Bruceine D ameliorates the balance of Th1/Th2 in a mouse model of ovalbumin-induced allergic asthma via inhibiting the NOTCH pathway

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Ying Nie
Bangkun Yang
Junfeng Hu
Lingling Zhang
Zhimin Ma


Bruceine D, NOTCH, ovalbumin-induced allergic asthma, T helper 1 cells, T helper 2 cells


Allergic asthma is a heterogeneous inflammatory disorder triggered by inhaled allergens, leading to airflow obstruction, bronchial inflammation, and airway hyperresponsiveness (AHR). T helper (Th) 2 cell-mediated immune response and airway inflammation are the key features of allergic asthma. Bruceine D (BD) is a bioactive compound extracted from the seeds of Brucea javanica. The present study aimed to investigate the effects of increased doses of BD on AHR, secretion of Th1-/Th2-associated cytokines, and inflammatory cell infiltration in ovalbumin (OVA)-induced allergic asthma mice. The results showed that BD reduced OVA-induced inflammatory cell infiltration and bronchial hyperresponsiveness into the peribronchial tissues and perivascular areas. Mice treated with BD also showed significantly decreased expressions of Th2-associated cytokines (i.e., interleukin (IL)-4, IL-5, and IL-13) and elevated production of Th1-associated cytokines (i.e., interferon gamma and IL-2) following OVA stimulation. BD treatment dose-dependently inhibited OVA-induced accumulation of inflammatory cells in asthmatic mice. Further analysis revealed that OVA exposure upregulated pulmonary expressions of NOTCH signaling receptors, a group of transmembrane proteins that communicate signals upon binding to transmembrane ligands expressed on adjacent cells, while BD treatment significantly abolished OVA-induced activation of the NOTCH pathway. In conclusion, BD protected mice against OVA-induced allergic asthma by reducing AHR and restoring the Th1/Th2 balance through the NOTCH signaling pathway. Our findings highlighted the potential of BD as a therapeutic agent for allergic asthma.

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1. Quirt J, Hildebrand KJ, Mazza J, Noya F, Kim H. Asthma. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):50. 10.1186/s13223-018-0279-0

2. Backman H, Räisänen P, Hedman L, Stridsman C, Andersson M, Lindberg A, et al. Increased prevalence of allergic asthma from 1996 to 2006 and further to 2016-results from three population surveys. Clin Exp Allergy. 2017;47(11):1426–1435. 10.1111/cea.12963

3. Pakkasela J, Ilmarinen P, Honkamäki J, Tuomisto LE, Andersén H, Piirilä P, et al. Age-specific incidence of allergic and non-allergic asthma. BMC Pulm Med. 2020;20(1):9. 10.1186/s12890-019-1040-2

4. Ramadan AA, Gaffin JM, Israel E, Phipatanakul W. Asthma and corticosteroid responses in childhood and adult asthma. Clin Chest Med. 2019;40(1):163–177. 10.1016/j.ccm.2018.10.010

5. Kim YM, Kim YS, Jeon SG, Kim YK. Immunopathogenesis of allergic asthma: more than the th2 hypothesis. Allergy Asthma Immunol Res. 2013;5(4):189–196. 10.4168/aair.2013.5.4.189

6. Azman S, Sekar M, Bonam SR, Gan SH, Wahidin S, Lum PT, et al. Traditional medicinal plants conferring protection against ovalbumin-induced asthma in experimental animals: a review. J Asthma Allergy. 2021;14:641–662. 10.2147/JAA.S296391

7. León B, Ballesteros-Tato A. Modulating Th2 cell immunity for the treatment of asthma. Front Immunol. 2021;12:637948. 10.3389/fimmu.2021.637948

8. Boonpiyathad T, Sözener ZC, Satitsuksanoa P, Akdis CA. Immunologic mechanisms in asthma. Semin Immunol. 2019;46:101333. 10.1016/j.smim.2019.101333

9. Koch S, Finotto S. Role of interferon-λ in allergic asthma. J Innate Immun. 2015;7(3):224–230. 10.1159/000369459

10. Subeki, Matsuura H, Takahashi K, Nabeta K, Yamasaki M, Maede Y, et al. Screening of Indonesian medicinal plant extracts for antibabesial activity and isolation of new quassinoids from Brucea javanica. J Nat Products. 2007;70(10):1654–1657. 10.1021/np070236h

11. Fan J, Ren D, Wang J, Liu X, Zhang H, Wu M, et al. Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo. Cell Death Dis. 2020;11(2):126. 10.1038/s41419-020-2317-3

12. Li L, Dong Z, Shi P, Tan L, Xu J, Huang P, et al. Bruceine D inhibits cell proliferation through downregulating LINC01667/MicroRNA-138-5p/Cyclin E1 axis in gastric cancer. Front Pharmacol. 2020;11:584960. 10.3389/fphar.2020.584960

13. Luo C, Wang Y, Wei C, Chen Y, Ji Z. The anti-migration and anti-invasion effects of Bruceine D in human triple-negative breast cancer MDA-MB-231 cells. Exp Ther Med. 2020;19(1):273–279. 10.3892/etm.2019.8187

14. Yang Y, Kong F, Ding Q, Cai Y, Hao Y, Tang B. Bruceine D elevates Nrf2 activation to restrain Parkinson’s disease in mice through suppressing oxidative stress and inflammatory response. Biochem Biophys Res Commun. 2020;526(4):1013–1020. 10.1016/j.bbrc.2020.03.097

15. Cheng Z, Yuan X, Qu Y, Li X, Wu G, Li C, et al. Bruceine D inhibits hepatocellular carcinoma growth by targeting β-catenin/jagged1 pathways. Cancer Lett. 2017;403:195–205. 10.1016/j.canlet.2017.06.014

16. Hua S, Liu F, Wang M. Emodin alleviates the airway inflammation of cough variant asthma in mice by regulating the notch pathway. Med Sci Monit. 2019;25:5621–5629. 10.12659/MSM.915080

17. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington (DC): National Academies Press (US); 2011. PMid: 21595115.

18. Tang Y, Huang W, Song Q, Zheng X, He R, Liu J. Paeonol ameliorates ovalbumin-induced asthma through the inhibition of TLR4/NF-κB and MAPK signaling. Evid Based Complement Alternat Med. 2018;2018:3063145. 10.1155/2018/3063145

19. D’Amato G, Vitale C, Molino A, Stanziola A, Sanduzzi A, Vatrella A, et al. Asthma-related deaths. Multidiscip Respir Med. 2016;11:37. 10.1186/s40248-016-0073-0

20. Bergeron C, Tulic MK, Hamid Q. Airway remodelling in asthma: from benchside to clinical practice. Can Respir J. 2010;17(4):e85–93. 10.1155/2010/318029

21. Brannan JD, Lougheed MD. Airway hyperresponsiveness in asthma: mechanisms, clinical significance, and treatment. Front Physiol. 2012;3:460. 10.3389/fphys.2012.00460

22. Chapman DG, Irvin CG. Mechanisms of airway hyper-responsiveness in asthma: the past, present and yet to come. Clin Exp Allergy. 2015;45(4):706–719. 10.1111/cea.12506

23. Kudo M, Ishigatsubo Y, Aoki I. Pathology of asthma. Front Microbiol. 2013;4:263. 10.3389/fmicb.2013.00263

24. Caminati M, Pham DL, Bagnasco D, Canonica GW. Type 2 immunity in asthma. World Allergy Organ J. 2018;11(1):13. 10.1186/s40413-018-0192-5

25. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5–17. 10.1016/j.cyto.2014.09.011

26. Ray A, Kolls JK. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol. 2017;38(12):942–954. 10.1016/

27. Larché M, Robinson DS, Kay AB. The role of T lymphocytes in the pathogenesis of asthma. J Allergy Clin Immunol. 2003;111(3):450–463; quiz 64. 10.1067/mai.2003.169

28. Patel TR, Sur S. IgE and eosinophils as therapeutic targets in asthma. Curr Opin Allergy Clin Immunol. 2017;17(1):42–49. 10.1097/ACI.0000000000000336

29. Okamoto M, Matsuda H, Joetham A, Lucas JJ, Domenico J, Yasutomo K, et al. Jagged1 on dendritic cells and Notch on CD4+ T cells initiate lung allergic responsiveness by inducing IL-4 production. J Immunol. 2009;183(5):2995–3003. 10.4049/jimmunol.0900692

30. Tindemans I, van Schoonhoven A, KleinJan A, de Bruijn MJ, Lukkes M, van Nimwegen M, et al. Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress. J Clin Investig. 2020;130(7):3576–3591. 10.1172/JCI128310