoma after the combined deletion of Akt isoforms. Cancer Cell. 2016, 29, 523–535.
[16]	Asselin, E.; Wang, Y.; Tsang, B.K. X-linked inhibitor of apoptosis protein activates the phosphatidylinositol 3-kinase/Akt pathway in rat granulosa cells during follicular development. Endocrinology. 2001, 142, 2451–2457.
[17]	Caitlin, B.; Jessica, L.R.; Jodie, P.; Melissa, O.; Linnea, A.; Stuart, D.S.; Paula, T.; Teresa, P.; Mary, L.H. Subfertility caused by altered follicular development and oocyte growth in female mice lacking PKB alpha/Akt1. Biol. Reprod. 2010, 82, 246–56.
[18]	Brown, C.; LaRocca, J.; Pietruska, J.; Ota, M.; Anderson, L.; Duncan Smith, S.; Weston, P.; Rasoulpour, T.; Hixon, M.L. Subfertility caused by altered follicular development and oocyte growth in female mice lacking PKBalpha/Akt11. Biol. Reprod. 2010, 82, 246–256.
[19]	Huang, J.Y.; Xu, M.; Wang, Y.Y.; Wen, D.T.; Lin, X.J. Effects of the kidney-supplementing and essence-filling herbal medicine Xianzi Yizhen capsule on the ovarian PI3K/AKT pathway in mice with premature ovarian failure model. Chin. J. Int. Med. 2018, 38, 1203–1208.
[20]	Sun, S.L.; Chen, H.; Zheng, X.X.; Ma, C.Y.; Yue, R.Q. Analysis on the level of IL-6, IL-21, AMH in patients with auto-immunity premature ovarian failure and study of correlation. Exp. Ther. Med. 2018, 16, 3395–3398.
[21]	Yang, M.; Lin, L.; Sha, C.; Li, T.; Zhao, D.; Wei, H.; Chen, Q.; Liu, Y.; Chen, X.; Xu, W. Bone marrow mesenchymal stem cell-derived exosomal miR-144-5p improves rat ovarian function after chemotherapy-induced ovarian failure by targeting PTEN. Lab Invest Actions. Lab Invest Actions. 2020, 100, 342–352.
[22]	Mahran, Y.F.; Badr, A.M.; Aldosari, A.; Bin-Zaid, R.; Alotaibi, H.N. Carvacrol and thymol modulate the cross-talk between TNF-α and IGF-1 signaling in radiotherapy-induced ovarian failure. Oxid. Med. Cell Longev. 2019, 2019, 3173745.
[23]	Stanley, J.A.; Arosh, J.A.; Burghardt, R.C.; Banu, S.K. A fetal whole ovarian culture model for the evaluation of CrVI-induced developmental toxicity during germ cell nest breakdown. Toxicol. Appl. Pharmacol. 2015, 289, 58–69.
[24]	Wang, M. Exploring the analgesic mechanism of electroacupuncture labor pain from MAPK/ERK signaling pathway. Guangxi Univ. Tradit. Chin. Med. 2016.
[25]	Arthur, J.S.C.; Ley, S.C. Mitogen-activated protein kinases in innate immunity. Nat. Rev. Immunol. 2013, 13, 679–692.
[26]	Zhu, C.F.; Qi, X.L.; Chen, Y.N.; Sun, B.; Dai, Y.L.; Gu, Y. PI3K/Akt and MAPK/ERK1/2 signaling pathways are involved in IGF-1-induced VEGF-C upregulation in breast cancer. J. Cancer Res. Clin. Oncol. 2011, 137, 1587–1594.
[27]	Li, Z.W.; Li, C.L.; Du, L.L.; Zhou, Y.; Wu, W. Human chorionic gonadotropin β induces migration and invasion via activating ERK1/2 and MMP-2 in human prostate cancer DU145 cells. PLoS One. 2013, 8, e54592.
[28]	Liu, T.; Lin, J.J.; Chen, C.; Nie, X.L.; Dou, F.F.; Chen, J.L.; Wang, Z.X.; Gong, Z.B. MicroRNA-146b-5p overexpression attenuates premature ovarian failure in mice by inhibiting the Dab2ip/Ask1/p38-Mapk pathway and γH2A.X phosphorylation. Cell Prolif. 2021, 54, e12954.
[29]	Yin, N.; Wang, Y.L.; Lu, X.Y.; Liu, R.R.; Zhang, L.S.; Zhao, W.; Yuan, W.W.; Luo, Q.Q.; Wu, H.; Luan, X.Y.; Zhang, H.Q. hPMSC transplantation restoring ovarian function in premature ovarian failure mice is associated with change of Th17/Tc17 and Th17/Treg cell ratios through the PI3K/Akt signal pathway. Stem Cell Res. Ther. 2018, 9, 37. doi: 10.1186/s13287-018-0772-x.
[30]	Zhou, J.L.; Yao, W.; Li, C.Y.; Wu, W.J.; Li, Q.F.; Liu, H.L. Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1α in mouse granulosa cells. Cell Death Dis. 2017, 8, e3001.
[31]	Alam, H.; Weck, J.; Maizels, E.; Park, Y.; Lee, E.J.; Ashcroft, M.; Hunzicker-Dunn, M. Role of the phosphatidylinositol-3-kinase and extracellular regulated kinase pathways in the induction of hypoxia-inducible factor (HIF)-1 activity and the HIF-1 target vascular endothelial growth factor in ovarian granulosa cells in response to follicle-stimulating hormone. Endocrinology. 2009, 150, 915–928.
[32]	Alam, H.; Maizels, E.T.; Park, Y.; Ghaey, S.; Feiger, Z.J.; Chandel, N.S.; Hunzicker-Dunn, M. Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) pathway is necessary for induction of select protein markers of follicular differentiation. J. Biol. Chem. 2004, 279, 19431–19440.
[33]	Baddela, V.S.; Sharma, A.; Michaelis, M.; Vanselow, J. HIF1 driven transcriptional activity regulates steroidogenesis and proliferation of bovine granulosa cells. Sci. Rep. 2020, 10, 3906.
[34]	Park, J.M.; Park, Y.J.; Koh, I.; Kim, N.K.; Baek, K.H.; Yun, B.O.; Lee, K.J.; Song, J.Y.; Lee,U.; Kwack, K.B. Association of an APBA3 Missense Variant with Risk of Premature Ovarian Failure in the Korean Female Population. J. Pers. Med. 2020, 10, 193.
[35]	Zhou, F.R.; Song, Y.F.; Liu, X.; Zhang, C.; Li, F.; Hu, R.N.; Huang, Y.J.; Ma, W.W.; Song, K.K.; Zhang, M.M. Si-Wu-Tang facilitates ovarian function through improving ovarian microenvironment and angiogenesis in a mouse model of premature ovarian failure. J. Ethnopharmacol. 2021, 280, 114431.
[36]	Wu, L.X.; Zhang, Z.H.; Pan, X.Y.; Wang, Z.C. Expression and contribution of the HIF-1α/VEGF signaling pathway to luteal development and function in pregnant rats. Mol. Med. Rep. 2015, 12, 7153–7159.
[37]	Yang, M.; Wang, L.; Wang, X.R.; Wang, X.Z.; Yang, Z.Q.; Li, J.X. IL-6 promotes FSH-induced VEGF expression through JAK/STAT3 signaling pathway in bovine granulosa cells. Cell Physiol. Biochem. 2017, 44, 293–302.