Letter to the Editor: Chaihu-Shugan-San in the treatment of atrophic gastritis

Abstract

Chronic atrophic gastritis, a recognized precursor of gastric cancer (GC), represents a highly relevant clinical issue. Early diagnosis and prevention are effective in reducing its incidence. An experimental animal study published in World Journal of Gastroenterology conducted by Song et al using traditional Chinese medicine and the Chaihu-Shugan-San (CSS) herbal mixture in the treatment of atrophic gastritis induced by N-methyl-N'-nitro-N-nitrosoguanidine showed impressive and promising results. Normalization of structural changes in atrophic gastritis was observed, including an increase in the thickness of the gastric mucosa and quantitative indices of gastric glands. A positive effect on the course of inflammation in the gastric mucosa was observed. Song et al identified specific interactions between CSS components and key targets, primarily the nuclear factor kappa B (NF-κB) signaling pathway, which is characterized by abnormal activity during inflammation and carcinogenesis. However, inhibition of the NF-κB signaling pathway leads to immunosuppression, which may negatively impact antitumor immunity. Thus, the study by Song et al offers real breakthrough prospects for the treatment of atrophic gastritis and prevention of GC using a traditional Chinese herbal mixture (CSS), taking into account the potential for assessing the state of immune defense under conditions of NF-κB pathway inhibition.

Key Words: Chaihu-Shugan-San; Atrophic gastritis; Stomach cancer; Nuclear factor kappa B; Treatment; Prevention

Core Tip: In their experimental article, Song et al presented results demonstrating the high efficacy of the traditional Chinese herbal mixture Chaihu-Shugan-San (CSS). They identified specific interactions between CSS components and key targets. Particular emphasis was placed on inhibition of the nuclear factor kappa B signaling pathway by CSS, accompanied by regression of inflammatory and structural changes in the gastric mucosa in N-methyl-N'-nitro-N-nitrosoguanidine-induced atrophic gastritis. Research using this traditional Chinese herbal mixture offers significant potential and a new strategy for the prevention and treatment of atrophic gastritis and gastric cancer.

TO THE EDITOR

We were drawn to an experimental study published in World Journal of Gastroenterology by Song et al[1] on application of the Chaihu-Shugan-San (CSS) herbal mixture in the treatment of atrophic gastritis. The results of the experiment were so impressive that we wanted to discuss it further.

Chronic atrophic gastritis is a precancerous condition that develops in the gastric mucosa as a result of a chronic inflammatory process. Atrophic gastritis significantly increases the risk of developing and progressing such a formidable disease as stomach cancer[2].

Gastric cancer (GC) is a global health problem posing a major threat to human life. According to experts, more than 1 million people suffer from GC, and 768000 people died from it in 2020[3]. Recent trends indicate an alarming increase in the incidence among people under 40 years of age[4]. China has the highest number of patients with GC in the world, ranking fourth in incidence and second in mortality[5,6].

Gastric carcinogenesis progresses through several stages in the following sequence: Normal gastric mucosa, which progresses to chronic superficial gastritis, then to chronic atrophic gastritis, then to intraepithelial neoplasia, eventually progressing to dysplasia[7].

Early diagnosis and prevention are currently a global priority for reducing the incidence of GC. Precancerous conditions in GC are the most critical conditions in terms of carcinogenesis[8]. Among the measures aiming to optimize the condition of the gastric mucosa, the guidelines for treating atrophic gastritis do not contain data on specific medications prescribed for prophylactic purposes as no such data are available. Obviously, insufficient knowledge of the molecular and cellular heterogeneity of intestinal metaplasia of the stomach should be considered to be among the most significant gaps in this regard. Therefore, some researchers are skeptical about the possibility of reverse atrophy in the gastric mucosa[9].

A series of studies on the treatment of atrophic gastritis with traditional Chinese medicine (TCM), particularly using herbal preparations and infusions, have yielded promising results and support the development of a novel strategy for the prevention of gastric carcinogenesis. The mechanisms of action of Chinese medicine are associated with strengthening the mucus bicarbonate barrier of the gastric mucosa, optimizing cell proliferation and apoptosis, improving microcirculation, modulating immune responses, and influencing the intestinal microbiota. Furthermore, it is clear that standardization in TCM, both in research and clinical practice, is essential for treatment optimization[10].

Thus, Song et al[1] conducted an experimental study on application of the CSS herbal collection in treatment of atrophic gastritis. The herbal collection CSS is a TCM agent, a classic remedy of the Ming Dynasty for the relief of clinical manifestations associated with liver congestion. The collection includes seven traditional Chinese medicinal herbs. Previous studies on the use of CSS in various diseases have shown a positive safety profile[11]. The drug has a pronounced positive effect on the motor activity of various parts of the gastrointestinal tract, as evidenced by the relief of dyspepsia symptoms in experimental animals[12].

The drug has a pronounced positive effect on the motor activity of various parts of the gastrointestinal tract, as evidenced by the relief of dyspepsia symptoms in experimental animals and gastroesophageal reflux disease when it is prescribed to patients with this disease.

A positive effect of CSS on the intestinal microbiota[1] has significant pathogenetic significance in the development and progression of gastrointestinal diseases. In recent years, the intestinal microbiota has received considerable attention and is considered a determining factor in deterioration of various aspects of a patient's health[13].

The application of CSS for treating atrophic gastritis has yielded striking results regarding its effect on normalization of structural changes characteristic of atrophic gastritis. This includes an increase in mucosa thickness and the quantitative indices of gastric glands. Furthermore, a significant effect on the intestinal microbiota and the course of the inflammation in the mucosa, the underlying cause of gastric mucosal atrophy, was observed[1].

When reading the scientific work by Song et al[1], I noted the high methodological level of the experimental study, which utilized modern, highly informative research methods. Using network pharmacology, Song et al[1] identified potential targets for the action of CSS in their study. Initially, a protein–protein interaction network was constructed for 75 common targets to understand the mechanisms underlying their putative effects. Therefore, several factors have been identified, such as interleukin (IL)-1, IL-6, tumor necrosis factor, BAX, BCL2, caspase-3/caspase-9, and NFKBIA, which provided the main therapeutic effect of CSS in the treatment of chronic gastritis. Using the "genetic information" function, it was revealed that all of them are mainly associated with the nuclear factor kappa B (NF-κB) signaling complex and the BAX-apoptotic complex. Specific interactions between bioactive components of CSS and key targets of the NF-κB signaling pathway have been identified. These data provide a rationale for the use of CSS in chronic atrophic gastritis. The free binding energy logarithm was estimated for six bioactive components, each having five potential active binding sites for interaction with IκBα.

Our attention was drawn to the data on NF-κB, given the importance of this signaling pathway in a wide range of pathophysiological processes. It included immune system functioning and neoplastic transformation, non-coding RNAs, etc. Particular interest was justified by the fact that the NF-κB signaling pathway is characterized by abnormal activity during inflammation and carcinogenesis[14].

NF-κB is a family of structurally related transcription factors, including RelA (also known as p65), RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52), which exist as homo- or heterodimers. NF-κB proteins share a conserved domain, known as the Rel homology domain, which mediates their dimerization, nuclear localization, DNA binding, and interaction with the inhibitory protein IκB[15]. The gene network controlled by NF-κB includes more than 300 genes involved in apoptosis, cell proliferation and differentiation, regulation of the oxidative status, immune response, hormonal signaling, etc.[16].

Abnormal activation of NF-κB contributes to the development of acute and chronic inflammatory diseases, primarily through abnormal induction of the genes encoding proinflammatory factors and metabolic disruption. Given the critical role of inflammation in stimulating oncogenesis, the proinflammatory effects of the NF-κB signaling pathway are closely linked to cancer development[17].

The NF-κB signaling pathway is closely related to the immune response involving macrophages, neutrophils, dendritic and T cells. Its positive influence as a central regulator can be observed throughout the entire course of acute inflammation: From injury to recovery[18]. The association between the NF-κB signaling pathway and the maintenance of cell viability has been studied, which is manifested through the induction of a number of apoptosis inhibitors, such as Bcl-2, Bcl-XL, c-IAP1, c-IAP2, and c-FLIP[18,19]. NF-κB also stimulates cell proliferation by inducing transcription of the genes involved in the cell cycle, such as cyclin D1[20]. The study by Song et al[1] demonstrates similar patterns of the relationship between NF-κB and the inflammatory and apoptotic processes.

In this study, atrophic gastritis was induced by exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a nitroso compound that mimics key processes associated with disease development and is a model for studying chronic gastric atrophy and oncogenesis. The molecular mechanisms of oncogenesis induced by MNNG exposure are associated with DNA damage and mutations in the key genes, such as TP53 and Ras. It modulates gene expression through epigenetic mechanisms, including DNA methylation, histone modification, and mRNA methylation. MNNG also promotes oxidative stress by increasing reactive oxygen species. Concomitantly, elevated levels of reactive oxygen species activate the NF-κB signaling pathway, followed by transcription of proinflammatory genes (including those encoding pro-IL-1β and pro-IL-18). It is accompanied by dysregulation of key signaling pathways, including PI3K/AKT/mTOR, and subsequently by suppression of apoptosis and autophagy. Key markers such as Bcl-2, Bax, Beclin-1, LC3, and ATG5 are altered[21].

Kogure et al[22] identified three phases of gastric mucosal changes in the development of oncogenesis under the influence of MNNG. The first stage lasts 16 weeks and is characterized by the presence of significant erosions and small dysplastic glands in the gastric antrum. The authors characterize the completion of this period of MNNG exposure to the gastric mucosa as the emergence of minor manifestations of atrophic gastritis.

Critical remarks. The experimental study by Song et al[1] on the therapeutic efficacy of CSS in the treatment of atrophic gastritis caused by MNNG exposure for 10 weeks suggests the prevalence of acute inflammation in the gastric mucosa in animals. It is evidenced by an increase in proinflammatory cytokines, which affects the area of influence of the NF-κB signaling pathway. In addition, there are previous studies that have shown that MNNG exposure in rats causes inflammatory processes in the gastric mucosa, their pathohistological manifestations being similar to those of intestinal-type GC in humans[23]. Therefore, it is obvious that metaplastic changes in all rats in the experiment should be treated with caution. Data on any other deviations in the characteristics of morphological changes in the gastric mucosa in animals that emerged after MNNG exposure would be no less interesting in presentation of the results of the study by Song et al[1].

There is a certain critical attitude regarding the extent to which the effect obtained from using CSS in animals with atrophic gastritis is reproducible in the human population.

The development of atrophic gastritis in humans is typically a long process, spanning decades. In most cases, both atrophic gastritis and the associated carcinogenesis are closely linked to patient age.

In this case, the occurrence of carcinogenesis creates certain prerequisites for gene mutations: In particular, DNA methylation in the absence of gene damage[24]. However, the development of atrophic gastritis in the experiment through exposure to MNNG (within 18–24 weeks) is associated with both methylation and DNA damage[25].

The results of the study by Song et al[1] related to the inhibitory effect of CSS on the NF-κB signaling pathway in the treatment of atrophic gastritis are undoubtedly impressive. However, as noted in scientific literature, due to the systemic and non-selective blockade of NF-κB signaling, a serious problem is the decrease in immune responses and increased susceptibility to infections. As mentioned earlier, NF-κB plays an important role in the organization of the acute inflammatory response to tissue damage and infectious agents. Moreover, immunosuppression caused by NF-κB inhibition can negatively affect antitumor immunity[18]. In light of these data, further research into the effect of CSS on various links of immune defense in atrophic gastritis is required.

There are a number of comments regarding the materials and methods. In experimental studies, the age of the animals is of great importance, which is not stated. The quantitative distribution of animals within groups should have been indicated. Given that a parametric research method was used, these data would have allowed one to assess the validity of its use. The 7-grade classification of gastric mucosal infiltration is not entirely clear when analyzing the morphological data. If this is a generally accepted classification, a citation is needed. Had this been the authors' own work, it would have required comparison with known classifications for assessing infiltration in gastritis. This could have demonstrated the appropriateness of the classification used in the study.

CONCLUSION

The relevance of this study is high. Thorough understanding of the context-dependent mechanisms by which CSS influences the pathophysiological development of atrophic gastritis offers potentially promising strategies for treating the disease and, consequently, preventing GC. Future studies of the immune system (the presence and severity of abnormalities) using CSS in the treatment of atrophic gastritis associated with NF-κB blockade will provide a definitive answer to the question of its widespread use in disease prevention, particularly as a second-line treatment after Helicobacter pylori eradication therapy.