Study on the mechanism of Huanglian Banxia medicine in the treatment of chronic atrophic gastritis
Chronic atrophic gastritis belongs to the category of “gastric distension” and “stomach pain” in traditional Chinese medicine. The etiology is often caused by insufficient positive qi, external pathogens invading the stomach, emotional disorders, and dietary disorders. The disease is in the spleen and stomach, and the nature of the disease is often mixed with deficiency and excess. “Qi stagnation, Qi deficiency, damp heat, blood stasis” run through the entire course of the disease and are emphasized at different stages. In treatment, methods such as clearing heat and resolving phlegm, nourishing qi and yin, and promoting blood circulation and unblocking collaterals are often used. Huanglian and Banxia are one of the commonly used drugs in traditional Chinese medicine clinical practice, and are also the recommended components of Lianpuyin, Huanglian Wendan Tang, and Banxia Xiexin Tang in the consensus of traditional Chinese medicine and integrated traditional Chinese and Western medicine diagnosis and treatment of chronic atrophic gastritis. They have a solid clinical foundation for the treatment of chronic atrophic gastritis. Related studies have found that the activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway during the pathogenesis of chronic atrophic gastritis can lead to abnormal proliferation, angiogenesis, and malignant transformation of gastric mucosal cells, ultimately leading to the occurrence and development of malignant tumors; The positive rate of Yes associated protein 1 (YAP1) in gastric mucosa of gastric cancer patients is significantly higher than that of normal gastric mucosa, chronic atrophic gastritis, and intestinal metaplasia patients. Its overexpression in gastric mucosa is closely related to the progression, lymph node metastasis, and poor prognosis of gastric cancer; Angiogenesis is an important factor affecting the prognosis of chronic atrophic gastritis and precancerous lesions of gastric cancer. Based on this, this study first used molecular docking to explore the relationship between the active ingredients of Huanglian Banxia medicine and the key targets of interleukin-1 β (IL-1 β) and interleukin-6 (IL-6) in the pathogenesis of chronic atrophic gastritis, IL-6) 、YAP1、STAT3、JAK2、 The binding affinity of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR); Then, a rat model of chronic atrophic gastritis was established through animal experiments, and intervention treatment was carried out using the decoction of Huanglian and Banxia; Finally, by detecting the expression of relevant targets in blood and gastric mucosal tissue, we aim to explore the mechanism of action of the drug in preventing and treating chronic atrophic gastritis, laying the foundation for subsequent research.

 

Huanglian and Banxia, as a common traditional Chinese medicine used in Banxia Xiexin Tang, Lianpu Yin, and Huanglian Wendan Tang, play the role of “ruler and minister” in various preparations. Huanglian is a perennial herbaceous plant belonging to the Ranunculaceae family. It mainly contains alkaloids, flavonoids, lignans, acidic components, etc. It has the effects of clearing heat, drying dampness, purging fire, and detoxifying; Pinellia ternata belongs to the Araceae family of the Araceae order. It contains various chemical components such as alkaloids, organic acids, sterols, amino acids, volatile oils, and inorganic elements. It has the effects of drying dampness, resolving phlegm, reducing nausea and vomiting. Huanglian Pinellia ternata is a combination of warm and cold herbs, without the concern of excessive medicinal properties. It is a combination of bitter and bitter herbs that can reduce bitterness, regulate qi flow, and clear and eliminate dampness. Together, it has the effects of stopping nausea, clearing heat and phlegm, dispelling stagnation, detoxifying and reducing swelling, and is in line with the etiology and pathogenesis of chronic atrophic gastritis. This study screened 13 main active ingredients in Huanglian and Banxia through strict Lipinski rules, including 8 Huanglian and 5 Banxia. Through molecular docking, it was found that the main active ingredients represented by berberine, methylcoptisine, etc. can bind to the core targets of chronic atrophic gastritis, IL-1 β, IL-6, YAP1, STAT3, JAK2, VEGF, EGFR, which to some extent represent the main pharmacological substance basis of Huanglian and Banxia in preventing and treating chronic atrophic gastritis.

Modern research has found that inflammation, as the main pathological change in the early stage of chronic atrophic gastritis, promotes the malignant transformation of the diseased gastric mucosal tissue under the action of “uncontrolled inflammation”, accelerating the early angiogenesis of cancer. Clinical and experimental studies have confirmed that the activation of inflammatory signaling pathways such as JAK2/STAT3, upregulation of pro-inflammatory cytokines (IL-6, IL-1 β, etc.), and activation of angiogenesis pathways (VEGF, EGFR, etc.) play an important role in the evolution of chronic atrophic gastritis gastric mucosa. YAP1, as a key transcriptional co activator in the Hippo signaling pathway, regulates cell growth, proliferation, and apoptosis. Under normal circumstances, YAP1 exists in the cytoplasm in the form of phosphorylation and participates in the regulation of organ and tissue regeneration. Under the influence of upstream abnormal signals such as uncontrolled inflammation, YAP1 undergoes dephosphorylation and enters the nucleus, promoting the expression of related cancer genes and cell proliferation, and determining the magnitude of carcinogenic activity. AKT1 is involved in the occurrence, development, infiltration, and metastasis of gastric cancer. Interference with AKT1 expression can inhibit the proliferation and migration of gastric cancer cells. Therefore, IL-1 β, IL-6, YAP1, STAT3, JAK2, AKT1, VEGF, and EGFR play important roles in the pathogenesis of chronic atrophic gastritis and are important targets for preventing and treating its progression towards malignancy.

In this experiment, under the long-term stimulation of complex conditions such as MNNG solution, hot salt, ethanol, and hunger and satiety disorders, feed containing ranitidine (a commonly used selective H2 receptor antagonist in clinical practice) was added to inhibit gastric acid secretion in model animals, promote the rapid conversion of nitrate into nitrite after drinking into the stomach, and accelerate modeling. Through HE pathological examination, it was found that this method successfully established a model of chronic atrophic gastritis. Vitamin enzyme extract is a common Western medicine used to treat chronic atrophic gastritis, mainly composed of riboflavin, flavin mononucleotide, various vitamins and amino acids. It has the effect of promoting the regeneration of gastric mucosal epithelium and glandular epithelium, and has strong comparative significance with multi-component traditional Chinese medicine. After testing various indicators, it was found that the inflammatory cytokines IL-6 and IL-1 β were significantly elevated in the blood of rats, forming an inflammatory microenvironment; Causing an increase in p-JAK2 and pSTAT3 levels, activating the JAK2/STAT3 signaling pathway, promoting uncontrolled inflammation, leading to the activation of VEGF and EGFR, accelerating early angiogenesis in cancer, and triggering YAP1 dephosphorylation (p-YAP1), leading to overexpression of AKT1, damaging gastric mucosal tissue morphology, and inducing chronic atrophic gastritis to evolve into malignant tumors. After the intervention and treatment of multiple active ingredients in Huanglian Banxia medicine, the expression of serum inflammatory cytokines IL-6 and IL-1 β was significantly inhibited, and the phosphorylation level of key indicators of the JAK2/STAT3 signaling pathway in gastric mucosal tissue was reduced. The activation of the pathway was inhibited, the inflammatory microenvironment was improved, the expression of VEGF and EGFR in the tissue was reduced, and tumor angiogenesis was affected. The overexpression of YAP1 and AKT1 was regulated to repair damaged tissue morphology, delay or block the malignant transformation of chronic atrophic gastritis, and thus exert a therapeutic effect on chronic atrophic gastritis. In this process, the combination of Huanglian Banxia at a medium dose had significant advantages and was superior to vitamin E, and no dose dependence was found. Therefore, we believe that Huanglian and Banxia are the core drugs for preventing and treating chronic atrophic gastritis, and their mechanisms of action are closely related to regulating inflammatory signaling pathways, inhibiting tumor angiogenesis, and other pathways.