BD is a clinically refractory disease, and its etiology and pathogenesis are still unclear. BD belongs to the category of fox confusion in traditional Chinese medicine. The pathogenesis is the accumulation of dampness and heat, and gas corrods qi and blood. Because of the fire of the heart and stomach, liver and gallbladder damp heat accumulation knot. The evil of fire, poison, dampness and heat invades the eyes, invades the oral cavity, and radiates down into the vulva. Therefore, the triad of ulcers is seen in the eyes, mouth, and pudendum. Gancao Xiexin decoction is a classic prescription for treating fox confusion in the Jingui Yaolue (Synopsis of the Golden Chamber) by Zhang Zhongjing. With liquorice Ganping fire detoxification for the king, with scutellaria, Rhizoma coptidis cold pathogenic heat, detoxification and dehumidification, Pinellia, dried ginger, heat dry dampness open Yin coagulation and dampness, Codonopsis ginseng, licorice, jujube health in the coke to dampness. This prescription of Xinkaikujiang treats fox confusion from the spleen and stomach, because the spleen and stomach are weak, and the transportation is not good, which is the root cause of damp-heat.
In this study, 201 active ingredients of Gancao Xiexin Decoction were screened out, and the active ingredient-target network showed that quercetin, wogonin, baicalein, and ginsenoside were the main active ingredients of Gancao Xiexin decoction. Quercetin is a flavonoid, which has chemopreventive and therapeutic effects on a variety of diseases, including inhibition of oxidative stress, cytokine and COX2 production [8]. Previous studies have shown that quercetin can reduce pain and inflammation related to arthritis, inhibit mechanical hyperalgesia, edema and leukocyte aggregation in mouse knee joints in a dose-dependent manner [9]. Its mechanism includes inhibiting the proliferation and gene level of pro-inflammatory cytokine (TNF-α) in human peripheral blood monocytes, reducing the expression of inflammatory factors such as IL-1β, IL-6, and matrix metalloproteinases (MMP3, MMP9), inhibiting the production of inflammatory mediators, and improving inflammatory symptoms. Animal studies have shown that quercetin can improve pain symptoms by inhibiting the activation of MMP-9 and MMP-2 in spinal microglia in mice. Levels of interleukin-17 (IL-17) and monocyte chemoattractant protein-1 (MCP-1) [10]. Baicalein is an inhibitor, which has the functions of antibacterial xanthine oxidase, anti-oxidation, immune regulation, and so on. It can effectively inhibit itching free radicals produced in the process of xanthine oxidation. Its hydroxyl structure also gives it free radical scavenging activity, and by regulating the arachidonic acid metabolism pathway, It can inhibit the production of cyclooxygenase, dehydrogenase, nuclear factor and cytokines and play a powerful antipyretic and analgesic effect. Animal experiments have shown that baicalein can inhibit macrophage inflammatory response induced by lipopolysaccharide and adenosine triphosphate [11]. Ginsenoside Rh2 isa tetracyclic triterpenoid saponin monomer [12]. In addition to promoting the apoptosis of tumor cells, ginsenoside Rh2 has a significant anti-inflammatory effect and can inhibit the inflammatory response induced by bacterial Lipopolisaccharide (LPS). Bi [13] et al. reported that Rh2-B2 modified by increasing water-soluble groups significantly inhibited the release of TNF-α, IL-6 and IL-1β from RAW264.7 macrophages. In addition, Rh2 inhibited the production of PGE2, ROS and MMP-9 in LPS-stimulated RAW264.7 macrophages, and inhibited the TNF-α-induced MMP-9 gelatinase activity in keratinocytes.
According to the PPI network, NTRK1, EGFR, CUL3, APP, TP53, MCM2, XPO1, ESR1, FN1, and HSP90AA1 may be the key targets of Gancao Xiexin decoction in the treatment of BD. NTRK1 is a specific high-affinity receptor for NGF, which is closely related to inflammatory response [14]. As a key signaling pathway in human body, EGFR mediates cell apoptosis and proliferation [15]. CUL3 is a ubiquitinated ligase E3 protein, belonging to the Cullin protein family. Fibronectin FN1 plays an important role in normal processes such as animal development, organ growth, cell adhesion, cell migration and hemostasis [16], and promotes cell proliferation and inhibits apoptosis by activating PI3K [17]. HSP are highly conserved stress-inducing factors that manage heat stress activation, promote T cell adhesion and migration, and enhance immune surveillance. It is involved in the pathogenesis of a variety of autoimmune and chronic inflammatory diseases.
According to KEGG pathway analysis, the main pathways involved in the treatment of BD by Gancao Xiexin decoction were inflammatory response and immune-related pathways. Involved in Human cytomegalovirus (HCMV) infection, Kaposi sarcoma-associated herpesvirus infection, AGE-RAGE signaling pathway in diabetic complications, Human T-cell leukemia virus 1 infection, TNF signaling pathway, etc. Liu[18] et al. found that HCMV-induced anti-PP150 antibody is a common autoantibody in autoimmune diseases, which provided a clear internal link between HCMV and autoimmune diseases. Studies have shown that the AGE-RAGE pathway can be involved in the resolution of inflammation, the maintenance of cellular homeostasis, and the repair and regeneration after injury. TNF-α can mediate cell-mediated necrosis and apoptosis through a variety of ways, which plays an important role in the occurrence and development of BD [3].
In summary, this study took the active components of Gancao Xiexin decoction as the research object, and explored the mechanism of Gancao Xiexin decoction in the treatment of BD by combining GEO differential analysis and network pharmacology, which provided a new reference for the treatment of BD. However, there are still some limitations in this study and further research is still needed to improve.