Research Progress on the Mechanism of Traditional Chinese Medicine in Treating Chronic Atrophic Gastritis

Abstract

Chronic atrophic gastritis (CAG) is a common type of chronic gastric disease characterized by high incidence and a certain tendency toward cancerization. In recent years, with the deepening of related research, it has been found that traditional Chinese medicine (TCM) exerts therapeutic effects on CAG through various signaling pathways. This article systematically reviews and summarizes the literature on TCM treatment of CAG, elaborating on the etiology and pathogenesis of CAG, new ideas from different physicians in treating CAG, and the effects of different TCM monomers and compound prescriptions on signaling pathways such as PI3K-AKT and JAK1/STAT3 to provide a reference for subsequent research on CAG.

 

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Keywords

chronic atrophic gastritis - traditional Chinese medicine - signaling pathways

Chronic atrophic gastritis (CAG) is a chronic disease characterized by gastric mucosal atrophy and reduction of intrinsic glands after varying degrees of damage, with or without intestinal metaplasia, and is one type of chronic gastritis.[1] The disease mainly manifests as epigastric distension, epigastric dull pain, belching, gastric upset, acid reflux, heartburn, nausea, and vomiting. Recent studies have shown that the incidence of CAG is increasing year by year, with a global prevalence of 10 to 30%, while the prevalence in China is 25.8%.[2] [3] CAG is an independent risk factor for gastric cancer, which ranks fourth in global malignant tumor mortality and fifth in incidence.[4] Therefore, research and prevention of CAG and its precancerous lesions are particularly important. Currently, modern medicine has not yet fully elucidated the etiology and pathogenesis of CAG, and there is no standardized, unified, or effective treatment plan. However, traditional Chinese medicine (TCM) has unique advantages in treatment, which applies the principles and methods of syndrome differentiation to conduct extensive clinical research and achieves certain therapeutic effects.

Traditional Chinese Medicine Understanding of the Etiology and Pathogenesis of Chronic Atrophic Gastritis

There is no record of the disease name “chronic atrophic gastritis” in ancient TCM texts. Based on the clinical manifestations of CAG patients, such as epigastric distension and dull pain, gastric upset, belching, poor appetite, acid reflux, and heartburn, it can be classified under the categories of “stomach stuffiness” “epigastric pain,” or “fullness.” Regarding the etiology and pathogenesis of CAG, many physicians from ancient to modern times have proposed different theories. Yuanfang Chao, a physician from the Sui Dynasty, first expounded the view in General Treatise on the Causes and Symptoms of Diseases (Zhu Bing Yuan Hou Lun) that “disharmony of nutrient and defensive qi leads to stagnation of visceral qi, resulting in stuffiness.” Dongyuan Li stated in Treatise on the Spleen and Stomach (Pi Wei Lun): “Sufficient primordial qi prevents damage to spleen and stomach qi.”[5] Professor Diangui Li, a master of TCM, believes that the formation of CAG with dysplasia is mainly related to turbid toxin, qi stagnation, phlegm obstruction, blood stasis, and deficiency, with turbid toxin accumulation being the key pathogenesis.[6] Professor Jingfan Xu, another national master of TCM, first proposed treating spleen and stomach diseases from the perspective of stasis. He believes that the spleen and stomach are the pivot of qi movement in the human body, and pathological factors such as qi stagnation, blood stasis, qi deficiency, and yin deficiency can lead to stasis during the occurrence and development of spleen and stomach diseases.[7] Professor Qiquan Liu, a nationally renowned TCM expert, believes that although the disease location of CAG is in the stomach, it is closely related to other organs such as the lung, liver, and spleen. The main pathogenesis is associated with liver qi stagnation, stomach yin deficiency, and unresolved lung heat.[8] Professor Delu Tian believes that CAG belongs to “deficiency stuffiness,” with spleen deficiency as the root and food stagnation and phlegm-heat interacting as contributing factors.[9]

Through the above discussion, it is found that the occurrence of CAG is fundamentally rooted in spleen and stomach deficiency, stimulated by factors such as dietary irregularities, external pathogens attack, emotional disturbances, and drug-induced damage, leading to dysfunction of spleen and stomach qi movement and resulting in qi stagnation, blood stasis, and dampness obstruction.[10]

 

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Treatment of Chronic Atrophic Gastritis with Traditional Chinese Medicine

The syndrome differentiation and treatment approach of TCM represents its unique advantage, not only improving clinical symptoms of CAG, but also demonstrating remarkable efficacy in reversing atrophy, intestinal metaplasia, and precancerous lesions. Contemporary TCM practitioners have developed various syndrome differentiation patterns for CAG based on their clinical experience. While Consensus on Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Chronic Atrophic Gastritis classifies CAG into six syndrome types, spleen–stomach deficiency syndrome and liver–stomach qi stagnation syndrome remain the most common in clinical practice.

Professor Diangui Li, a national master of TCM, pioneered the application of turbid-toxin theory in treating CAG and created the Huazhuo Jiedu Decoction, composed of Yinchen (Artemisiae Scopariae Herba), Huanglian (Coptidis Rhizoma), Baihuashe Shecao (Hedyotidis Diffusae Herba), Chuanxiong (Chuanxiong Rhizoma), Yanhusuo (Corydalis Rhizoma), Laifuzi (Raphani Semen), Zhishi (Aurantii Fructus Immaturus), Baizhu (Atractylodis Macrocephalae Rhizoma), Huoxiang (Pogostemonis Herba), Doukou (Amomi Fructus Rotundus).[11] This formula shows significant efficacy in alleviating epigastric pain, stuffiness, and sticky stool symptoms. Professor Diangui Li established different treatment methods based on turbid-toxin severity: turbid-dominant cases require turbid-resolving methods (dampness-percolating, bowel-clearing, aromatic turbid-dispersing, or heat-clearing dampness-drying), whereas toxin-dominant cases need detoxification approaches (heat-clearing or toxin-attacking). He further classified CAG into spleen–stomach deficiency type (mild CAG), blood stasis obstruction type (moderate CAG), and turbid-toxin excess type (severe CAG).[12] Nationally renowned TCM expert Professor Qiquan Liu advocates liver-focused CAG treatment through four methods: soothing liver and descending stomach, clearing liver and harmonizing stomach, softening liver and nourishing stomach, and tonifying liver and nourishing stomach corresponding to liver qi attacking stomach, liver–stomach heat stagnation, liver–stomach yin deficiency, and liver blood deficiency patterns respectively, achieving excellent clinical outcomes. Professor Xiang Zheng proposes stomach-nourishing and kidney-tonifying therapy, emphasizing kidney yang as gastric motility's driving force and kidney yin as stomach yin's source.[13] Professor Jing Li considers spleen–stomach qi-blood deficiency as CAG's core pathogenesis, developing the Qizhu Weiwei Formula to simultaneously treat spleen and stomach by activating blood, replenishing qi, removing stasis, and detoxifying, thereby restoring the action of the spleen and stomach to receive, decompose, transport and transform food, and descend qi movement.[14] [15] Professor Shuwen Shen's “toxin-stasis interlock” theory underpins the Jinguo Weikang Capsule containing Chinese herbs, such as Banzhilian (Scutellariae Barbatae Herba), Gouju (Ponciri Fructus), Zhushaqi (Polygoni Cillinerve Radix), Taizishen (Pseudostellariae Radix), which demonstrates significant efficacy against gastric precancerous lesions through qi-tonifying, yin-nourishing, nodule-dispersing, stasis-resolving, heat-clearing, and detoxifying actions.[16]

 

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Research on Signaling Pathways in Traditional Chinese Medicine Treatment of Chronic Atrophic Gastritis

In recent years, numerous studies have demonstrated that Chinese herbal monomers and compound formulations target signaling pathway mediation, regulating the release of inflammatory factors and cytokines as well as protein expression across multiple pathways from diverse perspectives, thereby providing new directions and novel approaches for clinical research on CAG.[17] [18] [19]

Chinese Herbal Monomers

Liu et al[20] demonstrated ginsenosides' inhibition of gastric cancer cell proliferation via PI3K/AKT pathway. Wang et al[21] found berberine upregulates LC3B protein expression in gastric mucosal epithelial cells, reduces inflammatory factors, and suppresses PI3K/Akt signaling in CAG rats, thus exerting effects of preventing and treating CAG. Duan et al[22] showed baicalin downregulates JAK1/STAT3 expression, effectively repairing gastric mucosa in CAG mice. Jin[23] discovered in the study on Huangqi Jianzhong Decoction and its individual component herbs' chemical constituents and in vivo metabolism that paeoniflorin can reduce the expression of various genes and proteins in gastric cancer cell nuclei, thereby exerting preventive and therapeutic effects against CAG progression. Ouyang et al[24] discovered Dendrobium polysaccharides inhibit JAKI/P-STAT3 signaling and gastric mucosal cell proliferation in CAG rats. Li et al[25] reported atractylenolide reduces COX-2 expression and gastric inflammation. Luo et al[26] demonstrated Sanqi (Notoginseng Radix et Rhizoma) elevates interleukin-6, nitric oxide synthase, gastrin, and somatostatin levels, exerting anti-inflammatory and mucosal repair effects.

 

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Chinese Herbal Formulations

He et al[27] found that Huanglian Wendan Decoction combined with quadruple therapy effectively regulates the expression levels of TGF-β1 and Smad3 proteins in gastric mucosa of CAG patients with spleen–stomach dampness-heat pattern, alleviates clinical symptoms such as belching, gastric upset, acid regurgitation, poor appetite, and epigastric and abdominal distending pain, accelerates gastric mucosal repair, and reduces inflammatory responses. Yuan et al[28] confirmed that Qifang Weitong Granules can inhibit the TGF-β/Smad signaling pathway, upregulate E-cadherin expression, downregulate ZEB2 and Vimentin expression, and suppress gastric epithelial–mesenchymal transition. Li et al[29] demonstrated that Jianpi Qinghua Huayu Decoction, composed of Dangshen (Codonopsis Radix) 10 g, Danshen (Salviae Miltiorrhizae Radix et Rhizoma) 10 g, Ezhu (Curcumae Rhizoma) 15 g, Baizhu (Atractylodis Macrocephalae Rhizoma) 15 g, Fuling (Poria) 15 g, Gancao (Glycyrrhizae Radix et Rhizoma) 5 g, Huanglian (Coptidis Rhizoma) 5 g, Dahuang (Rhei Radix et Rhizoma) 6 g, Pugongying (Taraxaci Herba) 20 g, Baihuashe Shecao (Hedyotidis Diffusae Herba) 20 g, Sanqi (Notoginseng Radix et Rhizoma) 3 g, Tufuling (Smilacis Glabrae Rhizoma) 15 g, Chenpi (Citri Reticulatae Pericarpium) 10 g, Banxiaqu (Pinelliae Fermentata) 10 g, may treat CAG by downregulating miR-21 expression in gastric mucosa of CAG rats, thereby releasing its inhibition on tumor suppressor genes and further regulating downstream signaling pathways of the PTEN gene. Anwei Decoction may prevent CAG progression by inhibiting the JAK1/STAT3 signaling pathway and regulating cell apoptosis.[30] Banxia Xiexin Decoction achieves therapeutic effects on CAG by modulating the TNF and PI3K-AKT signaling pathways, increasing PI3K expression and decreasing Akt expression in rat gastric mucosa, thereby blocking inflammatory progression and promoting apoptosis.[31] Kang et al[32] reported that Jianpi Huoxue Formula, composed of Jiangbanxia (Pinelliae Rhizoma Praeparatum) 10 g, Huanglian (Coptidis Rhizoma) 6 g, Huangqin (Scutellariae Radix) 8 g, Paojiang (Zingiberis Rhizoma Praeparatum) 3 g, Taizishen (Pseudostellariae Radix) 15 g, Dazao (Jujubae Fructus) 10 g, Kuxingren (Armeniacae Semen Amarum) 10 g, Houpo (Magnoliae Officinalis Cortex) 10 g, Gancao (Glycyrrhizae Radix et Rhizoma) 6 g, Sanqifen (Notoginseng Radix et Rhizoma Pulveratum) 3 g, combined with acupuncture significantly reduces NLR and IL-1β levels, regulates PGI, PGI/PGII, and G-17 levels in CAG patients with gastric collateral stasis pattern, potentially through influencing the TNF signaling pathway. Sun et al[33] discovered that Liu Junzi Decoction exerts anti-inflammatory effects in CAG by mediating NLRP3 to regulate the PI3K/AKT signaling pathway and inhibit inflammatory factor aggregation. Wang et al[34] demonstrated that Yiqi Huayu Zuwei Formula, composed of Shenghuangqi (Astragali Radix) 20 g, Ezhu (Curcumae Rhizoma) 5 g, Maozhuacao (Ranunculi Ternati Radix) 10 g, Yuzhizi (Akebiae Fructus) 10 g, Baihuashe Shecao (Hedyotidis Diffusae Herba) 12 g, Chaodangshen (Codonopsis Radix Praeparata) 15 g, Shengbaizhu (Atractylodis Macrocephalae Rhizoma) 10 g, Shengdiyu (Sanguisorbae Radix) 10 g, Pugongying (Taraxaci Herba) 12 g, Bailian (Ampelopsis Radix) 10 g, protects gastric mucosa in CAG mice by downregulating PI3K, AKT, and p-AKT protein expression and inhibiting PI3K/AKT pathway activation. Duan et al[35] found that Xiangsha Liujunzi Decoction may inhibit CAG progression by regulating LDHA expression, modulating glycolytic processes in cell metabolism, upregulating PTEN expression, and downregulating Akt and PI3K expression, thereby improving gastric mucosal pathology in rats.

Currently, Western medicine has certain limitations in treating CAG. TCM external therapies demonstrate unique advantages in CAG treatment, characterized by significant clinical efficacy, low cost, simplicity, easy promotion, and minimal adverse effects. Wei et al[36] reported that auricular acupoint therapy combined with conventional treatment effectively improves clinical symptoms such as gastric distension, poor appetite, fatigue, and emotional discomfort in CAG patients, alleviates negative emotions like irritability and sleep disturbances, enhances quality of life, and reduces complications. Yin et al[37] concluded in their meta-analysis of TCM external therapies for CAG that these methods are effective, with significantly higher total effectiveness rates, gastric mucosal scores, and Helicobacter pylori eradication rates compared with control group.

 

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Conclusion

TCM and comprehensive TCM therapies demonstrate significant advantages and unique characteristics in treating CAG, with proven efficacy. Under the theoretical guidance of holistic concepts and syndrome differentiation, TCM achieves remarkable clinical outcomes through the integration of four diagnostic methods, tailored treatment modifications based on patients' specific syndrome patterns and clinical features, and addressing both symptoms and root causes. However, several challenges remain in TCM treatment of CAG: ① The etiology and pathogenesis of CAG are relatively complex, and clinical syndrome differentiation varies among patients. Current clinical research primarily focuses on empirical formulas modified from renowned TCM masters and experts, which are numerous and relatively complicated. The lack of unified, standardized syndrome classification criteria hinders effective guidance for clinicians in prescription formulation. ② Research on the pathogenesis of CAG lacks multicenter, big-data randomized controlled trials, which to some extent limits the integration and broader application of TCM theory with clinical research.

 

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Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Jianxin Shen: Conceptualization, writing original draft, funding acquisition, project administration, and writing-review and editing. Ruxia Xue: Resources, and writing original draft. Dongshan Yin: Conceptualization, investigation, and methodology. Xiang Su: Conceptualization and investigation. Xiaofa Liu: Conceptualization and supervision. Jinfeng Sun: Conceptualization, writing original draft, and writing-review and editing.

• References

• 1 Li JX, Chen Y, Lyu B. et al. Consensus on integrated traditional Chinese and Western medicine diagnosis and treatment of chronic atrophic gastritis (2017). Chin J Integr Tradit West Med Dig 2018; 26 (02) 121-131
• 2 Wang LH, Li B, Li P. et al. TCM syndrome differentiation and treatment strategies for chronic atrophic gastritis. World J Integr Tradit West Med 2024; 15 (19) 2334-2338
• 3 Yin Y, Liang H, Wei N, Zheng Z. Prevalence of chronic atrophic gastritis worldwide from 2010 to 2020: an updated systematic review and meta-analysis. Ann Palliat Med 2022; 11 (12) 3697-3703
• 4 Sung H, Ferlay J, Siegel RL. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
• 5 Feng QH, Peng ZY, Cen JA. et al. Research progress on diagnosis and treatment of chronic atrophic gastritis with integrated traditional Chinese and Western medicine. Chin Med Mod Distance Educ China 2024; 22 (03) 141-144
• 6 Zhai FP, Wang LP, Li CL. et al. Li Diangui's clinical experience in treating chronic atrophic gastritis with dysplasia. Jiangsu J Tradit Chin Med 2021; 53 (05) 22-24
• 7 Jiang T, Ma J, Lu WM. National TCM master Xu Jingfan's experience in treating spleen-stomach diseases from the perspective of stasis. Zhonghua Zhongyiyao Zazhi 2020; 35 (09) 4436-4438
• 8 Zheng SH, Guo HL, Song CM. et al. Liu Qiquan's experience in treating chronic atrophic gastritis based on the theory of “six fu organs being unobstructed as tonification”. Liaoning J Tradit Chin Med 2024; 51 (04) 25-28
• 9 Zhang ZM, Guo ZL, Liu DM. et al. Tian Delu's experience in syndrome differentiation and treatment of chronic atrophic gastritis. Jiangsu J Tradit Chin Med 2022; 54 (09) 26-29
• 10 Zhao H, Yang QF. Famous TCM doctors' understanding of etiology and pathogenesis and medication rules for chronic atrophic gastritis. Lishizhen Med Mater Med Res 2018; 29 (06) 1518-1520
• 11 Wang YC, Cheng YR, Liu ZW. et al. Research progress on turbid-toxin theory in treating chronic atrophic gastritis with turbid-resolving and detoxifying methods. Hebei J Tradit Chin Med 2022; 44 (01) 152-156
• 12 Liu XF, Li DG, Wu JX. et al. Research progress on TCM treatment of chronic atrophic gastritis with Helicobacter pylori infection in recent five years. Hebei J Tradit Chin Med 2023; 45 (03) 519-523
• 13 He JJ, Yan HM, Zheng X. Zheng Xiang's experience in treating chronic atrophic gastritis with yin-nourishing methods. Forum Tradit Chin Med 2023; 38 (06) 57-59
• 14 Liu FX, Liu L, Bai G. et al. Advances in integrated traditional Chinese and Western medicine treatment of chronic atrophic gastritis. J Pract Tradit Chin Intern Med 2024; 38 (07) 13-15
• 15 Bai G, Tang XD, Zhou HL. et al. Discussion on treating chronic atrophic gastritis from the perspective of spleen deficiency and blood stasis. Zhonghua Zhongyiyao Xuekan 2021; 39 (09) 28-31
• 16 Song J, Wei YH, Meng KQ. et al. Professor Shen Shuwen's clinical experience and academic thoughts on treating chronic atrophic gastritis with TCM. World J Integr Tradit West Med 2022; 17 (08) 1539-1543
• 17 Jiang YP, Liu WF, Wu SS. et al. Research progress on signaling pathways related to traditional Chinese medicine treatment of chronic atrophic gastritis. China Med Herald 2022; 19 (36) 58-61
• 18 Ma QH, Liu FF, Wang JH. Effect of modified Shugan Hewei Decoction combined with conventional Western medicine on chronic atrophic gastritis with liver-qi invading stomach syndrome and its influence on miR-26a and miR-32 expression. Clin Res Pract 2024; 9 (08) 117-120
• 19 Xu XH, Yan HL, Xu ZX. et al. Exploring the impact of Helicobacter pylori infection on Hedgehog and NOX/NF-κB/STAT1 signaling pathways in chronic atrophic gastritis from the perspective of “dampness-heat causing stasis”. World Sci Technol-Mod Tradit Chin Med 2024; 26 (01) 137-144
• 20 Zhou ZH, Liang K, Cui B. et al. Research progress on signaling pathways related to traditional Chinese medicine intervention in Helicobacter pylori-negative chronic atrophic gastritis. Zhonghua Zhongyiyao Xuekan 2024; 42 (05) 82-88 ,279, 280
• 21 Wang J, Du PL, Dong JQ. et al. Effect of coptisine on PI3K/Akt/mTOR signaling pathway in rats with chronic atrophic gastritis. Chin J Exp Tradit Med Form 2024; 30 (18) 117-124
• 22 Duan LY, Zhu MY, Yu Y. et al. Effect of baicalin on JAK1 and STAT3 expression in mice with chronic atrophic gastritis. J Guangzhou Univ Tradit Chin Med 2024; 41 (01) 200-206
• 23 Jin ZD. Research progress on chemical constituents and in vivo metabolism of Huangqi Jianzhong decoction and its component herbs. Chin Tradit Herbal Drugs 2019; 50 (18) 4495-4501
• 24 Ouyang YM, Ling P, Li LH. et al. Effect and molecular mechanism of Dendrobium officinale polysaccharides on chronic atrophic gastritis in rats. Chin J Comp Med 2018; 28 (10) 67-72
• 25 Li D, Yu YQ, Gao HB. et al. Protective effect of atractylenolide I on gastric mucosa in rats with chronic atrophic gastritis. J Hebei Tradit Chin Med Pharmacol 2016; 31 (03) 5-8
• 26 Luo C, Sun Z, Li Z, Zheng L, Zhu X. Notoginsenoside R1 (NGR1) attenuates chronic atrophic gastritis in rats. Med Sci Monit 2019; 25: 1177-1186
• 27 He XG, Guo BG. Efficacy of Huanglian Wendan Decoction combined with bismuth quadruple therapy for H. pylori-associated chronic gastritis with spleen-stomach dampness-heat syndrome and its effect on TGF-β1 and Smad3 expression in gastric mucosa. J Sichuan Tradit Chin Med 2021; 39 (09) 93-96
• 28 Yuan TC, Chen GZ, Peng ZX. et al. Effect of Qifang Weitong Granules on epithelial-mesenchymal transition of human gastric adenocarcinoma AGS cells based on TGF-β/smad signaling pathway. Acta Chin Med 2021; 36 (01) 126-131
• 29 Li YT. Effect of Jianpi Qinghua Huayu Decoction on miR-21 and its target gene PTEN expression in gastric mucosa of HP-associated PLGC rats. Beijing: Beijing University of Chinese Medicine; 2021
• 30 Wang B. Effect of Anwei Decoction on JAK1/STAT3 signaling pathway in rats with chronic atrophic gastritis. Nanning: Guangxi University of Chinese Medicine; 2016
• 31 Ren XJ, Zhang ML, Zhao HH. et al. Research progress on mechanism of Banxia Xiexin Decoction in treating chronic atrophic gastritis. Liaoning Zhongyiyao Daxue Xuebao 2024; 26 (10) 65-69
• 32 Kang WT, Shi ZH, Liu S. et al. Clinical efficacy of Jianpi Huoxue Formula combined with acupuncture for chronic atrophic gastritis with gastric collateral stasis and its effect on inflammatory indicators and gastric mucosal function. Chin J Exp Tradit Med Form 2024; 30 (05) 103-110
• 33 Sun QS, Huang P, Li X. et al. Mechanism analysis of NLRP3-mediated Liujunzi Decoction in treating chronic atrophic gastritis and inflammation-cancer transformation. Acta Chin Med 2023; 38 (11) 2434-2442
• 34 Wang B, Song ZJ, Qiu L. et al. Experimental study on Yiqi Huayu Zuwei formula alleviating chronic atrophic gastritis by regulating PI3K/AKT signaling pathway. J Zhejiang Chin Med Univ 2023; 47 (10) 1123-1128
• 35 Duan YQ, Gong ZH, Wang LY. et al. Effect of Xiangsha Liujunzi Decoction on expression of PI3K signaling pathway-related factors in gastric tissue of rats with chronic atrophic gastritis. Zhongguo Zhongyiyao Xinxi Zazhi 2020; 27 (03) 33-38
• 36 Wei LP, Yu H. Effect of comprehensive auricular therapy on negative emotions in patients with chronic atrophic gastritis. Chin Med Mod Distance Educ China 2024; 22 (08) 98-101
• 37 Yin YX, Bu X, Qi XZ. Meta-analysis of external therapies of traditional Chinese medicine for chronic atrophic gastritis. Chin J Ethnomed Ethnopharm 2023; 32 (24) 75-80

Publication History

Received: 21 March 2025

Accepted: 09 July 2025

Article published online:
30 September 2025