Exploring the Mechanism of Xiaochaihu Tang’s “Same Treatment for Different Diseases” in Systemic Lupus Erythematosus and Glomerulonephritis Based on the “Immune Inflammation” Link
Dialectical treatment is the characteristic and essence of traditional Chinese medicine diagnosis and treatment, and treating different diseases with the same method is a concrete manifestation of TCM’s dialectical treatment approach. The use of modern technological means to reveal the biological basis and principle of action of treating different diseases with the same treatment is one of the key points in the modernization research of traditional Chinese medicine, and it is also an important part of further elaborating the scientific connotation of syndrome differentiation and treatment. Xiaochaihu Tang comes from the “Treatise on Cold Damage and Miscellaneous Diseases” and is composed of seven herbs including Chaihu, Huangqin, Ginseng, Pinellia ternata, Ginger, Licorice, and Jujube. It has the effect of relieving Shaoyang. The clinical addition and subtraction of traditional Chinese medicine can be widely used in the treatment of various diseases, such as type 2 diabetes, lung cancer, subacute thyroiditis and chronic hepatitis B liver fibrosis. In addition, it has good clinical effect on infectious diseases such as bacterial liver abscess and children’s respiratory tract infection. Clinical reports have shown that for patients with immune system diseases such as systemic lupus erythematosus and glomerulonephritis, Xiaochaihu decoction can significantly improve their immune indicators and restore normal immune status. Modern pharmacology has confirmed that Xiaochaihu Tang can exert pharmacological effects on different disease stages through multiple pathways such as regulating immunity, anti-inflammatory effects, endocrine regulation, anti liver fibrosis, and anti-tumor effects. Among these functional components, the regulation of immune function and intervention in inflammatory response by Xiaochaihu Tang may be their common basis.
Through preliminary research, the research team has developed a network robust platform for predicting the efficacy of traditional Chinese medicine. This platform can simulate the intervention of single herbs, traditional Chinese medicine formulas, and drug targets on disease networks. The specific implementation process involves deleting disease network nodes to simulate the disturbance of drugs on diseases. Deleting different nodes in the same disease network can lead to different changes in network structure and stability. The purpose of drug intervention on diseases is to maximize the impact on network stability and disrupt network structure. Evaluate the intervention effect of drugs on diseases by comparing the changes in network topology characteristics before and after drug intervention using perturbation rate. In addition, by constructing a random network and simulating the overall distribution of the impact of deleting nodes on the robustness of the random network (permutation test), the position of drugs in the overall distribution of real network disturbances is examined, and the disturbance intensity of drugs on the real network is objectively evaluated by calculating the corrected disturbance rate. Taking novel coronavirus pneumonia as an example, the platform has realized the potential effect analysis of commonly used classical prescriptions on novel coronavirus pneumonia, providing reliable reference for effective drug screening of novel coronavirus pneumonia.
Based on the previous foundation, in order to explore the mechanism and specific steps of Xiaochaihu Tang in treating diseases, this study takes systemic lupus erythematosus (SLE) and glomerulonephritis (GN) as examples of immune system diseases. Using the Gene Expression Omnibus (GEO) database, differential genes related to SLE and GN diseases are obtained to construct a disease network. The traditional Chinese medicine efficacy prediction analysis platform is used to analyze the intervention of Xiaochaihu Tang on the two diseases, and the reliability of the disease model is verified by comparing it with the intervention of marketed Western medicine on the disease network. Subsequently, GO analysis and KEGG analysis are conducted to reveal the same treatment of different diseases with Xiaochaihu Tang from the perspective of “immune inflammation”. The mechanism.

SLE and GN are both diseases caused by immune system abnormalities. Based on the GEO database screening, it was found that SLE targets numerous organs, including the skin, kidneys, respiratory system, cardiovascular system, nervous system, and gastrointestinal tract, and the pathogenic factors are complex. The pathogenesis of both involves genetics, immune system abnormalities, inflammatory reactions, and other factors. The GO analysis and KEGG analysis results of Xiaochaihu Tang intervention in SLE and GN, as well as their intersection targets, are closely related to immune inflammation, such as negative regulation of viral processes, interferon – β production, response to interferon – γ, cell response to interferon – γ, negative regulation of lymphocyte proliferation, positive regulation of cytokine biosynthesis, regulation of B cell proliferation, type I interferon signaling pathway, interferon gamma mediated signaling pathway and other biological processes, which may be mediated by participating in cytoplasmic DNA sensing pathway, NOD like receptor signaling pathway, B cell receptor signaling pathway and other signaling pathways.

The GO analysis and KEGG analysis of SLE showed that Xiaochaihu Tang may exert therapeutic effects by participating in biological processes such as lymphocyte proliferation, adaptive immune response regulation, and cytokine biosynthesis. Relevant signaling pathways include allograft rejection, EB virus infection, primary immunodeficiency, Toll like receptor signaling pathway, Th1 and Th2 cell differentiation, etc. Allogeneic transplant rejection can cause cellular and humoral immunity in the immune system, with macrophages being the main immune cells that secrete inflammatory cytokines to enhance adaptive immune responses and participate in acute and chronic rejection reactions. EB virus is a DNA virus that primarily targets B cells and epithelial cells, as well as T cells, NK cells, and smooth muscle cells, and has the ability to cause tumors. The Toll like receptor signaling pathway plays an important role in the pathogenesis of SLE. Studies have shown that topical application of Toll like receptor 7 (TLR7) agonists to the skin of mice can induce SLE disease, leading to organ damage caused by autoimmune diseases such as glomerulonephritis.

The GO analysis and KEGG analysis results of GN showed that Xiaochaihu Tang may achieve treatment of influenza A, TNF signaling pathway, cytoplasmic DNA sensing pathway, Legionellosis, NF – κ B signaling pathway, HIF-1 signaling pathway and other signaling pathways related to immunity and inflammation by participating in pattern recognition receptor signaling pathway, leukocyte mediated immune regulation, leukocyte proliferation regulation, neuroinflammatory response and other biological processes. The interferon (IFN) signaling pathway is a major component of innate immunity and plays an important role in host resistance to pathogens. Clinical studies have found that monocytes in active SLE patients have high expression of specific genes related to interferon regulation and granulocyte production, which can alleviate disease progression by inhibiting IFN expression.

Data analysis shows that SLE and GN may play a role through biological processes such as positive regulation of cytokine biosynthesis process, myeloid leukocyte differentiation regulation, response to γ – interferon and positive regulation of α – interferon production, and are closely related to cytoplasmic DNA induction pathway, NOD like receptor signal pathway, human immune response to tuberculosis, microglia pathogen phagocytosis pathway and other immune inflammatory signal pathways. Among them, the cytoplasmic DNA sensing pathway involves the binding of DNA present in mammalian cytoplasm to a dimeric enzyme called cGAS. This binding triggers an enzymatic reaction that leads to the formation of a circular signaling molecule, which in turn induces the synthesis of immune stimulating proteins called interferons. This triggers a strong innate immune response, and DNA that cannot be cleared in a timely manner in the cytoplasm participates in the occurrence of SLE and Aicardi Goutieres syndrome by activating the intracellular antiviral response; NOD like receptors mainly include NOD1 and NOD2. NOD1 and NOD2 recognize bacterial components through their leucine rich repeats (LRRs) and mediate the activation of NF – κ B through downstream effectors, leading to the release of pro-inflammatory cytokines that play a critical role in cellular inflammatory, immune, and stress responses.

The analysis of T/B cell function and signaling, NF – κ B signaling pathway, and type I interferon signaling pathway in the results of this article is consistent with the potential pathogenesis of SLE and GN in clinical studies. Belimumab, an approved drug for treating SLE, is an inhibitory monoclonal antibody against B-cell activating factor (BAFF). BAFF can promote B cell maturation and differentiation, is closely related to autoimmunity, and plays an important role in immune response. Interferon induced GTP binding protein MX1 targets viruses including negative stranded RNA virus and HBV. In clinical studies, MX1 can serve as a potential biomarker for diagnosing peripheral blood SLE and lupus nephritis activity in the kidneys. Through analysis, it was found that biological processes such as type I interferon signaling pathway, negative regulation of viral processes, response to interferon gamma, interferon gamma mediated signaling pathway, negative regulation of lymphocyte proliferation, interferon beta production, and regulation of B cell proliferation, as well as cytoplasmic DNA sensing pathway, NOD like receptor signaling pathway, and influenza A signaling pathway, all appeared in the GO and KEGG analysis results of Xiaochaihu Tang intervention in SLE, Xiaochaihu Tang intervention in GN, and Xiaochaihu Tang intervention in the intersection targets of SLE and GN (see Table 5), indicating that Xiaochaihu Tang is different from other signaling pathways. The potential mechanisms of treating diseases together may be closely related to these, and further in-depth research is needed in the future.

There are still shortcomings in this article, and the traditional Chinese medicine efficacy platform used in this article needs further improvement. Currently, it is not possible to consider the strength of the effect of traditional Chinese medicine targets on disease targets. For traditional Chinese medicines with more target components such as licorice and jujube, their inclusion will interfere with the disturbance results of the main drug on the disease network. Therefore, licorice and jujube were removed from the prediction of disease targets.

In summary, based on pharmacological prediction analysis and bioinformatics methods, this article takes Xiaochaihu Tang’s “treating different diseases with the same treatment” for SLE and GN as an example to systematically analyze the mechanism of action of Chaihu formula’s “treating different diseases with the same treatment”. It confirms that Xiaochaihu Tang can exert its therapeutic effect on SLE and GN by acting on the “immune inflammation” related disease links, which can provide reference and inspiration for future in-depth research on the mechanism of action of Xiaochaihu Tang’s “treating different diseases with the same treatment”, and lay the foundation for explaining the intervention links and mechanisms of traditional Chinese medicine formulas in diseases.