Exploring the material basis and medication rules of traditional Chinese medicine intervention in cytokine storm based on network pharmacology and data mining
Cytokines are an indispensable part of the body’s inflammatory response, and cytokine storm (CS) is a serious immune response caused by the abnormal expression of IL-6, IL-1, TNF – α, IFN and other cytokines in a short time after the body is infected with pathogenic microorganisms, which is considered to be one of the main mechanisms of the development of COVID-19. Clinical research shows that some patients with COVID-19 have mild symptoms in the early stage, but the main reason for the sudden exacerbation in the late stage is CS, and the severity is positively correlated with CS. For critically ill patients, CS can induce acute respiratory distress syndrome, multiple organ damage, and even death. Due to the relatively complex mechanism of CS, related diseases also progress rapidly, posing challenges for clinical treatment. Therefore, in recent years, the research and development of CS intervention regulators has become a hot topic.
Traditional Chinese medicine has significant therapeutic effects in the clinical treatment of diseases, and traditional Chinese medicine formulas have the advantages of multi-target, multi pathway, and high safety when intervening in diseases. The research methods of network pharmacology can integrate important information related to disease targets, ingredients, traditional Chinese medicine, etc; This study intends to adopt network pharmacology methods combined with data mining, taking CS related targets as the entry point, to explore the material basis and general rules of traditional Chinese medicine intervention in CS, in order to provide reference and guidance for related research and experimental verification of traditional Chinese medicine intervention in CS.

CS is an excessive immune response in the human body caused by stimulation, which activates and releases cytokines and chemokines in the body, leading to a disruption of the balance between pro-inflammatory and anti-inflammatory effects. Research has shown that the main culprit causing the deterioration and death of COVID-19 patients is CS, and inhibiting CS is the primary task in rescuing critically ill COVID-19 patients. The treatment of CS in Western medicine mainly relies on glucocorticoids. Although long-term high-dose use of glucocorticoids can achieve certain preventive and therapeutic effects, the toxic side effects it brings cannot be ignored. On the contrary, traditional Chinese medicine itself has the advantages of wide range of effects, diverse targets, and overall regulation, and has broad application prospects and research value in intervening and regulating CS. This study utilized network pharmacology and data mining methods, with CS related targets as the entry point, to screen compounds and traditional Chinese medicines that intervene in CS, and systematically predicted and explained the material basis and medication rules of traditional Chinese medicine intervention in CS.
The results showed that the targets with high degree rankings mainly include MAPK14, TNF, IL6, AKT1, MAPK1, VEGFA, IL1B, etc. Mitogen activated protein kinase (MAPK) plays an important role in cell proliferation, differentiation, inflammatory response, immune defense, and many other aspects. Research has shown that MAPK14 plays a key role in regulating cytokines (TNF – α, IL-6) and chemokines (CCL2, CCL4), and regulating the activation of MAPK14 can inhibit the release of inflammatory cytokines. In the early stages of COVID-19 infection, early inflammatory factors such as TNF – α and IL1B are rapidly secreted. Excessive early inflammatory cytokines can disrupt the anti-inflammatory pro-inflammatory balance in the body, further triggering the activation and release of cytokines and chemokines including IL-6 and IL-2, leading to uncontrolled CS. In addition, as TNF – α is the main inflammatory factor secreted by the body in the early stages of inflammation, it can increase the expression of intercellular adhesion molecules, enhance NF – κ B activity, and ultimately expand and sustain the inflammatory response through a positive feedback regulatory mechanism. IL-6 not only has multiple biological activities, but also serves as a pro-inflammatory mediator; At the same time, the level of IL-6 in the body is positively correlated with the severity of COVID-19 patients, indicating that it may play a key role in the anti-inflammatory response of traditional Chinese medicine. In addition, VEGFA, widely distributed in the brain, as an important angiogenic factor, may play a key role in brain inflammation in COVID-19 patients by promoting the aggregation of inflammatory cells and regulating the levels of angiopoietin II (Ang II).
Compounds with more corresponding targets in the target compound network, such as Tripterygium wilfordii Hook. f. and Curcumin, which are mapped to traditional Chinese medicine, will have smaller values in subsequent analysis and will not be discussed further. The compounds with high degree values mainly include quercetin, kaempferol, luteolin, isorhamnetin, naringenin, etc. Research has shown that quercetin can exert anti-inflammatory and protective effects on vascular endothelial cells by inhibiting the expression of NF – κ B p65 protein and reducing the secretion of inflammatory factors such as IL-6. Shanna phenol can significantly inhibit the activation of the MAPK pathway, reduce the production of inflammatory factors such as IL-8, IL-10, MDC, and effectively inhibit inflammation. Leyva-L ó pez et al. have demonstrated that solid wood rhinoceros toxin is an important pro-inflammatory cytokine regulator that can inhibit mediators such as reactive oxygen species and nitric oxide (NO) in inflammatory responses, reducing cytokine expression and secretion. In addition, naringin can reduce the levels of inflammatory factors such as TNF – α, IL-1B, and IL-18 in lung tissue by inhibiting the activation of LRP3 inflammasome. The molecular docking results showed that the selected high-value compounds had good binding activity with the core target; In addition, compounds such as baicalein and aloe emodin have also shown good docking activity in molecular docking.
The network of target compound and target compound traditional Chinese medicine intuitively presents the characteristics of multiple types, components, and targets of traditional Chinese medicine in intervening CS. At the same time, the compound degree values and corresponding target points also reflect the importance of traditional Chinese medicines such as Ginkgo biloba leaves, Patrinia scabra, and licorice in intervening in CS. Experimental results have shown that Ginkgo biloba leaves and their extracts can intervene in the Ghre lin Obestatin signaling pathway in mice, reduce the levels of cytokines such as TNF – α, IL-6, IL-8 in serum, alleviate inflammatory reactions, and improve lung function. Baijiang Grass can reduce the levels of IL-6, IL-8, and TNF – α in the serum of inflammatory model rats, and has the effect of clearing heat and detoxifying. It is the main adjuvant of Shufeng Jiedu Capsules. Dai et al found that liquorice, chrysanthemum, belamcanda, etc. are commonly used Chinese medicines for the treatment of COVID-19, and these Chinese medicines can effectively inhibit the production of cytokines such as TNF – α and IL-6. Qingfei Paidu Decoction, composed of liquorice, Shegan and other traditional Chinese medicines, as the main prescription for the treatment of COVID-19, can significantly reduce the release of proinflammatory factors and has strong anti-inflammatory activity in vivo and in vitro. Matrine, as the main component of Sophora flavescens, has been proved to be effective in the treatment of COVID-19; In addition, flavonoids contained in Sophora flavescens also have significant anti-inflammatory activity, which can significantly inhibit the release of pro-inflammatory cytokines such as NO, TNF – α, IL-6, and MCP-1.
The analysis of sexual taste shows that traditional Chinese medicine with the potential to intervene in CS mainly has bitter taste, and the most common medicinal properties are cold. According to traditional Chinese medicine theory, bitter herbs are believed to have the ability to release, dry, and firm; And it often has the effects of clearing heat, reducing qi reflux, promoting bowel movements, purging fire, and preserving yin. Patients with acute lung injury caused by CS often have symptoms such as dryness and heat accumulation, obstruction of internal organs and qi, bloating and fullness. The application of bitter Chinese medicine can play a role in ventilation, diarrhea, and clearing heat pathogens. Traditional Chinese medicine with a cold nature often has the effects of clearing heat and detoxifying, purging fire and cooling heat. However, COVID-19 caused by CS belongs to the category of “warm diseases” in traditional Chinese medicine, mainly manifested as fever, cough, etc. The application of cold Chinese medicine is in line with the basic treatment principles of traditional Chinese medicine for those with heat and cold. At the same time, traditional Chinese medicine with the potential to intervene in CS mostly enters the liver and lung meridians. The liver is the official organ of the general, and the lungs are the organs that promote and eliminate the body. The book “Su Wen · Yin Yang Ying Xiang Da Lun” records that “when the lungs are located above the diaphragm, their qi decreases; when the liver is located below the diaphragm, its qi rises; only when the liver rises can the lungs descend, and only when the lungs descend can the liver rise.” It can be seen that only when the liver and lungs rise and fall appropriately can the human body’s qi and blood flow smoothly, thereby restoring the patient’s respiratory function. From this, it can be seen that traditional Chinese medicine intervention in CS can start from clearing heat and eliminating fire, promoting blood circulation and removing blood stasis, and nourishing lung qi.
In summary, this study utilized methods such as network pharmacology, molecular docking, and data mining to systematically explore the potential pharmacological substance basis and medication rules of traditional Chinese medicine intervention in CS, with CS related targets as the entry point. To a certain extent, it provides theoretical support for traditional Chinese medicine intervention in CS and related diseases, and also provides new ideas for further developing drugs for CS intervention.