Uncovering the action mechanism of Shenqi Tiaoshen formula (参芪调肾方) in the treatment of chronic obstructive pulmonary disease through network pharmacology, molecular docking, and experimental verification

doi:10.19852/j.cnki.jtcm.20240610.002

Journal of Traditional Chinese Medicine ›› 2024, Vol. 44 ›› Issue (4): 770-783.DOI: 10.19852/j.cnki.jtcm.20240610.002

• Original articles • Previous Articles Next Articles

Uncovering the action mechanism of Shenqi Tiaoshen formula (参芪调肾方) in the treatment of chronic obstructive pulmonary disease through network pharmacology, molecular docking, and experimental verification

YANG Qinjun¹^,², YIN Dandan³, WANG Hui¹, GAO Yating²^,⁴^,⁵, WANG Xinheng¹^,², WU Di¹^,², TONG Jiabing²^,⁴^,⁵, WANG Chuanbo⁶(), LI Zegeng²^,⁴^,⁵()

1 School of Chinese Medicine, Anhui University of Chinese Medicine, Hefei 230038, China
2 Anhui Province Key Laboratory of the Application and Transformation of Traditional Chinese Medicine in the Prevention and Treatment of Major Pulmonary Diseases, Hefei 230031, China
3 Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
4 Institute of Traditional Chinese Medicine Respiratory Disease Prevention and Control, Anhui Academy of Traditional Chinese Medicine, Hefei 230031, China
5 Department of Respiratory, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, China
6 Department of Chinese Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China

Received:2023-02-22 Accepted:2023-06-15 Online:2024-08-15 Published:2024-06-10
Contact: Prof. LI Zegeng, Department of Respiratory, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, China. ahzyfb@sina.com; Chief physician WANG Chuanbo, Department of Chinese Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China. wangcb120@163.com Telephone: +86-13805516609
Supported by:
Joint Key Project of the National Natural Science Foundation of China: the Molecular Mechanism Research on Xin'an Medical's Syndrome Differentiation of "Guben Peiyuan" in Improving Self-Perception of Chronic Obstructive Pulmonary Disease (COPD) Patients by the Regulation of Inflammation-Immunity Network(U20A20398);Major Science and Technology Project of Anhui Province: Development of a Comprehensive Management Platform for COPD based on Cloud Data and Research on the Promotion of Traditional Chinese Medicine Techniques(201903a0702015);Collaborative Innovation Project of Public Health in Provincial Medical Colleges: Research on the Intervention Mechanisms and Product Development of Xinan Medical's “Guben Peiyuan” Method and “Yangyin Tongluo” Method for Major Chronic Diseases based on Evidence-based Medicine Evaluation(GXXT-2020-025)

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Abstract

Abstract:

OBJECTIVE: To reveal the potential underlying mechanism of the Shenqi Tiaoshen formula (参芪调肾方, SQTS) in the treatment of chronic obstructive pulmonary disease (COPD) by utilizing network pharmacology, molecular docking, and experimental verification.

METHODS: Multiple open-source databases and research related to Traditional Chinese Medicine or compounds were employed to screen active ingredients and corresponding potential targets of the SQTS. The protein-protein interaction network screened hub genes, the relevant molecular mechanism and gene regulation were initially identified through the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis, and molecular docking was used to confirm further the interaction of the main components bound to the core targets. In vivo experiments on the COPD combined Qi-deficiency syndrome rat model were performed to verify the intervention effects and predicted potential molecular mechanisms of the SQTS.

RESULTS: This study selected 156 active compounds and 326 candidate targets for treating COPD. Quercetin, Nobiletin, Kaempferol, Luteolin, Ginsenoside Rh2 and Formononetin were probably the main active compounds of SQTS in COPD treatment as they affected the most COPD-related targets, and interleukin-1 (IL-6), signal transducing activator of transcription 3 (STAT3), matrix metalloproteinase-9 (MMP9), vascular endothelial growth factor A (VEGFA), protein kinase B (AKT1), hypoxia-inducible factor-1α (HIF-1α), and forkhead box O3 (FoxO3) were identified as the hub genes associated with its therapeutic effect. KEGG analysis was mainly enriched in the signaling pathways closely related to inflammation, immunity and oxidative stress, such as HIF-1, tumor necrosis factor (TNF), phosphatidylinositol 3 kinase (PI3K)-AKT, FoxO, apoptosis, IL-17, and toll-like receptor. Molecular docking confirmed that the main active components shared a good affinity with the hub genes. In vivo experiments, the SQTS was found to improve the body weight, exhaustive swimming time, tail-hanging immobility time and struggle times, airway inflammation, lung functions, and inflammatory factors in the rat model of COPD. The up-regulation of p-PI3K, p-AKT, HIF-1α, FoxO3α, toll like receptor 4, VEGFA, Caspase 3, TNF-α, and IL-17 in COPD rats were down-regulated by SQTS, consistent with the network pharmacology results.

CONCLUSIONS: This study provides evidence that the SQTS plays a critical role in anti-inflammation via suppressing immune inflammation and oxidative stress related pathways, indicating that the SQTS is a candidate herbal drug for further investigation in treating COPD.

Key words: pulmonary disease, chronic obstructive, inflammation, network pharmacology, molecular docking simulation, experimental validation, Shenqi Tiaoshen formula

YANG Qinjun, YIN Dandan, WANG Hui, GAO Yating, WANG Xinheng, WU Di, TONG Jiabing, WANG Chuanbo, LI Zegeng. Uncovering the action mechanism of Shenqi Tiaoshen formula (参芪调肾方) in the treatment of chronic obstructive pulmonary disease through network pharmacology, molecular docking, and experimental verification[J]. Journal of Traditional Chinese Medicine, 2024, 44(4): 770-783.

Figures/Tables 6

Table 1 Key active ingredients and their topological parameters of SQTS in the treatment of COPD

MOL Id	Name	Degree	BC	CC	TC	Herbs
MOL000098	Quercetin	72	0.04720241	0.45654835	0.12767094	Renshen (Radix Ginseng), Huangqi (Radix Astragali Mongolici), Shanzhuyu (Fructus Macrocarpiii)
MOL000006	Luteolin	42	0.0199764	0.41306755	0.15736827	Semen Persicae
MOL005828	Nobiletin	38	0.00902303	0.401507	0.16578947	Chenpi (Pericarpium Citri Reticulataei)
MOL000422	Kaempferol	30	0.01607944	0.41398446	0.18351648	Renshen (Radix Ginseng), Huangqi (Radix Astragali Mongolici),Taoren (Semen Persicae)
MOL005320	Arachidonic Acid	29	0.02892894	0.41398446	0.163746	Renshen (Radix Ginseng), Baijiezi (Semen Sinapis)
MOL000546	Diosgenin	24	0.00554195	0.39554613	0.18587824	Renshen (Radix Ginseng)
MOL000358	Sitosterol	21	0.01046093	0.38414006	0.16056166	Chenpi (Pericarpium Citri Reticulataei), Yizhiren (Fructus Alpiniae Oxyphyllae)
MOL001924	Paeoniflorin	21	0.00274493	0.3569378	0.22208884	Huangqi (Radix Astragali Mongolici)
MOL008583	Beta-Sitosterol	20	0.01385171	0.40411701	0.19143646	Renshen (Radix Ginseng), Huangqi (Radix Astragali Mongolici), Chenpi (Pericarpium Citri Reticulataei), Taoren ( Semen Persicae)
MOL007088	Cryptotanshinone	19	0.00420619	0.39139559	0.20705957	Renshen (Radix Ginseng)
MOL001638	Phorbol	19	0.00257052	0.35899904	0.21307301	Renshen (Radix Ginseng)
MOL005344	Ginsenoside Rh2	18	0.00369042	0.38813736	0.22120596	Renshen (Radix Ginseng)
MOL000392	Formononetin	18	0.00318226	0.38100102	0.22580645	Huangqi (Radix Astragali Mongolici)
MOL007424	Artemisinin	17	0.00337229	0.37412237	0.19847939	Renshen (Radix Ginseng), Huangqi (Radix Astragali Mongolici)
MOL005320	Arachidonate	17	0.00283547	0.38493292	0.21191085	Renshen (Radix Ginseng)
MOL000492	(+)-Catechin	16	0.00888835	0.39139559	0.22904412	Taoren (Semen Persicae), Rougui (Cortex Cinnamomi Cassia)
MOL002341	Hesperetin	15	0.0014985	0.37714863	0.27407407	Chenpi (Pericarpium Citri Reticulataei)
MOL000354	Isorhamnetin	12	0.00370155	0.3786802	0.26265823	Huangqi (Radix Astragali Mongolici), Shanzhuyu (Shanzhuyu (Fructus Macrocarpiii)
MOL000737	Morin	11	0.0019528	0.3786802	0.30074328	Renshen (Radix Ginseng)
MOL004328	naringenin	10	9.95E-04	0.36532811	0.25774648	Chenpi (Pericarpium Citri Reticulataei)

Table 1 Key active ingredients and their topological parameters of SQTS in the treatment of COPD

MOL Id	Name	Degree	BC	CC	TC	Herbs
MOL000098	Quercetin	72	0.04720241	0.45654835	0.12767094	Renshen (Radix Ginseng), Huangqi (Radix Astragali Mongolici), Shanzhuyu (Fructus Macrocarpiii)
MOL000006	Luteolin	42	0.0199764	0.41306755	0.15736827	Semen Persicae
MOL005828	Nobiletin	38	0.00902303	0.401507	0.16578947	Chenpi (Pericarpium Citri Reticulataei)
MOL000422	Kaempferol	30	0.01607944	0.41398446	0.18351648	Renshen (Radix Ginseng), Huangqi (Radix Astragali Mongolici),Taoren (Semen Persicae)
MOL005320	Arachidonic Acid	29	0.02892894	0.41398446	0.163746	Renshen (Radix Ginseng), Baijiezi (Semen Sinapis)
MOL000546	Diosgenin	24	0.00554195	0.39554613	0.18587824	Renshen (Radix Ginseng)
MOL000358	Sitosterol	21	0.01046093	0.38414006	0.16056166	Chenpi (Pericarpium Citri Reticulataei), Yizhiren (Fructus Alpiniae Oxyphyllae)
MOL001924	Paeoniflorin	21	0.00274493	0.3569378	0.22208884	Huangqi (Radix Astragali Mongolici)
MOL008583	Beta-Sitosterol	20	0.01385171	0.40411701	0.19143646	Renshen (Radix Ginseng), Huangqi (Radix Astragali Mongolici), Chenpi (Pericarpium Citri Reticulataei), Taoren ( Semen Persicae)
MOL007088	Cryptotanshinone	19	0.00420619	0.39139559	0.20705957	Renshen (Radix Ginseng)
MOL001638	Phorbol	19	0.00257052	0.35899904	0.21307301	Renshen (Radix Ginseng)
MOL005344	Ginsenoside Rh2	18	0.00369042	0.38813736	0.22120596	Renshen (Radix Ginseng)
MOL000392	Formononetin	18	0.00318226	0.38100102	0.22580645	Huangqi (Radix Astragali Mongolici)
MOL007424	Artemisinin	17	0.00337229	0.37412237	0.19847939	Renshen (Radix Ginseng), Huangqi (Radix Astragali Mongolici)
MOL005320	Arachidonate	17	0.00283547	0.38493292	0.21191085	Renshen (Radix Ginseng)
MOL000492	(+)-Catechin	16	0.00888835	0.39139559	0.22904412	Taoren (Semen Persicae), Rougui (Cortex Cinnamomi Cassia)
MOL002341	Hesperetin	15	0.0014985	0.37714863	0.27407407	Chenpi (Pericarpium Citri Reticulataei)
MOL000354	Isorhamnetin	12	0.00370155	0.3786802	0.26265823	Huangqi (Radix Astragali Mongolici), Shanzhuyu (Shanzhuyu (Fructus Macrocarpiii)
MOL000737	Morin	11	0.0019528	0.3786802	0.30074328	Renshen (Radix Ginseng)
MOL004328	naringenin	10	9.95E-04	0.36532811	0.25774648	Chenpi (Pericarpium Citri Reticulataei)

Table 2 Hub genes and topological parameters of SQTS in the treatment of COPD

No.	Genes	MCC Score	Degree	BC	CC	No.	Genes	MCC Score	Degree	BC	CC
1	IL6	35984	37	1372.918	0.088484	16	MMP3	15176	18	630.5442	0.086957
2	IL-10	35462	35	1809.186	0.08755	17	SRC	14002	57	5644.229	0.090909
3	STAT3	31522	61	5542.987	0.090909	18	PTPN11	12264	47	3391.096	0.08941
4	FGF2	30368	23	479.668	0.087632	19	HGF	12036	26	536.7057	0.088015
5	MMP9	30354	20	776.8301	0.087388	20	EGFR	11516	34	1353.179	0.089241
6	MMP1	30270	19	1158.218	0.086689	21	TGFB1	10140	17	667.4372	0.088042
7	VEGFA	21138	33	2017.926	0.089184	22	HRAS	8178	37	1310.815	0.088847
8	CREBBP	20170	40	6223.5	0.089952	23	CTNNB1	7684	40	2212.381	0.089552
9	EP300	19440	46	3923.157	0.089952	24	TNF	7342	38	2301.604	0.089156
10	ESR1	18860	27	592.0106	0.088959	25	MAPK1	7254	50	4258.772	0.090269
11	AKT1	18046	51	5545.408	0.090211	26	TP53	6782	48	4923.421	0.089638
12	MYC	16968	21	437.7729	0.088291	27	IL1B	6708	26	1063.439	0.087878
13	HIF1A	15504	23	755.6755	0.088374	28	CXCL8	6672	17	281.1361	0.087225
14	FOXO3	15434	24	1057.897	0.088624	29	ERBB2	5858	20	298.4991	0.087687
15	MMP2	15200	17	326.8929226	0.086769231	30	JAK21	5259	20	298.4991	0.087687

Figure 1 KEGG enrichment analysis, pathway classification summary, and the key pathway core genes A: KEGG enrichment analysis. B: classification summary of the KEGG-enrichment pathway. C: core genes of the key enrichment pathways. KEGG: Kyoto Encyclopedia of Genes and Genomes.

Figure 2 Effects of body weight, exhaustive swimming test and tail suspension test of rats in each group A: body weight; B: tail suspension struggle times; C: tail suspension immobility time. D: Exhaustive swimming time. CON group: normal saline 1 mL/kg, 21 d; MOD group: normal saline 1 mL/kg, 21 d; SQTS group: SQTS 14.94 g/kg, 21 d. CON: Control group; MOD: model group; SQTS: Shenqi Tiaoshen formula. The data represent the mean ± standard deviation using one-way analysis of variance (n = 6). aP < 0.05 vs model group; bP < 0.05 vs control group.

Figure 3 Changes of lung tissue pathology, lung functions and plasma inflammatory factors of the rats in each group A: HE staining (×200, Scale bar = 100 μm). A1: CON group; A2: MOD group; A3: SQTS group. B: the airway inflammation score; C: the MAN score; D: the MLI score; E: the FVC change; F: the FEV0.1/FVC% change; G: the Cdyn change; H: the RE change; I: plasma levels of IL-13; J: plasma levels of IFN-γ; K: plasma levels of TNF-α; L: plasma levels of interleukin-1β; M: plasma levels of IL-10. CON group: normal saline 1 mL/kg, 21 d; MOD group: normal saline 1 mL/kg, 21 d; SQTS group: SQTS 14.94 g/kg, 21 d. HE: hematoxylin-eosin; CON: control; MOD: model; SQTS: Shenqi Tiaoshen Formula; MAN: mean alveolar numbers score; MLI: mean linear interval; FVC: forced expiratory vital capacity; FEV0.1/FVC%: 0.1 s forced expiratory volume/forced expiratory vital capacity; Cdyn: pulmonary dynamic compliance; RE: resistance of expiration; IL-13: interleukin-13; IFN-γ: interferon-γ; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; IL-10: interleukin-10. The Data represent the mean ± standard deviation using one-way analysis of variance (n = 6). aP < 0.05 vs control group; bP < 0.05 vs model group.

Figure 4 Core proteins of the KEGG enrichment pathway were detected by Western blotting A: Western blotting was performed to analyze the expression of p-PI3K, p-AKT, p-mTOR, HIF-1α, FoXO3α, TLR4, VEGFA, caspase-3 and MMP9 in the lung tissues. B-J: image J software was used to evaluate the protein expression quantitatively. B: relative expression of p-PI3K; C: relative expression of p-AKT; D: relative expression of p-mTOR; E: relative expression of HIF-1α; F: relative expression of FoxO3α; G: relative expression of TLR4; H: relative expression of VEGFA; I: relative expression of caspase-3; J: relative expression of MMP9. CON group: normal saline 1mL/kg, 21 d; MOD group: normal saline 1 mL/kg, 21 d; SQTS group: SQTS 14.94 g/kg, 21 d. CON: control; MOD: model; SQTS: Shenqi Tiaoshen Formula; p-PI3K: phospho-phosphatidylinositol 3 kinase; p-AKT: phospho-protein kinase B; p-mTOR: phospho-mammalian target of rapamycin; HIF-1α: hypoxia-inducible factor-1α; FoXO3α: forkhead box O3α; TLR4: toll-like receptor 4; VEGFA: vascular endothelial growth factor A; MMP9: matrix metalloproteinase-9. The Data represent the mean ± standard deviation using one-way analysis of variance (n = 6). aP < 0.05 vs control group; bP < 0.05 vs model group.

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Uncovering the action mechanism of Shenqi Tiaoshen formula (参芪调肾方) in the treatment of chronic obstructive pulmonary disease through network pharmacology, molecular docking, and experimental verification

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