Traditional Chinese medicine in the treatment of Helicobacter pylori-related gastritis: The mechanisms of signalling pathway regulations

Abstract

Helicobacter pylori-associated gastritis (HPAG) is a common condition of the gastrointestinal tract. However, extensive and long-term antibiotic use has resulted in numerous adverse effects, including increased resistance, gastrointestinal dysfunction, and increased recurrence rates. When these concerns develop, traditional Chinese medicine (TCM) may have advantages. TCM is based on the concept of completeness and aims to eliminate pathogens and strengthen the body. It has the potential to prevent this condition while also boosting the rate of Helicobacter pylori eradication. This review elaborates on the mechanism of TCM treatment for HPAG based on cellular signalling pathways, which reflects the flexibility of TCM in treating diseases and the advantages of multi-level, multi-pathway, and multi-target treatments for HPAG.

Key Words: Helicobacter pylori; Helicobacter pylori-associated gastritis; Traditional Chinese medicine; Signalling pathway; Eliminate pathogens; Strengthen the body

Core Tip: Traditional Chinese medicine (TCM) emerges as a promising area for intervention in the face of Helicobacter pylori-associated gastritis (HPAG). In this review, we go over the several signalling mechanisms that TCM uses to influence HAPG. TCM regulates the expression of related genes and proteins through signalling pathways to inhibit inflammatory response, improve oxidative stress, promote gastric mucosal proliferation, avoid epithelial-mesenchymal transition, and prevent cancer. The effect of TCM on HPAG has been observed at multiple levels and pathways. These studies suggest that TCM treatment will become a trend in the treatment of HPAG.

INTRODUCTION

Helicobacter pylori (H. pylori) is a microaerophilic Gram-negative bacterium that colonises the interface between the gastric mucus layer and gastric antral mucosal epithelial cells[1,2]. H. pylori infection is the major cause of chronic gastritis, known as H. pylori-associated gastritis (HPAG), which clinically manifests as various degrees of stomach and epigastric pain, including epigastric distension, belching, acid vomiting, dullness, and loose stools. The initial pathological stage of this infection is characterised by gastric mucosal inflammation. As the condition progresses, it may lead to more severe outcomes including chronic atrophic gastritis (CAG), and intestinal metaplasia, ultimately increasing the risk of cancer development[3-5]. Globally, the H. pylori infection rate is nearly 50%, rising to as high as 90% in some developing countries. H. pylori infection usually occurs during childhood and is frequently accompanied by family aggregation[6,7].

H. pylori harbours a genetic fragment, approximately 40 kb in size, identified as the cag pathogenicity island, which encodes the type IV secretion system (T4SS) and the virulence protein cytotoxin-associated gene A (CagA)[8,9]. Research has revealed that alterations in signalling pathways inside stomach mucosal epithelial cells can result from H. pylori infection[10]. T4SS and other virulence factors of H. pylori are transported into host gastric mucosal cells through needle-like structures. Activating nuclear factor kappa B (NF-κB) causes the release of pro-inflammatory cytokine interleukin (IL)-8[11]. IL-8 recruits antigen presenting cell, such as dendritic cells, monocytes and neutrophils[12,13]. H. pylori can activate the recombinant myeloid differentiation factor 88 (MyD88) and tumor necrosis factor (TNF) receptor 1 signalling pathways after invasion of host gastric mucosal cells. Macrophages were induced to secrete IL-1, IL-6, IL-12, TNF-α, and interferon-γ[14,15]. Macrophages can phagocytose and destroy pathogens while simultaneously acting as antigen-presenting cells that are generally polarised to classically activated macrophages (M1 macrophages, M1) and immune-regulatory macrophages (M2)[16,17]. M1 macrophages produce high inducible nitric oxide synthase and pro-inflammatory molecules such as TNF-α, IL-6, IL-12, IL-1, while M2 macrophages produce IL-10, transforming growth factor-β (TGF-β), vascular endothelial growth factor, epidermal growth factor[11,15,17]. Common treatment methods for eradicating H. pylori infection involve triple therapy, combining proton-pump inhibitors with antibiotics, or quadruple therapy[18]. However, H. pylori eradication rates have reduced due to increased antibiotic resistance. Therefore, there is an urgent need to identify novel and effective molecular targets.

Traditional Chinese medicine (TCM) not only possesses inhibitory and bactericidal properties against H. pylori, but also exhibits enhanced efficacy in attenuating infection. Furthermore, these substances contribute to the amelioration of both the pathological manifestations and symptomatic expression of HPAG[19,20]. TCM emphasises the importance of individualised treatment specifically tailored to each person’s unique constitution and distinct patterns of disharmony. This personalised approach may prove to be more effective in addressing the specific symptoms experienced by individuals infected with H. pylori. Chinese herbs have indicated that certain herbal compounds, extracts, and active constituents not only inhibit and eradicate H. pylori but also demonstrate increased efficacy in mitigating infection and ameliorating pathological damage and symptoms of HPAG. In clinical practice, most modern Western medicine treatment methods are combined with the TCM concept of evidence-based treatment. This integrates the Western medicine approach to “disease” with the Chinese medicine “evidence” treatment method, emphasising individualised treatment. Yu et al[21] found that patchouli alcohol may not change the gut microbiota when exerting its anti-H. pylori effects. Some traditional Chinese medicines are not influenced by the pH of the gastrointestinal tract, and certain TCM or their active ingredients exhibit evident inhibitory and bactericidal effects on both susceptible and resistant bacteria[22]. As basic research findings progress, a broader range of TCM options will become available for the clinical treatment of H. pylori infections, and the synthesis of clinical experiences will provide novel directions and concepts for future basic research. This study further elaborated on the molecular mechanisms of TCM in treating HPAG, focusing on cell signalling pathways, to provide a scientific basis for exploring potential therapeutic approaches.

TCM PERSPECTIVES ON THE PATHOGENESIS AND TREATMENT PRINCIPLES OF HPAG

In recent years, an increasing number of researchers have begun exploring TCM mono-and combination therapies. TCM emphasises the importance of individualised treatment specifically tailored to each person’s unique constitution and distinct patterns of disharmony. This personalised approach may prove to be more effective in addressing the specific symptoms experienced by individuals infected with H. pylori. Owing to the technical nature of the diagnosis, traditional Chinese medical theory does not have a precise name for HPAG. Chinese medical theory places this disease as “Weitong” which describes stomach-ache; or “fullness” which refers to stomach fullness and discomfort, “acid vomiting” and “noisy” which refers to a condition in which the stomach is empty, seems to be hungry but not hungry, seems to be spicy but not spicy, seems to be painful but not painful, and is inexplicable and sometimes stops[23].

H. pylori is classified as “Xie Qi” (vital energy) in TCM, which has the properties of “heat” and “poison”. This attribute varies depending on the individual’s physical condition. However, some patients exhibit Yang deficiency and Yin excess, or cold from Yin, and wet from Yin, and so on. According to the Yellow Emperor’s Classic of Internal Medicine, which states “Zheng qi cun nei, Xie bu ke gan”, the primary internal cause of H. pylori infection is identified as a deficiency in “Zheng Qi” (vital energy). The pathogenesis of HPAG is generally characterized by damp-heat invasion, blood stasis, qi stagnation, and spleen and stomach weakness. TCM doctors believe that H. pylori is classified under the category of “Xie Qi”, which is closely associated with Damp-heat and toxins[24]. “Xie Qi” contrasts with “Zheng Qi”, referring to the body’s resistance against diseases, a concept of the body’s ability to self-regulate, and self-recovery. TCM emphasises enhancing Zheng Qi and eliminating Xie Qi to maintain health and balance. Ruan et al[25] collected 400 cases of H. pylori-related CAG and counted the number of TCM syndromes from the highest to lowest as follows: Spleen-stomach damp heat > spleen-stomach deficiency and cold > intermingling of cold and heat > liver-stomach discord > deficiency of stomach Yin > stasis of stomach vessels. At the beginning of the onset of HPAG, the pathogenesis of chronic superficial gastritis at the beginning can involve gastric disturbances and pain. The disease course was prolonged, resulting in CAG. Based on the principle of strengthening the body and eliminating pathogenic factors, TCM achieves the purpose of inhibiting H. pylori, balancing Yin and Yang. The treatment principle of TCM is to clear away heat, detoxify and remove dampness, strengthen the spleen and stomach and “Yi Qi” for those with deficiency[26]. Numerous controlled clinical trials have substantiated that TCM, when combined with Western medicine, is more effective than Western medicine alone in treating H. pylori infection, while also reducing the incidence of adverse effects. In pursuing TCM research for treating HPAG, adhering to two fundamental principles: Holistic concepts and evidence-based treatment, is imperative. As research on TCM deepens, its mechanisms of action will become better understood, facilitating its wider acceptance and utilisation by clinicians, thereby enhancing its role. The approach of TCM treatment of HPAG is shown in Figure 1.

Figure 1 The approach of traditional Chinese medicine therapy for Helicobacter pylori-related gastritis. H. pylori: Helicobacter pylori; CagA: Cytotoxin-associated gene A; VacA: Vacuolating cytotoxin A.

HERB MEDICINES (EXTRACTS OR ACTIVE INGREDIENT)

The phosphatidylinositol 3-kinase/protein kinase B signalling pathway

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway plays a pivotal role in regulating cell growth, metabolism, survival, and proliferation[27,28]. Upon activation, PI3K binds to Akt and stimulates its phosphorylation[29]. It helps activate NF-κB by adding a phosphate group to it and moving it into the cell’s nucleus. This action increases the production of substances that cause inflammation[30]. Additionally, this pathway regulates the reduction of cytochrome c and apoptotic proteins, increases the transcription of anti-apoptotic genes, and participates in carcinogenesis[31,32]. Phosphatase and tensin homolog (PTEN), a phosphatase and tensin homologue deleted on chromosome ten, is closely linked to the activation of the PI3K/Akt signalling pathway in human gastric tissue[33]. Loss of PTEN function leads to an increase in the PI3K/Akt pathway, which in turn phosphorylates downstream signalling proteins, such as forkhead box O, to stimulate cell growth and proliferation[34]. Phosphatidylinositol triphosphate is the most important substrate of PTEN and its loss can lead to the accumulation of intracellular phosphatidylinositol triphosphate. It can cause the imbalance of the PTEN/PI3K/Akt signalling pathway, activate the Akt, phosphorylate substrates containing serine/threonine residues which play a wide range of biological effects, and then mediate the release of inflammatory factors and inhibit cell apoptosis[35,36]. Therefore, the PI3K/Akt signalling pathway and its upstream and downstream molecules may be targets for the treatment of various inflammatory diseases.

Polygonum capitatum is a perennial herbaceous plant belonging to the Polygonum family. This has the effects of clearing away heat and diuresis. Its major chemical components include flavonoids, lignans, volatile oils, terpenes, and tannins[37]. Zhao et al[38] found that Polygonum polygonum can inhibit the urease activity of H. pylori, downregulate urease genes encoding urease a and urease b, and inhibit urease synthesis, thus reducing the activity of H. pylori in acidic environments. Wang et al[39] discovered that Polygonum clouds increase the expression of PTEN and inhibit the activation of the PI3K/Akt pathway, thereby reducing H. pylori-induced stomach mucosal inflammation. Syzygium aromaticum, also known as the clove, belongs to the Myrtaceae family. It is native to Indonesia, but is now grown in tropical areas worldwide. The buds of cloves are dried and used as spices, and their unique fragrance and medicinal properties render them valuable in many cultures. It is often used to treat symptoms such as spleen and stomach diseases, kidney diseases, impotence, hiccups, vomiting, colds, and heart diseases[40]. It has been found that the active ingredients of clove are mainly concentrated in essential oil, flavonoids, terpenoids, and sterols. Han et al[41] found that eugenol in the essential oil of clove had an antibacterial effect in vitro, and the minimum inhibitory concentration range of eugenol was 2.50-5.00 μg/mL. It was found that the extract of syzygium aromaticum prevented the aberrant activation of the PI3K/Akt and mitogen-activated protein kinase (MAPK) signalling pathways to treat H. pylori infection[42]. Based on the above research results, it can be concluded that TCM can reduce the inflammation of gastric mucosal epithelial cells caused by H. pylori infection, reduce cell apoptosis, and protect the gastric mucosa by mediating the PI3K/Akt signalling pathway.

MAPK signalling pathway

The MAPK signalling system in eukaryotic cells is activated by cellular stress and inflammatory cytokines to transmit various extracellular signals that regulate physiological and pathological events, cell proliferation, stress, inflammation, and apoptosis[43,44]. This pathway primarily consists of primarily of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), ERK5, and p38 MAPK[45]. Each pathway is highly specific and is involved in different biological effects, but there are also interactions in some segments. Among these, ERK1/2, p38 MAPK, and JNK are the most widely studied. ERK1/2 is primarily involved in cell proliferation and differentiation. p38 MAPK regulates apoptosis and the inflammatory response. JNK is mainly influenced by stress stimuli and plays a role in cellular stress responses, differentiation and apoptosis[46]. After H. pylori infection, the MAPK signalling pathway is activated, including ERK1/2, JNK and p38 MAPK, which can induce the secretion of pro-inflammatory cytokines, such as IL-8[47-49]. Additionally, p38 MAPK acts as an upstream signal in the inflammatory pathway, facilitating activation of the NF-κB signalling pathway[50].

The rhizome of Alpinia officinarum is widely used in medicine and is well-known for its stomach-warming characteristics, ability to reduce nausea, and ability to alleviate discomfort caused by cold temperatures[51,52]. In vitro studies have confirmed that Alpinia officinarum rhizoma extract can inhibit H. pylori infection[53]. Studies in animals have demonstrated that an ethyl acetate extract from the rhizome of Alpinia officinarum inhibits the phosphorylation process in the MAPK signalling pathway, specifically targeting ERK1/2, JNK, and p38 MAPK to alleviate gastric mucosal inflammation in H. pylori-infected mice[54]. Baicalin, which is extracted from the dried root of Scutellaria baicalensis Georgi, is an isoflavone with various pharmacological effects. It is reported to have antibacterial, antiulcer, antitumour, diuretic, anti-inflammatory, antidiabetic, and antioxidant[55]. Baicalin and its extract indirectly inhibited urease activity and H. pylori growth, and the inhibitory effect was proportional to the concentration of baicalin[56]. Studies have shown that baicalin significantly reduces the expression of P-p38 MAPK and B-cell associated X protein, while increasing the expression of B-cell lymphoma-2 in GES-1 cells, and plays an anti-inflammatory, pro-proliferative, and anti-apoptotic role in alleviating H. pylori-induced cell damage[57]. Dandelion, which belongs to the family Asteraceae, possesses anti-inflammation, anti-bacterial, and anti-tumour effects. It contains numerous medicinal compounds, including phenolics, sterols, flavonoids, and polysaccharides[58]. Dandelion inhibits the phenolic components of H. pylori urease[59]. Tian and Huang[60] discovered that dandelion polysaccharide treatment in rats infected with H. pylori suppressed the MAPK/ERK pathway, reduced inflammation, and preserved the stomach mucosa. Based on the aforementioned findings, TCM is believed to preserve the gastric mucosa via modulation of the MAPK signalling pathway, reducing cell apoptosis, promoting cell proliferation, and reducing inflammation of gastric mucosal epithelial cells caused by H. pylori infection.

Wnt/β-catenin signalling pathway

The Wnt signalling pathway is an evolutionarily conserved and complex signalling cascade critical for stem cell renewal, proliferation, and differentiation during development and cancer progression[61]. Currently, there are at least three Wnt signalling pathways: The canonical Wnt pathway (Wnt/β-catenin), the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway, among which canonical Wnt pathway is the most widely and fully studied pathway[62]. H. pylori infection can elevate aquaporin 5 expression in gastric epithelial cells (GECs) and activate the Wnt/β-catenin pathway, contributing to gastritis development[63]. The infection triggers tumour necrosis factor-induced protein release, which activates the Wnt/β-catenin pathway via the CagA protein. This leads to GEC proliferation and mesenchymal transition[64].

Ferulic acid is a phenolic compound derived from Angelica sinensis and Ligusticum chuanxiong, among other medicinal plants. It has several pharmacological effects, including anti-inflammatory, analgesic, anti-influenza virus, anticancer, vasodilatory, and brain protective effects[65]. Studies have found that ferulic acid prevents aberrant activation of the Wnt/β-catenin signal pathway, lowers inflammatory factor production, and decreases H. pylori colonisation and stomach mucous membrane inflammation[66]. Patchouli alcohol, a tricyclic sesquiterpene, is derived from the leaves or stems of the patchouli plant (Pogostemon cablin). Research has confirmed that it has a variety of pharmacological activities, such as anti-inflammatory, analgesic, anti-influenza virus, anti-tumour, vasodilatory, and brain protection[67]. Recently, it was reported that patchouli alcohol has a protective effect on the gastric mucosa, has a highly selective action on H. pylori, and does not affect other gastrointestinal flora. Its mechanism of action is different from that of existing antibacterial drugs has a good safety profile[68]. Liu et al[69] found that when HPAG mice with complex gastric precancerous lesions were orally administered patchouli alcohol, their gastric mucosa was protected. The potential mechanisms include blocking NF-κB and Wnt/β-catenin signalling pathway activation, reducing inflammatory cytokine levels, mitigating inflammatory-induced gastric mucosal damage, and averting epithelial-mesenchymal transition. The aforementioned study findings suggest that TCM substances have the ability to inhibit the Wnt/β-catenin signalling pathway and reduce H. pylori colonisation, reduce inflammation of the stomach mucous membrane, stop the epithelial-mesenchymal transition, and stop the development of cancer.

Nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signalling pathway

Under normal physiological conditions, cells naturally produce low levels of reactive oxygen species (ROS), which are vital for the maintenance of cellular homeostasis and function. However, the presence of H. pylori dramatically alters this balance in GECs[70]. ROS production is significantly increased by the activation of nicotinamide adenine dinucleotide phosphate oxidase. Consequently, this surge results in ROS accumulation, leading to the upregulation of various cytokines, including IL-8[12]. Extracellular inflammatory cytokines exacerbate ROS formation. This escalation, in turn, intensifies the inflammation and epithelial damage caused by H. pylori infection[71,72]. Overproduction of ROS can lead to mitochondrial dysfunction[73]. Following H. pylori infection of the stomach mucosa, ROS levels increase, causing oxidative stress, and inducing GEC growth and invasion. An increase in ROS levels can cause substantial gastric mucosal injury, delay the healing of gastric mucosal tissue, and produce precancerous lesions in the gastric mucosa. When ROS in the body surpasses the metabolic level of the body, cells can resist chronic oxidative stress by increasing the activity of antioxidant enzymes such as superoxide dismutase, nitric oxide, catalase and glutathione peroxidase, and reducing the damage of tissue DNA, protein, and lipid. Glutathione is naturally in human cells of free radical scavenger, is one of the important indicators to measure the body’s antioxidant capacity, due to its itself contains the characteristics of the free sulphur and have strong ability for electrons or protons of the hydrogen, can quickly and effectively remove free radicals in the body (e.g., H₂O₂)[74,75]. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates oxidative stress and inflammation in the body, maintains the cellular redox balance, and senses cellular oxidative stress. Nrf2 can stimulate the activity of antioxidant defence components such as ROS, superoxide dismutase, glutathione peroxidase, and heme oxygenase 1 (HO-1)[76]. Additionally, activation of Nrf2-related antioxidant defence systems prevents cellular senescence[77,78]. HO-1, a pivotal effector of Nrf2-dependent cellular responses, not only stabilises the intracellular environment but also fortifies the cell’s adaptive response to stress. Moreover, it protects against the transformation of normal cells into tumour cells by thwarting ROS-mediated carcinogenesis[79]. Normal conditions result in a combination of Nrf2 and Kelch-like associated protein 1 (Keap1) in the cytoplasm, which stabilises the cell and increases the expression of antioxidants and enzymes to basic expression levels[80]. When Nrf2 is stimulated by exogenous oxidative stressors, it separates from Keap1 and uses nuclear translocation to attach to an antioxidant response element (ARE)[81]. Nrf2/ARE exerts anti-inflammatory and antioxidant stress effects via controlling the expression of downstream genes, including HO-1 and other antioxidant protein genes. The Nrf2/HO-1 signalling pathway and its target genes, which are primary regulators of antioxidant defence and anti-inflammation, play significant roles in H. pylori infection.

Resveratrol is a natural polyphenol found mainly in grapes, Polygonum cuspidatum, peanuts, blueberries, mulberries, cassia seeds, and other plants. Pharmacological studies have shown that resveratrol has various pharmacological effects, including anti-inflammatory and antioxidant effects[82]. Zhang et al[83] found that resveratrol can improve the histological infiltration score of gastric mucosa, inhibit the phosphorylation of IkappaBalpha (IκBα) induced by H. pylori, and activate the Nrf2/HO-1 pathway. It has a significant effect on oxidative stress and inflammation in H. pylori-infected mucosa. Rhein is an anthraquinone compound that mainly exists in traditional Chinese medicines such as rhubarb and aloe vera. It has various pharmacological benefits, including antibacterial, antiviral, anti-tumour, anti-inflammatory, and anti-oxidative effects[84]. Rhein boosts anti-inflammatory and antioxidant benefits in CAG via the Nrf2 and MAPK signalling pathways[85]. Based on the above results, it can be concluded that TCM monomers and compounds can improve the antioxidant defence ability of the body by mediating the Nrf2/HO-1 signalling pathway, thereby improving damage to gastric mucosal epithelial cells caused by oxidative stress and inflammation.

NF-κB signalling pathway

NF-κB is a key transcriptional regulator of cell activation and cytokine production[86]. The mammalian NF-κB family is composed of five proteins in mammals: P50 (NF-κB1), P52 (NF-κB2), REL (cREL), REL-A (P65) and REL-B. When exposed to stimuli such as H. pylori infection, the signal is conveyed to the cytoplasm via receptors, activating NF-κB inducing kinase by phosphorylation. This activation subsequently triggers the IκB kinase complex. IκB kinase catalyzes the phosphorylation of I-κBα (Ser32, Ser36) and I-κBβ (Ser19, Ser32), resulting in the dissociation of I-κB from NF-κB and its subsequent degradation[87,88]. Finally, NF-κB translocates to the nucleus, where it modulates the transcription of a multitude of genes, thus playing a pivotal role in the regulation of cellular functions. TLRs recognise pathogen-associated molecules on the surface of immune cells and play essential roles in activating signal transduction pathways. Signals generated by TLRS recruit proinflammatory cytokines and chemokines through the NF-κB signal transduction pathway and specific pathogen-associated molecular patterns to promote inflammatory responses and also activate the immune system[89,90]. After recognising the pathogen-associated molecular patterns, the TLR signalling pathway can be divided into two categories: The MyD88 dependent pathway and MyD88 independent pathway. MyD88 is a family of adaptor protein molecules, which can activate IL-1 receptor-associated kinase and further interact with TNF-α, releasing more inflammatory factors and causing damage to tissues and organs[91]. H. pylori attaches to the GECs of the host and translocates the CagA protein into the cytoplasm via T4SS, subsequently activating the NF-κB-inducing kinase and IκB kinase α/β. This causes phosphorylation of IκBα, resulting in its breakdown. NF-κB enters the nucleus and activates the transcription of inflammatory genes[92].

Berberine, also known as Huang Lian Su, is an isoquinoline alkaloid obtained from Rhizoma coptidis, Scutellaria baicalensis and Phellodendron amurense[93]. It has various biological functions such as anti-diabetic, diuretic, anti-tumour, anti-bacterial, anti-oxidant, and anti-inflammatory properties[94]. Lu et al[95] found that berberine reduced the damage caused by stomach inflammation caused by H. pylori. Its main mechanism of anti-inflammatory effect is blocking the NF-κB signalling pathway. Ma et al[96] found that ethyl acetate extract of Alpiniae Officinarum Rhizoma also has the effect of therapy for HPAG, and its mechanism was related to inhibition of the expression of NF-κB signalling pathway-related proteins. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade various components of extracellular matrix (ECM) and regulate a variety of cell surface receptors or signalling molecules. The elevated MMP-9 levels in gastric mucosa infected with H. pylori can be reversed by eradication of the infection[97,98]. According to the results of the aforementioned study, TCM substances can prevent H. pylori infection-induced activation of NF-κB and associated gene transcription. This reduces inflammatory damage and inhibits inflammatory reactions.

HERB FOUMULAS

San-Ren decoction

San-Ren decoction is derived from “Wen bing Tiao bian” compiled by Ju-Tong Wu in the Qing Dynasty, which activates qi and clears dampness and heat. It is an effective prescription for the treatment of chronic gastritis with spleen-stomach dampness and heat syndrome[99]. The four main substances found in San-Ren decoction are luteoloside, amygdalin, magnolol, and adenosine[100]. Jiang et al[101] found that San Ren decoction improved the symptoms of HPAG rats with spleen-stomach damp-heat syndrome, inhibited inflammatory responses and functional dyspepsia, and reduced apoptosis of gastric mucosal epithelial cells. The mechanism may be related to the regulation of the Akt/NF-κB pathway.

Wei-Fu-Chun table

The Wei-Fu-Chun table comprises three herbs: Ginseng, fragrant tea vegetables, and fried citrus aurantium, which mainly contain naringin, ginsenoside, oridonin, and epirubicin[102]. Its quality standard was recorded in the “Chinese Pharmacopeia” (2010, 2015, and 2020 editions) and Wei-Fu-Chun was granted a Chinese innovation patent. The State Drug Administration of China has authorized Wei-Fu-Chun as the sole Chinese patented medication for the treatment of precancerous stomach cancer lesions. It can replenish Qi, strengthen the spleen Qi, remove blood stasis and phlegm, and boost blood circulation. It is effective in the treatment of CAG, gastroduodenal ulcers, chronic superficial gastritis, and other gastrointestinal diseases, with few adverse reports.

The Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway, stimulated by cytokines, is a cascade of multiple effects that plays a significant role in the immune system and immune response; it is not only involved in cell proliferation, differentiation, and apoptosis, but also plays a critical role in these processes[103]. Its transduction is mediated by extracellular signalling factors such as ligands, tyrosine kinase-related receptors, JAK, and STAT[104]. Extracellular signalling factors include ILs, chemotactic factors, and epidermal growth factor growth, among others. JAK, a tyrosine protein kinase, consists of four members: JAK1, JAK2, JAK3, and tyrosine kinase 2[105]. STAT is a class of cytoplasmic proteins that binds to DNA in the regulatory region of the target gene family, which is a direct downstream substrate of the JAK family[106]. Studies have demonstrated that dysregulation of JAK/STAT signalling is a driving force in the pathogenesis of various cancers and immune system diseases[107]. Clinical studies have shown that H. pylori infection can increase IL-6 expression and that IL-6 can activate the JAK2/STAT3 signalling pathway, which activates STAT3, initiates the expression of related genes, and plays a role in regulating inflammation, immunity, cell proliferation, and apoptosis[108]. Wang et al[109] found that the Wei-Fu-Chun table has a substantial effect on H. pylori-infected CAG rats. The mechanism of action may be related to the inhibition of the IL-6/JAK2/STAT3 signalling pathway and the expression of NF-κB.

Mie-You decoction

The Mie-You decoction is an empirical formula for TCM doctors that is mainly used for the spleen-stomach damp-heat syndrome of HPAG[110]. A network pharmacological study revealed that the main active ingredients were quercetin, naringenin, nobiletin, β-sitosterol, and luteolin through a network pharmacology study[111]. Mie-You decoction has been found to reduce oxidative stress in mice with damp-heat syndrome of the HPAG by modulating the Keap1/Nrf2/ARE pathway and improving gastric mucosal pathological injury[112]. Yu et al[113] demonstrated that Mie-You decoction may inhibit the expression of TLR4, NF-κB, p65, and downstream factors by interfering with TLR4/NF-κB signalling pathway to address HPAG with spleen-stomach damp-heat syndrome in rats.

Qilian Wendan decoction

The Qilian Wendan decoction is an empirical prescription for TCM doctors, which strengthens Qi and prevents pathogens. Studies have found that this can affect the expression of NF-κB p65, and IκBα in the gastric mucosa of mice with HPAG (spleen deficiency and dampness heat syndrome). Thus, inhibiting the occurrence of inflammatory response, so as to achieve the purpose of treating HPAG[114].

Qibei Xiaoyong decoction

Qibei Xiaoyong decoction uses Astragali Radix as the main medicine, which has the effects of clearing spleen and stomach damp-heat, detoxifying and removing carbuncle, and repairing ulcer. Studies have found that this can reduce oxidative stress response and inhibit the expression of NF-κB signalling pathway, improve the clinical symptoms of patients with H. pylori-positive gastric ulcer, relieve gastric inflammatory response, and promote ulcer repair and reduce the risk of recurrence[115].

Jinghua Weikang capsule

The Jinghua Weikang capsule is composed of Chenopodium ambrosioides L. and Adina Pilulifera(lam)Franch. These two drugs play a role in regulating Qi, dispersing cold, relieving pain, and clearing heat. In recent years, Jinghua Weikang capsule is a patented medicine (Z10970067) approved by the State Food and Drug Administration for gastric ulcers, duodenal ulcers, and chronic gastritis, which aimed to inhibit diseases caused by H. pylori and has been widely employed in the field of anti-H. pylori-related peptic ulcer and gastritis and has been recommended by several guidelines/consensus[116]. An in vitro study demonstrated that the essential oil of Chenopodium ambrosioides L. shows an anti-H. pylori effect by inhibiting biofilm formation[117]. Ye et al[118] found that Jinghua Weikang Capsule can effectively reduce the expression of NF-κB p65 in the protein level of HPAG in mice.

Jianpi Qinghua decoction

Jianpi Qinghua decoction is prescribed by Professor Qian-Gou Li, a famous national TCM doctor. The main prescription was composed of Radix Codonopsis, Poria, and Rhizoma Atractylodis Macrocephalae. This is mainly based on the syndrome differentiation of HPAG, which belongs to the spleen-stomach damp-heat syndrome or other syndromes with damp-heat syndrome. Liu et al[119] found that Jianpi Qinghua decoction can inhibit H. pylori to a certain extent. This effect may be attributed to the restoration of heat shock protein 70 expression in gastric tissue, inhibition of the NF-κB signalling pathway, and reduction in the progression of the inflammatory response, all of which help prevent damage to the gastric tissue and safeguard the gastric mucosa.

Zuo-Jin-Pill

Zuo-Jin-Pill is derived from “Danxi Xinfa” and is composed of Rhizoma coptidis and Evodiae officinalis in a ratio of 6:1. It is a commonly used prescription in clinical practice for reducing heat and fire, reflux, and emesis and is included in the “Chinese Pharmacopoeia” (2020 edition)[120]. Wen et al[121] found that Zuo-Jin-Pill reduced the histological destruction of gastric tissue and downregulated serum biochemical markers in rats with H. pylori-induced CAG. Furthermore, it may enhance the H. pylori-induced damage to GECs, suppress the inflammatory response, impede the mRNA and protein expression of relative jumonji domain-containing protein2B (JMJD2B), block the high-mobility group box 1/NF-κB signalling pathway, and lessen the harm to gastric mucosal cells.

Banxia Xiexin decoction

Banxia Xiexin decoction is a traditional Chinese herbal prescription, which comes from “Treatise on Febrile Diseases” written by Zhong-Jing Zhang in the Eastern Han Dynasty, which has been found to inhibit H. pylori in vitro and in vivo[122]. Studies have found that this mainly contains baicalin, baicalein, wogonoside, wogonin, scutellarin, berberine, coptisine, and ginsenoside[123].

The TGF-β is mostly released and accumulated as a complex in the ECM. TGF-β induces the synthesis of ECM proteins and regulates cell proliferation, apoptosis, embryogenesis, immune regulation, and differentiation[124,125]. The TGF-β superfamily and it is corresponding receptors and intracellular signal transduction molecules, mainly the small mothers against decapentaplegic homolog (Smad) protein family, form a signalling pathway that affects the occurrence and development of diseases and regulates the transcription of target genes. The Smads protein family exists in the vast majority of cells and tissues. It is a substrate of the TGF-β receptor and an important molecule in intracellular biological signal transduction[126]. TGF-β considerably reduces mucosal inflammation in the digestive tract[127]. Elevated TGF-β1 expression in the stomach mucosa during H. pylori infection promotes bacterial adhesion and host cell colonisation[128]. Huang et al[129] discovered that Banxia Xiexin decoction-medicated serum groups can minimise the damage to GES-1 cells induced by H. pylori, promote the proliferation of GES-1 cells, treat H. pylori-related peptic ulcers, and improve the quality of ulcer healing. The mechanism may be related to the regulation of the TGF-β/Smad signalling pathway.

Biling Weitong granule

Biling Weitong granule is an empirical prescription by Professor Jian-Hua Dong, a master of TCM. This prescription was included in the list of essential Chinese patent medicines for emergency use in TCM hospitals nationwide in 1997 and in the Chinese Pharmacopoeia (2020 edition) issued by the State Administration of Traditional Chinese Medicine[130]. Clinical studies have shown that Biling Weitong granule combined with quadruple therapy can effectively reduce the clinical symptoms of H. pylori-induced CAG, inhibit inflammatory responses, protect the gastric mucosa, and improve H. pylori eradication. The mechanism may be related to decreasing TGF-β1 activation[131].

Wei-Su granule

Wei-Su granule is a nationally protected variety of traditional Chinese medicine produced by Yangzijiang Pharmaceutical Co., LTD, and is an empirical prescription of Professor Jian-Hua Dong. It has the effects of drying dampness, regulating the motion of the qi, and normalising the functions of the spleen and stomach. Zhou et al[132] established a high-performance liquid chromatography fingerprint analysis method for Wei-Su granules and found 21 peaks calibrated by the fingerprint of Weisu granules and seven chemical components (ferulic acid, naringin, naringin, hesperidin, neohesperidin, quercetin, and oleanolic acid).

The Hippo pathway is an evolutionarily conserved signalling cascade that regulates tumorigenesis-related cell differentiation, tissue regeneration, stem cell self-renewal, and organ size related to tumorigenesis[133]. Transcriptional coactivator with the PDZ-binding motif (TAZ) is an important transcriptional coactivator that is negatively regulated by the Hipposa pathway, which induces the expression of growth-promoting genes. Therefore, it promotes organ regeneration after injury[134]. The Hippo signalling system is activated during H. pylori infection[135]. Hippo nuclear kinase large tumour suppressor 2 has been shown to protect gastric cells from infection-induced epithelial-mesenchymal transition, metaplasia, and high-risk precancerous transdifferentiation in gastric cancer[136]. Hui et al[137] found that Wei-Su granules contribute to the improvement of stomach pathological damage and the inflammatory response when used to treat H. pylori-induced atrophic gastritis by suppressing the Hippo/TAZ.

SAFETY AND SIDE EFFECTS OF TCM

Ensuring the safety of TCM interventions in HPAG is a key consideration for the pursuit of overall health. Concurrently, as the number and scope of TCM applications have grown, there have been reports of adverse reactions, raising widespread concerns about their safety. Recognising and preventing the side effects of Chinese medicine is related to its development. First, TCM is a natural product with a complicated composition, making it difficult to assess its toxicity[138]. Second, the population of TCM consumers varies by area, as do their genetic background, age composition, and disease conditions, making adverse reactions difficult to predict. Finally, established pharmacological and toxicological experimental models cannot adequately reflect the safety of TCM, making it particularly vital to better understand its toxicity and monitor adverse reactions of TCM[139-141]. TCM adverse events can have several causes of toxicity, but generally speaking, there are two main causes. First, the body factors are not recognised, and during the medication process, the contraindications of disease, syndrome, and constitution are disregarded. This can easily result in the mistreatment and abuse of patients, causing serious adverse reactions. The second is the inherent characteristics of TCM, including its complexity and incorrect applications of harmful TCM. In the clinical application process, it is necessary to improve doctors’ awareness of the toxicity of TCM, strengthen training in TCM, and disseminate drug safety information effectively. We should strengthen the monitoring of side effects when using TCM products, improve the safety of drug use, take positive measures to prevent adverse reactions, and further standardise the safety evaluation of TCM preparations. Patients should also receive health education regarding TCM.

CHALLENGES AND PROSPECTS

One of the reasons why TCM has rarely been used in clinical treatment on a broad scale is the lack of knowledge regarding its composition and mechanism of action, although the multi-target benefits of TCM remain unchanged. Relevant pharmacological investigations have produced some results; however, further research is needed to fully understand the precise mechanism of anti-HPAG action. Science and technology are rapidly developing. Systematic research at the molecular, genetic, and physiological levels; standardisation and safety evaluation of active ingredients; analysis of the body’s pathways for the digestion, absorption, and metabolism of TCM; improved rate of functional factor utilisation; and clarification of the mechanism of TCM have all contributed to the widespread use of its bioactive substances. Referring to the international standards of drug production quality management and good agricultural practices, the entire process (planting, collection, processing, and storage to transport) should adhere to strict quality control standards, and the quality standards of Chinese medicinal materials should be in line with international standards.

Research on the prevention and treatment of HPAG based on the fundamental theory of TCM and syndrome differentiation and treatment has been actively conducted, and TCM with definite curative effects, stability, and not easily resistant to resistance has been developed. The most priceless gifts from nature are natural goods such as herbal remedies, which have had a profound impact on human health.

CONCLUSION

TCM and natural medicine have long been used to treat HPAG. TCM treatments are adaptable and diverse. It gives equal priority to eradicating pathogens and boosting health and can improve the eradication rate of H. pylori while inhibiting the disease. Studies have demonstrated that many herbal compounds and active substances have bidirectional regulatory actions, which can be applied to the treatment of various clinical disorders through the advantages of “balancing Yin-Yang”[142]. TCM can be used to treat HPAG by regulating various signalling pathways, such as PI3K/Akt, MAPK, JAK/STAT, TGF-β/Smad, Hippo/TAZ, and other signalling pathways, thus maintaining inflammatory interaction balance, improving oxidative stress, promoting inflammatory cell apoptosis, boosting gastric mucosa proliferation, avoiding epithelial-mesenchymal transition, and preventing gastric mucosal cells from developing into cancer. The results are presented in Figure 2, Table 1, and Table 2. From the standpoint of signalling pathways, this review clarifies the mechanisms and potential of TCM in the treatment of HPAG. This finding is significant and warrants further research.

Figure 2 The signalling pathways of traditional Chinese medicine in the treatment of Helicobacter pylori-related gastritis. H. pylori: Helicobacter pylori; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; MAPK: Mitogen-activated protein kinase; NF-κB: Nuclear factor kappa B; TGF: Transforming growth factor; JAK: Janus activated kinase; STAT: Signal transducer and activator of transcription; TAZ: Transcriptional coactivator with the PDZ-binding motif; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase 1; IL: Interleukin; TNF: Tumor necrosis factor; ARE: Antioxidant response element; GSH-Px: Glutathione peroxidase; CAT: Catalase; SOD: Superoxide dismutase; MDA: Malondialdehyde; MPO: Myeloperoxidase; PGE2: Prostaglandin E2; HSP70: Heat shock protein70.

Table 1 The effects of extracts or active ingredient from herb medicines on Helicobacter pylori-associated gastritis.

Ref.	Active ingredient	Experiments of the TCM group		Related signaling pathway	Mechanisms/results	Outcome
		In vitro	In vivo
Wang et al[39], 2018	Polygonum capitatum extract	-	Rats	PI3K/AKT	↑PTEN	Polygonum capitatum prevents the release of inflammatory factors, and stimulates the proliferation of gastric mucosa cells to repair damaged tissues
					↓PI3K, AKT
Peng et al[42], 2022	Syzygium aromaticum extract	GES-1	-	PI3K/AKT, MAPK	↓p-PI3K, p-AKT, p-MAPK	The active components of syzygium aromatic extract played a therapeutic role in HPAG through the synergistic regulation of the PI3K/Akt and MAPK signalling pathways
Ma et al[54], 2020; Ma et al[96], 2021	Alpiniae Officinarum Rhizoma extract	-	Mice	MAPK	↓p-ERK1/2, P-JNK, p38MAPK, IL-8	The Alpiniae Officinarum Rhizoma extract played a therapeutic role in HPAG through regulation of the and MAPK and NF-κB signalling pathways
		GES-1	Mice	NF-κB	↓IKKβ, p-IKKα/β, NF-κBp65, p-NF-κBp65, p-IκBα, IL-8
Deng and Wan[57], 2017	Baicalin	GES-1	-	MAPK	↑Bcl-2, ↓IL-1β, p-p38 MAPK, IL-8, Bax	Baicalin markedly decreased the apoptosis of gastric mucosal epithelial cells, improved proliferation, and alleviated inflammation
Tian and Huang[60], 2019	Dandelion polysaccharide	-	Rats	MAPK	↑IL-10	Dandelion polysaccharide can reduce the inflammatory response of gastric mucosa in rats with HPAG by inhibiting the MAPK/ERK signalling pathway, so as to play a protective role in gastric mucosa
					↓p-ERK1/2, IL-6, TNF-α, PGE2, iNOS, COX-2
Jia et al[66], 2024	Ferulic acid	-	Mice	Wnt/β-catenin	↓Wnt2, β-catenin, TNF-α, IL-8	Ferulic acid can reduce H. pylori colonization and gastric mucosal inflammation through inhibitory effects of the Wnt/β-catenin signalling pathway
Liu et al[69], 2022	Patchouli alcohol	-	Mice	Wnt/β-catenin, NF-κB	↓Wnt2, β-catenin, NF-κB	Patchouli alcohol reduces the inflammatory response of gastric mucosa and prevent the epithelial-mesenchymal transition of gastric mucosal cells through the synergistic regulation of the Wnt/β-catenin and NF-κB signalling pathway
Zhang et al[83], 2015	Resveratrol	-	Mice	Nrf2/HO-1, NF-κB	↑HO-1, Nrf2	Resveratrol might play a therapeutic role in HPAG through the anti-oxidant, anti-inflammatory, regulation of the NF-κB and Nrf2/HO-1 signalling pathway
					↓MPO, LPO, IL-8, iNOS, p-IκBα
Liu et al[85], 2023	Rhein	-	Mice	Nrf2/HO-1, MAPK	↑HO-1, Nrf2	Rhein can regulate the MAPK and Nrf2/HO-1 signalling pathway to inhibit gastric inflammation of HPAG
					↓p-JNK1/2, p-p38MAPK, TNF-α, COX-2, IL-6, IL-1β, PGE2
Lu et al[95], 2021	Berberine	GES-1	Mice	NF-κB	↓TNF-α, IL-6, IL-8, COX-2, NF-κB p65, NF-κB p50, CagA	Berberine can inhibit gastric inflammation and virulence of H. pylori by inhibiting the effective activation of the NF-κB signalling pathway

TCM: Traditional Chinese medicine; ↑: Increased; ↓: Decreased; H. pylori: Helicobacter pylori; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; PTEN: Phosphatase and tensin homolog; p-PI3K: Phosphorylation of phosphatidylinositol 3-kinase; p-AKT: Phosphorylation of protein kinase B; MAPK: Mitogen-activated protein kinase; p-MAPK: Phosphorylation of mitogen-activated protein kinase; HPAG: Helicobacter pylori-associated gastritis; p-JNK: Phosphorylation of c-Jun N-terminal kinase; p-ERK1/2: Phosphorylation of extracellular signal-regulated kinase1/2; IL: Interleukin; NF-κB: Nuclear factor-kappa B; IKK: Inhibitor Kappa B kinase; p-IKK: Phosphorylation of inhibitor kappa B kinase; IκB: Inhibitor of nuclear factor-κB; p-IκB: Phosphorylation of inhibitor of nuclear factor-κB; iNOS: Inducible nitric oxide synthase; COX-2: Cyclooxygenase-2; PGE2: Prostaglandin E2; CagA: Cytotoxin-associated gene A; LPO: Lipid peroxidation; MPO: Myeloperoxidase; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase-1; TNF: Tumor necrosis factor; Bax: B-cell associated X protein; Bcl-2: B-cell lymphoma-2.

Table 2 The effects of herb formulas on Helicobacter pylori-associated gastritis.

Ref.	Herb formulas	Ingredients	Experiments of the TCM group		Related signaling pathway	Mechanisms/results	Outcome
			In vitro	In vivo
Jiang et al[101], 2024	San-Ren decoction	Ku Xing Ren (Semen Armeniacae Amarum), Zhi Ban Xia (Pinelliae Rhizoma Praeparata), Hua Shi (Talcum), Yi Yi Ren (Semen Coicis), Tong Cao (Medulla tetrapanacis), Bai Dou Kou (Amomi Fructus Rotundus), Dan Zhu Ye (Herba Lophatheri), Hou Po (Cortex Magnoliae Officinalis)	-	Rats	AKT/NF-κB	↑IL-10, IL-4, Bcl-2	San-Ren decoction can decrease stomach epithelial cell apoptosis and regulate the Akt/NF-κB signalling pathway, which can ameliorate the inflammatory response and functional dyspepsia in HPAG
						↓Caspase-3, Bax, Akt, NF-κB p65
Wang et al[109], 2022	Wei-Fu-Chun table	Ren Shen (Radix Ginseng), Zhi Qiao (Fructus Aurantii), Xiang Cha Cai (Isodon)	-	Rats	JAK/STAT	↓IL-6, JAK, STAT, NF-κB	Wei-Fu-Chun table can inhibit the JAK/STAT signalling pathway to improve the gastric mucosal inflammation symptoms of HPAG
Yan[112], 2023; Yu et al[113], 2014	Mie-You decoction	Huang Qin (Radix Scutellariae), Pu Gong Ying (Herba Taraxaci), San Qi (Radix notoginseng), Bai Ji (Rhizoma Bletillae), Qing Pi (Pericarpium Citri Reticulatae Viride), Chen Pi (Pericarpium Citri Reticulatae), Hai Piao Xiao (Endoconcha Sepiae)	-	Mice	Nrf2/HO-1, NF-κB	↑Keap1, Nrf 2, HO-1, SOD	Mie-You decoction can inhibit the oxidative stress response and the expression of TLR4, NF-κB65 and downstream factors by interfering with TLR4/NF-κB65 signalling pathway to achieve the purpose of treating HPAG
						↓MDA, NF-κB, TLR4, TNF-α, IL-8
Zheng[114], 2019	Qilian Wendan decoction	Huang Qi (Radix Astragalie), Huang Lian (Rhizoma Coptidis), Zhi Qiao (Fructus Aurantii), Zhu Ru (Caulis Bambusae in Taenia), Zhi Ban Xia (Pinelliae Rhizoma Praeparata), Chen Pi (Pericarpium Citri Reticulatae), Fu Ling (Poria), Pu Gong Ying (Herba Taraxaci), Gan Cao (Radix Glycyrrhizae)	-	Mice	NF-κB	↓NF-κB p65, IκBα	Qilian Wendan decoction can reduce H. pylori colonization in the stomach, and improve the pathological morphological damage of HPAG
Wang et al[115], 2024	Qibei Xiaoyong decoction	Huang Qi (Radix Astragalie), Pu Gong Ying (Herba Taraxaci), Zhe Bei Mu (Bulbus Fritillariae Thunbergii), Ku Shen (Radix Sophorae flavescentis), Hai Piao Xiao (Endoconcha Sepiae), Ren Shen (Radix Ginseng), Chai Hu (Radix Bupleuri), Bai Ji (Rhizoma Bletillae), San Qi (Radix notoginseng), Huang Lian (Rhizoma Coptidis), Pu Huang (Pollen Typhae), Wu Ling Zhi (Faeces Trogopterori), Gan Cao (Radix Glycyrrhizae)	-	Human	NF-κB	↑SOD, NO	Qibei Xiaoyong decoction can significantly improve oxidative stress and inflammation caused by HPAG
						↓NF-κB, MDA, TNF-α, IL-8, MMP-9
Ye et al[118], 2015	Jinghua Weikang capsule	Tu Jing Jie (Herba Chenodii Ambrosiodis), Shui Tuan Hua (Adina pilulifera)	-	Mice	NF-κB	↓NF-кBp65	Jinghua Weikang capsule have anti-inflammatory effect on HPAG by reducing the expression level of NF-κB p65
Liu et al[119], 2021	Jianpi Qinghua decoction	Dang Shen (Radix Codonopsis), Fu Ling (Poria), Bai Zhu (Rhizoma Atractylodis Macrocephalae), Huang Lian (Rhizoma Coptidis), Da Huang (Radix et Rhizoma Rhei), Pu Gong Ying (Herba Taraxaci), Dan Shen (Radix Salviae Miltiorrhizae), Gan Cao (Radix Glycyrrhizae)	-	Rats	NF-κB	↑HSP70	Jianpi Qinghua decoction can inhibit and kill H. pylori to a certain extent, reduce the progression of inflammatory reaction, so as to reduce gastric tissue damage and protect gastric mucosa
						↓NF-кBp65
Wen et al[121], 2022	Zuo-Jin-Pill	Huang Lian (Rhizoma Coptidis), Wu Zhuyu (Rhizoma Coptidis)	GES-1	Mice	HMGB1/NF-κB	↓IL-6, MCP-1, PGE2, TNF-α, VEGF, HMGB1, JMJD2B, COX-2, NF-κB p65, MYD88, TLR4	Zuo-Jin-Pill exerts therapeutic effects on H. pylori-induced CAG by inhibiting the JMJD2B/COX-2/VEGF axis and HMGB1/NF-κB signalling pathway
Huang et al[129], 2018	Banxia Xiexin decoction	Zhi Ban Xia (Rhizoma Pinelliae), Huang Qin (Radix Scutellariae), Gan Jiang (Rhizoma Zingiberis), Ren Shen (Radix Ginseng), Huang Lian (Rhizoma Coptidis), Da Zao (Jujubae Fructus), Gan Cao (Radix Glycyrrhizae)	GES-1	-	TGF-β/Smad	↑Smad2/3, TGF-β1, p-Smad2/3	Banxia Xiexin decoction can reduce the damage of gastric mucosal epithelial cells induced by H. pylori, promote the proliferation of gastric mucosal epithelial cells
						↓Smad7, p-Smad7, LPO, IL-8, iNOS, p-IκBα
Su et al[131], 2023	Biling Weitong granule	Bi Cheng Qie (Fructus Litseae), Wu Zhu Yu (Fructus Evodiae), Xiang Fu (Rhizoma Cyperi), Chuan Lian Zi (Fructus toosendan), Yan Hu Suo (Rhizoma corydalis), Huang Lian (Rhizoma Coptidis), Da Huang (Radix et Rhizoma Rhei), Fo Shou (Fructus Citri Sarcodactylis), Xiang Yuan (Fructus Citri), Hai Piao Xiao (Endoconcha Sepiae), Wa Leng Zi (Concha Arcae)	-	Human	TGF-β/Smad	↓IL-6, TNF-α, EGF, TGF-β1	The combination of Biling Weitong granule and quadruple therapy can significantly improve the eradication rate of H. pylori, and can significantly increase the relief rate of upper abdominal pain in patients with gastric ulcer, and improve the clinical efficacy
Hui et al[137], 2023	Wei-Su granule	Zi Su Geng (Caulis Perillae), Xiang Fu (Rhizoma Cyperi), Chen Pi (Pericarpium Citri Reticulatae), Fo Shou (Fructus Citri Sarcodactylis), Xiang Yuan (Fructus Citri), Zhi Qiao (Fructus Aurantii), Ji Nei Jin (Endothelium Corneum Gigeriae Galli), Bin Lang (Semen Arecae)	-	Rats	Hippo/TAZ	↑LATS2	Wei-Su granule has great potential and specific therapeutic value in innovative drug development for HPAG
						↓TAZ

↑: Increased; ↓: Decreased; TCM: Traditional Chinese medicine; AKT: Protein kinase B; NF-κB: Nuclear factor-kappa B; IL: Interleukin; Bax: B-cell associated X protein; Bcl-2: B-cell lymphoma-2; HPAG: Helicobacter pylori-associated gastritis; JAK: c-Jun N-terminal kinase; STAT: Signal transducer and activator of transcription; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase-1; Keap1: Kelch-like associated protein 1; SOD: Superoxide dismutase; TLR: Toll-like receptor; MDA: Malondialdehyde; TNF: Tumor necrosis factor; IκBα: IkappaBalpha; H. pylori: Helicobacter pylori; NO: Nitric oxide; MMP-9: Matrix metalloproteinase 9; HSP70: Heat shock protein70; HMGB1: High mobility group box 1; MCP-1: Monocyte chemoattractant protein-1; PGE2: Prostaglandin E2; VEGF: Vascular endothelial growth factor; JMJD2B: Jumonji domain-containing protein2B; COX-2: Cyclooxygenase-2; CAG: Chronic atrophic gastritis; MYD88: Myeloid differentiation factor 88; Smad2/3: Small mothers against decapentaplegic homolog 2/3; LPO: Lipid peroxidation; iNOS: Inducible nitric oxide synthase; p-IκBα: Phosphorylation of IkappaBalpha; EGF: Epidermal growth factor; TAZ: Transcriptional coactivator with PDZ-binding motif; LATS2: Large tumor suppressor 2.

It can be seen that TCM treatment of HPAG has the unique advantages of multi-component, multi-target, multi-pathway, and other holistic regulation and has good therapeutic effects. Owing to the long course of the disease and widespread use of antibiotics in recent years, HPAG treatment is facing a serious trend of drug resistance. The application and promotion of TCM can eliminate H. pylori, reduce inflammatory reactions, and protect the gastric mucosa. Based on the characteristics of TCM, it is vital to investigate their use in preventing the occurrence and recurrence of HPAG. In the future, we can further explore which signalling pathways are specifically activated by TCM in the treatment of HPAG and how TCM can treat HPAG holistically through multiple pathways.

ACKNOWLEDGEMENTS

We are grateful to the funding organizations for their financial support, which allowed us to conduct this research and contribute to the advancement of knowledge in our profession. The funders were not involved in the study design, data collection and analysis, publication decisions, or manuscript writing.