Mechanism of 2,6-DMBQ attenuates airway inflammatory responses in asthmatic mice via the mTOR signaling pathway

LI Juan; LI Shu-Fang; XIONG Xiao-Man; YANG Qiu-Yan; XIE Xue-Li; ZHANG Yan-Li

doi:10.7499/j.issn.1008-8830.2411067

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Chinese Journal of Contemporary Pediatrics ›› 2025, Vol. 27 ›› Issue (4) : 472-479. DOI: 10.7499/j.issn.1008-8830.2411067

EXPERIMENTAL RESEARCH

Mechanism of 2,6-DMBQ attenuates airway inflammatory responses in asthmatic mice via the mTOR signaling pathway

LI Juan, LI Shu-Fang, XIONG Xiao-Man, YANG Qiu-Yan, XIE Xue-Li, ZHANG Yan-Li

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Abstract

Objective To investigate the therapeutic effects and mechanisms of 2,6-dimethoxy-1,4-benzoquinone (2,6-DMBQ) in a mouse model of asthma. Methods SPF-grade BALB/c mice were randomly divided into 7 groups (n=8 each group): normal control group, ovalbumin (OVA) group, dimethyl sulfoxide+corn oil group, budesonide (BUD) group, and low, medium, and high dose 2,6-DMBQ groups. An asthma mouse model was established by OVA induction, followed by corresponding drug interventions. Non-invasive lung function tests were performed to measure airway hyperresponsiveness, and enzyme-linked immunosorbent assay was used to determine levels of interleukin (IL)-17, IL-10, and serum immunoglobulin E in bronchoalveolar lavage fluid. A cell counter was employed to detect eosinophil counts in bronchoalveolar lavage fluid, while hematoxylin-eosin staining and periodic acid-Schiff staining were used to assess lung tissue pathological changes. Western blot was conducted to examine the expression of proteins related to the mammalian target of rapamycin pathway (p-AKT/AKT and p-p70S6K/p70S6K), and a fully automated biochemical analyzer was used to evaluate liver and kidney functions. Results Compared with the normal control group, the OVA group showed increased enhanced pause values, inflammation scores from hematoxylin-eosin staining, positive area from periodic acid-Schiff staining, percentage of eosinophils, IL-17/IL-10 ratio, serum immunoglobulin E levels, and relative expression levels of p-AKT/AKT and p-p70S6K/p70S6K (P<0.05). The BUD group and the medium and high dose 2,6-DMBQ groups exhibited decreased values for these indicators compared to the OVA group (P<0.05). Conclusions 2,6-DMBQ can inhibit the mTOR pathway to alleviate airway inflammation in asthmatic mice, possibly by mitigating the imbalance between Th17 and regulatory T cells.

Key words

Bronchial asthma / 2,6-Dimethoxy-1,4-benzoquinone / Mammalian target of rapamycin pathway / Th17/Treg imbalance / Mouse

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LI Juan, LI Shu-Fang, XIONG Xiao-Man, YANG Qiu-Yan, XIE Xue-Li, ZHANG Yan-Li. Mechanism of 2,6-DMBQ attenuates airway inflammatory responses in asthmatic mice via the mTOR signaling pathway[J]. Chinese Journal of Contemporary Pediatrics. 2025, 27(4): 472-479 https://doi.org/10.7499/j.issn.1008-8830.2411067

References

1 Zhang D, Zheng J. The burden of childhood asthma by age group, 1990-2019: a systematic analysis of Global Burden of Disease 2019 data[J]. Front Pediatr, 2022, 10: 823399. PMID: 35252064. PMCID: PMC8888872. DOI: 10.3389/fped.2022.823399.
2 Mendy A, Mersha TB. Comorbidities in childhood-onset and adult-onset asthma[J]. Ann Allergy Asthma Immunol, 2022, 129(3): 327-334. PMID: 35595004. PMCID: PMC10265950. DOI: 10.1016/j.anai.2022.05.005.
3 Liu Y, Liu H, Shao Q, et al. Majie cataplasm alleviates asthma by regulating Th1/Th2/Treg/Th17 balance[J]. Int Arch Allergy Immunol, 2024, 185(9): 900-909. PMID: 38749400. DOI: 10.1159/000538597.
4 Allen DB, Bielory L, Derendorf H, et al. Inhaled corticosteroids: past lessons and future issues[J]. J Allergy Clin Immunol, 2003, 112(3 Suppl): S1-S40. PMID: 14515117. DOI: 10.1016/s0091-6749(03)01859-1.
5 Ma J, Liu Y, Sun Y, et al. Increased pneumonia risk associated with concomitant use of inhaled corticosteroids and benzodiazepines: a pharmacovigilance analysis[J]. Lung, 2024, 202(5): 673-681. PMID: 39191908. DOI: 10.1007/s00408-024-00741-y.
6 Chen H, Sun J, Huang Q, et al. Inhaled corticosteroids and the pneumonia risk in patients with chronic obstructive pulmonary disease: a meta-analysis of randomized controlled trials[J]. Front Pharmacol, 2021, 12: 691621. PMID: 34267661. PMCID: PMC8275837. DOI: 10.3389/fphar.2021.691621.
7 Patil SH, Kumar V, Nandan D. Effect of long-term medium to high-dose inhaled budesonide on bone mineral density in children with asthma: a cross-sectional study[J]. J Asthma, 2023, 60(12): 2130-2136. PMID: 37294051. DOI: 10.1080/02770903.2023.2220815.
8 Kim JY, Park CS, Jang SK, et al. The significance of p-AKT1 as a prognostic marker and therapeutic target in patients with hormone receptor-positive and human epidermal growth factor receptor-2-positive early breast cancer[J]. J Breast Cancer, 2022, 25(5): 387-403. PMID: 36314765. PMCID: PMC9629968. DOI: 10.4048/jbc.2022.25.e43.
9 Basnet R, Bahadur Basnet B, Gupta R, et al. Mammalian target of rapamycin (mTOR) signalling pathway: a potential target for cancer intervention: a short overview[J]. Curr Mol Pharmacol, 2024, 17(1): e310323215268. PMID: 36999689. DOI: 10.2174/1874467217666230331081959.
10 Zou Z, Tao T, Li H, et al. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges[J]. Cell Biosci, 2020, 10: 31. PMID: 32175074. PMCID: PMC7063815. DOI: 10.1186/s13578-020-00396-1.
11 Marques-Ramos A, Cervantes R. Expression of mTOR in normal and pathological conditions[J]. Mol Cancer, 2023, 22(1): 112. PMID: 37454139. PMCID: PMC10349476. DOI: 10.1186/s12943-023-01820-z.
12 Ma B, Athari SS, Mehrabi Nasab E, et al. PI3K/AKT/mTOR and TLR4/MyD88/NF-κB signaling inhibitors attenuate pathological mechanisms of allergic asthma[J]. Inflammation, 2021, 44(5): 1895-1907. PMID: 33860870. DOI: 10.1007/s10753-021-01466-3.
13 Zhang Y, Xu B, Luan B, et al. Myeloid-derived suppressor cells (MDSCs) and mechanistic target of rapamycin (mTOR) signaling pathway interact through inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in asthma[J]. Am J Transl Res, 2019, 11(9): 6170-6184. PMID: 31632585. PMCID: PMC6789223.
14 Zhang Y, Jing Y, Qiao J, et al. Activation of the mTOR signaling pathway is required for asthma onset[J]. Sci Rep, 2017, 7(1): 4532. PMID: 28674387. PMCID: PMC5495772. DOI: 10.1038/s41598-017-04826-y.
15 Son HJ, Jang YJ, Jung CH, et al. 2,6-Dimethoxy-1,4-benzoquinone inhibits 3T3-L1 adipocyte differentiation via regulation of AMPK and mTORC1[J]. Planta Med, 2019, 85(3): 210-216. PMID: 30199902. DOI: 10.1055/a-0725-8334.
16 Zu X, Ma X, Xie X, et al. 2,6-DMBQ is a novel mTOR inhibitor that reduces gastric cancer growth in vitro and in vivo[J]. J Exp Clin Cancer Res, 2020, 39(1): 107. PMID: 32517736. PMCID: PMC7285595. DOI: 10.1186/s13046-020-01608-9.
17 Jeong HY, Choi YS, Lee JK, et al. Anti-inflammatory activity of citric acid-treated wheat germ extract in lipopolysaccharide-stimulated macrophages[J]. Nutrients, 2017, 9(7): 730. PMID: 28698513. PMCID: PMC5537844. DOI: 10.3390/nu9070730.
18 Kim MH, Jo SH, Ha KS, et al. Antimicrobial activities of 1,4-benzoquinones and wheat germ extract[J]. J Microbiol Biotechnol, 2010, 20(8): 1204-1209. PMID: 20798583. DOI: 10.4014/jmb.1004.04037.
19 Zeng Z, Cheng M, Li M, et al. Inherent differences of small airway contraction and Ca2+ oscillations in airway smooth muscle cells between BALB/c and C57BL/6 mouse strains[J]. Front Cell Dev Biol, 2023, 11: 1202573. PMID: 37346175. PMCID: PMC10279852. DOI: 10.3389/fcell.2023.1202573.
20 De Vooght V, Vanoirbeek JA, Luyts K, et al. Choice of mouse strain influences the outcome in a mouse model of chemical-induced asthma[J]. PLoS One, 2010, 5(9): e12581. PMID: 20830207. PMCID: PMC2935354. DOI: 10.1371/journal.pone.0012581.
21 Ito T, Bekki K, Fujitani Y, et al. The toxicological analysis of secondary organic aerosol in human lung epithelial cells and macrophages[J]. Environ Sci Pollut Res Int, 2019, 26(22): 22747-22755. PMID: 31172435. DOI: 10.1007/s11356-019-05317-5.
22 Wang C, Huang CF, Li M. Sodium houttuynia alleviates airway inflammation in asthmatic mice by regulating FoxP3/RORγT expression and reversing Treg/Th17 cell imbalance[J]. Int Immunopharmacol, 2022, 103: 108487. PMID: 34959187. DOI: 10.1016/j.intimp.2021.108487.
23 Zou XL, Chen ZG, Zhang TT, et al. Th17/Treg homeostasis, but not Th1/Th2 homeostasis, is implicated in exacerbation of human bronchial asthma[J]. Ther Clin Risk Manag, 2018, 14: 1627-1636. PMID: 30233198. PMCID: PMC6132476. DOI: 10.2147/TCRM.S172262.
24 Wei C, Huang L, Zheng Y, et al. Selective activation of cannabinoid receptor 2 regulates Treg/Th17 balance to ameliorate neutrophilic asthma in mice[J]. Ann Transl Med, 2021, 9(12): 1015. PMID: 34277815. PMCID: PMC8267324. DOI: 10.21037/atm-21-2778.
25 Guan Y, Ma Y, Tang Y, et al. MiRNA-221-5p suppressed the Th17/Treg ratio in asthma via RORγt/Foxp3 by targeting SOCS1[J]. Allergy Asthma Clin Immunol, 2021, 17(1): 123. PMID: 34863307. PMCID: PMC8643019. DOI: 10.1186/s13223-021-00620-8.
26 Wang J, Cheng Y. The interaction of hsa_circ_0002594 and eIF4A3 promotes T-helper 2 cell differentiation by the regulation of PTEN[J]. Clin Exp Med, 2023, 23(3): 887-895. PMID: 35870031. DOI: 10.1007/s10238-022-00862-9.
27 Shan Y, Wu J, Dai X, et al. Jiangqi pingxiao formula regulates dendritic cell apoptosis in an autophagy-dependent manner through the AMPK/mTOR pathway in a murine model of OVA-induced asthma[J]. J Ethnopharmacol, 2024, 321: 117405. PMID: 37952734. DOI: 10.1016/j.jep.2023.117405.
28 Huang X, Yu H, Xie C, et al. Louki Zupa decoction attenuates the airway inflammation in acute asthma mice induced by ovalbumin through IL-33/ST2-NF-κB/GSK3β/mTOR signalling pathway[J]. Pharm Biol, 2022, 60(1): 1520-1532. PMID: 35952388. PMCID: PMC9377271. DOI: 10.1080/13880209.2022.2104327.
29 Woodcock HV, Eley JD, Guillotin D, et al. The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis[J]. Nat Commun, 2019, 10(1): 6. PMID: 30602778. PMCID: PMC6315032. DOI: 10.1038/s41467-018-07858-8.
30 Zou W, Ding F, Niu C, et al. Brg1 aggravates airway inflammation in asthma via inhibition of the PI3K/Akt/mTOR pathway[J]. Biochem Biophys Res Commun, 2018, 503(4): 3212-3218. PMID: 30149919. DOI: 10.1016/j.bbrc.2018.08.127.
31 Xie X, Zu X, Laster K, et al. 2,6-DMBQ suppresses cell proliferation and migration via inhibiting mTOR/AKT and p38 MAPK signaling pathways in NSCLC cells[J]. J Pharmacol Sci, 2021, 145(3): 279-288. PMID: 33602509. DOI: 10.1016/j.jphs.2021.01.003.
32 Leclercq G, Haegel H, Toso A, et al. JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy[J]. J Immunother Cancer, 2022, 10(1): e003766. PMID: 35064010. PMCID: PMC8785208. DOI: 10.1136/jitc-2021-003766.
33 Brambilla G, Robbiano L, Cajelli E, et al. Cytotoxic, DNA-damaging and mutagenic properties of 2,6-dimethoxy-1,4-benzoquinone, formed by dimethophrine-nitrite interaction[J]. J Pharmacol Exp Ther, 1988, 244(3): 1011-1015. PMID: 3252018.