Based on data mining and network pharmacology research, the mechanism of action of the high-frequency drug Xin An Gu Ben Pei Yuan in the treatment of chronic obstructive pulmonary disease is studied
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by restricted airflow, abnormal gas exchange, high mucus secretion, and pulmonary arterial hypertension. COPD is often named after the symptoms of lung distension, cough, and wheezing in traditional Chinese medicine. The main pathogenesis of the disease is deficiency, phlegm, and blood stasis, with qi deficiency as the foundation. It often begins in the lungs, spreads to the spleen, and ends in the kidneys. If the functions of the lungs, spleen, and kidneys are disrupted, and if the metabolism of body fluids is abnormal, it will result in phlegm retention, blood stasis, phlegm turbidity, and water retention. Qi supplementation is one of the important treatment principles for COPD. Traditional Chinese medicine has a clear therapeutic effect, with the ability to improve cough and asthma symptoms and enhance quality of life.

The New An Gu Ben Pei Yuan School, as the most representative branch of medical school in New An Medicine, advocates the academic proposition of “cultivating and nourishing the spleen and kidneys, and caring for the vital energy”. By consolidating and protecting the human body’s acquired foundation, it achieves the goal of supporting the body, eliminating evil, treating diseases, and curing illnesses. The key to strengthening the foundation lies in consolidating the qi of the lungs, spleen, and kidneys, while the core of nourishing the essence lies in nourishing the imbalance between qi, blood, yin, and yang. Wang Wenqi, a physician in Xiuning during the Qing Dynasty, once said, “The spleen is the official of the granary… If one coughs for a long time and fails to nourish, it is necessary to cultivate the spleen element to nourish the mother and her children. Cheng Wenyu, a famous doctor from Shexian County, said: “The deficiency of lung gold is often caused by the drying up of kidney water… If yin is damaged at the bottom and yang is isolated at the top… it is because although cough is in the lungs, it is in the kidneys. The New An Gu Ben Pei Yuan Theory is characterized by regulating qi and blood, strengthening the spleen and stomach, and supplementing kidney qi. It has outstanding features in the prevention and treatment of COPD and has clear therapeutic effects.

This article uses association rules to mine the commonly used drug pairs for treating COPD in the New An Gu Ben Pei Yuan medical case, which are the combination of ginseng (Ginseng Radix et Rhizoma, GRR) and astragalus (Astragli Radix, AR). Ginseng Huangqi contains numerous ingredients, and the mechanism of treating COPD is still unclear. Conducting network pharmacology research on the combination of ginseng and astragalus can further clarify the active ingredients and targets of ginseng and astragalus, and analyze their mechanism of action in treating COPD. This can provide a theoretical basis for the treatment of COPD with ginseng and astragalus, and is also of positive significance for interpreting the theory of Xin An Gu Ben Pei Yuan.

 

Coughing, wheezing, shortness of breath, worsening of movement, and fear of wind are common symptoms of lung qi deficiency syndrome, which were first seen in the pathological process of COPD. The progressive development of lung qi deficiency affects the spleen and progresses to lung spleen qi deficiency, accompanied by symptoms such as poor appetite, bloating or bloating in the epigastric region, or loose stools; As the condition progresses, symptoms of kidney qi deficiency such as excessive breathing, shallow breathing, and insufficient Qi intake may appear, indicating a deficiency of lung, spleen, and kidney qi. The stable treatment of COPD mainly focuses on tonifying the lungs, spleen, and kidneys, while also considering promoting qi circulation, resolving phlegm, and promoting blood circulation. Effective prevention and treatment during the stable period have a positive impact on reducing the frequency of acute attacks, improving patient experience, delaying pathological changes, and disease progression.

Under the guidance of the theory of strengthening the foundation and nourishing the essence, Xin’an medical experts restore the function of qi and blood in the organs by tonifying the qi of the lungs, spleen, and kidneys, and eliminating pathological products such as phlegm, blood stasis, and water retention, which is highly compatible with the treatment of stable COPD. By analyzing the medication patterns in the target database using Apriori association rules, it was found that the combination of ginseng and astragalus had the highest confidence in treating COPD. Represented by Wang Ji, a physician at Xin’an Medical School who focuses on strengthening the foundation and nurturing the element, believes that “ginseng and astragalus not only nourish yang, but also nourish yin”. In clinical practice, they are skilled in using ginseng and astragalus to strengthen the spleen and stomach, nourish qi and blood, and balance yin and yang. Chen Jiamo, a medical expert from Qimen in the Ming Dynasty, wrote in his book “Bencao Mengqi”: “Ginseng can relieve wheezing and cough, unblock blood vessels, and eliminate yin fire… When the lungs are cold and affected by evil, it can cause shortness of breath and shortness of breath, and is suitable for use in cases of deficiency and wheezing. The Herbal Preparation by Wang Ang, a famous doctor of Shexian County, said: “Astragalus is processed to invigorate the central nervous system, invigorate the vital energy, warm the triple energizer, strengthen the spleen and stomach… If the spleen and stomach are relaxed, the lung qi will be strong and the muscle surface will be firm, and the central nervous system will strengthen the surface. The two drugs are popular with doctors in Xin’an. They are used together to strengthen the central nervous system, invigorate the spleen, invigorate the lung, and cultivate the earth, which is consistent with the basic pathogenesis of lung and spleen deficiency syndrome in the stable phase of COPD. Modern clinical research shows that the prescription with ginseng and astragalus as the monarch drug has a good therapeutic effect on the stability of COPD. Dou and other researchers found that the self prepared lung and kidney tonifying decoction (Dangshen, Shenghuangqi, Wuqi) Weizi, etc.) can reduce the TCM syndrome score of patients with chronic obstructive pulmonary disease, lung and kidney qi deficiency, increase PaO2, and reduce CO2 retention.

By using the cytoNCA plugin in Cytoscape 3.7.2, 33 active ingredients from Panax ginseng and Astragalus membranaceus were identified. Referring to the degree ranking and combining with research literature, it was found that components such as kaempferol, ginsenoside Rh2, and hederagenin play important roles. Shannai phenol is a low molecular weight yellow compound with a diphenylpropane structure, formed by the condensation of 4-coumaroyl CoA and three malonyl CoA. It can inhibit the occurrence of inflammatory reactions by suppressing the binding activity of NF – κ B and myeloid differentiation factor 88 (MYD88). Ginsenoside Rh2 is one of the main bioactive saponins in ginseng. Structurally, Rh2 can be divided into two types: S-type and R-type. Among them, the 20 (S) – Rh2 monomer is the main configuration isolated from Chinese herbal medicine. Studies have shown that ginsenoside Rh2 effectively inhibits microglial activation and the production of pro-inflammatory cytokines by regulating the TGF – β 1/Smad pathway. Ivy saponin is a naturally occurring triterpenoid compound with a hydroxymethyl group at the C-4 position of the A ring. It is highly insoluble in water and can inhibit the nuclear translocation of NF – κ B and p-I κ B α, thereby inhibiting the activation of NF – κ B, suppressing endotoxin induced cellular NF – κ B levels, and exerting anti-inflammatory effects on NF – κ B nuclear translocation.

Through GO functional analysis of intersecting targets, it was found that ginseng astragalus may regulate molecular functions such as transcription factor binding, receptor regulation, signal receptor activation, ligand activity, etc. in the cytoplasmic nucleus, extracellular matrix, and outer mitochondrial membrane regions, exerting antioxidant stress, delaying inflammation, and inhibiting biological processes such as cell apoptosis and epithelial cell proliferation. KEGG pathway enrichment analysis showed that these targets are involved in PI3K Akt signaling pathway, IL-17 signaling pathway, TNF signaling pathway, HIF-1 signaling pathway, cytokine receptor interaction signaling pathway, Toll like receptor signaling pathway, Jak STAT signaling pathway, MAPK signaling pathway, T cell receptor signaling pathway, Th17 cell differentiation, and Foxo signaling pathway. Using the ytoHubba plugin in Cytoscape, the top ten core genes with degree values were screened. Based on literature and KEGG enrichment analysis, Toll like receptors (TLRs) and Th17 cell differentiation signaling pathways were selected for in-depth analysis. The core genes enriched in the two pathways were identified as AKT1, IL6, CXCL8, MAPK1, and TNF – α. TLRs are key pattern recognition receptors in innate immunity. Under the influence of factors such as smoking, harmful gases, and microorganisms, TLRs form transmembrane signal transduction, and then regulate the transcription, translation, and expression of inflammatory genes through the MYD88 dependent NF – κ B pathway. They produce and release inflammatory factors such as IL-6, IL-8, COX-2, PGE2, etc. While damaging cells, they also act as endogenous ligands and bind to surface receptors such as neutrophils and NK cells, synthesizing and releasing a large number of inflammatory mediators and recruiting inflammatory cells, leading to the amplification and persistence of the pulmonary inflammatory response cascade. TLR2, TLR4, and TLR9 are all involved in the pathogenesis of COPD, among which TLR4 is considered the main TLRs that maintain the COPD inflammatory response. T helper cell 17 (Th17) is a special subset of helper T lymphocytes that primarily secretes interleukin 17 (IL-17) and other inflammatory cytokines. In chronic airway inflammatory diseases, Th17 binds to receptors on the surfaces of fibroblasts, epithelial cells, and smooth muscle cells, triggering an immune response that induces neutrophil proliferation and aggregation, leading to airway epithelial damage and mediating fibrosis; Compared with Th17 cells, Treg cells have immune regulatory functions and secrete anti-inflammatory cytokines to enhance immune tolerance and inhibit inflammatory responses. Th17/Treg imbalance is considered an important cause of COPD. AKT is a highly conserved serine/threonine protein kinase in evolution. The activation of AKT can inhibit the transcriptional activity of FOXO3a and induce the involvement of the p53/p21 pathway in cigarette induced aging of bronchial epithelial cells. IL-6, as one of the cytokines, can promote the Th17 (helper T cell 17) differentiation pathway and induce the production of pro-inflammatory cytokines such as IL-17 (interleukin 17) and CXCL8 (chemokine 8), promoting the development of COPD. CXCL8 is a mediator of neutrophil inflammation. CXCL8 and other chemokines secreted by pulmonary macrophages coordinate the transport of neutrophils (PMNs) to the lungs under external stimuli (cigarette smoke, air pollutants). The secretion of proteases produced by the accumulation of neutrophils and other inflammatory cells can lead to sustained and extensive tissue damage, as well as stimulate airway epithelium to contract and increase its permeability to inflammatory cells, participating in the pathogenesis of COPD. TNF – α is an important inflammatory mediator that can synergistically activate the NF – κ B system of inflammatory cells with cigarette smoke, LPS, etc. It stimulates the release of cytokines such as IL-8, increases the number of neutrophils, and induces the release of matrix metalloproteinases (MMP-9, MMP-12, etc.), damaging the pulmonary alveolar wall and exacerbating the progression of COPD. MAPK1 (mitogen activated protein kinase 1) is an intracellular serine/threonine protein kinase that is highly conserved during evolution and located in the cytoplasm before activation into the nucleus. It can alter gene expression by phosphorylating transcription factors, promote the production of inflammatory factors such as TNF – α, IL-1, IL-6, induce a series of inflammatory and immune responses, and thus play a role in the pathogenesis of COPD. AKT1, IL6, CXCL8, TNF – α, and MAPK1 are key targets enriched in the Toll like receptor signaling pathway and Th17 cell differentiation signaling pathway. There are also interactive regulatory effects between these genes, which may affect the onset and progression of COPD through inflammatory immunity.

In order to further verify the reliability of network pharmacology results, molecular docking technology was used to perform molecular docking between core components and key targets. The results showed that the binding energies of core components kaempferol, ginsenoside Rh2, and hederagenin with AKT1, IL6, CXCL8, MAPK1, and TNF – α were all less than -21.4 kJ/mol. Among them, the binding energy of AKT1 with ginsenoside Rh2 and hederagenin was -44.8 kJ/mol, indicating strong binding activity between them. The above results indicate that AKT1, IL6, CXCL8, MAPK1, and TNF – α may be important targets for the action of ginseng astragalus.

In summary, through data mining, it has been confirmed that doctors from Xin’an Medical’s Gu Ben Pei Yuan Pai make good use of ginseng astragalus medicine in the treatment of COPD. A “compound target” network was constructed using network pharmacology methods to analyze the interaction between ginseng astragalus components, targets, and signaling pathways as a whole. It is speculated that ginseng astragalus synergistically acts on multiple targets such as AKT1, IL6, CXCL8, MAPK1, and TNF – α through potential pharmacological components such as kaempferol, ginsenoside Rh2, and hederagenin, and exerts anti-inflammatory and immune regulating effects on COPD through Toll like receptor signaling pathways and Th17 cell differentiation signaling pathways. The mechanism of ginseng and astragalus drugs in treating COPD through multiple components, targets, and pathways has been preliminarily revealed. Subsequent experimental studies can be conducted on the ginseng astragalus drug pair to screen the main components of the drug for their effects on cigarette smoke induced airway epithelial cell models, detect the expression of core target proteins, and explore the key mechanisms of action in depth, providing new directions and basis for the development of COPD treatment drugs.