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Journal of Traditional Chinese Medicine >

2026 , Vol. 46 >Issue 3: 517 - 529

DOI: https://doi.org/10.19852/j.cnki.jtcm.2026.03.001

Original Articles

Activation of the nucleus nuclear factor erythroid 2-related factor 2 via ghrelin/growth hormone secretagogue receptor 1a signaling by Yueju pill (越鞠丸) confers cardioprotective and antidepressant effects

  • JING Yunjia ,
  • YE Zhaoyi ,
  • ZHU Yan ,
  • GAO Xin ,
  • CHEN Xi ,
  • WANG Kaixuan ,
  • HUANG Dafeng ,
  • HU Yue ,
  • JIANG Jiancong
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  • 1 Cardiovascular Division, Yixing Traditional Chinese Medicine Hospital, Yixing 214299, China
    2 School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
    3 Cardiovascular Division, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210014, China
Prof. JIANG Jiancong, Cardiovascular Division, Yixing Traditional Chinese Medicine Hospital, Yixing 214299, China. 15371072272@163.com,Telephone: +86-510-87927059

Received date: 2025-01-07

  Accepted date: 2025-08-29

  Online published: 2026-06-08

Supported by

Yixing City Outstanding Medical Talent Award: To Explore the Regulation of Ghrelin by Yueju Pill and its Similar Prescriptions Based on the Simultaneous Treatment of Heart and Brain Theory(Q202354)

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Abstract

OBJECTIVE: To investigate the efficacy and mechanistic foundations of the Traditional Chinese Medicine Yueju pill (YJP, 越鞠丸) for treating the complex comorbidity of heart failure and depression.

METHODS: C57BL/6 male mice were used to establish a robust congestive heart failure (CHF) model with concomitant depressive manifestations. Echocardiographic assessments were conducted to evaluate cardiac structure and function in the mice. Depression-related behavioral tests and the detection of monoamine neurotransmitters were performed to assess the antidepressant-like effectiveness of YJP. Western blot analysis was conducted to measure the expression levels of key components in the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO1) antioxidant pathway, NRF2/brain-derived neurotrophic factor (BDNF) pathway, and ghrelin/growth hormone secretagogue receptor (GHS-R)1a pathway in the myocardium and hippocampus. To explore the mechanistic role of the ghrelin/GHS-R1a pathway, the ghrelin receptor antagonist D-Lys3-growth hormone-releasing peptide-6 was introduced to enable the iterative evaluation of the aforementioned parameters.

RESULTS: YJP improved cardiac dysfunction and myocardial fibrosis and markedly ameliorated depressive behaviors. It also improved neuron damage, boosted the growth of dendritic spines to enhance synaptic plasticity, and alleviated monoamine neurotransmitter imbalances. Additionally, the NRF2/BDNF, ghrelin/GHS-R1a, and NRF2/HO1 antioxidant pathways were promoted by YJP, with the increased expression of key components of the three pathways. The addition of a GHS-R1a antagonist impaired the antidepressant and cardioprotective effects of YJP.

CONCLUSIONS: YJP effectively improved cardiac dysfunction and depressive-like behaviors in mice by activating NRF2 viamediation of the ghrelin/GHS-R1a signaling axis within both the myocardial and hippocampal domains.

Key words： depression; heart failure; NF-E2-related factor 2; ghrelin; receptors, ghrelin; Yueju pill

Cite this article

JING Yunjia , YE Zhaoyi , ZHU Yan , GAO Xin , CHEN Xi , WANG Kaixuan , HUANG Dafeng , HU Yue , JIANG Jiancong . Activation of the nucleus nuclear factor erythroid 2-related factor 2 via ghrelin/growth hormone secretagogue receptor 1a signaling by Yueju pill (越鞠丸) confers cardioprotective and antidepressant effects[J]. Journal of Traditional Chinese Medicine, 2026 , 46(3) : 517 -529 . DOI: 10.19852/j.cnki.jtcm.2026.03.001

References

1. Sbolli M, Fiuzat M, Cani D, O'Connor CM. Depression and heart failure: the lonely comorbidity. Eur J Heart Fail 2020; 22: 2007-17.
2. Crump C, Sundquist J, Kendler KS, Sieh W, Edwards AC, Sundquist K. Risks of depression and suicide after diagnosis with heart failure: a national cohort study. JACC Heart Fail 2022; 10: 819-27.
3. Poletti V, Pagnini F, Banfi P, Volpato E. The role of depression on treatment adherence in patients with heart failure-a systematic review of the literature. Curr Cardiol Rep 2022; 24: 1995-2008.
4. Li ZW, Zhao HM, Wang J. Metabolism and chronic inflammation: the links between chronic heart failure and comorbidities. Front Cardiovasc Med 2021; 5: 650278.
5. Patrick M, Miller B, Will B, Bena JF, Morrison SL, Siegmund LA. Anxiety and depression moderate the relationship between quality of life and self-care in patients with heart failure. Geriatric Nursing 2022; 44: 54-9.
6. Xie DY, Xiong K, Su XL, et al. Identification of an endogenous glutamatergic transmitter system controlling excitability and conductivity of atrial cardiomyocytes. Cell research 2021; 31: 951-64.
7. Zhu ZH(Yuan dynasty). Dan Xi Xin Fa. Beijing: People's Medical Publishing House, 2005: 361.
8. Wang W, Zhou T, Jia R, et al. Nmda receptors and l-arginine/nitric oxide/cyclic guanosine monophosphate pathway contribute to the antidepressant-like effect of Yueju pill in mice. Biosci Rep 2019; 39: BSR20190524.
9. Zhang HL, Sun Y, Qian SY, et al. Yueju-ganmaidazao decoction confers rapid antidepressant-like effects and the involvement of suppression of NMDA/NO/CGMP signaling. J Ethnopharmacol 2020; 250: 112380.
10. Zhang HL, Sun Y, Yau SY, et al. Synergistic effects of two naturally occurring iridoids in eliciting a rapid antidepressant action by up-regulating hippocampal pacap signalling. Br J Pharmacol 2022; 179: 4078-91.
11. Guo LT, Wang SQ, Su J, et al. Baicalin ameliorates neuroinflammation-induced depressive-like behavior through inhibition of toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway. J Neuroinflammation 2019; 16: 95.
12. Li YJ, Song W, Tong Y, et al. Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27A/SYK/NF-κB axis. J Neuroinflammation 2021; 18: 1.
13. Shi SQ, Yan H, Chen Y, et al. Pharmacokinetic study of precisely representative antidepressant, prokinetic, anti-inflammatory and anti-oxidative compounds from fructus aurantii and magnolia bark. Chemico-Biological Interactions 2020; 315: 108851.
14. Han QQ, Huang HJ, Wang YL, et al. Ghrelin exhibited antidepressant and anxiolytic effect via the p38-mapk signaling pathway in hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 2019; 93: 11-20.
15. Yang CY Yang P, Yang CY Yang P. Gw29-e 1601 ghrelin partially protects against heart failure after myocardial infarction by increasing the bcl-2/bax ratio in a ghs-r1a-dependent manner. J Am Coll Cardiol 2018; 72: C49.
16. Hosoda H. Effect of ghrelin on the cardiovascular system. Biology (Basel) 2022; 11: 1190.
17. Wang M, Qian L, Li J, et al. Ghsr deficiency exacerbates cardiac fibrosis: role in macrophage inflammasome activation and myofibroblast differentiation. Cardiovasc Res 2020; 116: 2091-102.
18. Wu SJ, Liao XY, Zhu ZJ, et al. Antioxidant and anti-inflammation effects of dietary phytochemicals: the NRF2/NF-κB signalling pathway and upstream factors of Nrf2. Phytochemistry 2022; 204: 113429.
19. Yamamoto M, Kensler TW, Motohashi H. The keap1-Nrf2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev 2018; 98: 1169-203.
20. Wang Q, Liu AD, Li TS, Tang Q, Wang XC, Chen XB. Ghrelin ameliorates cardiac fibrosis after myocardial infarction by regulating the Nrf2/NADPH/ROS pathway. Peptides 2021; 144: 170613.
21. Ma S, Feng J, Lin XY, et al. Nicotinamide riboside alleviates cardiac dysfunction and remodeling in pressure overload cardiac hypertrophy. Oxid Med Cell Longev 2021; 2021: 5546867.
22. Iyer KA, Alix K, Eltit JM, et al. Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test. Psychopharmacology (Berl) 2019; 236: 2093-104.
23. Alburges ME, Narang N, Wamsley JK. A sensitive and rapid hplc-ecd method for the simultaneous analysis of norepinephrine, dopamine, serotonin and their primary metabolites in brain tissue. Biomed Chromatogr 1993; 7: 306-10.
24. Cui LL, Li S, Wang SM, et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther 2024; 9: 30.
25. Malhi GS, Mann JJ. Depression. Lancet 2018; 392: 2299-312.
26. Cao QQ, Zou QM, Zhao X, et al. Regulation of bdnf transcription by Nrf2 and mecp2 ameliorates mptp-induced neurotoxicity. Cell Death Discov 2022; 8: 267.
27. Cheng YJ, Chen B, Xie WQ, et al. Ghrelin attenuates secondary brain injury following intracerebral hemorrhage by inhibiting nlrp3 inflammasome activation and promoting Nrf2/ARE signaling pathway in mice. International Immunopharmacology 2020; 79: 106180.
28. Wang L, Zhang X, Xiong XX, et al. Nrf2 regulates oxidative stress and its role in cerebral ischemic stroke. Antioxidants (Basel) 2022; 11: 2377.
29. Wang H, Zhou XM, Wu LY, et al. Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury. J Neuroinflammation 2020; 17: 188.
30. George M, Tharakan M, Culberson J, Reddy AP, Reddy PH. Role of Nrf 2 in aging, alzheimer's and other neurodegenerative diseases. Ageing Res Rev 2022; 82: 101756.
31. Li HL, Zhuang WW, Xiong TQ, et al. Nrf2 deficiency attenuates atherosclerosis by reducing LOX-1-mediated proliferation and migration of vascular smooth muscle cells. Atherosclerosis 2022; 347: 1-16.
32. Gutierrez-Cuevas J, Galicia-Moreno M, Monroy-Ramirez HC, et al. The role of Nrf2 in obesity-associated cardiovascular risk factors. Antioxidants (Basel) 2022; 11: 235.
33. Chen QM. Nrf 2 for cardiac protection: Pharmacological options against oxidative stress. Trends Pharmacol Sci 2021; 42: 729-44.
34. Facchinetti MM. Heme-oxygenase-1. Antioxid Redox Signal 2020; 32: 1239-42.
35. Ross D, Siegel D. The diverse functionality of NQO1 and its roles in redox control. Redox Biol 2021; 41: 101950.
36. Chen QM. Nrf 2 for protection against oxidant generation and mitochondrial damage in cardiac injury. Free Radic Biol Med 2022; 179: 133-43.
37. Brandes MS, Zweig JA, Tang A, Gray NE. Nrf2 activation ameliorates oxidative stress and improves mitochondrial function and synaptic plasticity, and in a53t α-synuclein hippocampal neurons. Antioxidants (Basel) 2021; 11.
38. Howick K, Chruscicka B, Felice D, et al. Behavioural characterization of ghrelin ligands, anamorelin and hm01: appetite and reward-motivated effects in rodents. Neuropharmacology 2020; 168: 108011.
39. Gray SM, Page LC, Tong J. Ghrelin regulation of glucose metabolism. J Neuroendocrinol 2019; 31: e12705.
40. Smith A, Woodside B, Abizaid A. Ghrelin and the control of energy balance in females. Front Endocrinol (Lausanne) 2022; 13: 904754.
41. Gross JD, Zhou Y, Barak LS, Caron MG. Ghrelin receptor signaling in health and disease: a biased view. Trends Endocrinol Metab 2023; 34: 106-18.
42. Rouault AAJ, Buscaglia P, Sebag JA. Mrap 2 inhibits β-arrestin recruitment to the ghrelin receptor by preventing GHSR1a phosphorylation. J Biol Chem 2022; 298: 102057.
43. Li N, Xiao KW, Mi X, et al. Ghrelin signaling in dCA1 suppresses neuronal excitability and impairs memory acquisition via PI3K/ AKT/GSK-3β cascades. Neuropharmacology 2022; 203: 108871.
44. Jasek-Gajda E, Jurkowska H, Jasinska M, Lis GJ. Targeting the MAPK/ERK and PI3K/AKT signaling pathways affects Nrf2, Trx and GSH antioxidant systems in leukemia cells. Antioxidants (Basel) 2020; 9: 633.
45. Edvardsson CE, Vestlund J, Jerlhag E. A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats. Eur J Pharmacol 2021; 899: 174039.
46. Li W, Ali T, Zheng C, et al. Anti-depressive-like behaviors of apn ko mice involve Trkb/BDNF signaling related neuroinflammatory changes. Mol Psychiatry 2022; 27: 1047-58.
47. Murphy SE, Capitao LP, Giles SLC, Cowen PJ, Stringaris A, Harmer CJ. The knowns and unknowns of SSRI treatment in young people with depression and anxiety: efficacy, predictors, and mechanisms of action. Lancet Psychiatry 2021; 8: 824-35.
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