Traditional Chinese medicine for chronic atrophic gastritis: Efficacy, mechanisms and targets

Abstract

Chronic atrophic gastritis (CAG) is an important stage of precancerous lesions of gastric cancer. Effective treatment and regulation of CAG are essential to prevent its progression to malignancy. Traditional Chinese medicine (TCM) has shown multi-targeted efficacy in CAG treatment, with advantages in enhancing gastric mucosal barrier defense, improving microcirculation, modulating inflammatory and immune responses, and promoting lesion healing, etc. Clinical studies and meta-analyses indicate that TCM provides significant benefits, with specific Chinese herbal compounds and monomers demonstrating protective effects on the gastric mucosa through mechanisms including anti-inflammation, anti-oxidation, and regulation of cellular proliferation and apoptosis, etc. Finally, it is pointed out that the efficacy of TCM in the treatment of CAG requires standardized research and unified standards, and constantly clarifies and improves the evaluation criteria of each dimension of gastric mucosal barrier function.

Key Words: Traditional Chinese medicine; Gastric mucosal barrier; Chronic atrophic gastritis; Therapeutic efficacy; Treating target

Core Tip: Traditional Chinese medicine (TCM) exerts a protective influence on chronic atrophic gastritis through multiple mechanisms, such as enhancing the gastric mucosal “mucus-bicarbonate” barrier, regulating cell proliferation and apoptosis, ameliorating microcirculation, modulating immune responses, and influencing intestinal microecology. Specific TCM compounds and monomers, for instance, berberine, morroniside, and notoginsenoside R1, exhibit therapeutic potential by targeting inflammation, oxidative stress, and gastric mucosal defense. It is evident that TCM is a potential treatment. Nevertheless, the standardization of TCM research and clinical practices is indispensable for optimizing the management of chronic atrophic gastritis.

INTRODUCTION

Chronic atrophic gastritis (CAG) represents a major subtype of chronic gastritis. CAG is a gastric disorder distinguished by the deterioration of the gastric mucosal epithelium, potentially resulting in the formation of intestinal gland metaplasia and/or pseudopyloric gland metaplasia[1-3]. The onset of CAG is not easily noticeable, and it does not have any distinct clinical symptoms. The condition frequently presents as discomfort in the upper abdomen, a feeling of fullness, pain in the upper part of the abdomen, heartburn, nausea, bad breath, and other symptoms[4]. It is worth noting that there is no direct relationship connecting the intensity of the ailment to the manifestation of symptoms[5].

Gastric cancer (GC) is a significant health issue worldwide, which poses a serious threat to human life on a large scale. In 2023, the United States documented 26500 fresh instances of stomach cancer, resulting in 11130 fatalities[6]. China holds the highest number of GC patients globally, ranking fourth in incidence and second in mortality[7,8]. Since 1978, the World Health Organization acknowledged that CAG is strongly associated with the initiation and advancement of GC. CAG is a significant phase within the growth of precancerous lesions of GC (PLGC). PLGC stands for stomach mucosa alterations that may indicate the development of malignancy. Typically, it pertains to the occurrence of intestinal metaplasia (IM) and dysplasia based on CAG pathology, also known as intraepithelial neoplasia (IN). PLGC is a separate and influential factor that elevates the likelihood of GC development. Correa[9] suggested that the development of intestinal type gastric adenocarcinoma (which accounts for about 80% of GC cases) follows this sequence: Normal mucosa, which advances to chronic superficial gastritis, then to CAG, followed by IM, progressing to dysplasia, and finally resulting in GC[9-11] (Figure 1). A meta-analysis conducted in Asian countries revealed that the overall prevalence of precancerous gastric lesions, specifically CAG as well as IM, was 26.1% and 22.9%, respectively[12]. A cohort study conducted in the Netherlands revealed that patients with CAG had a yearly occurrence of GC of 0.1% within five years of being diagnosed[13]. PLGC holds a pivotal function in the Correa cascade reaction of GC, and intervening in PLGC is a secondary preventative method for GC. Nevertheless, modern medicine is currently lacking particular medications for PLGC[14]. Hence, the primary objective is to prevent the conversion of CAG to GC by implementing efficient treatment and control measures. Preventing the malignant transformation of CAG is a prominent topic in contemporary research.

Figure 1 The pattern of development from normal mucosa to gastric cancer (gastroscopy and pathological map) (H&E, × 100). A: Normal gastric mucosa; B: Chronic non-atrophic gastritis; C: Chronic atrophic gastritis (atrophy, intestinalization); D: Dysplasia; E: Gastric cancer.

Helicobacter pylori (H. pylori) designated to be a class I carcinogen that is widely acknowledged at an international level. There is a prevailing belief that the presence of H. pylori infection has been recognized as the primary cause of the onset and progression of CAG and is strongly linked to the gastric mucosa damage[15,16]. The main therapies for H. pylori infection are antibiotics, proton pump inhibitors, gastric mucosal protection agents, and medicines that regulate gastrointestinal motility. CAG is caused by H. pylori infection. These medications have the ability to completely eliminate H. pylori. H. pylori infection can be treated to reduce inflammation in the stomach lining and alleviate symptoms including abdominal discomfort and dyspepsia. However, there are still many controversies about whether they can reverse gastric mucosal atrophy and IM, and long-term use may result in antibiotic resistance while elevating the risk for renal injury and osteoporotic fractures[17]. Another common type of CAG is bile reflux-related CAG. Currently, there is a belief that focusing on enhancing the body’s ability to defend and repair the mucosal lining could be a promising approach for treating damage to the gastric mucosal barrier caused by bile reflux[18]. Proton pump inhibitor, gastric mucosal protective agents and other treatments are often used in clinical practice[19].

Traditional Chinese medicine (TCM) has been widely studied in clinical as well as experimental settings for the therapy of CAG in recent years. The findings demonstrate that TCM possesses the attributes of multi-channel and multi-target comprehensive intervention. It exhibits a distinct therapeutic impact on CAG and effectively regulates all aspects of the gastric mucosal protection mechanism[20]. TCM has obvious advantages in enhancing the defense ability of gastric mucosa, improving mucosal microcirculation, regulating inflammation and immune response, and improving the quality of lesion healing (Figure 2). The inverse relationship between IM and dysplasia linked to CAG is also seen. It has the ability to effectively reduce or even prevent the malignant evolution of CAG into GC. A recent study has shown that a lack of glioma stem cells is a significant contributing factor to the progression of CAG within both mice and humans[21]. A naturally occurring peptide derived from the concentrated solution of Kangfuxin (an ethanol-based extract derived from the desiccated body of Periplaneta americana)[21] has the ability to stimulate gastric stem cells while promoting regeneration for the gastric epithelium in an experimental AG model. Additionally, it can enhance the viability of atrophic gastric organoids obtained from patients. This study provided additional evidence that the peptide functions by enhancing the stability of the epidermal growth factor (EGF)-EGF receptor complex and selectively triggering downstream extracellular regulated protein kinases and signal transducer and activator of transcription 1 (STAT1) signaling pathways. A meta-analysis was conducted, which involved 42 publications and 3874 patients having AG[22]. The findings revealed that the utilization of TCM decoction, either alone or in conjunction with western medicine, resulted in enhanced clinical symptoms in patients with AG [relative risk (RR) = 1.28; 95% confidence interval (CI): 1.22-1.34]. Moreover, the usage of TCM decoction demonstrated greater advantages in terms of pathological alterations (RR = 1.42; 95%CI: 1.30-1.54) contrasted with western medicine alone. TCM has significant potential for both preventing and treating CAG.

Figure 2 Traditional Chinese medicine can repair gastric mucosal barrier lesions through different levels of gastric mucosal protection, improve the defense mechanism of the mucosal barrier, and prevent the further progress of chronic atrophic gastritis and precancerous lesions of gastric cancer. PGE2: Prostaglandin E2; EGF: Epidermal growth factor; VEGF: Vascular endothelial growth factor; TFFs: Trefoil factors; HSP70: Heat shock protein 70; H. pylori: Helicobacter pylori; SCFAs: Short-chain fatty acids; IL: Interleukin; TNF: Tumor necrosis factor; CAG: Chronic atrophic gastritis; PLGC: Precancerous lesions of gastric cancer.

In summary, while modern medicine is precise in the examination and diagnosis of CAG, it has limitations in treatment. Allopathic medicine therapy faces problems such as resistance and associated adverse reactions[23]. TCM can not only improve patients’ clinical symptoms but also block and reverse gastric mucosal atrophy and IM, thereby enhancing the quality of life for patients. TCM treatment has the characteristics of stable curative effect, high safety, low drug resistance and low price, which can reduce the adverse reactions of allopathic therapy[24]. In this paper, the results of basic experiments, clinical trials, systematic reviews and meta-analyses were summarized and analyzed. Based on the protection of gastric mucosa at all levels, its underlying processes of TCM in the therapy of CAG were reviewed, and all potential TCM monomers were introduced in detail (Table 1).

Table 1 The specific target of traditional Chinese medicine function.

Compound or monomer	Efficiency	Ref.
Weifuchun	TNF-α↓, IL-6↓, ALP↓, Bcl-2↓, CDK4↓, VCAM1↓, HIF-1α↓, HES6↓, Bcl-2↓, CDK4↓, IL-1β↓, CDX2↓, NF-κbp65↓, IKKβ↓, IL-8↓, IL-4↓	[59,93]
Jianpiyiqi formula	Wnt1↓, Wnt5a↓, β-catenin↓, cyclin D1↓, MMP7↓, GSK-3β↑, Lgr5↑, Sox2↑, PCNA↑, Ki67↑	[65,66]
Xianglian Huazhuo granules	TFRC↓, ROS↓, GPX4↑, SLC7A11↑, SLC40A1↑	[69]
Weierning tablets	IL-1β↓, IL-6↓, IL-8↓, IL-10↓, TNF-α↓, γ-IFN↓	[70]
Moluodan	TNF-α↓, PI3K-AKT↓	[71]
Zhiwei Fangbian capsule	LDH↓, SDH↑, Na+-K+ -ATP enzyme↑, Ca2+-Mg2+-ATP enzyme↑	[82]
Yiqifumai	CD11b↓, CD18↓	[83]
Chaishao Liujun decoction	IL-1β↓, IL-6↓, Shh↑, Ptch1↑, Gli1↑	[89]
Qinghua Yin	IL-1β↓, IL-6↓, TLR4↓, TRIF↓	[90]
Zuojin Pill	G-17↓, IL-8↓, TNF-α↓, IL-6↓, IL-1β↓, TGF-β1↓, PI3K-AKT, p-mTOR, P70S6K↓, PTEN↑, LC3-II↑, Beclin-1↑, PGE2↓, VEGF↓, HMGB1↓, MyD88↓, RAGE mRNA↓, NF-κB p65↓, RAS↓, COX-2↓, MCP-1↓, LysoPC↓, pyridoxamine↑	[91,98,99]
Jianwei Xiaozhang tablets	COX-2↓, P53↓, TFF2↓	[103]
Geranylgeranyl acetone	HSP70↑	[105]
Andrographolide sodium bisulfite	GSH↑, CAT↑, SOD↑, MDA↓, PGE2↑, COX-1↑, COX-2 mRNA↑, HSP70↑, Bcl-2↑, Bax↓	[107]
Astragaloside IV	MDA↓, TNFα ↓, MCP1↓, HSP70↑, Bcl-2↑, PLCγ ↑	[108]
Berberine	TNF-α↓, IFN-γ↓, NOS2↓, CCR7↓, IRF-8↓, TGF-β1↑, IL-10↑, IL-4↑, STAT6↑, Chil3↑, IL-17↓, CXCL1↓, CXCL9↓, Ifit3↓, IRF1↓, Ifit1↓, Upp1↓, USP18↓, Nlrc5↓, IL-8↓, IL-6↓, IL-1β↓, PI3K↓, p-AKT/AKT↓, p-mTOR/mTOR↓, P70S6K↓, PTEN↑, LC3-II↑, Beclin-1↑	[137-139]
Morroniside	GAS↑, MTL↓, TNF-α, IL-6↓, IL-1β↓, Bcl-2↑, Bax↓, caspase-3↓, caspase-9↓, p-NF-κB p65↓, p-IKKα/β↓, IκB-α↑, CD34↑	[148,150]
Saponin R1	GAS↑, SS↑, MTL↑, IL-6↓, IL-1β↓, PGE2↓, NOS↓, ET↓, sIgA↑, GSH↑, Bcl-2↓, Bax↑, MPO↓, MDA↓, p-NF-κB p65↓, p-IKKα/β↓	[153,154]
Erianin	HRAS↓, AKT↓, p-AKT↓, MDM2↓, Cyclin D1↓, p-Gsk3β↓, p21↑	[72]
Rutaecarpine	IL-18↓, IL-1β↓, SHH↑, Gli↑, SMO↑	[74]
Rhein	TNF-α↓, COX-2↓, IL-6↓, IL-1β↓, PGE2↓, JNK↓, p38↓, Nrf2↑, HO-1↑	[96]

TNF-α: Tumor necrosis factor-alpha; IL-6: Interleukin-6; ALP: Alkaline phosphatase; Bcl-2: B-cell lymphoma 2; CDK4: Cyclin-dependent kinase 4; VCAM1: Vascular cell adhesion molecule 1; HIF-1α: Hypoxia-inducible factor 1-alpha; HES6: Hairy and enhancer of split family BHLH Transcription factor 6; IL-1β: Interleukin-1 beta; CDX2: Caudal-related homeobox transcription factor 2; NF-κbp65: Nuclear factor-kappaB transcription factor P65; IKKβ: Inhibitor of nuclear factor kappa-b kinase subunit beta; IL-8: Interleukin-8; IL-4: Interleukin-4; Wnt1: Wingless-related integration site 1; Wnt5a: Wingless-related integration site 5a; MMP7: Matrix metalloproteinase 7; GSK-3β: Glycogen synthase kinase 3 beta; Lgr5: Leucine-rich repeat-containing g-protein coupled receptor 5; Sox2: SRY-box transcription factor 2; PCNA: Proliferating cell nuclear antigen; Ki67: PP1 gamma-Ki67; TFRC: Transferrin receptor; ROS: Reactive oxygen species; GPX4: Glutathione peroxidase 4; SLC7A11: Solute carrier family 7 member 11; SLC40A1: Solute carrier family 40 member 1; IL-10: Interleukin-10; IFN-γ: Interferon-gamma; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; LDH: Lactate dehydrogenase; SDH: Succinate dehydrogenase; CD11b: Cluster of differentiation 11b; CD18: Cluster of differentiation 18; Shh: Sonic hedgehog; Ptch1: Patched 1; Gli1: Glioma-associated oncogene homolog 1; TLR4: Toll-like receptor 4; TRIF: Tir-domain-containing adapter-inducing interferon-β; G-17: Gastrin-17; TGF-β1: Transforming growth factor beta 1; p-mTOR: Phosphorylated mechanistic target of rapamycin; P70S6K: 70-kda ribosomal protein s6 kinase; PTEN: Phosphatase and tensin homolog; LC3-II: Microtubule-associated protein 1A/1B-light chain 3; PGE2: Prostaglandin E2; VEGF: Vascular endothelial growth factor; HMGB1: High mobility group box 1; MyD88: Myeloid differentiation primary response 88; RAGE mRNA: Receptor for advanced glycation end products mRNA; RAS: Rat sarcoma virus; COX-2: Cyclooxygenase-2; MCP-1: Monocyte chemoattractant protein-1; LysoPC: Lysophosphatidylcholine; P53: Cellular tumor antigen p53; TFF2: Trefoil factor 2; HSP70: Heat shock protein 70; GSH: Glutathione; CAT: Catalase; SOD: Superoxide dismutase; MDA: Malondialdehyde; COX-1: Cyclooxygenase-1; Bax: Bcl-2-associated x protein; PLCγ: Phospholipase C gamma; NOS2: Nitric oxide synthase 2; CCR7: C-C motif chemokine receptor 7; IRF-8: Interferon regulatory factor 8; STAT6: Signal transducer and activator of transcription 6; Chil3: Chitinase-like protein 3; IL-17: Interleukin-17; CXCL1: C-X-C motif chemokine ligand 1; CXCL9: C-X-C motif chemokine ligand 9; Ifit3: Interferon-induced protein with tetratricopeptide repeats 3; IRF1: Interferon regulatory factor 1; Ifit1: Interferon-induced protein with tetratricopeptide repeats 1; Upp1: Uridine phosphorylase 1; USP18: Ubiquitin specific peptidase 18; Nlrc5: NOD-like receptor family caspase recruitment domain family domain-containing 5; GAS: Gastrin; MTL: Motilin; p-NF-κB p65: Phosphorylated nuclear factor-kappaB transcription factor P65; p-IKKα/β: Phosphorylated inhibitor of nuclear factor kappa-b kinase alpha/beta; IκB-α: Inhibitor of nuclear factor kappa-b alpha; CD34: Cluster of differentiation 34; SS: Somatostatin; NOS: Nitric oxide synthase; ET: Endothelin; sIgA: Secretory immunoglobulin A; MPO: Myeloperoxidase; HRAS: Harvey rat sarcoma viral oncogene homolog; MDM2: Murine double minute 2; IL-18: Interleukin-18; Gli: Glioma-associated oncogene homolog; SMO: Smoothened; PGE2: prostaglandin E2; JNK: c-Jun N-terminal kinase; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase 1.

CLINICAL EFFICACIES OF TCM IN CAG TREATMENT

Chinese herbal compound for CAG treatment

Chinese herbal compound focuses on overall reconciling the imbalance of the human body. Through the compatibility of various medicinal materials, it contains a variety of active ingredients, acts on multiple biological targets, and plays a synergistic role at multiple levels[24,25], aiming to achieve the treatment of CAG. The Chinese herbal compound demonstrates favorable efficacy and a strong safety profile, such as Xiangsha Liujunzi decoction (XSLJZD), Banxia Xiexin decoction (BXXXD), Huangqi Jianzhong decoction (HQJZD), Jianpi Yiqi decoction (JPYQD) and so on[26-42].

The XSLJZD originates from the Qing Dynasty’s ancient medical text, ‘Ancient and Modern Medical Methodology’. The main functions are tonifying middle and replenishing qi; invigorating spleen and harmonizing stomach, drying dampness and resolving phlegm. It is widely used in gastritis, functional dyspepsia and other digestive system diseases[26-28]. A meta-analysis containing 14 studies included 1434 cases[29]. The findings demonstrated that XSLJZD exhibited superior benefits contrasted with conventional treatment methods, including western medicine or other TCM, for treating CAG. The intervention has been shown to enhance the clinical cure rate (RR = 1.90, 95%CI: 1.29-2.79, P = 0.001), improve the clinical effective rate (RR = 0.24, 95%CI: 0.18-0.30, P < 0.00001), considerably reduce gastric mucosal atrophy (RR = 1.57, 95%CI: 1.17-2.11, P = 0.003), and is considered relatively safe[29].

BXXXD originates from the ‘Treatise on Cold Damage and Miscellaneous Diseases’. It has the functions of tonifying middle and replenishing qi, reconciling cold and warm. Studies have shown that BXXXD is widely used in a variety of digestive system diseases[30-36], which can reduce the value of H. pylori and reduce gastric mucosal inflammation[37]. A meta-analysis which is a systematic review that combines the results of many randomized controlled trials (RCTs), includes 26 RCTs with 1985 patients[38]. The findings demonstrated that BXXXD exhibited more efficacy contrasted with the control cohort (consisting of Chinese patent medicine and western medicine), with a RR of 1.29 and a 95%CI ranging from 1.24 to 1.35 and a P value of less than 0.00001. Additionally, BXXXD was shown to have a higher level of safety, as indicated by a mean difference (MD) of 0.33 and a 95%CI ranging from 0.18 to 0.58, with a P value of 0.0002. Furthermore, this study demonstrated that BXXXD not only alleviated symptoms including abdominal discomfort and eructation but also had more pronounced benefits in suppressing H. pylori, enhancing its associated inflammation, mitigating gland atrophy, and reducing stomach mucosal dysplasia.

The HQJZD, which originates from the ‘Synopsis of Golden Chamber’, is a medicinal formula specifically formulated to increase the temperature of the spleen and provide nourishment to the stomach. As a result, it is well-suited for the therapy of several types of chronic gastrointestinal disorders[39]. A meta-analysis included 13 studies, which involved 1269 patients[40]. The findings demonstrated that the HQJZD cohort had a substantially higher overall effective rate contrasted with the control cohort (RR = 1.24; 95%CI: 1.18-1.30, P < 0.001). The H. pylori clearance rate was found to have a RR of 1.20, with a 95%CI ranging from 0.5 to 1. The value of P is 0.38. The symptoms of a stomachache are indicated by an MD score of -0.009. The results showed a substantial improvement in the 63 participants, with a 95%CI ranging from -0.68 to -0.58 and a P value less than 0.001. Additionally, the recurrence rate was reduced, with a RR of 0.15 and a 95%CI ranging from 0.04 to 0.66, with a P value of 0.01.

JPYQD possesses the ability to enhance the function of the spleen and increase the energy levels in the body. A meta-analysis revealed that the utilization of JPYQD as a standalone treatment (RR = 1.41; 95%CI: 1.27-1.57; P < 0.00001) and JPYQD in conjunction with western medicine (RR = 1.27; 95%CI: 1.17-1.38; P < 0.00001) exhibited superior effectiveness contrasted with western medicine by itself[41]. Additionally, JPYQD had a potential ameliorative impact on symptoms including abdominal discomfort, distention, eructation, and exhaustion, with no instances of severe side effects documented in the chosen trials.

Furthermore, one meta-analysis comprised a cumulative number of 12 RCTs, involving 1140 patients[42]. The outcomes revealed that the experimental cohort combined with TCM intervention on the basis of conventional western medicine treatment had better clinical efficacy. Through the analysis of the association rules of all included Chinese herbal compounds, seven core Chinese herbal medicines (Paeoniae Radix Alba, Atractylodes Macrocephala, Rhizoma Pinelliae, Citrus, Codonopsis Radix, Salviae Miltiorrhizae Radix et Rhizoma, Coptis Chinensis Rhizoma) were identified. The primary active compounds identified through molecular docking research were naringenin, luteolin, and quercetin. Using TCM decoction alone or combined with western medication was more effective than using western medicine alone in improving clinical symptoms (RR = 1.28; 95%CI: 1.22-1.34). Additionally, the use of TCM decoction showed better results in pathological alterations (RR = 1.42; 95%CI: 1.30-1.54). In general, the administration of a TCM compound for CAG enhances the clinical symptoms experienced by patients and exerts a beneficial influence on the histological level. The personalized treatment and general conditioning of TCM compounds offer significant benefits in the management of CAG.

Chinese patent medicine for CAG treatment

Recently, because of the progress of TCM as well as its global recognition, several Chinese patent medicine companies have gained entry into international markets. They have successfully registered various Chinese patent medicines as non-prescription or prescription drugs in regions and countries that primarily rely on Western medicine, including the European Union, Russia, and Singapore[43]. Several Chinese patent drugs, including Weifuchun (WFC), Weisu Granules, Moluodan (MLD), Xiangsha Yangwei pills (XSYWP), and others, have been developed for the clinical therapy of CAG. Chinese patent medicine has the characteristics of stable quality, accurate dose and convenient use. It is easy to be accepted by patients and has good curative effect on chronic gastritis[44,45]. It is worthy of further clinical research and application.

WFC serves as a Chinese patent medication that consists of red ginseng, Rabdosia amethystoides, and Fructus aurantii[46]. It was authorized by the China Food and Drug Administration in 1982 and has since been extensively utilized for treating chronic gastritis and PLGC[47,48]. A meta-analysis was conducted, which encompassed 15 studies involving 1488 patients[49]. The findings indicated that the effectiveness of WFC was superior to the control cohort (comprising western medicine, placebo, and other Chinese patent medicine), with a RR of 1.52 and a 95%CI ranging from 1.41 to 1.63. However, there was no notable disparity in safety between the two cohorts. The WFC cohort demonstrated a higher level of improvement in the histology of gastric mucosa contrasted with the control cohort (RR = 1.42; 95%CI: 1.20-1.68; P < 0.0001). Additionally, the WFC cohort showed greater inhibition of H. pylori. The effectiveness of H. pylori was substantially higher, with a RR of 1.26 (95%CI: 1.03-1.55; P = 0.02). A clinical investigation including 76 patients with PLGC demonstrated that the administration of WFC (three times daily for a duration of 24 weeks) resulted in a significant reduction in the extent of glandular atrophy, IM, and H. pylori infection[47]. WFC demonstrated efficacy rates of 76.47% and 62.5% in mitigating glandular atrophy and IM, respectively; however, the eradication rate of H. pylori was not reported. The prevalence of H. pylori was 61.71%.

Weisu granules consist of perilla granules, fragrant granules, tangerine peel, citron, bergamot, Fructus aurantii, areca nut, Radix aurantii, and other ingredients. These ingredients enhance the secretion function of the gastric mucosa, reduce pathological damage to the gastric mucosa, and expedite the healing process of gastric mucosal damage[50]. A prospective study enrolled 120 patients who were randomly allocated into two cohorts: A control cohort (60 patients treated with WFC three times a day, 4 tablets each time, for 6 weeks) as well as an experimental cohort (60 patients treated with Weisu granules three times a day, 15 g each time, for 6 weeks)[48]. The serum levels of gastrin 17 (G-17), prostaglandins I (PG I), as well as PG II were found to be decreased in both cohorts. This indicates that both WFC and Weisu granules have the ability to reduce the inflammatory response and clinical symptoms. Moreover, the experimental cohort exhibited a superior overall efficacy rate in comparison to the control cohort (P < 0.05). The result of H. pylori is affirmative. The abundance of H. pylori was markedly reduced in the experimental cohort contrasted with the control cohort (P < 0.05), and the frequency of negative conversion of H. pylori was noted. MLD is a widely used Chinese patent medication that consists of 18 different types of traditional Chinese herbs, including lily, poria, scrophulariae, and aconite. It possesses the capabilities of regulating gastrointestinal motility, safeguarding the mucosa, suppressing acid secretion, enhancing blood flow in the mucosa, providing analgesic effects, and more[51,52]. An examination of a meta-analysis was conducted, which consisted of seven investigations, including 1143 patients[53]. The findings indicated that, when contrasted with folic acid or vitamin D, MLD alone exerted a significant positive impact on the rate of improvement in pathological examination (RR = 1.73, 95%CI: 1.48-2.02, P < 0.00001). The combined use of MLD has been shown to substantially elevate the success rate of pathological examination (RR = 1.37, 95%CI: 1.23-1.52, P < 0.00001), gastroscopy (RR = 1.37, 95%CI: 1.18-1.60, P < 0.0001), and symptom relief (RR = 1.25, 95%CI: 1.13-1.38, P < 0.0001). These findings suggest that MLD can delay ailment advancement and mitigate clinical manifestations. In a study that followed strict randomization and double-blind protocols, a parallel controlled trial was conducted[54]. The participants included individuals between the ages of 18 and 70 who had been identified as having moderate to severe atrophy and/or moderate to severe IM, with or without the presence of low-grade dysplasia, and H. pylori participants who tested negative for H. pylori were recruited. The subjects were arbitrarily allocated to various treatment cohorts: The MLD cohort (1 package, 3 times a day) consisted of 166 cases, the folic acid cohort had 168 cases, the combined cohort (MLD + folic acid) had 84 cases, and the high-dose MLD cohort (2 packages, 3 times a day) had 84 cases. The findings indicated that the rate of dysplasia elimination in the MLD cohort was 82.8%, surpassing that of the folic acid cohort (53.9%, P = 0.006). Furthermore, no significant adverse effects connected to the medication were found. The safety and efficacy of the MLD 1 package (9 g), administered three times a day for one year, in treating PLGC, particularly stomach precancerous lesions, can be inferred. To investigate the effects of a treatment on patients with CAG and dysplasia, a randomized, double-blind study was carried out. Patients were randomly allocated to different treatment groups, and both the patients and researchers were unaware of the treatment they received. 196 individuals participated in the trial. The participants were divided into two cohorts, the MLD cohort and the folic acid cohort, based on a ratio of 2:1. The MLD cohort received a dosage of 9 g three times a day for a duration of 6 months, while the folic acid cohort received a dosage of 5 mg three times a day for the same duration. The results showed a substantial decrease in the dysplasia score of the MLD cohort (P = 0.002), while folic acid did not demonstrate a meaningful drop (P = 0.513). MLD outperformed folic acid in enhancing the ratings of symptoms including epigastric pain and bile reflux as observed during gastroscopy (P < 0.05).

XSYWP consist of a combination of 12 traditional Chinese medicinal herbs, including common aucklandia root, amomum kernel, white atractylodes rhizome, dried tangerine peel, and poria. It has the ability to increase the temperature and balance the acidity of the stomach, enhance the functioning of the spleen, eliminate excess moisture, stimulate the flow of vital energy, and alleviate discomfort. The meta-analysis study comprised 18 RCTs, involving 1720 individuals with chronic gastritis, including both CAG and chronic superficial gastritis[55]. The outcomes of the meta-analysis indicated that the effectiveness of XSYWP combined with western medicine in managing chronic gastritis was markedly superior to that of standard western medication (P < 0.05). The relapse frequency associated with XSYWP, whether used independently or in tandem with traditional western medicine, was notably reduced contrasted with that of conventional western medicine by itself (P < 0.05) when considering recurrence rates. Regarding adverse responses, no significant adverse effects have been reported when XSYWP is used with western treatment.

The recognition of these Chinese patent medicines lies not only in their clinical efficacy, but also in the fact that they provide strong evidence and support for the internationalization and modernization of Chinese medicine. Upcoming investigations ought to investigate the precise mechanism of action of Chinese patent medications and refine the therapy of CAG, and promote the application and registration of more Chinese patent medicines worldwide.

THE IMPACT OF TCM ON GASTRIC MUCOSAL BARRIER SYSTEM

The stomach’s protective barrier is the gastric mucosa. Gastric mucosa shields underlying tissues from harm caused by components of gastric juice and external irritants that affect the gastric mucosa. It holds a pivotal function in preserving normal functioning for the stomach[56]. Wallace and Granger[57] divided the complex gastric mucosal protection system into five defense levels (Figure 3). The first layer is a barrier composed of local mucus-bicarbonate-phospholipids. The second layer is composed of epithelial cells. The third layer is the mucosal microcirculation. The fourth layer is the mucosal immune system. The fifth layer is the repair and reconstruction factors. The barriers at all levels coordinate with each other to maintain the integrity of the gastric mucosa. There is still much room for effective management of CAG, especially in promoting good repair of gastric mucosal barrier and interfering with its malignant transformation.

Figure 3 There are five defense layers in the gastric mucosal protection system. The first layer is a barrier composed of local mucus-bicarbonate-phospholipids. The second layer is composed of epithelial cells. The third layer is the mucosal microcirculation. The fourth layer is the mucosal immune system. The fifth layer is the repair and reconstruction factors. NK cells: Natural killer cells; DC: Dendritic cells.

Strengthening the “mucus-bicarbonate-phospholipid” barrier

The first layer of gastric mucosal protection system is mainly composed of a variety of defensive substances secreted by gastric mucosa and distributed on the surface of gastric mucosal epithelium, including mucus, bicarbonate, surface-active phospholipids, immunoglobulins (mainly immunoglobulin A) and antimicrobial substances (lactoferrin, etc.), so it is also known as mucus-bicarbonate barrier. Mucus-bicarbonate barrier serves as a vital part of the protective mechanism of gastric mucosa[58]. An intact and continuous mucus barrier can block large harmful substances such as certain bacteria, toxins, drugs, etc., and slows the penetration of small molecules such as ethanol, bile, free radicals, and H⁺. Relevant studies have shown that a variety of TCMs and their active ingredients extracts can improve the defense ability of gastric mucosal epithelial surface by regulating the “mucus-bicarbonate-phospholipid” barrier on the surface of gastric mucosa. Wang et al[59] based on a combination of computational strategies and experiments, revealed that WFC may inhibit the development of CAG to GC by affecting phospholipid metabolism. A cellular experiment showed that MLD promoted phospholipid accumulation and inhibited 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced proliferation of GES-1 cells[60]. Zuojin pills (ZJP) consists of Coptis Chinensis and Cornus officinalis, and animal studies found that adhesive microspheres loaded with Rhizoma Coptidis and Cornu Cervi Pantotrichum alkaloids could slow the release of the drug for more than 12 hours, possessed gastric mucoadhesive properties, and could attenuate the gastric injury by lowering the mucosal damage index and increasing the amount of gastric mucous membrane mucus[61].

Regulating cellular processes in the gastric mucosa

The gastric mucosal epithelial barrier consists of epithelial cells and intercellular junctions, which collectively create a comprehensive defense barrier to prevent the infiltration of invasive agents[62]. The epithelial cells of the stomach mucosa undergo continuous renewal, with a complete turnover typically occurring within a period of 3 to 7 days[63]. This property facilitates the rapid repair and preservation of the injured epithelium. The proliferation and apoptosis of CAG gastric mucosa are experiencing an imbalance. Multiple empirical investigations have demonstrated that various TCM and their extracted active ingredients, as well as Chinese medicine compounds, can enhance the production of protective chemicals in the gastric mucosa. They also have the ability to regulate cell growth and programmed cell death, thereby providing treatment for CAG (Figure 4).

Figure 4 Traditional Chinese medicine treats chronic atrophic gastritis from the proliferation and apoptosis of gastric mucosa cells perspective. Traditional Chinese medicine promotes gastric cell proliferation via pathways such as Hedgehog, Wnt/β-catenin, and runt-related transcription factor 3/transforming growth factor-beta/Smad. Concurrently, it regulates apoptosis through the phosphoinositide 3-kinase/protein kinase B, YY1/miR-320a/transferrin receptor, and nuclear factor-kappaB p65/cyclooxygenase-2/B-cell lymphoma 2 pathways, thereby maintaining gastric mucosal health and preventing the progression of chronic atrophic gastritis. The picture highlights the role of traditional Chinese medicine in balancing cell proliferation and apoptosis to promote gastric mucosal repair. TCM: Traditional Chinese medicine; RUNX3: Runt-related transcription factor 3; TGF-β: Transforming growth factor-beta; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase b; TFRC: Transferrin receptor; NF-κB: Nuclear factor-kappaB; COX-2: Cyclooxygenase-2; Bcl-2: B-cell lymphoma 2; CAG: Chronic atrophic gastritis.

Jianpi Tongluo Jiedu Recipe (JPTLJDR) may promote apoptosis through the nuclear factor-kappaB transcription factor P65 (NF-κBp65)/cyclooxygenase-2 (COX-2)/B-cell lymphoma 2 (Bcl-2) pathway, thereby affecting PLGC patients (treated by JPTLJDR one dose per day for six successive months)[64]. JPTLJDR down-regulates the mRNA expression levels of Wingless-related integration site 1 (Wnt1), Wnt5a, β-catenin, cell cycle protein D1, and matrix metalloproteinase 7, and up-regulates the mRNA expression level of glycogen synthase kinase 3 beta, and treats CAG through the Wnt/β-catenin signaling pathway[65]. Another study found that Jianpi Yiqi Recipe enhanced Wnt signaling and promoted the restricted proliferation as well as normal differentiation of gastric stem cells, thus enhancing gastric mucosal atrophy in CAG rats[66]. Weiqi decoction can reverse the upregulation of Ki67 protein expression in the pylorus of CAG rats, increase cell proliferation, down-regulate the expression of caspase-3 protein, reduce cell apoptosis, and attenuate gastric atrophy, IM, and mucosal microcirculation disturbance in CAG rats[67]. Xianglian Huazhuo granules can reverse the pathology of CAG through multiple pathways[68]. Guo et al[69] showed that Xianglian Huazhuo granules could effectively suppress MNNG-induced proliferation of gastric epithelial cells, promote apoptosis, inhibit iron death, attenuate CAG to improve the pathological state and ultrastructure of gastric mucosa, and ultimately impede the progression of CAG via regulating the YY1/miR-320a/transferrin receptor signaling pathway. It was found that Weierning tablets (WENT), which have the impacts of strengthening the spleen, dispelling dampness, regulating qi, and relieving pain, had a positive effect on improving CAG and reversing IM. A study treated 70 male CAG rats with WENT (intragastric injection of a mixture of 2% sodium salicylate and 30% alcohol, along with the free consumption of 0.1% ammonium hydroxide) and showed that WENT could reduce gastric mucosal epithelial cell apoptosis and maintain the integrity of the gastric mucosal barrier by regulating the expression of Bax, Cleaved-caspase 9, Bcl-2, and cytochrome c. It could reduce the protein expression of caudal-related homeobox transcription factor 2, Muc2, sonic hedgehog (Shh), glioma-associated oncogene homolog 1, and smoothened, reverse the gastric mucosal IM, and block the progression of CAG[70]. Molecular biology studies in the CAG rat model showed that MLD treatment substantially reduced the expression levels of tumor necrosis factor-alpha (TNF-α), phosphoinositide 3-kinase (PI3K), and PI3K-protein kinase B (AKT), prompting that MLD was effective in alleviating gastric mucosal atrophy by regulating the TNF/PI3K/AKT signaling pathway[71]. A cellular experiment revealed that MLD inhibited MNNG-induced proliferation of GES-1 cells (human gastric epithelial cells), promoted apoptosis and differentiation, and reduced inflammation levels[60].

Furthermore, research has demonstrated that erianin has the ability to hinder the G2/M phase cell cycle by means of the PI3K/AKT signaling pathway and induce cell apoptosis, thus providing a potential treatment for PLGC[72]. Dehydroevodiamine, a quinazoline alkaloid derived from Chinese herbal medicine, has been shown to alleviate gastric histological injury in gastric tissue and improve gastric epithelial cell injury and mitochondrial dysfunction induced by MNNG in CAG rats[73]. The study revealed that the impact of RUT on CAG rats (MNNG) primarily involved the amelioration of histological damage. The SHH pathway upregulation and downstream apoptotic pathway downregulation are linked to RUT’s protective effect, leading to improved survival of gastric cells[74]. Additionally, the extract of Ginkgo biloba leaves[75] has been found to enhance the expression of tight junction proteins including occludens 1, occludens 2, occludens 3, occludin, as well as claudin 3a, specifically in fish models.

TCM can contribute to treating CAG by controlling the activity of certain genes that can cause cancer. Research has shown that long-term inflammation can lead to GC[76]. A compound called WFC has been found to slow down the growth of CAG to GC via regulation of the immune system, reducing inflammation, and preventing cell death and growth[59]. Other studies have also shown that WFC can control the activity of genes that promote or suppress tumors by affecting specific signaling pathways including NF-κB, runt-related transcription factor 3/transforming growth factor-beta (TGF-β)/Smad, Hedgehog, as well as Wnt[77]. It was also found that WFC had an inhibitory effect on the expression of the biomolecule Hairy and enhancer of split 6, which is associated with cancer progression in chronic gastritis (P < 0.05)[59].

Improving gastric mucosal microcirculation

Gastric mucosal microcirculation can provide mucosal cells with oxygen, various nutrients and gastrointestinal peptide hormones to maintain their normal functions, including the synthesis and secretion of mucus, surface active phospholipid and bicarbonate, secretion of gastric acid, cell renewal, proliferation and repair, and timely and effectively eliminate cell metabolites, reverse diffusion of H⁺ and damage factors in the mucosa, thereby maintaining the relative stability of the local microenvironment[78]. The protective factors of gastric mucosal microcirculation include nitric oxide (NO) and endothelin, etc. Dysfunction of gastric mucosal microcirculation regulation and decreased gastric mucosal blood flow can lead to gastric mucosal injury[79]. The microcirculation disorders including thrombosis and bleeding described in modern pathology are basically similar to the understanding of “chronic disease entering collaterals” in TCM. TCM drugs for promoting blood circulation and removing blood stasis can increase the circulation perfusion of mucosal tissue and ensure the energy metabolism of the mucosal epithelium. As early as the 1980s, the relationship between TCM and microcirculation attracted global attention[80]. In China, TCM for promoting blood circulation and removing blood stasis has achieved fruitful results in the therapy of CAG[81]. Zhiwei Fangbian capsule can promote the energy metabolism and ATPase activity in gastric mucosa cells of CAG rats with Qi-deficiency and blood-stasis syndrome, thereby protecting the function of gastric mucosa cells[82]. Yiqi Fumai is a Chinese herbal compound preparation. Its pretreatment can reduce lipopolysaccharide-induced microcirculation disturbance in the digestive system of rats[83]. Yam extract can improve the pathological changes of the gastric mucosa in aged CAG rats by reactivating the inhibited SHH signaling pathway, improving the gastric microcirculation blood flow and oxidative stress response, reducing the expression of NO and malondialdehyde, and inhibiting the progression of the disease[84]. Ishikawa et al[85] showed that vascular endothelial growth factor (VEGF) protects mucosal microvessels and improves microcirculation to exert cytoprotective effects.

Modulating gastric mucosal immunity

The immune system of gastric mucosa is mainly composed of “alert” cells including mast cells, macrophages, T lymphocytes. T lymphocyte immune response plays a crucial role in flp-mediated gastric mucosal injury[86]. The inflammatory immune response is an important pathophysiological mechanism of mucosal damage caused by H. pylori. More and more research have found that H. pylori can come into contact with the gastric mucosa epithelium and establish a persistent infection within the host, leading to a more complex inflammatory immune response[87]. H. pylori infection leads to a Th-dominated immune response, and H. pylori can stimulate the expression of Th-type cytokines such as interleukin (IL)-12, IL-18, TNFα, as well as FNY in gastric mucosa, which are substantially upregulated[88]. Compound prescription of Chinese medicine (e.g., BXXXD, Chaishao Liujun decoction, and Qinghua Yin), prepared prescription (Chinese medicine) (such as ZJP and WFC capsule), and Monomers of Chinese medicine [such as berberine (BBR) and rhubarb acid] can exert beneficial effects on CAG by regulating gastric mucosal immunity, inflammation, as well as oxidative stress.

Basic research has found that by modulating the hedgehog signaling pathway, kaempferol, the primary component of Chaishao Liujun decoction, can reduce IL-6 and IL-1β levels, thus exerting a therapeutic effect in the treatment of CAG[89]. Qinhuayin can significantly improve the histopathological alterations in the gastric mucosa of CAG rats, and its mechanism may involve the suppression of inflammatory factors IL-6 as well as IL-8, including the inhibition of toll-like receptor 4/tir-domain-containing adapter-inducing interferon (IFN)-β mRNA and protein expression[90]. The intervention of ZJP also decreased the levels of G-17 and inflammatory factors IL-8, TNF-α, IL-6, and IL-1β, inhibited the expression of TGF-β1, PI3K and its downstream signals p-AKT, p-mechanistic target of rapamycin (mTOR), as well as 70-kda ribosomal protein s6 kinase, and promoted the expression levels of phosphatase and tensin homolog, microtubule-associated protein 1A/1B-light chain 3, as well as Beclin-1[91]. Studies have shown that WFC can inhibit IL-1β, IL-4, IL-6, IL-8, as well as TNF-α via the NF-κB pathway, improve gastric mucosal macrophage aggregation, and improve IM[92,93]. BXXXD can decrease local inflammatory cell infiltration in the gastric mucosa of CAG rats, enhance gastric mucosa morphology, increase gastric mucosa thickness, and increase the amount of gastric glands[94].

Rhein, a key element found in TCM including rhubarb and aloe vera, has been found to have beneficial impacts in reducing swelling, inflammation, and oxidative stress in various diseases[95]. In a study conducted on mice with CAG induced by H. pylori infection and a high-salt diet, Rhein (given at a dosage of 100 mg/kg, administered once per day, over a period of 8 weeks) was shown to alleviate damage to the gastric mucosa. This effect is believed to be mediated through the activation of nuclear factor erythroid 2-related factor 2, and mitogen-activated protein kinase (MAPK) signaling pathways, leading to anti-inflammatory and antioxidant effects[96].

Promoting defense factors expression

The mucosal repair process is extremely complex and is a hotspot in recent research on gastric mucosal protection mechanisms, involving many cellular and molecular factors, as well as growth factors such as PG, EGF, VEGF, as well as basic fibroblast growth factor. PG is an active substance with multiple physiological functions within the human body and is an important factor to defend and repair gastric mucosa. It is widely present within the gastric mucosa, with prostaglandin E2 (PGE2) being the most abundant, and its biological activity is strong, playing a major protective role. Studies have shown that PGE2 provides protective effects after the gastric mucosal barrier is damaged, to counteract damage caused by gastric acid, alcohol, indomethacin, or acid retrodiffusion[97]. Chinese herbal medicine can promote the level of PGE2[65,67], which has the impacts of improving local gastric mucosa hemodynamics, reducing inflammatory responses, and enhancing the protective barrier of gastric mucosa.

The ZJP treatment, administered at doses of 0.63, 1.26, and 2.52 g/kg for a duration of 4 weeks, has been found to have a dose-dependent effect on CAG rats with H. pylori infection. This treatment effectively reduces the levels of serum IL-6, monocyte chemoattractant protein-1, PGE2, TNF-α, and VEGF, improves gastric tissue inflammatory lesions, and promotes the proliferation of GES-1 cells. The therapeutic effect of ZJP may be due to its ability to suppress the JMJD2B/COX-2/VEGF axis and the high mobility group box 1/NF-κB signaling pathway[98]. Tong et al[99] showed that ZJP can substantially improve gastric tissue pathological damage and improve PGI and PGI/II levels to improve CAG. EGF is essential for maintaining the integrity of the gastrointestinal mucosa and promoting the repair of any damage that occurs. It can effectively inhibit gastric acid secretion to prevent damage to the gastric mucosa[100]. The trefoil factor family is a cohort of small molecule peptides secreted by the gastric and intestinal mucus cells, mainly present in the vesicles of mucus protein secretion, and participate in the intracellular assembly of mucus proteins and epithelial tissue reconstruction, promoting epithelial repair of damaged tissue and strengthening the epithelial barrier defense mechanism[101,102]. Chen and Dong[103] experimental research showed that Jianwei Xiaozhang tablets could promote the self-repair of gastric mucosal lesion tissue and enhance the defense mechanism of the mucosal barrier, and its mechanism of action was to downregulate the levels of trefoil factor 2, P53, and COX-2.

Heat shock protein 70 (HSP70) can both play an adaptive cellular protective role inside the lining of the stomach and reduce the inflammatory reactions[104]. Research has revealed that geranylgeranylacetone can substantially induce the synthesis of HSP70, thereby slowing down the progression of AG pathology[105]. Schisandra chinensis Bail can also affect the synthesis of HSP in gastric smooth muscle[106]. Andrographolide sodium bisulfite can upregulate HSP70, activate the COX-mediated synthesis of PGE2, and exercise a defensive function in the stomach[107]. Astragaloside IV[108] can safeguard the gastric mucosa by augmenting the expression of HSP70.

Regulating gastrointestinal microecology

The gastrointestinal tract is the most extensive microecosystem within the human body. The intestinal microbiota assumes a vital part in the functioning and upkeep of the gastrointestinal mucosal barrier. The mucous layer in the gastrointestinal mucosal barrier is divided into two parts: The inner layer is a tightly connected layer that secretes protective polypeptides with antimicrobial properties and is relatively sterile; the outer layer is thicker and looser, with a large amount of intestinal flora and its products[109,110]. Intestinal flora are involved in the maintenance of biological, chemical, immune and mechanical barriers of the gastrointestinal mucosa by resisting colonization by foreign microorganisms, secreting mucus factors and related metabolites, activating immune cells to produce antibodies and cytokines, and promoting intercellular tight junctions and mucosal repair[111,112]. With the deepening of intestinal flora research, it has been found that intestinal flora can accelerate the risk of gastrointestinal IN, and intestinal flora may facilitate the development and progression of GC[113,114].

It was revealed that the therapeutic effects of Xiaojianzhong decoction (XJZ) were closely related to bile acid (BA)-associated microorganisms as well as metabolic processes. Some scholars used the multi-omics approach to study the mechanism of XJZ on intestinal microorganisms in CAG rats. XJZ was found to have the ability to manage intestinal flora problems in CAG rats, particularly in relation to bacteria involved in BA metabolism including Butyricimonas, Desulfovibrio, Bacteroides, Parabacteroides, Acetobacter, and Alistipes, as revealed by 16S rRNA gene sequencing analysis. Molecular docking analysis reveals that the specific metabolites controlled by XJZ exhibit favorable binding interactions with targets associated with BA[115]. Huangqi Jianzhong Tang may treat CAG by affecting the binding of BAs metabolism, and is closely related to acid-producing Bacteroides and Prevotella copri[116]. Animal experiments found that Qinghua Yin improves CAG may be associated with regulating the intestinal microbial community: Qinghua Yin treatment increased the relative abundance of Firmicutes in rat gut the most (90.7%), and due to the enrichment of beneficial bacteria, especially rumenococcus, lactobacilli and bifidobacterium[117]. Huazhuo Jiedu decoction has the ability to modulate the variety, microbial composition, and abundance of the intestinal microbial population in rats with CAG[118]. Following administration of Huazhuo Jiedu decoction, the herbal cohort exhibited a greater relative abundance of Turicibacter contrasted with the model cohort. Conversely, the relative abundance of Desulfococcus and Escherichia was lower in the herbal cohort than in the model cohort.

Shihu granules have a considerable effect on improving the pathological condition of the gastric mucosa in rats with MNNG-induced CAG. This improvement is likely due to the regulation of the relative abundance of Lactobacilli and Turicibacter[119]. Astragalus has the ability to safeguard against the intestinal microbial metabolic problem caused by CAG. It may target Acetobacter and Escherichia, as well as 7-keto-3A12-α-hydroxyalkanoic acid and deoxycholic acid, as potential mechanisms of action[120].

TCM MONOMERS WITH POTENTIAL FOR GASTRIC MUCOSA REPAIR AND PROTECTION

Currently, as analytical chemistry and pharmacology research advances, there is also rapid progress in studies exploring the pharmacological impacts of natural components of TCM[121,122]. These studies offer a theoretical foundation for drug research and development. Researchers are increasingly focusing on the natural components of TCM because of their low toxicity, high efficacy, ability to target several areas, and ability to regulate multiple pathways[123-125]. Figure 5 shows the structure of three TCM monomers and their effects on CAG. Each of these monomers possesses unique bioactive properties that align with different mechanisms of gastric mucosal protection. BBR is well-known for its anti-inflammatory and antibacterial effects, which may help in managing CAG by reducing inflammation and inhibiting H. pylori infection. Morroniside has demonstrated anti-apoptotic and anti-inflammatory properties, which can be beneficial in preventing further mucosal damage in CAG patients. Notoginsenoside R1 (NGR1), a unique compound in Panax notoginseng, has shown promise in enhancing microcirculation and reducing oxidative stress, making it a suitable candidate for protecting and repairing the gastric mucosa. Collectively, these TCM monomers target multiple pathways in gastric mucosal defense and repair, thus providing a comprehensive approach to CAG management.

Figure 5 The structure of monomers and their effect on chronic atrophic gastritis. The diagram outlines the protective mechanisms of three traditional Chinese medicine monomers: Berberine, morroniside, and notoginsenoside R1. These monomers influence host responses such as inflammation, apoptosis, autophagy, angiogenesis, and etc., which contribute to the prevention and treatment of gastric mucosal disorders. H. pylori: Helicobacter pylori.

BBR

BBR is a pentacyclic isoquinoline alkaloid that occurs naturally and is derived from Huanglian, a traditional Chinese medication. Its chemical formula is C20H19NO5. BBR is obtained from the stems and roots of Berberis species, including Berberis aristata[126], Berberis darwinii[127], Berberis Petiolaris[128], and others. Huanglian had extensive usage in TCM 1400 years ago[129]. Initial pharmacological investigations discovered that BBR possesses a suppressive impact on a range of Gram-positive and Gram-negative bacteria and is efficacious in the management of intestinal infections and bacterial dysentery[130,131]. BBR has been authorized by the State Food and Drug Administration of China for the therapy of diarrhea and dysentery due to its diverse sources, affordability, and few side effects. As global research on the pharmacological impacts of BBR progresses, numerous studies have discovered that BBR possesses anti-inflammatory, anti-cancer, anti-ulcer, antibacterial, and immune regulation properties[132]. These properties make BBR a potential treatment for various diseases, including cancer, digestive disorders, metabolic disorders, cardiovascular diseases, and nervous system disorders[133]. BBR can directly interact with H in the digestive tract. Eradicate H. pylori by disrupting its habitat and inhibiting its growth. The H. pylori infection could be managed by controlling mucosal inflammation, regulating macrophage polarization, and subsequently reversing mucosal atrophy[134]. BBR can also suppress the function of H. pylori. The enzyme responsible for acetylating arylamine compounds is known as H. pylori arylamine n-acetyltransferase[135,136]. BBR induces the activation of the IL-4-STAT6 signaling pathway, which exerts anti-inflammatory effects both in vivo and in vitro in the presence of H. pylori infection[137], thereby reducing the damage to the gastric mucosa caused by H. pylori[138]. BBR decreases the levels of G-17 and pro-inflammatory factors IL-8, TNF-α, IL-6, as well as IL-1β. It also reduces the expression of TGF-β1 axis-related signaling and increases the expression of phosphatase and tensin homolog, microtubule-associated protein 1A/1B-light chain 3, as well as Beclin-1. Additionally, BBR improves the condition of gastric mucosal tissue injury in CAG rats[139]. Furthermore, BBR suppresses the activity of pro-inflammatory cytokines by targeting the IFN regulatory factor 8/IFN-γ signaling pathway[138]. IFN-γ induces apoptosis in gastric epithelial cells, which is crucial for the transition of gastritis to atrophic gastritis[140]. BBR suppresses cell growth by blocking the TGF-β1/PI3K/AKT signaling pathway and promoting apoptosis[141]. BBR has the ability to decrease the expression of autophagy signals including PI3K, p-AKT, and mTOR, and it may also enhance the healing of gastric mucosal tissue injury in CAG mice[139]. Mφs, short for macrophages, are a crucial type of cell involved in the body’s natural defense system and have significant functions in inflammation, controlling the activation of lymphocytes, eliminating cellular waste, and combating pathogens[142]. BBR suppresses the mRNA production of M1-polarized macrophages and enhances the mRNA production of M2-polarized macrophages via stimulating the IL-4/STAT6 signaling pathway[137]. To summarize, BBR shows promising therapeutic promise for the prevention and therapy of CAG. However, there is still a relative dearth of related research in this area. Hence, additional cellular and animal models, together with clinical research, are required to ascertain the safety and efficacy of BBR in correcting these precancerous lesions.

Morroniside

Morroniside serves as a cyclic enol-ether terpene glycoside molecule with the chemical formula C17H26O11. It is primarily present in Cornus officinalis, a TCM, at the highest concentration, and it is also a component of Cornus officinalis as an indicator for quality control of Chinese herbal medicines. Morroniside, a monomeric small-molecule chemical, has been scientifically demonstrated to possess many biological properties, such as anti-inflammatory, anticoagulant, anti-apoptotic, anti-oxidative stress, as well as tissue repair promotion. It not only treats digestive system diseases, but also possesses multiple pharmacological effects such as neuroprotection, cardioprotection, bone and joint protection, etc.[143-148].

In a CAG rat model (MNNG combined with irregular diet induction), morroniside increased serum gastrin secretion and decreased TNF-α, IL-6, and IL-1β levels[149]. The expression of Bcl-2 was increased in the gastric mucosa tissue, but the expression of Bax, cleaved caspase-3, and caspase-9 was decreased. Simultaneously, the expression level of p-NF-κBp65 and inhibitor of kappa B kinaseα/β protein was decreased, while the expression of inhibitor of kappaB alpha was increased, indicating that morroniside can prevent CAG by inhibiting inflammation and apoptosis.

Additionally, various diseases or pathological processes can cause vascular damage, and CD34+ cells generated from bone marrow have the ability to transform into endothelial cells, participating within vascular repair and regeneration[150]. Morroniside may promote the mobilization, proliferation, migration, as well as differentiation of CD34+ cells by upregulating VEGF expression, thereby participating in the regeneration and repair of damaged blood vessels[151]. Therefore, our hypothesis suggests that morroniside may have a role in the healing of microcirculation vessels in the stomach mucosa, and further research in this area may be conducted in the future.

NGR1

Sanqi refers to the dehydrated root and rhizome of the plant species Panax notoginseng (Burk.) F. H. Chen, a plant in the genus Panax. It is mainly produced in Yunnan and Guangxi, with a sweet and slightly bitter taste and a warm nature. It has the characteristic of stopping bleeding without leaving blood clots and dissolving blood stasis without harming the body’s normal function. The main active compound in Sanqi is glycosides, and among them, NGR1 is a unique component of Sanqi and one of the main components of Sanqi saponins. NGR1, with the chemical formula C47H80O18, exhibits anti-apoptotic, antioxidant, and anti-inflammatory properties[152]. Additionally, it demonstrates anti-tumor and immunological regulatory effects[153].

NGR1 has a multilink and comprehensive protective effect on CAG. Treatment with NGR1 (5, 10, and 20 mg/kg) in CAG rats (MNNG induced) can substantially increase serum gastrin and somatostatin levels, secretory immunoglobulin A and glutathione levels. The concentrations of motilin, prostaglandin (PGE2), NO synthase, and endothelin were reduced in a manner that depended on the dosage. Additionally, the levels of serum IL-1β and IL-6 decreased[154].

In addition, NGR1 reduced the excessive permeability of blood vessels, the generation of inflammatory cytokines, the activation of NF-κB, and the loss of tight junction proteins in the colon caused by ischemia/reperfusion[155]. Furthermore, NGR1 also enhanced energy metabolism during ischemia/reperfusion. NGR1 has a protective effect on gastrointestinal mucosa, but whether there is a specific target of NGR1 is still unknown, and the pharmacological mechanism of NGR1 remains to be further explored.

CONCLUSION

To sum up, Chinese medicine has the ability to facilitate the healing of gastric mucosal injury and provides significant protection to the gastric mucosal barrier by leveraging the body’s own defensive mechanisms. These mechanisms include enhancing the gastric mucosal ‘mucus-bicarbonate’ barrier, regulating gastric mucosal cell proliferation, apoptosis, and epithelial tight junctions, improving gastric mucosal microcirculation, modulating immunity, inhibiting inflammatory responses and oxidative stress, upregulating various defense factors, and regulating intestinal microorganisms. Based on these protective mechanisms, TCM has become an important and effective method for the prevention and treatment of CAG, with specific clinical efficacy, particularly in treating precancerous digestive diseases, functional gastrointestinal disorders, and other related conditions. According to their pharmacokinetic action, mucosal protective agents are divided into exogenous and endogenous types. Exogenous protectants enhance gastric mucosa protection by promoting mucus secretion and increasing bicarbonate, while endogenous agents stabilize cell membranes, boost mucosal protective factors, increase blood flow, and exhibit antioxidative effects. TCM can be classified as an endogenous mucosal protective agent and plays a crucial role in safeguarding gastrointestinal mucosa, which has attracted growing attention and interest.

Although TCM has made many achievements in the treatment of CAG, there are also many shortcomings in reality. For example, some clinical research trials are not standardized in design, the criteria for determining efficacy are not reasonable, there is a lack of unified TCM diagnostic and typing criteria for CAG, the number of clinical samples is too small, the dynamic observation is lacking, and there are few multi-center, double-blind randomized controlled studies. In terms of basic experiments, there are methodological limitations in the establishment of animal models, which may cause the models to not accurately reflect the clinical effects and mechanisms of TCM treatment. These problems are priorities and difficulties point in the development of TCM. We should be focus on the following in the future: A unified Chinese medicine identification standard and efficacy determination standard should be formulated; the evaluation standard of the dimensions of gastric mucosal barrier function should be clarified and perfected.

Meanwhile comparative observation and study were carried out on various indexes of blood gastric function, endoscopic signs and clinical manifestations of CAG, such as the comparative observation and study of blood biochemical indicators of gastric mucosa related pepsinogen, gastrin, H. pylori and clinical signs of CAG. In order to find out the inner connection and improve the accuracy of TCM clinical diagnosis of CAG, we are also looking for TCM monomers or combinations that can effectively protect the gastric mucosal barrier, help the eradication of H. pylori, and fight against bile reflux, which is also the key point of TCM preventive treatment of CAG. The close relationship between gastric mucosal barrier and CAG should be further explored, and it is also in urgent need of the monomer or compound of TCM, which could effectively protect the gastric mucosal barrier and reverse CAG.

ACKNOWLEDGEMENTS

I would like to sincerely thank teachers for their invaluable contributions to the development of this manuscript.