Shenqi Buzhong Formula ameliorates mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease by activating the AMPK/SIRT1/PGC-1α pathway

doi:10.12122/j.issn.1673-4254.2025.05.09

Abstract

Abstract:

Objective To explore the mechanism of Shenqi Buzhong (SQBZ) Formula for alleviating mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease (COPD) in light of the AMPK/SIRT1/PGC-1α pathway. Methods Fifty male SD rat models of COPD, established by intratracheal lipopolysaccharide (LPS) instillation, exposure to cigarette smoke, and gavage of Senna leaf infusion, were randomized into 5 groups (n=10) for treatment with saline (model group), SQBZ Formula at low, moderate and high doses (3.08, 6.16 and 12.32 g/kg, respectively), or aminophylline (0.024 g/kg) by gavage for 4 weeks, with another 10 untreated rats as the control group. Pulmonary function of the rats were tested, and pathologies and ultrastructural changes of the lung tissues were examined using HE staining and transmission electron microscopy. The levels of SOD, ATP, MDA, and mitochondrial membrane potential in the lungs were detected using WST-1, colorimetric assay, TBA, and JC-1 methods. Flow cytometry was used to analyze ROS level in the lung tissues, and the protein expression levels of P-AMPKα, AMPKα, SIRTI, and PGC-1α were detected using Western blotting. Results The rat models of COPD showed significantly decreased lung function, severe histopathological injuries of the lungs, decreased pulmonary levels of SOD activity, ATP and mitochondrial membrane potential, increased levels of MDA and ROS, and decreased pulmonary expressions of P-AMPKα, SIRTI, and PGC-1α proteins. All these changes were significantly alleviated by treatment with SQBZ Formula and aminophylline, and the efficacy was comparable between high-dose SQBZ Formula group and aminophylline group. Conclusion SQBZ Formula ameliorates mitochondrial dysfunction in COPD rats possibly by activating the AMPK/SIRT1/PGC-1α pathway.

Key words: chronic obstructive pulmonary disease, Shenqi Buzhong Formula, mitochondrial dysfunction, mitochondrial biogenesis, AMPK/SIRT1/PGC-1α pathway

Lu ZHANG, Huanzhang DING, Haoran XU, Ke CHEN, Bowen XU, Qinjun YANG, Di WU, Jiabing TONG, Zegeng LI. Shenqi Buzhong Formula ameliorates mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease by activating the AMPK/SIRT1/PGC-1α pathway[J]. Journal of Southern Medical University, 2025, 45(5): 969-976.

Figures/Tables 7

Fig.1 Effect of Shenqi Buzhong Formula on food intake in rats. **P<0.01 vs Control group; #P<0.05, ##P<0.01 vs Model group.

Fig.2 Effect of Shenqi Buzhong Formula on lung function in COPD rats. **P<0.01 vs Control group; #P<0.05, ##P<0.01 vs Model group.

Fig.3 Effect of Shenqi Buzhong Formula on histopathological injuries in the lung tissue of COPD rats (HE staining, original magnification: ×200). A: Control group; B: Model group; C: SQBZ-L group; D: SQBZ-M group; E: SQBZ-H group; F: APL group.

Fig.6 Effects of Shenqi Buzhong Formula on ATP content in lung tissues of COPD rats. **P<0.01 vs Control group. #P<0.05, ##P<0.01 vs Model group.

Fig.7 Effects of Shenqi Buzhong Formula on MDA and SOD levels in COPD rats. **P<0.01 vs Control group. #P<0.05, ##P<0.01 vs Model group.

Fig.8 Effects of Shenqi Buzhong Formula on mitochondrial morphology of rat alveolar type II epithelial cells (×10000). A: Control group; B: Model group; C: SQBZ-L group; D: SQBZ-M group; E: SQBZ-H group; F: APL group.

Fig.9 Effects of Shenqi Buzhong Formula on protein expressions of P-AMPKα, AMPKα, SIRTI, and PGC-1α in the lung tissues of COPD rats. **P<0.01 vs Control group. #P<0.05, ##P<0.01 vs Model group. A: Control; B: Model; C: SQBZ-L; D: SQBZ-M; E: SQBZ-H; F: APL.

References 36

1	Global Initiative for Chronic Obstructive Lung Disease.Global strategy for the diagnosis,management,and prevention of chronic obstructive pulmonary disease(2024 report)[EB/OL].[2023-11-15]..
2	WHO reveals leading causes of death and disability worldwide : 2000-2019. Retrieved Dec 10,2020,from
3	Adeloye D, Song P, Zhu Y, et al. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis[J]. Lancet Respir Med, 2022, 10(5): 447-58.
4	郑锋. 吸入糖皮质激素和支气管扩张剂对COPD患者肺功能的影响及副作用对比[J]. 泰山医学院学报, 2018, 39(7): 782-4.
5	Zou X, Huang Q, Kang T, et al. An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophages[J]. Biol Direct, 2025, 20(1): 4.
6	Ryter SW, Rosas IO, Owen CA, et al. Mitochondrial dysfunction as a pathogenic mediator of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis[J]. Ann Am Thorac Soc, 2018, 15(): S266-72.
7	Hara H, Kuwano K, Araya J. Mitochondrial quality control in COPD and IPF[J]. Cells, 2018, 7(8): E86.
8	Li CL, Liu JF, Liu SF. Mitochondrial dysfunction in chronic obstructive pulmonary disease: unraveling the molecular nexus[J]. Biomedicines, 2024, 12(4): 814.
9	徐菁菁, 田燕歌, 梅雪, 等. 线粒体质量控制在呼吸系统疾病中的研究进展[J]. 中国比较医学杂志, 2024, 34(6): 161-71.
10	龙清华, 朱麒行, 麦合丽娅·艾斯卡尔, 等. 酸枣仁汤通过激活AMPK/SIRT1/PGC-1α信号通路改善阿尔茨海默病模型小鼠线粒体功能障碍[J]. 中国药理学通报, 2023, 39(7): 1256-62.
11	Liu C, Cao Q, Chen Y, et al. Rhein protects retinal Müller cells from high glucose-induced injury via activating the AMPK/Sirt1/PGC-1α pathway[J]. J Recept Signal Transduct Res, 2023, 43(2): 62-71.
12	李成伟, 臧敏, 高文军, 等. COPD稳定期中医证型与HRCT表型的相关性分析[J]. 浙江临床医学, 2018, 20(2): 257-8, 261.
13	康馨匀, 付建梅, 高娜, 等. 稳定期COPD患者中医辨证分型与肺功能、炎症指标的关系[J]. 四川中医, 2022, 40(12): 48-52.
14	李建生, 李素云, 余学庆. 慢性阻塞性肺疾病中医诊疗指南(2011版)[J]. 中医杂志, 2012, 53(1): 80-4. DOI: 10.3969/j.issn.1004-7484(s).2013.12.744
15	丁焕章. 新安固本培元方辨证治疗COPD稳定期患者的多中心随机平行对照与代谢调控研究[D]. 合肥: 安徽中医药大学, 2024.
16	许浩燃. 参芪补中方治疗慢阻肺稳定期肺脾气虚证的临床疗效观察及其对模型大鼠TNF-α、IL-6、IL-1β的影响[D]. 合肥: 安徽中医药大学, 2024.
17	赵芳, 王洪新, 杨育红. 黄芪甲苷改善高糖诱导内皮细胞线粒体功能障碍[J]. 辽宁中医杂志, 2024, 51(1): 153-6.
18	石洪洋, 董慧, 刘嘉, 等. 人参皂苷Rg₁对心肌细胞氧化应激损伤的抑制作用[J]. 中草药, 2023, 54(24): 8117-26. DOI: 10.7501/j.issn.0253-2670.2023.24.016
19	Sun C, Zhang X, Yu F, et al. Atractylenolide I alleviates ischemia/reperfusion injury by preserving mitochondrial function and inhibiting caspase-3 activity[J]. J Int Med Res, 2021, 49(2): 300060521993315.
20	赵小亮, 郭正磊, 杨超福, 等. 半夏多糖的制备和表征及抗氧化和免疫增强活性研究[J]. 中成药, 2024, 46(3): 1013-8. DOI: 10.3969/j.issn.1001-1528.2024.03.048
21	Zhang J, Zhang M, Zhang WH, et al. Total flavonoids of in ula Japonica alleviated the inflammatory response and oxidative stress in LPS-induced acute lung injury via inhibiting the sEH activity: Insights from lipid metabolomics[J]. Phytomedicine, 2022, 107: 154380.
22	张晨宇, 刘波, 袁志军, 等. 基于Hepcidin/OPG-RANKL轴探讨当归多糖改善大鼠肾性贫血线粒体功能异常的作用机制[J]. 中药材, 2020, 43(7): 1697-701. DOI: 10.13863/j.issn1001-4454.2020.07.031
23	Piao Z, Song L, Yao L, et al. Schisandrin restores the amyloid β‑induced impairments on mitochondrial function, energy metabolism, biogenesis, and dynamics in rat primary hippocampal neurons[J]. Pharmacology, 2021, 106(5/6): 254-64.
24	张少华, 徐丹, 闫雪娇, 等. 不同脏腑虚损对慢性阻塞性肺疾病患者病情及线粒体功能的影响[J]. 世界科学技术-中医药现代化, 2018, 20(3): 446-52. DOI: 10.11842/wst.2018.03.018
25	蒙婷. SIRT5调控琥珀酰化修饰与COPD线粒体功能障碍相关性及益气固表丸对其影响的研究[D]. 乌鲁木齐: 新疆医科大学, 2021.
26	Veluthakal R, Esparza D, Hoolachan JM, et al. Mitochondrial dysfunction, oxidative stress, and inter-organ miscommunications in T2D progression[J]. Int J Mol Sci, 2024, 25(3): 1504.
27	金洁, 黄敏轩, 马红映, 等. 线粒体损伤在慢性阻塞性肺疾病发病机制中的研究进展[J]. 中国现代医生, 2023, 61(7): 91-5. DOI: 10.3969/j.issn.1673-9701.2023.07.022
28	左秋南. 线粒体靶向拮抗剂SS-31在香烟诱导的气道炎症与氧化应激中的作用探讨[D]. 成都: 四川大学, 2021.
29	何丽玲, 胡慧. 强记汤通过激活AMPKα/SIRT1/PGC-1α信号通路减轻D-半乳糖诱导的认知损伤和线粒体功能障碍[J]. 中国病理生理杂志, 2024, 40(10): 1906-15. DOI: 10.3969/j.issn.1000-4718.2024.10.015
30	Popov LD. Mitochondrial biogenesis: an update[J]. J Cell Mol Med, 2020, 24(9): 4892-9.
31	Picca A, Lezza AMS, Leeuwenburgh C, et al. Fueling inflamm-aging through mitochondrial dysfunction: mechanisms and molecular targets[J]. Int J Mol Sci, 2017, 18(5): E933.
32	Yuan Y, Tian Y, Jiang H, et al. Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury[J]. Front Mol Neurosci, 2023, 16: 1224964.
33	Zhu C, Zhang Z, Zhu YS, et al. Study on the role of Dihuang Yinzi in regulating the AMPK/SIRT1/PGC-1α pathway to promote mitochondrial biogenesis and improve Alzheimer's disease[J]. J Ethnopharmacol, 2025, 337: 118859.
34	宁静华, 张鑫, 张钰哲. AMPK: 多样性调控机制与疾病治疗新视角[J]. 中国比较医学杂志, 2024, 34(2): 167-78.
35	Jia LD, Liu XF, Liu XG, et al. Bufei Yishen formula protects the airway epithelial barrier and ameliorates COPD by enhancing autophagy through the Sirt1/AMPK/Foxo3 signaling pathway[J]. Chin Med, 2024, 19(1): 32.
36	Wang RC, Liu Y, Jiang Y, et al. Shenling Baizhu San alleviates central fatigue through SIRT1-PGC-1α‑Mediated mitochondrial biogenesis[J]. J Ethnopharmacol, 2025, 339: 119110.

[1]	Liming WANG, Hongrui CHEN, Yan DU, Peng ZHAO, Yujie WANG, Yange TIAN, Xinguang LIU, Jiansheng LI. Yiqi Zishen Formula ameliorates inflammation in mice with chronic obstructive pulmonary disease by inhibiting the PI3K/Akt/NF-κB signaling pathway [J]. Journal of Southern Medical University, 2025, 45(7): 1409-1422.
[2]	Huaiwen XU, Li WENG, Hong XUE. CXCL12 is a potential therapeutic target for type 2 diabetes mellitus complicated by chronic obstructive pulmonary disease [J]. Journal of Southern Medical University, 2025, 45(1): 100-109.
[3]	Li MEI, Lu ZHANG, Di WU, Huanzhang DING, Xinru WANG, Xian ZHANG, Yuhang WEI, Zegeng LI, Jiabing TONG. Liuwei Buqi Formula delays progression of chronic obstructive pulmonary disease in rats by regulating the NLRP3/caspase-1/GSDMD pyroptosis pathway [J]. Journal of Southern Medical University, 2024, 44(11): 2156-2162.
[4]	Qinjun YANG, Hui WANG, Shuyu XU, Cheng YANG, Huanzhang DING, Di WU, Jie ZHU, Jiabing TONG, Zegeng LI. Shenqi Tiaoshen Formula alleviates airway inflammation in rats with chronic obstructive pulmonary disease and kidney qi deficiency syndrome by inhibiting ferroptosis via regulating the Nrf2/SLC7A11/GPX4 signaling pathway [J]. Journal of Southern Medical University, 2024, 44(10): 1937-1946.
[5]	Mengmeng CHENG, Xinguang LIU, Yanxin WEI, Xiaoxiang XING, Lan LIU, Nan XIN, Peng ZHAO. Tongsai Granules inhibit autophagy and macrophage-mediated inflammatory response to improve acute exacerbations of chronic obstructive pulmonary disease in rats [J]. Journal of Southern Medical University, 2024, 44(10): 1995-2003.
[6]	XU Guiling, GONG Zhaoqian, WANG Junrao, MA Yanyan, XU Maosheng, CHEN Meijia, HU Dapeng, LIANG Jianpeng, ZHAO Wengqu, ZHAO Haijin. Effects of type 2 inflammation on bronchodilator responsiveness of large and small airways in chronic obstructive pulmonary disease [J]. Journal of Southern Medical University, 2024, 44(1): 93-99.
[7]	WU Di, WANG Xiaole, GAO Yating, TONG Jiabing, YANG Qinjun, DING Huanzhang, ZHANG Lu, LI Zegeng. Shenqi Wenfei Formula alleviates chronic obstructive pulmonary disease in rats with pulmonary qi deficiency syndrome by regulating NLRP3/GSDMD pyroptosis pathway [J]. Journal of Southern Medical University, 2023, 43(9): 1500-1508.
[8]	WANG Min, ZHANG Qian, XU Guiling, HUANG Shuyu, ZHAO Wenqu, LIANG Jianpeng, HUANG Junwen, CAI Shaoxi, ZHAO Haijin. Association between vitamin D level and blood eosinophil count in healthy population and patients with chronic obstructive pulmonary disease [J]. Journal of Southern Medical University, 2023, 43(5): 727-732.
[9]	XU Chen, LI Chunying, WANG Sheng. Yifei Jianpi recipe improves cigarette smoke-induced inflammatory injury and mucus hypersecretion in human bronchial epithelial cells by inhibiting the TLR4/NF-κB signaling pathway [J]. Journal of Southern Medical University, 2023, 43(4): 507-515.
[10]	WAN Lu, QIAN Yuchi, NI Wenjing, LU Yuxin, LI Wei, PAN Yan, CHEN Weidong. Linagliptin improves diabetic kidney disease in rats by promoting mitochondrial biogenesis through the AMPK/PGC-1α/TFAM pathway [J]. Journal of Southern Medical University, 2023, 43(12): 2053-2060.
[11]	. Comparison of different evaluation systems for assessing disease severity and treatment efficacy in patients with chronic obstructive pulmonary disease [J]. Journal of Southern Medical University, 2021, 41(7): 1119-1124.
[12]	WANG Xiaole, ZHU Jie, GAO Yating, WU Fan, YANG Qinjun, TONG Jiabing, ZHANG Xingxing, WANG Chuanbo, WU Di, LI Zegeng. Liuwei Buqi capsule modulates immune function by targeting multiple immune cell subsets in lung tissue of patients with COPD [J]. Journal of Southern Medical University, 2021, 41(10): 1492-1500.
[13]	. Lung sounds can be used as an indicator for assessing severity of chronic obstructive pulmonary disease at the initial diagnosis [J]. Journal of Southern Medical University, 2020, 40(02): 177-182.
[14]	. Delayed diagnosis is associated with greater disease severity of chronic obstructive pulmonary disease [J]. Journal of Southern Medical University, 2018, 38(12): 1448-.
[15]	. Correlation between expressions of myeloperoxidase and eosinophil cationic protein in sputum and clinical features of asthma-chronic obstructive pulmonary disease overlap [J]. Journal of Southern Medical University, 2018, 38(10): 1215-.