Study on the Material Basis and Mechanism of Qingfei Paidu Decoction in Treating COVID-19 Based on Network Pharmacology
Since December 2019, China’s novel coronavirus pneumonia (COVID-19) epidemic has developed rapidly, and the World Health Organization has declared COVID-19 a public health emergency (PHEIC) of international concern. According to the Diagnosis and Treatment Plan for Pneumonia Caused by novel coronavirus (Trial Version 5) issued by the National Health Commission, the common clinical manifestations of COVID-19 are fever, cough, myalgia, fatigue (fatigue), and digestive tract symptoms, dyspnea and other symptoms. In imaging examinations, lung CT shows different imaging features according to different stages. Among them, severe cases present with diffuse lesions in both lungs, appearing as “white lungs”, commonly accompanied by bronchial inflation sign and vascular passage.

According to traditional Chinese medicine, the majority of viral infections of pneumonia are caused by exogenous febrile diseases caused by cold pathogens. In the Treatise on Cold Damage, winter is the most common season for cold pathogens, which damage the skin surface. Due to the cold nature and the fact that cold is a yin pathogen, it can easily damage yang qi. Therefore, cold pathogens can inhibit yang qi, leading to the stagnation of wei yang and preventing its release. The main manifestations of typhoid fever syndrome include fever and chills, strong headache, lack of sweating, and floating pulse. If the external cold pathogen is severe or the body’s yang qi is insufficient, the cold pathogen can penetrate directly into the body, damaging the spleen and kidneys, forming symptoms such as chills, coldness in the limbs, shivering, diarrhea, etc. In the Yellow Emperor’s Inner Canon, the prevalent and highly contagious “external fever” is called “epidemic ulcer”. In terms of etiology, “epidemic ulcer” is considered a disease of abnormal luck. The “Treatise on the Origins and Symptoms of Various Diseases” states: “Those who suffer from diseases during the current period should be warm in spring but instead of cold, hot in summer but instead of cold, cool in autumn but instead of hot, and cold in winter but instead of warm. They do not have their own characteristics from time to time. They are those who have similar rates of illness throughout the year.” The “Su Wen · Ci Fa Lun” also has a similar discourse, which states: “When we hear the arrival of the five epidemics, they are all susceptible to infection, regardless of their size, and have similar symptoms.” It is generally believed that most common “exogenous heat diseases” are also infectious, but their infectivity varies to some extent. Fever usually does not cause epidemics. Warm epidemic “belongs to a class of highly contagious diseases that can cause epidemics among” exogenous fever “.

The National Administration of Traditional Chinese Medicine has piloted the use of Qingfei Detox Decoction to treat COVID-19 infected pneumonia patients and has achieved good therapeutic effects. Qingfei Detox Decoction is an optimized combination of several classic formulas for treating exogenous febrile diseases caused by cold pathogens, as described in Zhang Zhongjing’s “Treatise on Cold Damage and Miscellaneous Diseases” during the Han Dynasty. Given that the mechanism of action of Qingfei Detoxification Decoction in treating COVID-19 is not fully elucidated, and due to the complex composition and numerous targets of traditional Chinese medicine formulas, this study uses network pharmacology methods to explore the known bioactive components and targets of traditional Chinese medicine formulas from a systematic and holistic perspective. Furthermore, based on network topology analysis, molecular docking, GO enrichment analysis, and KEGG pathway enrichment analysis, the mechanism of action of Qingfei Detoxification Decoction in treating COVID-19 is analyzed, providing a theoretical basis for the treatment of COVID-19 with Qingfei Detoxification Decoction

According to statistics, 82% of COVID-19 patients present with cough and 31% with shortness of breath, indicating that the main site of the disease is in the lungs. 11% of patients experienced muscle pain, and 8% experienced headaches, indicating that the secondary site of the disease is in the respiratory tract. The Yellow Emperor’s Inner Canon believes that “exogenous fever” is a type of disease characterized by fever as the main symptom due to the sensation of six pathogenic factors. In addition to fever, typhoid fever, and warm diseases, other illnesses such as heatstroke, malaria, and dysentery also belong to the category of “exogenous fever”. The book “Su Wen · Re Lun” states: “When a person’s injury is caused by cold, it is called illness heat. Although heat is not fatal, those who are affected by both cold and illness will not be exempt from death.” This indicates that the name of a fever is based on its symptoms, and high heat intensity is caused by the inability of its yang qi to escape, resulting in sweating and dispersing. In the “Su Wen · Qi Qi Tong Tian Lun”, it is discussed that “due to cold, desire is like movement, daily life is like shock, and the air is floating.” In the “Ling Shu · Sui Lu Lun”, it is said that “cold causes the skin to be urgent and the knee system to be closed, the pores to be blocked and blocked, and the yang energy cannot escape and gather on the surface, so fever can be seen. In addition to injuring cold and warm diseases, when cold pathogens invade the skin, muscles, and bones, there will be symptoms such as skin cold heat, muscle cold heat, and bone cold heat, and corresponding changes can occur when they are absorbed into compatible organs.” This shows that the clinical manifestations of COVID-19 patients are consistent with the description of external heat caused by cold pathogens in traditional Chinese medicine.

According to the analysis of the formula for Qingfei Detox Decoction, it is made by modifying and cutting “Maxing Ganshi Decoction” and “Shegan Mahuang Decoction”. Ma Xing Gan Shi Tang is mainly used for treating symptoms such as fever, bloating, pain, cough, cold stagnation, and even blockage caused by toxins. Clinical practice has shown that this formula has significant clinical effects on combating epidemic viruses. She Gan Ma Huang Tang is a expectorant with the effects of warming the lungs and promoting diuresis, reducing qi and eliminating phlegm, and treating cold phlegm stagnation, lung stagnation, and throat obstruction syndrome. Clinical practice has proven that this formula has good clinical effects on tracheal inflammation, asthma, pulmonary inflammation, etc.

This article uses the research methods of network pharmacology to explore the effective blood entering components of Qingfei Detoxification Decoction, constructs an “active ingredient target” interactive network diagram, screens 302 active ingredients and 32 disease co acting targets of Qingfei Detoxification Decoction, and obtains 10 significant effective compounds and 5 key targets based on network topology analysis, involving 28 significant biological processes and 144 significant pathways. The mechanism of Qingfei Detoxification Decoction in treating COVID-19 is explained from the perspective of targets and signaling pathways. Among the 10 significantly effective compounds, quercetin has good expectorant and cough suppressant effects, as well as a certain anti asthmatic effect; Luteolin has various pharmacological activities, such as anti-inflammatory, anti allergic, uric acid lowering, anti-tumor, antibacterial, antiviral, etc. It is mainly used clinically for cough suppression, phlegm removal, anti-inflammatory, uric acid lowering, and treatment of cardiovascular diseases. Other studies have shown that luteolin binds to the S2 protein of the severe acute respiratory syndrome (SARS) coronavirus, inhibiting the virus from entering host cells; Naringenin has various pharmacological activities such as anti-inflammatory, antioxidant, anticancer, anti-tumor, antiviral, and anti fibrotic effects; Kaempferol, as a common flavonoid compound, has anti infective, anti-inflammatory, anti-cancer and other effects; Beta sitosterol has cholesterol lowering, cough relieving, expectorant, tumor inhibiting, and tissue repairing effects, and is commonly used in chronic bronchitis. Its anti-inflammatory mechanism involves inhibiting the activity of inflammatory mediators such as PGE2, bradykinin, and histamine, as well as suppressing free cell migration. Stigmasterol, also known as stigmasterol or sterol, is a plant sterol with strong physiological and surface activities, including anti-inflammatory, antioxidant, anticancer, and cholesterol lowering effects. Scutellaria baicalensis has a long history of medicinal use in China. Baicalein and wogonin are the main active ingredients of Scutellaria baicalensis, which have antibacterial and antiviral effects, scavenging of oxygen free radicals, antioxidant, antipyretic, analgesic, anti-inflammatory, and immune function regulating effects. Isorhamnetin has cough and phlegm relieving effects, while nobiletin has antifungal, anti allergic, anti-inflammatory, anticancer, anti thrombotic, anti epileptic, anti coagulation, anti cholinesterase and other effects. In the molecular docking experiment, the significant effective ingredient quercetin in Qingfei Detoxification Decoction showed good docking with the key target TPGS2 for COVID-19 treatment, indicating that the compounds contained in Qingfei Detoxification Decoction may have potential anti COVID-19 effects. To further elucidate the role of Qingfei Detox Decoction in regulating key targets, this study identified five key targets through GO enrichment analysis. Among them, hydrogen peroxide synthase I and II (PTGS1 and PTGS2) mainly regulate hemoglobin binding and dioxygenase activity, participate in inflammatory responses, and enhance pro-inflammatory mediators; Inducible nitric oxide synthase (NOS2) can act as a biological mediator in various processes, including neurotransmission, antimicrobial, and anti-tumor activity; Peroxisome proliferator activated receptor (PPARG) plays an important role in various inflammations. PPARG can inhibit the activity of various transcription factors, including nuclear factor kappa B (NF – κ B) and activator protein, thereby regulating the anti-inflammatory response of cells and playing a protective role in various diseases; Mitogen activated protein kinase 14 (MAPK14) is a member of the MAP kinase family, involved in various processes such as cell proliferation, differentiation, transcriptional regulation, and development, and promoting the regulation and activation of inflammatory cytokines. Through pathway analysis of key targets, it was found that the main pathway includes the IL-17-related signaling pathway, which activates downstream pathways including NF – κ B, MAPK, and C/EBP through corresponding receptors, inducing the expression of antimicrobial peptides, cytokines, and chemokines, playing a crucial role in both acute and chronic inflammatory responses; The tuberculosis related pathway, in which Mycobacterium tuberculosis is transmitted through the air and through the circulatory system to other parts of the body, mainly attacks the lungs, interferes with the maturation of phagosomes, antigen presentation, cell apoptosis, and host immune system, and establishes persistent or latent infections; Tumor necrosis factor (TNF), as an important cytokine, can induce various intracellular signaling pathways, including apoptosis and cell survival, as well as inflammation and immunity; The mitogen activated protein kinase (MAPK) signaling pathway is regulated by extracellular signal related kinases such as ERK, JUN, P38, and ERK5, which are involved in various cellular functions including cell proliferation, differentiation, and migration; The Th17 cell differentiation pathway is involved in the immune response of extracellular microorganisms and autoimmune disease-related processes, regulating IL-17 expression, which is crucial for immune and host protection; Ptx and ACT are the main protein toxins of Bordetella pertussis in the pertussis related signaling pathway, which can inhibit multiple downstream pathways; Human Cytomegalovirus (HCMV) is an enveloped double stranded DNA virus in the human cytomegalovirus infection signaling pathway, belonging to the β – herpesvirus family. It induces activation of the PI3-K/AKT pathway.

Qingfei Detoxification Decoction may regulate physiological processes such as metabolism, transcription, and inflammatory response through biological functions such as cytokine receptor binding, antioxidant activity, phosphatase binding, heme binding, MAP kinase activity, protein phosphatase binding, peroxidase activity, and oxidoreductase activity. In addition, it may exert anti-inflammatory and immune regulatory effects through related signaling pathways such as IL-17, TNF, MAP, and Tuberculosis. This study used network pharmacology and bioinformatics methods to preliminarily verify the pharmacological mechanism of Qingfei Detox Decoction, and explained at the molecular level that Qingfei Detox Decoction intervenes in the occurrence and development of COVID-19 from multiple components, targets, and pathways through multi-faceted collaboration.