Jianpiyiqi formula ameliorates chronic atrophic gastritis in rats by modulating the Wnt/β‑catenin signaling pathway
- Authors:
- Published online on: June 15, 2021 https://doi.org/10.3892/etm.2021.10310
- Article Number: 878
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Copyright: © Yan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Chronic atrophic gastritis (CAG) is a common digestive-tract disease characterized by gastric gland atrophy, decreased number of gastric glands and chronic inflammation (1). The typical clinical symptoms of patients with CAG include reduced appetite, nausea and acid reflux (2). Helicobacter pylori (H. pylori) infection, smoking, drinking and immune abnormalities may lead to the development of CAG (3). Furthermore, CAG is a precancerous state of gastric cancer (GC). Therefore, effective and timely treatment of CAG may help prevent the occurrence of GC (4,5). Proton pump inhibitors, antibiotics, folic acid, vitamins and gastric mucosal protective agents are frequently used as conventional treatments for patients with CAG (6). However, there is a lack of specific drugs that may reverse the atrophy of patients with CAG in clinical practice.
Jianpiyiqi formula, also called Weiwei No. 1, is a type of Traditional Chinese Medicine (TCM) formula and is used to treat CAG in clinical settings (7). Jianpiyiqi formula is not a commercial product and there is currently a lack of effective commercial formulas for treating CAG in the clinic. Jianpiyiqi formula is composed of 12 Chinese medicinal herbal components/ingredients: Dangshen, Baizhu, Fuling, Gancao, Chenpi, Banxia, Muxiang, Sharen, Ezhu, Baihuasheshecao, Yunmushi and Yujin (Table I). It is mainly used for patients with CAG with a weak spleen and stomach, qi stagnation and blood stasis according to the theory of TCM (8). However, the pharmacological mechanisms of action of the Jianpiyiqi formula for improving CAG remained elusive. In the present study, a CAG rat model induced by N-methyl-N'-nitro-N-nitrosoguanidine and ranitidine was constructed to assess the molecular pharmacology of the Jianpiyiqi formula.
The gastric mucosa of patients with CAG is continuously damaged by various pathogenic factors and it cannot be repaired within a sufficient time period (1). It has been reported that the damage repair and proliferation of gastric epithelial cells are closely associated with the Wnt/β-catenin signaling pathway (9-12). H. pylori infection is associated with the expression of β-catenin in CAG with intestinal metaplasia (13). GC has been associated with increased expression of the Wnt/β-catenin signaling pathway, which may promote abnormal proliferation of gastric gland cells and then induce tumors (14). To date, a limited number of studies have investigated the association between CAG and the Wnt/β-catenin signaling pathway (15). Therefore, the aim of the present study was to clarify the pharmacological mechanisms of action of Jianpiyiqi formula in the treatment of CAG via the Wnt/β-catenin signaling pathway.
Materials and methods
Reagents
N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was purchased from Tokyo Chemical Industry Co., Ltd. Ranitidine hydrochloride was purchased from Shanghai Hengshan Pharmaceutical Co., Ltd. Liquiritin, hesperidin, lobetyolin, curdione, costunolide and atractylenolide II were purchased from Chengdu Must Bio-Technology Co., Ltd. The H&E staining kit and prostaglandin E2 (PGE2) ELISA kit (cat. no. H099-1) were purchased from Nanjing Jiancheng Bioengineering Institute. Methanol and acetonitrile were purchased from EMD Millipore. Ethanol, acetic acid, xylene and formaldehyde were purchased from Sinopharm Chemical Reagent Co., Ltd. The gastrin (GAS), pepsin (PP), and somatostatin (SS) ELISA kits were purchased from Elabscience, Inc. Wnt1 was purchased from Abcam Co., Ltd. The β-catenin, glycogen synthase kinase-3β (GSK-3β) and cyclin D1 antibodies and the goat anti-rabbit and anti-mouse IgG secondary antibodies were purchased from Cell Signaling Technology, Inc. The PCR primers for Wnt1, Wnt5a, β-catenin, GSK-3β, cyclin D1, MMP7 and GAPDH were produced by Nanjing Genscript Biological Technology Co., Ltd. TRIzol® reagent, Maxima First Strand cDNA Synthesis Reverse transcription PCR kit and Maxima SYBR Green/ROX quantitative PCR kit were obtained from Thermo Fisher Scientific, Inc.
Preparation of Jianpiyiqi formula water extract
All of the medicinal herbs used to prepare Jianpiyiqi formula were purchased from Jiangsu Province Integrated Chinese and Western Medicine Hospital (Nanjing, China). All had their identity confirmed by Professor Shihui Qian (Chinese Medicine Plant Resources Laboratory, Jiangsu Province Institute of Traditional Chinese Medicine) and stored in a dry and ventilated laboratory cabinet. One batch weighed 146 g and consisted of 12 Chinese medicinal herbs/ingredients: Dangshen, Baizhu, Fuling, Gancao, Chenpi, Banxia, Muxiang, Sharen, Ezhu, Baihuashshecao, Yunmushi and Yujin (Table I). The 146-g herbal mixture was placed in a round-bottomed flask and soaked for 0.5 h in 1.46 liter water. The water containing the herbs was boiled for 0.5 h continuously. The water extract was naturally cooled to room temperature was then filtered and collected for the first time. Subsequently, 0.73 liter water was added to the round-bottomed flask, followed by continuous boiling for 0.5 h. The water extract was naturally cooled to room temperature was filtered and collected for a second time. The twice collected water extracts were concentrated to 48.7 ml (equivalent to a drug concentration of 3 g/ml) using a vacuum rotary evaporator and stored at -80˚C in an ultra-low temperature refrigerator.
Animals
A total of 20 male Sprague Dawley rats [body weight, 200±20 g; age, 6-8 weeks; animal quality certificate no. SCXK (Su) 2019-0001] were purchased from the Laboratory Animal Center of Nantong University. All rats were kept under a 12-h light/dark cycle and housed at the Laboratory Animal Center of Jiangsu Province Institute of Traditional Chinese Medicine (Nanjing, China). The animals had ad libitum access to food and water in an environment with a temperature of 20˚C and a humidity of 50%. Animal experimental operations complied with the Guidelines of Welfare and Ethics of Laboratory Animals (issued by the General Administration of Quality Supervision, Inspection and Quarantine of the P.R. China) and the Guide for the Care and Use of Laboratory Animals (issued by the US National Institutes of Health). The animal experiment of the present study was approved by the Ethics Committee of Jiangsu Province Integrated Chinese and Western Medicine Hospital (Nanjing, China; approval no. AEWC-20160810-12).
Establishment of CAG rat model
The 20 male Sprague Dawley rats were randomly divided into a blank group, model group, positive control drug group (2.7 mg/kg folate and 13.5 mg/kg teprenone) and Jianpiyiqi formula group (13.2 g/kg crude drug). A total of 5 rats were in each group. The rats in the CAG model groups were freely provided with drinking water containing 150 µg/ml MNNG and with food containing 0.03% ranitidine. The construction of the CAG rat model lasted 24 weeks. Subsequently, the rats were administered the drugs via gavage in positive control drug group and Jianpiyiqi formula group. Rats in the blank group and model group were gavaged with sterile water. The experiment was terminated after 8 weeks of treatment. Body weight and daily food intake were recorded. All rats were anesthetized by intraperitoneal injection of 30 mg/kg (body weight) sodium pentobarbital. Subsequently, 20 ml blood was collected from the abdominal aorta of the live anesthetized rats. After the blood was collected completely, the rats died naturally due to the exsanguination.
High-performance liquid chromatography (HPLC) analysis
Liquiritin, hesperidin, lobetyolin, curdione, costunolide and atractylenolide II were prepared to a solution of 1 mg/ml in methanol. The six compounds were mixed at equal proportions for HPLC analysis. Jianpiyiqi formula water extraction solution (3 g/ml crude drug) was diluted to 1 g/ml solution with methanol for HPLC analysis. All samples were separated using a C18 chromatographic column (5 µm; 250x4.6 mm) in a Waters 2695 HPLC system and detected in a Waters 2489 detector (Waters Corp.). Mobile phrases were water containing 0.1% formic acid (solvent A) and acetonitrile (solvent B). The mobile phase elution procedure was as follows: Solvent A was varied from 95 to 85% from 0 to 30 min, solvent A was varied from 85 to 70% from 30 to 45 min, solvent A was varied from 70 to 30% from 45 to 55 min and solvent A remained at 30% from 55 to 60 min. The column temperature was 30˚C, the sample loading volume was 25 µl, the flow rate was 1 ml/min and the detection wavelength was 230 nm.
H&E staining
The gastric tissues of the rats were fixed in 4% formalin at 25˚C for 24 h and underwent routine ethanol dehydration and paraffin embedding. The embedded tissues were cut into 5-µm slices using a Leica Biosystems RM2245 wheel slicer (Leica Microsystems GmbH). The slices were baked in an oven at 60˚C for 2 h and were then dewaxed and rehydrated. Subsequently, the slices were stained with hematoxylin (Nanjing Jiancheng Bioengineering Institute) at 25˚C for 3 min and eosin (Nanjing Jiancheng Bioengineering Institute) at 25˚C for 30 sec. The stained slices were dehydrated with ethanol, cleared with xylene, mounted on glass slides with neutral balsam and covered with coverslips. The rat gastric tissues were imaged using the Olympus CKX-41 inverted light microscope (Olympus Corporation) at x100 magnification. The atrophy and inflammation of gastric glands were scored according to the visual analogue scale of the new Sydney system (16,17). The pathology scoring was carried out independently by two examiners, and the mean value was finally taken.
ELISA
The contents of GAS (cat. no. E-EL-R0472c; Elabscience, Inc.), PP (cat. no. E-EL-R0719c; Elabscience, Inc.), SS (cat. no. E-EL-R0914c; Elabscience, Inc.) and PGE2 (cat. no. H099-1; Nanjing Jiancheng Bioengineering Institute) in rat serum were detected according to the manufacturer's protocols for the ELISA kits. The rat serum was added to the coated 96-well microplate. The antibodies and HRP-conjugated streptomycin were added to the plate. Subsequently, the 96-well microplate was sealed with parafilm and incubated at 37˚C for 1 h. The solution in the wells was then completely discarded. The microplate was washed five times with washing buffer and incubated with diaminobenzidine (DAB) chromogenic reagent at 37˚C for 10 min, and reaction termination solution was then immediately added. The optical density (OD) value of all wells was measured at the wavelength of 450 nm using a Tecan M200 pro automatic microplate reader (Tecan Group, Ltd.). According to the standard curve linear regression equation and the OD values of the samples in each group, the corresponding sample concentration was calculated.
Immunohistochemistry (IHC)
The paraffin-embedded stomach tissues were cut into 3-µm slices. After the slices were baked, the slides were submersed in citrate unmasking solution for antigen retrieval and boiled at 100˚C for 5 min. The slices were incubated with 3% hydrogen peroxide for 10 min and blocked with 0.5 ml blocking solution for 1 h at room temperature. The slides were coated with 0.2 ml Wnt1 (1:300 dilution; cat. no. ab15251; Abcam), β-catenin (1:300 dilution; cat no. 7074; Cell Signaling Technology, Inc.), GSK-3β (1:300 dilution; cat no. 7074; Cell Signaling Technology, Inc.) and cyclin D1 (1:300 dilution; cat no. 7074; Cell Signaling Technology, Inc.) primary antibodies and incubated overnight at 4˚C. The slices were then incubated with 0.2 ml HRP-conjugated secondary antibody (1:500 dilution; cat no. 7074; Cell Signaling Technology, Inc.) in a humidified chamber at 25˚C for 1 h. The slides were incubated with 0.5 ml DAB solution for 5 min and the sections were counterstained with hematoxylin at 25˚C for 30 sec. The slides were mounted with neutral balsam mounting medium and covered using coverslips. The rat gastric tissues were imaged using the Olympus CKX-41 inverted light microscope (Olympus Corporation) at x100 magnification. Staining of the IHC sections was determined using Image-Pro Plus 6.0 software (Media Cybernetics, Inc.).
Reverse transcription-quantitative (RT-q)PCR
The total RNA was extracted from rat gastric tissues using TRIzol reagent. The extracted RNA was reverse transcribed into the complementary DNA using the Maxima First Strand cDNA Synthesis Reverse transcription PCR kit according to the manufacturer's protocol. The reaction conditions were 25˚C for 10 min, 50˚C for 15 min and 85˚C for 5 min. The relative mRNA expression levels of Wnt1, Wnt5a, β-catenin, GSK-3β, cyclin D1 and MMP7 were detected using Applied Biosystems StepOnePlus fluorescence quantitative PCR equipment (Applied Biosystems; Thermo Fisher Scientific, Inc.) with the Maxima SYBR Green/ROX quantitative PCR kit according to the manufacturer's protocol. The thermal cycling conditions were: One cycle of 95˚C for 15 min, then 40 cycles of 95˚C for 15 sec, 60˚C for 30 sec and 72˚C for 30 sec. The relative mRNA expression was analyzed and calculated using the 2-∆∆Cq method (18), with the housekeeping gene GAPDH used as a control gene. The sequences of all qPCR primers are listed in Table II.
Statistics analysis
Values are expressed as the mean ± standard deviation. Differences between groups were analyzed using one-way ANOVA followed by Tukey's post hoc test. P<0.05 was considered to indicate a statistically significant difference. The data were analyzed using SPSS 22.0 software (IBM Corp.) and graphs were plotted using GraphPad Prism 5.0 software (GraphPad Software, Inc.).
Results
HPLC chromatogram of Jianpiyiqi formula
The TCM prescription Jianpiyiqi formula is an extract of 12 Chinese medicinal herbs/ingredients (Table I). The chemical composition of the formula is complex. In the present study, Jianpiyiqi formula was prepared and its HPLC chromatogram was examined (Fig. 1A). The HPLC analysis indicated that relatively high concentrations of liquiritin and hesperidin were present in the extract (Fig. 1A). HPLC results showed hesperidin was the major active component of Jianpiyiqi formula. The six compounds liquiritin, hesperidin, lobetyolin, curdione, costunolide and atractylenolide II were used as controls to identify the pharmaceutically relevant components of the formula (Fig. 1B).
Effect of Jianpiyiqi formula on body weight, food intake, gastric morphology and pathology of rats with CAG
After the establishment of the CAG rat model induced by MNNG and ranitidine, the therapeutic effect of Jianpiyiqi formula on CAG was evaluated. The experimental results demonstrated that compared with the blank group, the body weight and feed intake of the rats were decreased, and gastric mucosal atrophy and inflammation appeared in the model group. Jianpiyiqi formula significantly improved the body weight and the food intake of the rats (Fig. 2A and B). All rat stomachs were cut along the side of the large curve and gastric morphology was imaged using a camera. Compared with that in the blank group, the stomach tissue in the model group appeared slightly paler and had fewer gastric folds. Furthermore, Jianpiyiqi formula and the positive control drugs improved gastric morphology (Fig. 2C). Subsequently, the rat gastric tissue was stained with H&E for pathological observation. Atrophy and inflammation of gastric tissues were scored according to the new Sydney system (16). Marked gastric atrophy and inflammation were observed in the CAG model group. After Jianpiyiqi formula treatment, the atrophy and inflammation of gastric glands was improved. Furthermore, the positive control drugs significantly improved gastric atrophy (Fig. 2D-F).
Effect of Jianpiyiqi formula on GAS, PP, SS and PGE2 in rats with CAG
Next, the gastric mucosa-related factors were detected to evaluate the curative effect of Jianpiyiqi formula on CAG. The contents of GAS, PP, SS and PGE2 in rat serum were measured via ELISAs. Compared with those in the blank group, the contents of GAS, PP, SS and PGE2 were decreased in the CAG rat model group. It was indicated that the positive control drugs significantly increased the content of SS. In addition, Jianpiyiqi formula significantly improved the secretion of gastric mucosa-related factors (GAS, PP, SS and PGE2) in the serum of CAG rats (Fig. 3).
Effect of Jianpiyiqi formula on the protein expression levels of Wnt1, β-catenin, GSK-3β and cyclin D1 in rats with CAG
The Wnt/β-catenin signaling pathway was previously reported to be closely associated with the efficacy of Jianpiyiqi formula in rats with CAG (13). The in situ protein expression levels of Wnt1, β-catenin, GSK-3β and cyclin D1 in gastric tissues were detected via IHC. The results indicated that compared with the blank group, the protein expression levels of Wnt1, β-catenin and cyclin D1 were increased and the protein expression of GSK-3β was decreased in the model group. Furthermore, compared with that in the model group, the protein expression of GSK-3β was significantly increased and the protein expression levels of Wnt1 and β-catenin were significantly decreased in the positive control drug group. It was also observed that Jianpiyiqi formula significantly decreased the protein expression levels of Wnt1, β-catenin and cyclin D1 and increased the expression of GSK-3β in rats with CAG (Fig. 4).
Effect of Jianpiyiqi formula on gene expression levels of Wnt1, Wnt5a, β-catenin, GSK-3β, cyclin D1 and MMP7 in rats with CAG
The relative mRNA expression levels of Wnt1, Wnt5a, β-catenin, GSK-3β, cyclin D1 and MMP7 in rat gastric tissues were detected via RT-qPCR. The results demonstrated that the gene expression levels of Wnt1, Wnt5a, β-catenin, cyclin D1 and MMP7 were significantly increased and the gene expression levels of GSK-3β were significantly decreased in the CAG model group as compared with those in the blank group. In the positive control drug group, no evident change in the mRNA expression of GSK-3β was observed, while the mRNA expression levels of Wnt5a, β-catenin, MMP7 and cyclin D1 were decreased compared with those in the model group. Furthermore, Jianpiyiqi formula significantly decreased the gene expression of Wnt1, Wnt5a, β-catenin, cyclin D1 and MMP7 and significantly increased the gene expression of GSK-3β compared with that in the model group (Fig. 5). Therefore, based on the results of the IHC and RT-qPCR experiments, it was suggested that Jianpiyiqi formula significantly inhibited the Wnt/β-catenin signaling pathway in rats with CAG.
Discussion
CAG is frequently accompanied by intestinal metaplasia and intraepithelial neoplasia, which are considered precancerous lesions of GC (PLGC) (19). Therefore, it is urgent to identify novel and effective treatments for CAG. In recent years, significant progress has been made in the treatment of patients with CAG using TCM (20,21). Previous in vivo studies have indicated that TCM formulations are able to improve gastric mucosal atrophy, including Modified Sijunzi Decoction (22), Weiqi Decoction (23), Banxia Xiexin Decoction (24) and Huangqi Jianzhong Tang (25). Jianpiyiqi formula is a TCM prescription that may be used to effectively treat CAG in the clinic (7,8). However, the mechanisms of action of Jianpiyiqi formula in the treatment of CAG have remained to be elucidated. The mixture of pharmacologically active components in the water extract of the formula is complex. To the best of our knowledge, no previous study reported on the analysis of Jianpiyiqi formula by HPLC. Thus, the present study first constructed the HPLC chromatogram of Jianpiyiqi formula for drug quality control and subsequent investigation of its pharmacological mechanisms. Liquiritin and hesperidin were identified and major components of the formula. Although previous studies suggested that liquiritin and hesperidin have anti-inflammatory and tumor preventive properties (26,27), the two compounds do not represent all components of the formula. The effects of liquiritin and hesperidin on CAG need to be verified by further experiments in the future.
It has been reported that the Wnt signaling pathway serves an important role in the proliferation of gastric mucosal epithelium (12). Furthermore, the proliferation of gastric mucosal epithelial cells in patients with CAG is inhibited or delayed (1). Numerous studies have indicated that the Wnt/β-catenin signaling pathway is related to GC (11,14). CAG is a gastric precancerous disease, which is different from GC. However, limited studies have investigated the relationship between CAG and the Wnt/β-catenin signaling pathway (13,15). Therefore, it is worthwhile investigating whether the mechanisms of action of Jianpiyiqi formula in the treatment of CAG involve the Wnt/β-catenin signaling pathway.
In the present study, the MNNG-induced CAG rat model was established (28) and was used to evaluate the effect of Jianpiyiqi formula on CAG. It was indicated that the formula significantly improved gastric atrophy and reduced stomach inflammation. Furthermore, GAS, PP, SS and PGE2 are closely associated with the development of CAG (1,4,29-31). GAS was able to promote the proliferation of gastric mucosal cells and increase gastric acid and pepsinogen secretion. Furthermore, PP promoted food digestion, while SS had a strong inhibitory effect on gastric acid secretion. It has been reported that PGE2 is able to regulate the relaxation and contraction of blood vessels and exert a protective effect on gastric mucosal cells (29-31). The present study demonstrated that Jianpiyiqi formula significantly increased the contents of GAS, PP, SS and PGE2 in rats with CAG.
The canonical Wnt/β-catenin signaling pathway serves an important role in regulating gastric cell proliferation (32,33). Wnt ligands specifically bind to the Frizzled receptors and then activate the disheveled family proteins. The activation of disheveled proteins leads to the inactivation of GSK-3β. As a result of the accumulation and migration of β-catenin from the cytoplasm to the nucleus, β-catenin is able to upregulate the expression of related genes (12). Furthermore, Wnt signal transduction may be closely associated with the pathogenesis of CAG. The present study reported that the Wnt/β-catenin signaling pathway was upregulated in the CAG rat model. It was also identified that Jianpiyiqi formula inhibited the activation of the Wnt/β-catenin signaling pathway in CAG. Due to the consistency of rat modelling, the error of rat gene expression in the group was small. There is currently no gold standard for the treatment of CAG in the clinic. According to the specific symptoms of patients with CAG, corresponding treatment drugs are given. Folate, as a vitamin, is able to improve gastric mucosal damage and teprenone is a gastric mucosal protective agent (34,35). In the present study, the positive control drugs selected for the rat model of CAG were folate and teprenone, as these have a certain effect to improve gastric atrophy according to previous experimental results (23,25). Furthermore, the positive control drugs inhibited the expression levels of Wnt signal-related genes. Collectively, it was indicated that the therapeutic effect of Jianpiyiqi formula on CAG was more potent compared with that of the positive control drugs.
In conclusion, the present study demonstrated that Jianpiyiqi formula significantly ameliorated gastric gland atrophy and gastric mucosal inflammation in rats with CAG. Furthermore, Jianpiyiqi formula was demonstrated to inhibit the Wnt/β-catenin signaling pathway; the experimental evidence and proposed pathway are summarized in Fig. 6. According to the present results, the Wnt signaling pathway may serve an important role in the transition process from CAG to PLGC. However, these results should be further confirmed by additional experiments in the future. Overall, it was suggested that due to its promising efficacy, Jianpiyiqi formula may be more widely used in the clinical treatment of CAG.
Acknowledgements
Not applicable.
Funding
Funding: This study was supported by the National Natural Science Foundation of China (grant nos. 81804071 and 81573966).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Author's contributions
The animal experiments were performed by ZY and TX. HPLC analysis was conducted by ZA. Immunohistochemistry and RT-qPCR were performed by WC and YX. ZY and FZ were the major contributors to the design of the study and writing of the manuscript. All authors confirm the authenticity of all the raw data and all authors read and approved the final manuscript.
Ethics approval and consent to participate
The animal experiment of the present study was approved by the Ethics Committee of Jiangsu Province Integrated Chinese and Western Medicine Hospital (Nanjing, China; approval no. AEWC-20160810-12).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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