Network pharmacology and experimental validation to investigate the effects of Fructus Psoraleae on the HPA and HPG axes of young rats

  • Jiayi Shan Department of Pediatrics of Traditional Chinese Medicine, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510150, China
  • Hui Qi The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
  • Zilun Wu The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
  • Ran Li The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
  • Yuanyuan Song The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
  • Chuanying Liu The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
  • Jiacong Xiao The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
  • Wenjia Zhong Department of Pharmacy, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510230, China
  • Ying Zhang Department of Pediatrics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510230, China
Keywords: Fructus Psoraleae; biomechanics; network pharmacology; HPA axis; HPG axis; precocious puberty
Article ID: 1576

Abstract

To investigate the effects of Fructus Psoraleae (FP) on both the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis in juvenile rats across pre-pubertal and post-pubertal stages, as well as to explore its potential implications for biological mechanical properties, a multidisciplinary approach combining network pharmacological analysis, animal experimentation, and biomechanical assessment was employed. Fructus Psoraleae’s potential pharmacological components and targets were identified via the TCMSP database. A GEO search for “precocious puberty” facilitated differential gene analysis with GEO2R. Protein interactions were examined using String, while DAVID analyzed biological processes. Molecular docking was performed using CB-Dock for validation. The effects of Fructus Psoraleae (FP) on the expression of endocrine-related proteins in the HPA and HPG axes of young rats were assessed via enzyme-linked immunosorbent assay (ELISA). Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to evaluate the expression levels of relevant genes. Computational analysis revealed that FP contains 11 potential pharmacodynamic components and 19 potential targets associated with precocious puberty-related disorders. Notably, compounds such as isopsoralidin, bavachin, and psoralidin exhibited strong binding affinity to acetylcholinesterase (ACHE) targets. KEGG pathway analysis indicated their involvement in significant biological pathways, including the HIF-1 signaling pathway and AMPK signaling pathway. The ELISA results demonstrated notable differences between the FP group and the control group. During the pre-pubertal phase, the FP group exhibited significantly lower levels of corticotropin-releasing hormone (CRH) compared to the control group (P < 0.05). Conversely, in the post-pubertal stage, the FP group showed elevated levels of gonadotropin-releasing hormone (GnRH) relative to the control group (P < 0.01). From a biomechanical view, variations in hormone concentration may be linked to the regulatory effects of blood flow shear stress on the secretory activity of hypothalamic neurons. Furthermore, qRT-PCR analysis showed that estrogen receptor 1 (ESR1) expression was significantly upregulated in the FP group during the pre-pubertal stage (P < 0.01), while ACHE expression was notably reduced in the FP group during the post-pubertal period (P < 0.001). The findings suggest that Fructus Psoraleae does not exert a significant effect on the gonadal axis during the pre-pubertal phase; however, it may have the potential to activate the gonadal axis during the post-pubertal phase. Biomechanical factors may play a significant role in modulating these effects, offering fresh insights into the mechanism by which Fructus Psoraleae exerts its influence on the endocrine system.

References

1. Latronico AC, Brito VN, Carel JC. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol. 2016; 4(3): 265-74. doi: 10.1016/S2213-8587(15)00380-0

2. Partsch CJ. Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Human Reproduction Update. 2001; 7(3): 292-302. doi: 10.1093/humupd/7.3.292

3. Kim SH, Huh K, Won S, et al. A Significant Increase in the Incidence of Central Precocious Puberty among Korean Girls from 2004 to 2010. PLOS ONE. 2015; 10(11): e0141844. doi: 10.1371/journal.pone.0141844

4. Soriano-Guillén L, Corripio R, Labarta JI, et al. Central Precocious Puberty in Children Living in Spain: Incidence, Prevalence, and Influence of Adoption and Immigration. The Journal of Clinical Endocrinology & Metabolism. 2010; 95(9): 4305-4313. doi: 10.1210/jc.2010-1025

5. Brito VN, Spinola-Castro AM, Kochi C, et al. Central precocious puberty: revisiting the diagnosis and therapeutic management. Archives of Endocrinology and Metabolism. 2016; 60(2): 163-172. doi: 10.1590/2359-3997000000144

6. Parent AS, Teilmann G, Juul A, et al. The Timing of Normal Puberty and the Age Limits of Sexual Precocity: Variations around the World, Secular Trends, and Changes after Migration. Endocrine Reviews. 2003; 24(5): 668-693. doi: 10.1210/er.2002-0019

7. Tong X, Yang Y, Gong S, et al. Data Mining and Network Pharmacology Analysis of Kidney-Tonifying Herbs on the Treatment of Renal Osteodystrophy Based on the Theory of “Kidney Governing Bones” in Traditional Chinese Medicine. Evidence-Based Complementary and Alternative Medicine. 2022; 2022: 1-13. doi: 10.1155/2022/1116923

8. Cutia CA, Christian-Hinman CA. Mechanisms linking neurological disorders with reproductive endocrine dysfunction: Insights from epilepsy research. Frontiers in Neuroendocrinology. 2023; 71: 101084. doi: 10.1016/j.yfrne.2023.101084

9. Allen JO, Mezuk B, Byrd DR, et al. Mechanisms of Cardiometabolic Health Outcomes and Disparities: What Characteristics of Chronic Stressors are Linked to HPA-Axis Dysregulation?. Journal of Aging and Health. 2022; 34(3): 448-459. doi: 10.1177/08982643221085903

10. Chen L, Chen S, Sun P, et al. Psoralea corylifolia L.: a comprehensive review of its botany, traditional uses, phytochemistry, pharmacology, toxicology, quality control and pharmacokinetics. Chinese Medicine. 2023; 18(1). doi: 10.1186/s13020-022-00704-6

11. Luo Y, Liu Q, Lei X, et al. Association of estrogen receptor gene polymorphisms with human precocious puberty: a systematic review and meta-analysis. Gynecological Endocrinology. 2015; 31(7): 516-521. doi: 10.3109/09513590.2015.1031102

12. Yang L, Tang K, Qi Y, et al. Potential metabolic mechanism of girls’ central precocious puberty: a network analysis on urine metabonomics data. BMC Systems Biology. 2012; 6(S3). doi: 10.1186/1752-0509-6-s3-s19

13. Cheuiche AV, da Silveira LG, de Paula LCP, et al. Diagnosis and management of precocious sexual maturation: an updated review. European Journal of Pediatrics. 2021; 180(10): 3073-3087. doi: 10.1007/s00431-021-04022-1

14. Belchetz PE, Plant TM, Nakai Y, et al. Hypophysial Responses to Continuous and Intermittent Delivery of Hypothalamic Gonadotropin-Releasing Hormone. Science. 1978; 202(4368): 631-633. doi: 10.1126/science.100883

15. Yang WJ, Ko KH, Lee KH, et al. The different effects of gonadotropin-releasing hormone agonist therapy on body mass index and growth between normal-weight and overweight girls with central precocious puberty. Annals of Pediatric Endocrinology & Metabolism. 2017; 22(1): 49. doi: 10.6065/apem.2017.22.1.49

16. Boldrin PK, Resende FA, Höhne APO, et al. Estrogenic and mutagenic activities of Crotalaria pallida measured by recombinant yeast assay and Ames test. BMC Complementary and Alternative Medicine. 2013; 13(1). doi: 10.1186/1472-6882-13-216

17. Newill H, Loske R, Wagner J, et al. Oxidation products of stigmasterol interfere with the action of the female sex hormone 17β‐estradiol in cultured human breast and endometrium cell lines. Molecular Nutrition & Food Research. 2007; 51(7): 888-898. doi: 10.1002/mnfr.200700025

18. Sriraman S, Ramanujam GM, Ramasamy M, et al. Identification of beta-sitosterol and stigmasterol in Bambusa bambos (L.) Voss leaf extract using HPLC and its estrogenic effect in vitro. Journal of Pharmaceutical and Biomedical Analysis. 2015; 115: 55-61. doi: 10.1016/j.jpba.2015.06.024

19. Miao L, Jiao C, Shao R, et al. Bakuchiol suppresses oestrogen/testosterone-induced Benign Prostatic Hyperplasia development through up-regulation of epithelial estrogen receptor β and down-regulation of stromal aromatase. Toxicology and Applied Pharmacology. 2019; 381: 114637. doi: 10.1016/j.taap.2019.114637

20. Lim SH, Ha TY, Kim SR, et al. Ethanol extract ofPsoralea corylifoliaL. and its main constituent, bakuchiol, reduce bone loss in ovariectomised Sprague–Dawley rats. British Journal of Nutrition. 2008; 101(7): 1031-1039. doi: 10.1017/s0007114508066750

21. Ge L, Cui Y, Liu B, et al. ERα and Wnt/β catenin signaling pathways are involved in angelicin dependent promotion of osteogenesis. Molecular Medicine Reports. 2019. doi: 10.3892/mmr.2019.9999

22. Park JW, Kim DH, Ahn HN, et al. Activation of Estrogen Receptor by Bavachin from Psoralea corylifolia. Biomolecules and Therapeutics. 2012; 20(2): 183-188. doi: 10.4062/biomolther.2012.20.2.183

23. Wang X, Ji Q, Hu W, et al. Isobavachalcone prevents osteoporosis by suppressing activation of ERK and NF-κB pathways and M1 polarization of macrophages. International Immunopharmacology. 2021; 94: 107370. doi: 10.1016/j.intimp.2021.107370

24. Wang Y, Wang Y, Chen Y, et al. HDAC5 inhibits ovarian angiogenesis in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome. Folia Histochemica et Cytobiologica. 2022; 60(3): 260-270. doi: 10.5603/fhc.a2022.0024

25. Heydarzadeh S, Moshtaghie AA, Daneshpoor M, et al. Regulators of glucose uptake in thyroid cancer cell lines. Cell Communication and Signaling. 2020; 18(1). doi: 10.1186/s12964-020-00586-x

26. Samaan E, Ramadan NM, Abdulaziz HMM, et al. DPP-4i versus SGLT2i as modulators of PHD3/HIF-2α pathway in the diabetic kidney. Biomedicine & Pharmacotherapy. 2023; 167: 115629. doi: 10.1016/j.biopha.2023.115629

27. Chen X, Zheng M, Fei X, et al. Analysis of the efficacy of Dabuyin pill combined with gonadotropin-releasing hormone analogue in the treatment of central precocious puberty girls based on network pharmacology. Translational Pediatrics. 2023; 12(3): 364-374. doi: 10.21037/tp-23-111

28. Lu G, Wu Z, Shang J, et al. The effects of metformin on autophagy. Biomedicine & Pharmacotherapy. 2021; 137: 111286. doi: 10.1016/j.biopha.2021.111286

29. Guo P, Zeng M, Liu M, et al. Isolation of Calenduloside E from Achyranthes bidentata Blume and its effects on LPS/D-GalN-induced acute liver injury in mice by regulating the AMPK-SIRT3 signaling pathway. Phytomedicine. 2024; 125: 155353. doi: 10.1016/j.phymed.2024.155353

30. Baumgartner C, Yadav AK, Chefetz I. AMPK-like proteins and their function in female reproduction and gynecologic cancer. Regulation of Downstream Targets. 2023. doi: 10.1016/bs.apcsb.2022.11.016

31. Zeng B, Huang Y, Xu J, et al. The FOXO transcription factor controls insect growth and development by regulating juvenile hormone degradation in the silkworm, Bombyx mori. Journal of Biological Chemistry. 2017; 292(28): 11659-11669. doi: 10.1074/jbc.m117.777797

32. Xu ML, Luk WKW, Liu EYL, et al. Differentiation of erythroblast requires the dimeric form of acetylcholinesterase: Interference with erythropoietin receptor. Chemico-Biological Interactions. 2019; 308: 317-322. doi: 10.1016/j.cbi.2019.06.006

33. Vastagh C, Farkas I, Csillag V, et al. Cholinergic control of GnRH neuron physiology and luteinizing hormone secretion in male mice: involvement of ACh/GABA co-transmission. The Journal of Neuroscience. 2024. doi: 10.1523/jneurosci.1780-23.2024

34. Leonard ST, Hearn JK, Catling AD, et al. Gonadal hormones modulate the potency of the disruptive effects of donepezil in male rats responding under a nonspatial operant learning and performance task. Behavioural Pharmacology. 2010; 21(2): 121-134. doi: 10.1097/fbp.0b013e328337be3a

35. Klüver N, Yang L, Busch W, et al. Transcriptional Response of Zebrafish Embryos Exposed to Neurotoxic Compounds Reveals a Muscle Activity Dependent hspb11 Expression. PLoS ONE. 2011; 6(12): e29063. doi: 10.1371/journal.pone.0029063

36. Yi LT, Li YC, Pan Y, et al. Antidepressant-like effects of psoralidin isolated from the seeds of Psoralea Corylifolia in the forced swimming test in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2008; 32(2): 510-519. doi: 10.1016/j.pnpbp.2007.10.005

37. Granata L, Fanikos M, Brenhouse HC. Early life adversity accelerates hypothalamic drive of pubertal timing in female rats with associated enhanced acoustic startle. Hormones and Behavior. 2024; 159: 105478. doi: 10.1016/j.yhbeh.2024.105478

38. Yu J, Li XF, Tsaneva-Atanasova K, et al. Chemogenetic activation of PVN CRH neurons disrupts the estrous cycle and LH dynamics in female mice. Frontiers in Endocrinology. 2024; 14. doi: 10.3389/fendo.2023.1322662

39. Ghizzoni L, Vottero A, Street ME, et al. Dose-dependent inhibition of growth hormone (GH)-releasing hormone-induced GH release by corticotropin-releasing hormone in prepubertal children. The Journal of Clinical Endocrinology & Metabolism. 1996; 81(4): 1397-1400. doi: 10.1210/jcem.81.4.8636340

40. Wang YT, Wu QH, Chen L, et al. Effects of sub-chronic exposure to microcystin-LR on the endocrine system of male rats. Science of The Total Environment. 2024; 906: 166839. doi: 10.1016/j.scitotenv.2023.166839

41. Yang R, You X, Tang X, et al. Corticotropin-releasing hormone inhibits progesterone production in cultured human placental trophoblasts. Journal of Molecular Endocrinology. 2006; 37(3): 533-540. doi: 10.1677/jme.1.02119

42. Kauffman AS, Navarro VM, Kim J, et al. Sex differences in the regulation of Kiss1/NKB neurons in juvenile mice: implications for the timing of puberty. American Journal of Physiology-Endocrinology and Metabolism. 2009; 297(5): E1212-E1221. doi: 10.1152/ajpendo.00461.2009

Published
2025-02-27
How to Cite
Shan, J., Qi, H., Wu, Z., Li, R., Song, Y., Liu, C., Xiao, J., Zhong, W., & Zhang, Y. (2025). Network pharmacology and experimental validation to investigate the effects of Fructus Psoraleae on the HPA and HPG axes of young rats. Molecular & Cellular Biomechanics, 22(3), 1576. https://doi.org/10.62617/mcb1576
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Article