2,6-DMBQ通过mTOR通路抑制支气管哮喘小鼠气道炎症反应的作用机制

doi:10.7499/j.issn.1008-8830.2411067

摘要
图/表
参考文献(33)
相关文章 (15)
点击分布统计
下载分布统计

全文: PDF (808 KB) [HTML]
输出: BibTeX | EndNote (RIS) 背景资料

摘要目的探究2,6-二甲氧基-1,4-苯醌（2,6-dimethoxy-1,4-benzoquinone, 2,6-DMBQ）在哮喘小鼠中的治疗作用及其机制。方法将SPF级BALB/c小鼠随机分为正常对照组、卵清蛋白（ovalbumin, OVA）组、融媒组、布地奈德（budesonide, BUD）组、2,6-DMBQ低、中、高剂量组，每组8只。采用OVA诱导法建立哮喘小鼠模型并给予相应药物干预。使用无创肺功能仪测定小鼠气道高反应性，ELISA法测定支气管肺泡灌洗液中白细胞介素（interleukin, IL）-17、IL-10和血清免疫球蛋白E水平，细胞计数仪检测支气管肺泡灌洗液中嗜酸性粒细胞数，苏木精-伊红染色和过碘酸-希夫染色评估肺组织病理变化，Western blot检测肺组织哺乳动物雷帕霉素靶蛋白通路相关蛋白（p-AKT/AKT、p-p70S6K/p70S6K）表达情况，全自动生化分析仪测定肝肾功能。结果与正常对照组相比，OVA组增强呼吸间歇值、苏木精-伊红染色炎性评分和过碘酸-希夫染色阳性面积、嗜酸性粒细胞百分比、IL-17/IL-10比值、血清免疫球蛋白E水平、p-AKT/AKT和p-p70S6K/p70S6K蛋白相对表达量升高（P<0.05）；与OVA组相比，BUD组和2,6-DMBQ中、高剂量组上述指标降低（P<0.05）。结论 2,6-DMBQ可抑制哺乳动物雷帕霉素靶蛋白通路减轻哮喘小鼠气道炎症，可能通过减轻辅助性T细胞17/调节性T细胞失衡发挥作用。

	服务

	把本文推荐给朋友
	加入我的书架
	加入引用管理器
	E-mail Alert
	RSS
	作者相关文章
	李娟
	李舒芳
	熊晓曼
	杨秋雁
	谢雪丽
	张艳丽

关键词 ：支气管哮喘, 2, 6-二甲氧基-1, 4-苯醌, 哺乳动物雷帕霉素靶蛋白通路, Th17/Treg失衡, 小鼠

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

收稿日期: 2024-11-13

基金资助:河南省重点研发与推广专项（科技攻关）（232102310323）。

通讯作者: 张艳丽，女，主任医师。Email：zylandzyy@126.com。 E-mail: zylandzyy@126.com

作者简介: 李娟，女，硕士研究生，住院医师；

引用本文:

李娟,李舒芳,熊晓曼等. 2,6-DMBQ通过mTOR通路抑制支气管哮喘小鼠气道炎症反应的作用机制[J]. 中国当代儿科杂志, 2025, 27(4): 472-479.

LI Juan,LI Shu-Fang,XIONG Xiao-Man et al. Mechanism of 2,6-DMBQ attenuates airway inflammatory responses in asthmatic mice via the mTOR signaling pathway[J]. CJCP, 2025, 27(4): 472-479.

链接本文:

http://www.zgddek.com/CN/10.7499/j.issn.1008-8830.2411067 或 http://www.zgddek.com/CN/Y2025/V27/I4/472

	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.
	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.