RESUMEN
The potential role of the transient receptor potential Vanilloid 1 (TRPV1) non-selective cation channel in gastric carcinogenesis remains unclear. The main objective of this study was to evaluate TRPV1 expression in gastric cancer (GC) and precursor lesions compared with controls. Patient inclusion was based on a retrospective review of pathology records. Patients were subdivided into five groups: Helicobacter pylori (H. pylori)-associated gastritis with gastric intestinal metaplasia (GIM) (n = 12), chronic atrophic gastritis (CAG) with GIM (n = 13), H. pylori-associated gastritis without GIM (n = 19), GC (n = 6) and controls (n = 5). TRPV1 expression was determined with immunohistochemistry and was significantly higher in patients with H. pylori-associated gastritis compared with controls (p = 0.002). TRPV1 expression was even higher in the presence of GIM compared with patients without GIM and controls (p < 0.001). There was a complete loss of TRPV1 expression in patients with GC. TRPV1 expression seems to contribute to gastric-mucosal inflammation and precursors of GC, which significantly increases in cancer precursor lesions but is completely lost in GC. These findings suggest TRPV1 expression to be a potential marker for precancerous conditions and a target for individualized treatment. Longitudinal studies are necessary to further address the role of TRPV1 in gastric carcinogenesis.
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Infecciones por Helicobacter , Neoplasias Gástricas , Canales Catiónicos TRPV , Humanos , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/patología , Carcinogénesis/metabolismo , Carcinogénesis/patología , Estudios Retrospectivos , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Helicobacter pylori/patogenicidad , Metaplasia/metabolismo , Metaplasia/patología , Gastritis/metabolismo , Gastritis/patología , Gastritis/microbiología , Adulto , Inmunohistoquímica , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Jianwei Xiaoyan Granule (JWXYG) is the traditional Chinese medicine preparation in Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, which has been widely used in clinical treatment of chronic atrophic gastritis (CAG). However, the material basis and potential mechanism of JWXYG in the treatment of CAG are not clear. PURPOSE: To explore the material basis and potential mechanism of JWXYG in the treatment of CAG. METHODS: In this study, the components of JWXYG were analyzed by HPLC-Q-TOF-MS/MS. Then, the CAG model in rats established by a composite modeling method and MC cell model induced by MNNG were used to explore the improvement effect of JWXYG on CAG. Finally, the potential mechanism of JWXYG in the treatment of CAG was preliminarily predicted based on network pharmacology and validated experimentally. RESULTS: Thirty-one components of JWXYG were analyzed through HPLC-Q-TOF-MS/MS, such as albiflorin, paeoniflorin, lobetyolin firstly. Research results in vivo showed that the gastric mucosa became thinner, intestinal metaplasia appeared, the number of glands was reduced, the serum levels of PG I and PG II increased and the contents of G17 and IL-6 reduced in CAG model rats. After 4 weeks of JWXYG (2.70 g/kg) administration, these conditions were significantly improved. In addition, cell viability, migration, and invasion of MNNG-induced MC cells was inhibited by JWXYG treatment (800 µg/mL). Furthermore, the results of network pharmacology indicated that HIF-1 and VEGF signaling pathways might play important roles in the therapeutic process. Then the results of Western blot, immunohistochemistry and immunofluorescence confirmed that with JWXYG treatment, the increased expression of HIF-1α, VEGF and VEGFR2 in gastric issue of CAG rats were restrained. Eventually, potential components of JWXYG in the treatment of CAG were predicted through molecular docking to elucidate the material basis. CONCLUSION: JWXYG could inhibit angiogenesis by regulating HIF-1α-VEGF pathway to exert therapeutic effects on CAG. Our study explored the potential mechanisms and material basis of JWXYG in the treatment of CAG and provides experimental data for the clinical rational application of JWXYG.
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Medicamentos Herbarios Chinos , Gastritis Atrófica , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ratas Sprague-Dawley , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Animales , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/patología , Gastritis Atrófica/metabolismo , Medicamentos Herbarios Chinos/farmacología , Masculino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Enfermedad Crónica , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Modelos Animales de Enfermedad , Farmacología en RedRESUMEN
OBJECTIVE: To explore the mechanism of Xianglian Huazhuo formula (, XLHZ) blocking the development of chronic atrophic gastritis (CAG) to gastric cancer (GC) through bioinformatics analysis and in vitro. METHODS: Pathological morphology of gastric mucosa of rats were observed. High-throughput sequencing was used to analyze the miRNA expression profile of gastric mucosa. The miRanda, miRDB and miRWalk databases were used to predict the differential target genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for differential target genes. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify the differentially expressed miRNAs and target genes. Western blot, EdU, wound healing and flow cytometry were used to observe the effect of XLHZ on epithelial-mesenchymal transition (EMT) markers, proliferation, migration, apoptosis and cell cycle of CAG cells in vitro. RESULTS: A total of five differentially expressed miRNAs and four differential target genes were screened in this study. GO analysis showed that the target genes were enriched in regulation of neuron development, regulation of transcription factor activity and regulation of RNA polymerase. KEGG pathways database differences in gene enrichment of target genes in the Wnt signaling pathway, Phospholipase D signaling pathway and mitogen-activated protein kinase signaling pathway. qRT-PCR confirmed that miRNAs and its target genes were consistent with the screening results. In vitro, our study revealed that XLHZ could increase the expression of E-cadherin, decrease the expression of transforming growth factor ß1, vimentin and ß-catenin, inhibite the proliferation and migration of CAG cells, cause cell cycle arrest at G0/G1 and G2/M phase, induce the apoptosis of CAG cells, and prevent the progression of CAG to GC. CONCLUSION: This study provided a new idea for the mechanism of blocking the progression of CAG to GC by XLHZ, which may be related to the expression of miR-20a-3p, miR-320-3p, miR-34b-5p, miR-483-3p and miR-883-3p and their target genes transferrin receptor, nuclear receptor subfamily 4 member 2, delta like canonical Notch ligand 1 and a kinase anchor protein 12 in CAG. In the future, we will continue to investigate the linkage between the active ingredients of XLHZ and the relevant miRNAs and their target genes, so as to provide more sufficient experimental basis for clinically effective prevention of CAG to GC.
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Medicamentos Herbarios Chinos , Gastritis Atrófica , Secuenciación de Nucleótidos de Alto Rendimiento , MicroARNs , Neoplasias Gástricas , Gastritis Atrófica/genética , Gastritis Atrófica/metabolismo , Ratas , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Animales , Humanos , Masculino , Medicamentos Herbarios Chinos/farmacología , Proliferación Celular , Apoptosis/genética , Transición Epitelial-Mesenquimal/genética , Ratas Sprague-Dawley , Mucosa Gástrica/metabolismo , Movimiento CelularRESUMEN
Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and precancerous lesion in stomach cancer. Abnormal activation cellular ferroptosis further damages gastric tissue, which is susceptible to inflammation. Luteolin has powerful anti-inflammatory and regulatory potential for cellular ferroptosis. We aimed to clarify the involvement of luteolin in inflammation and ferroptosis during CAG. Luteolin targets were searched to identify intersecting genes in the chronic atrophic gastritis disease database. The AGE-RAGE pathway is a potential target of luteolin for the treatment of chronic atrophic gastritis and a binding site between luteolin and RAGE was predicted through a computer simulation of molecular docking. We established a CAG rat model using N-methyl-N-nitro-N-nitroguanidine. The therapeutic effect of luteolin on CAG was detected using western blotting, qPCR, hematoxylin and eosin staining, lipid oxidation (MDA), and Fe2+ assays. Luteolin inhibited the AGE-RAGE signaling pathway and reduced the inflammatory response in gastric tissues. Additionally, luteolin downregulated the concentration of (MDA) and Fe2+, and CAG downregulated the expression levels of ACSL4 and NOX1 and upregulated the expression levels of FIH1 and GPX4 ferroptosis-related proteins, thus inhibiting the ferroptosis of gastric tissue cells, which had a therapeutic effect on CAG.
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Ferroptosis , Gastritis Atrófica , Luteolina , Transducción de Señal , Ferroptosis/efectos de los fármacos , Luteolina/farmacología , Luteolina/uso terapéutico , Animales , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patología , Gastritis Atrófica/genética , Ratas , Transducción de Señal/efectos de los fármacos , Masculino , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Productos Finales de Glicación Avanzada/metabolismo , Modelos Animales de Enfermedad , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Ratas Sprague-Dawley , Enfermedad Crónica , Simulación del Acoplamiento Molecular , Humanos , Antiinflamatorios/farmacologíaRESUMEN
BACKGROUND: Chronic atrophic gastritis (CAG) is a global digestive system disease and one of the important causes of gastric cancer. The incidence of CAG has been increasing yearly worldwide. PURPOSE: This article reviews the latest research on the common causes and future therapeutic targets of CAG as well as the pharmacological effects of corresponding clinical drugs. We provide a detailed theoretical basis for further research on possible methods for the treatment of CAG and reversal of the CAG process. RESULTS: CAG often develops from chronic gastritis, and its main pathological manifestation is atrophy of the gastric mucosa, which can develop into gastric cancer. The drug treatment of CAG can be divided into agents that regulate gastric acid secretion, eradicate Helicobacter. pylori (H. pylori), protect gastric mucous membrane, or inhibit inflammatory factors according to their mechanism of action. Although there are limited specific drugs for the treatment of CAG, progress is being made in defining the pathogenesis and therapeutic targets of the disease. Growing evidence shows that NF-κB, PI3K/AKT, Wnt/ ß-catenin, MAPK, Toll-like receptors (TLRs), Hedgehog, and VEGF signaling pathways play an important role in the development of CAG.
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Gastritis Atrófica , Transducción de Señal , Humanos , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Gastritis Atrófica/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Enfermedad Crónica , Helicobacter pylori/efectos de los fármacos , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologíaRESUMEN
Chronic atrophic gastritis (CAG), characterized by inflammation and erosion of the gastric lining, is a prevalent digestive disorder and considered a precursor to gastric cancer (GC). Coptis chinensis France (CCF) is renowned for its potent heat-clearing, detoxification, and anti-inflammatory properties. Zuojin Pill (ZJP), a classic Chinese medicine primarily composed of CCF, has demonstrated effectiveness in CAG treatment. This study aims to elucidate the potential mechanism of CCF treatment for CAG through a multifaceted approach encompassing network pharmacology, molecular docking, molecular dynamics simulation and experimental verification. The study identified three major active compounds of CCF and elucidated key pathways, such as TNF signaling, PI3K-Akt signaling and p53 signaling. Molecular docking revealed interactions between these active compounds and pivotal targets like PTGS2, TNF, MTOR, and TP53. Additionally, molecular dynamics simulation validated berberine as the primary active compound of CCF, which was further confirmed through experimental verification. This study not only identified berberine as the primary active compound of CCF but also provided valuable insights into the molecular mechanisms underlying CCF's efficacy in treating CAG. Furthermore, it offers a reference for refining therapeutic strategies for CAG management.
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Coptis , Medicamentos Herbarios Chinos , Gastritis Atrófica , Simulación de Dinámica Molecular , Farmacología en Red , Humanos , Coptis/química , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/metabolismo , Simulación del Acoplamiento Molecular , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Berberina/química , Berberina/uso terapéutico , Berberina/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Background: The Zuojin Pill (ZJP) is widely used for treating chronic atrophic gastritis (CAG) in clinical practice, effectively ameliorating symptoms such as vomiting, pain, and abdominal distension in patients. However, the underlying mechanisms of ZJP in treating CAG has not been fully elucidated. Purpose: This study aimed to clarify the characteristic function of ZJP in the treatment of CAG and its potential mechanism. Methods: The CAG model was established by alternant administrations of ammonia solution and sodium deoxycholate, as well as an irregular diet. Therapeutic effects of ZJP on body weight, serum biochemical indexes and general condition were analyzed. HE staining and AB-PAS staining were analyzed to characterize the mucosal injury and the thickness of gastric mucosa. Furthermore, network pharmacology and molecular docking were used to predict the regulatory mechanism and main active components of ZJP in CAG treatment. RT-PCR, immunohistochemistry, immunofluorescence and Western blotting were used to measure the expression levels of apoptosis-related proteins, gastric mucosal barrier-associated proteins and PI3K/Akt signaling pathway proteins. Results: The results demonstrated that ZJP significantly improved the general state of CAG rats, alleviated weight loss and gastric histological damage and reduced the serum biochemical indicators. Network pharmacology and molecular docking found that ZJP in treating CAG by inhibiting inflammation, suppressing apoptosis, and protecting the gastric mucosal barrier via the PI3K/Akt signaling pathway. Further experiments confirmed that ZJP obviously modulated the expression of key proteins involved in gastric mucosal cell apoptosis, such as Bax, Bad, Apaf-1, cleaved-caspase-3, cleaved-caspase-9, Cytochrome C, Bcl-2, and Bcl-xl. Moreover, ZJP significantly reversed the protein expression of Occludin, ZO-1, Claudin-4 and E-cadherin. Conclusion: Our study revealed that ZJP treats CAG by inhibiting the PI3K/Akt signaling pathway. This research provided a scientific basis for the rational use of ZJP in clinical practice.
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Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Mucosa Gástrica , Gastritis Atrófica , Simulación del Acoplamiento Molecular , Ratas Sprague-Dawley , Animales , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/patología , Gastritis Atrófica/metabolismo , Ratas , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Masculino , Enfermedad Crónica , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Apoptosis/efectos de los fármacos , Farmacología en Red , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Chronic atrophic gastritis (AG) is initiated mainly by Helicobacter pylori infection, which may progress to stomach cancer following the Correa's cascade. The current treatment regimen is H. pylori eradication, yet evidence is lacking that this treatment is effective on later stages of AG especially gastric gland atrophy. Here, using AG mouse model, patient samples, gastric organoids, and lineage tracing, this study unraveled gastric stem cell (GSC) defect as a crucial pathogenic factor in AG in mouse and human. Moreover, a natural peptide is isolated from a traditional Chinese medicine that activated GSCs to regenerate gastric epithelia in experimental AG models and revitalized the atrophic gastric organoids derived from patients. It is further shown that the peptide exerts its functions by stabilizing the EGF-EGFR complex and specifically activating the downstream ERK and Stat1 signaling. Overall, these findings advance the understanding of AG pathogenesis and open a new avenue for AG treatment.
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Modelos Animales de Enfermedad , Gastritis Atrófica , Células Madre , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/metabolismo , Animales , Ratones , Humanos , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Medicina Tradicional China/métodos , Péptidos/farmacología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/efectos de los fármacos , Infecciones por Helicobacter/tratamiento farmacológico , Enfermedad Crónica , Transducción de Señal/efectos de los fármacosRESUMEN
Radix Astragali (Huangqi in Chinese, HQ) is a commonly used Chinese herbal medicine for thousands of years. In this study, A classic prescription Huangqi Jianzhong tang (HQJZ) was selected to evaluate the important effect of HQ on rats with chronic atrophic gastritis (CAG) from the perspective of intestinal flora in cecal contents samples. Traditional pharmacological indicators, including weight change, pathological examination and biochemical indicators showed that HQ exerted favorable contribution to HQJZ against CAG, where the efficiencies of HQ and HQJZ were better than HY (HQJZ prepared without HQ). An accurate strategy was adopted to screen out the differential metabolites in the metabolomis analysis of intestinal flora in cecal contents samples based on the optimal screening factors, including VIP (importance of variables in projection), FC (fold change), AUROC (area under the receiver operating characteristic curve) and -ln(p-value), which were evaluated based on their interpreting, grouping, and predicting abilities of the performed orthogonal partial least-squares-discriminate analysis (OPLS-DA) models. Ten altered differential metabolites were obtained and associated with the intestinal flora, which HQ exerted the important metabolic contributions to HQJZ. The efficacy on the diversity of intestinal flora and their correlations with the altered metabolites further showed the important role of HQ in HQJZ composition. This work provided valuable approach for looking for potential biomarkers associated with metabolomics research with more accuracy, and provided new insights into the mechanisms to explain the efficacy of HQ contributing to HQJZ formula.
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Medicamentos Herbarios Chinos , Gastritis Atrófica , Microbioma Gastrointestinal , Ratas , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/química , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/metabolismo , Astragalus propinquusRESUMEN
PURPOSE: Atrophic gastritis, one of the processes leading to gastric cancer (GC), is closely related to Helicobacter pylori (HP) infection. This study aimed to understand how HP causes chronic inflammation that leads to ulcers and stomach problems. METHODS: Twenty-eight CAG patients were included in the study (9 HP-infected and 19 HP-uninfected). Endoscopy, histopathology, and high-throughput mRNA sequencing were performed. Differentially expressed genes (DEGs) were validated via qRT-PCR. RESULTS: Principal component analysis (PCA) results showed that more than 88.9 â% of the samples were classified into the HP (+) group. A total of 157 DEGs were identified, of which 38 were up-regulated and 119 were down-regulated. The DEGs were mainly enriched in the biological process (BP) terms associated with immune system process, adaptive immune response, G protein-coupled receptor signaling pathway, as well as point to numerous key pathways, including fat digestion and absorption, retinol metabolism, steroid hormone biosynthesis, ascorbate and aldarate metabolism, and chemical carcinogenesis. APOA1, APOA4, FOXP3, NR1H4, ABCG5, ACTA1, CCL19, CCR7, CYP3A4, and PDCD had the highest degrees in protein-protein interaction network as the hub genes; they were also included into the transcription factor (TF)-target network except for PDCD. APOA1 and CYP3A4 were extremely significantly up-regulated in HP (+) CAG patients compared with the HP (-) CAG patients, while FOXP3, CCR7 and CCL19 were significantly down-regulated. CONCLUSION: The expression of APOA1, CYP3A4, FOXP3, CCR7, and CCL19 are the potential indicators for CAG to GC development, being the biomarkers to predict progression of CAG and poor prognosis of GC.
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Gastritis Atrófica , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Gastritis Atrófica/genética , Gastritis Atrófica/complicaciones , Gastritis Atrófica/metabolismo , Citocromo P-450 CYP3A , Receptores CCR7 , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Factores de Transcripción Forkhead , ARNRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Weierning tablet (WEN) is a traditional Chinese patent medicine widely used in clinical for chronic atrophic gastritis (CAG) therapy for years. However, the underlying mechanisms of WEN on anti-CAG are still unveiled. AIM OF THE STUDY: The present study aimed to elucidate the characteristic function of WEN on anti-CAG and to illuminate its potential mechanism. METHODS: The CAG model was established by gavage rats with a modeling solution (consisting of 2% sodium salicylate and 30% alcohol) with irregular diets and free access to 0.1% ammonia solution for two months on end. An enzyme-linked immunosorbent assay was used to measure the serum levels of gastrin, pepsinogen, and inflammatory cytokines. qRT-PCR was applied to measure mRNA expressions of IL-6, IL-18, IL-10, TNF-α, and γ-IFN in gastric tissue. Pathological changes and the ultrastructure of gastric mucosa were examined by hematoxylin and eosin staining and transmission electron microscopy, respectively. AB-PAS staining was applied to observe the intestinal metaplasia of gastric mucosa. Immunohistochemistry and Western blot were used to measure the expression levels of mitochondria apoptosis-related proteins and Hedgehog pathway-related proteins in gastric tissues. Expressions of Cdx2 and Muc2 protein were determined by immunofluorescent staining. RESULTS: WEN could dose-dependently lower the serum level of IL-1ß and the mRNA expressions of IL-6, IL-8, IL-10, TNF-α, and γ-IFN in gastric tissue. Also, WEN significantly alleviated the collagen deposition in gastric submucosa, regulated the expressions of Bax, Cleaved-caspase9, Bcl2, and Cytochrome c to reduce the apoptosis of gastric mucosa epithelial cells, and maintained the integrity of the gastric mucosal barrier. Moreover, WEN could reduce protein expressions of Cdx2, Muc2, Shh, Gli1, and Smo, and reverse intestinal metaplasia of gastric mucosa to block the progress of CAG. CONCLUSION: This study demonstrated a positive effect of WEN on improving CAG and reverse intestinal metaplasia. These functions were related to the suppression of gastric mucosal cells' apoptosis and the inhibition of Hedgehog pathways' activation.
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Gastritis Atrófica , Ratas , Animales , Gastritis Atrófica/metabolismo , Interleucina-10/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Proteínas Hedgehog/metabolismo , Mucosa Gástrica/patología , Metaplasia/metabolismo , Metaplasia/patología , ARN Mensajero/metabolismoRESUMEN
Although most well-differentiated gastric neuroendocrine tumors (gNETs) arise from enterochromaffin-like (ECL) cells in patients with autoimmune metaplastic atrophic gastritis (AMAG), the morphologic spectrum of these type 1 ECL-cell gNETs is not well defined. The extent of metaplastic progression in the background mucosa of AMAG patients with gNETs is likewise unclear. Here we report the histomorphology of 226 gNETs, including 214 type 1 gNETs (78 cases from 50 AMAG patients) pooled from a population with high AMAG prevalence. Most type 1 gNETs were ≤1.0 cm, of low grade, and multifocal, consistent with the results of previous reports. However, a high proportion (70/214, 33%) displayed unusual gNET morphologies not previously appreciated in AMAG patients. Unlike other type 1 gNETs with conventional neuroendocrine tumor morphologies, unconventional type 1 gNETs displayed cribriform networks of atrophic cells embedded within myxoid matrix (secretory-cribriform variant, 59%), sheets of deceptively bland discohesive cells resembling inflammatory infiltrates (lymphoplasmacytoid variant, 31%), or wreath-like arrangements of columnar cells wrapped around collagenous cores (pseudopapillary variant, 14%). Another unusual feature was that unconventional gNETs grew laterally within the mucosa (50/70, 71%) and were only rarely sampled from the submucosa (3/70, 4%). These features also differed from the conspicuous radial nodules (99/135, 73%) and frequent submucosal involvement (57/135, 42%) observed for conventional gNETs (P < .0001). Irrespective of morphology, type 1 gNETs were nearly always detected at first AMAG diagnosis (45/50, 90%) and tended to persist thereafter (34/43, 79%), despite similar clinical symptoms and laboratory values between AMAG patients with gNETs and those without. However, unlike AMAG patients without gNETs (n = 50), the background mucosa in patients with gNETs (n = 50) had already progressed to the morphologic equivalent of end-stage metaplasia (P < .0001). This included diffuse loss of parietal cells (92% vs 52%), complete intestinal metaplasia (82% vs 40%), and pancreatic metaplasia (56% vs 6%). Thus, type 1 ECL-cell gNETs are morphologically heterogeneous with a high prevalence of unconventional gNET morphologies. They tend to present silently at first AMAG diagnosis as multifocal lesions that persist within fields of mature metaplasia.
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Enfermedades Autoinmunes , Gastritis Atrófica , Tumores Neuroendocrinos , Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Células Similares a las Enterocromafines/metabolismo , Células Similares a las Enterocromafines/patología , Tumores Neuroendocrinos/patología , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Gastritis Atrófica/diagnóstico , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patología , Neoplasias Gástricas/patología , Lesiones Precancerosas/patología , Metaplasia/patología , Mucosa Gástrica/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Weifuchun capsule (WFC) is a traditional Chinese patent medicine for chronic atrophic gastritis (CAG) in clinic. However, the mechanism of action of WFC for CAG still remains unclear due to its complex composition. AIM OF THE STUDY: The study was projected to uncover the mechanism of action of WFC and the corresponding pharmacodynamic substance of WFC against CAG as well as providing a standard example for the research of traditional Chinese medicine (TCM) from the perspective of the network and the system. MATERIALS AND METHODS: We identified the compounds of WFC through LC-MS/MS analysis and performed a systematic network targets analysis for WFC in the treatment of CAG which thoroughly described the mechanism of action of WFC for CAG. Based on analysis integrating omics data and algorithms, we focused on the specific immune regulatory role of WFC in the treatment of CAG, especially on a hub pathway, Toll-like receptor signaling pathway and thus deciphered the role of WFC in immune regulation, anti-inflammation and mediation of HES6. In experiments part, MNNG-GES-1-cell line and rat models were used to validate our findings. RESULTS: In this study, compounds of WFC are identified through LCâMS/MS and network target analysis is performed to dissect the specific immunoregulatory effect as well as mediation of HES6, a newly discovered biomolecule related to gastritis carcinoma progression, of WFC on CAG through the Toll-like receptor signaling pathway. Based on cell line and rat models, we verify the mechanism of action of WFC for CAG in inhibiting inflammatory cytokines, regulating immune cells like T cells and macrophages, related genes including TLR2 and CD14. It is also validated that WFC inhibits the expression of HES6 (P < 0.05). CONCLUSION: Based on the combination of computational strategy and experiments, our study offers a comprehensive analysis to reveal the role of WFC in regulating immune response, inhibiting inflammation in the treatment of CAG, and provides a standard example for the research of TCM from the perspective of the network and the system.
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Medicamentos Herbarios Chinos , Gastritis Atrófica , Ratas , Animales , Gastritis Atrófica/metabolismo , Cromatografía Liquida , Enfermedad Crónica , Espectrometría de Masas en Tándem , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Receptores Toll-LikeRESUMEN
BACKGROUND: 5-Hydroxytryptamine (5-HT) and stem cells marker G-protein-coupled receptor 5 (LGR5) are associate with gastrointestinal inflammation and tumorigenesis. But the relationship between 5-HT and LGR5 is unclear. OBJECTIVE: To explore the expression and correlation of 5-HT and LGR5 in gastric mucosa of patients with gastritis and gastric cancer (GC). METHODS: A total of 41 patients with GC and 98 patients with chronic gastritis were included in this study. The expression of TPH1 mRNA, LGR5 mRNA and ß-catenin mRNA in gastric mucosa were explored by Real-time Quantitative polymerase chain reaction (qPCR). 5-HT-positive cells and LGR5-positive cells in gastric mucosa were detected by immunohistochemistry stains. The co-localization of 5-HT and chromogranin A (CgA), 5-HT receptor4 (5-HTR4) and LGR5 were detected by multiplex immunofluorescence. RESULTS: The expression of 5-HT and LGR5 in patients with GC was significantly higher than patients with chronic gastritis (p < 0.05). The positive rate of 5-HT and LGR5 increased sequentially in the patients with non-atrophic gastritis, intestinal metaplasia and GC, which were 18.52%, 35.56% and 75.61% for 5-HT, and 27.78%, 40.91% and 95.12% for LGR5, respectively. The expression of 5-HT and LGR5 was positively correlated in gastritis and GC patients (p < 0.05). Moreover, the expression level of TPH1 mRNA and LGR5 mRNA was also positively correlated in gastritis patients (r = 0.7377, p < 0.001). Besides, 5-HT was partially co-localized with CgA, and 5-HTR4 was co-localized with LGR5 in gastric mucosa. CONCLUSION: The increase of 5-HT synthesis in gastric mucosa may have an impact on LGR5-positive gastric epithelial stem cells.
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Gastritis Atrófica , Gastritis , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Serotonina , Gastritis/metabolismo , Mucosa Gástrica/metabolismo , Gastritis Atrófica/metabolismo , Células Madre/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
BACKGROUND AND GOALS: There are currently no standard treatments for chronic atrophic gastritis and traditional Chinese medicine may be effective. This study aims to investigate the efficacy and safety of Weierkang pills in treating chronic atrophic gastritis. MATERIALS AND METHODS: There were 108 patients in our study. They were randomly assigned to 2 groups. In group A, patients received Weierkang pills and patients in group B received folic acid combined with teprenone. Symptoms, endoscopic scores, and biopsy specimens were compared at baseline and 3 months after treatment. Meanwhile, the expressions of vascular endothelial growth factor and trefoil factor 3 (TFF3) in biopsy specimens were also compared. RESULTS: Our study showed that the total effective rates of atrophy/intestinal metaplasia in group A reached the same level as group B (51.7% vs. 40.0%, P =0.419). Weierkang significantly improved the total effective rate of atrophy/intestinal metaplasia in gastric angle compared with group B (64.7% vs. 33.3%, P =0.024). Weierkang can significantly lower the total Kyoto risk score (2.6±1.1 vs. 3.3±1.0, P =0.002) and atrophy score (1.4±0.6 vs. 1.8±0.5, P =0.001) after treatment. In addition, Weierkang improves symptoms (1.3±1.3 vs. 2.3±1.8, P =0.003) and epigastric pain (0.2±0.4 vs. 0.5±0.6, P =0.041). The expression of TFF3 in gastric mucosa decreased significantly after treatment with Weierkang ( P =0.002). CONCLUSIONS: Weierkang can improve the endoscopic appearance and pathologic changes of chronic atrophic gastritis patients. Symptoms also improved. TFF3 may be involved the pathophysiology mechanism.
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Gastritis Atrófica , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/uso terapéutico , Mucosa Gástrica/patología , Atrofia/metabolismo , Atrofia/patología , Metaplasia/metabolismo , Metaplasia/patología , Infecciones por Helicobacter/tratamiento farmacológico , Neoplasias Gástricas/patologíaRESUMEN
Huangqi Jianzhong Tang (HQJZ) is a famous traditional Chinese medicine formula widely used in the treatment of gastrointestinal diseases in China. In this study, an ultra-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) was used to study the pharmacokinetics of 12 prototypical components and one metabolite in HQJZ in normal and chronic atrophic gastritis rats. The results showed that the area under the concentration-time curve and peak concentration of most flavonoids and flavonoid glycosides were decreased, and the half-life and mean residence time were significantly increased, which indicated that the absorption of drugs in disease was decreased less and for longer in vivo. Then, an integrated pharmacokinetic study was carried out using the pharmacokinetic parameter model integration of each component. The results showed that the absorption of drugs in vivo with disease was reduced, and the absorption speed of flavonoids and flavonoid glycosides was accelerated. This study will provide the basis for the clinical medication safety of HQJZ.
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Medicamentos Herbarios Chinos , Gastritis Atrófica , Ratas , Animales , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/metabolismo , Espectrometría de Masas en Tándem/métodos , Medicamentos Herbarios Chinos/química , Cromatografía Liquida , Flavonoides/análisis , Glicósidos , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Helicobacter pylori (H. pylori) infection involves multiple factors internal and external to the host. Among the internal factors, the immune response plays a fundamental role in the process of antigen presentation, lymphocytic response and cytokine-mediated regulatory response that are directly as sociated with disease progression and prognosis. OBJECTIVE: To compare the immune response in gas tric mucosa of H. pylori infected patients in two regions comparing the risk of developing gastric can cer. PATIENTS AND METHOD: 71 participants with symptoms of dyspepsia were included. The samples for biopsies were collected from different regions of the gastric mucosa; the identification of H. pylori was carried out by culture and polymerase chain reaction (PCR) of the ureA gene. For the characteri zation of the histopathological alterations and the immunophenotyping of lymphocytes, anti-human mouse monoclonal antibodies specific for each antigen were used: T lymphocytes: CD3 and CD8; B lymphocytes: CD20; Natural Killer Cells: CD56; Macrophages: CD68. RESULTS: The prevalence of H. pylori was 83.1%, the predominant types of gastritis were chronic gastritis and multifocal atrophic gastritis with intestinal metaplasia (63.4% and 22.5%, respectively). The cellular response was charac terized mainly by polymorphonuclear lymphocytes and positive anti-CD8 reactivity both in stroma and epithelium. CONCLUSIONS: Multifocal atrophic gastritis was more prevalent in the high-risk region for gastric cancer (GC) while non-atrophic gastritis and the expression of CD3 and CD8 antigens in the foveolar epithelium was higher in the low-risk region.
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Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Animales , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastritis/metabolismo , Gastritis/patología , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/patología , Humanos , Inmunofenotipificación , Ratones , Neoplasias Gástricas/etiología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
OBJECTIVE: The effect of active ingredients of Chaishaoliujun Decoction (CD) on chronic atrophic gastritis (CAG) was screened by network pharmacological method and verified by preliminary experiment. METHODS: Firstly, the active ingredients and drug targets of CD were retrieved in TCMSP database; CAG-related targets from PharmGkb, OMIM, GeneCards and DrugBank databases were collected as well. Secondly, the drug targets and disease targets were mapped to obtain the intersection targets. PPI network and active ingredient-common target network were constructed for the intersection targets obtained and KEGG enrichment analysis was also carried out. Finally, the core active ingredient (kaempferol), effective targets (IL-1ßãIL-6) and hedgehog signaling pathway were verified by animal experiments. RESULTS: There were 137 active ingredients, 243 potential target so and 48 intersection targets with CAG in CD. 147 KEGG enrichment pathways were obtained, mainly involving JAK/STAT signaling pathway, PI3K/Akt signaling pathway, hedgehog signaling pathway, etc. The results of animal experiments showed: The content of IL-1ß and IL-6 in model group was significantly increased compared with the normal group, while the mRNA and protein expressions of Shh, Ptch1 and Gli1 were also significantly decreased (P < 0.05); compared with model group, the content of IL-1ß and IL-6 in the vitacoenzyme group, the CD group and the kaempferol group were significantly decreased, while the mRNA and protein expressions of Shh, Ptch1 and Gli1 were significantly increased (P < 0.05). CONCLUSION: Kaempferol, the active ingredient of CD, could reduce the levels of IL-6 and IL-1ß by regulating hedgehog signaling pathway so as to play a role in the treatment of CAG. Hence this paper could provide the methodological basis and theoretical basis for further revealing the pharmacological mechanism of CD.
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Medicamentos Herbarios Chinos/farmacología , Gastritis Atrófica , Proteínas Hedgehog/metabolismo , Quempferoles/farmacología , Animales , Modelos Animales de Enfermedad , Flavonoides/farmacología , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Medicina Tradicional China , Farmacología en Red , Ratas , Transducción de SeñalRESUMEN
BACKGROUND & AIMS: The homeostasis of the gastrointestinal epithelium relies on cell regeneration and differentiation into distinct lineages organized inside glands and crypts. Regeneration depends on Wnt/ß-catenin pathway activation, but to understand homeostasis and its dysregulation in disease, we need to identify the signaling microenvironment governing cell differentiation. By using gastric glands as a model, we have identified the signals inducing differentiation of surface mucus-, zymogen-, and gastric acid-producing cells. METHODS: We generated mucosoid cultures from the human stomach and exposed them to different growth factors to obtain cells with features of differentiated foveolar, chief, and parietal cells. We localized the source of the growth factors in the tissue of origin. RESULTS: We show that epidermal growth factor is the major fate determinant distinguishing the surface and inner part of human gastric glands. In combination with bone morphogenetic factor/Noggin signals, epidermal growth factor controls the differentiation of foveolar cells vs parietal or chief cells. We also show that epidermal growth factor is likely to underlie alteration of the gastric mucosa in the precancerous condition atrophic gastritis. CONCLUSIONS: Use of our recently established mucosoid cultures in combination with analysis of the tissue of origin provided a robust strategy to understand differentiation and patterning of human tissue and allowed us to draw a new, detailed map of the signaling microenvironment in the human gastric glands.
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Tipificación del Cuerpo/efectos de los fármacos , Proteína Morfogenética Ósea 4/farmacología , Diferenciación Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Células Epiteliales/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Proteínas Portadoras/farmacología , Linaje de la Célula , Células Cultivadas , Microambiente Celular , Células Principales Gástricas/efectos de los fármacos , Células Principales Gástricas/metabolismo , Células Principales Gástricas/ultraestructura , Células Epiteliales/metabolismo , Células Epiteliales/ultraestructura , Mucosa Gástrica/metabolismo , Mucosa Gástrica/ultraestructura , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patología , Regulación del Desarrollo de la Expresión Génica , Humanos , Organoides , Células Parietales Gástricas/efectos de los fármacos , Células Parietales Gástricas/metabolismo , Células Parietales Gástricas/ultraestructura , Vía de Señalización WntRESUMEN
BACKGROUND & AIMS: The immune compartment is critical for maintaining tissue homeostasis. A weak immune response increases susceptibility to infection, but immune hyperactivation causes tissue damage, and chronic inflammation may lead to cancer development. In the stomach, inflammation damages the gastric glands and drives the development of potentially preneoplastic metaplasia. Glucocorticoids are potent anti-inflammatory steroid hormones that are required to suppress gastric inflammation and metaplasia. However, these hormones function differently in males and females. Here, we investigate the impact of sex on the regulation of gastric inflammation. METHODS: Endogenous glucocorticoids and male sex hormones were removed from mice using adrenalectomy and castration, respectively. Mice were treated with 5α-dihydrotestosterone (DHT) to test the effects of androgens on regulating gastric inflammation. Single-cell RNA sequencing of gastric leukocytes was used to identify the leukocyte populations that were the direct targets of androgen signaling. Type 2 innate lymphoid cells (ILC2s) were depleted by treatment with CD90.2 antibodies. RESULTS: We show that adrenalectomized female mice develop spontaneous gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) but that the stomachs of adrenalectomized male mice remain quantitatively normal. Simultaneous depletion of glucocorticoids and sex hormones abolished the male-protective effects and triggered spontaneous pathogenic gastric inflammation and SPEM. Treatment of female mice with DHT prevented gastric inflammation and SPEM development when administered concurrent with adrenalectomy and also reversed the pathology when administered after disease onset. Single-cell RNAseq of gastric leukocytes revealed that ILC2s expressed abundant levels of both the glucocorticoid receptor (Gr) and androgen receptor (Ar). We demonstrated that DHT treatment potently suppressed the expression of the proinflammatory cytokines Il13 and Csf2 by ILC2s. Moreover, ILC2 depletion protected the stomach from SPEM development. CONCLUSIONS: Here, we report a novel mechanism by which glucocorticoids and androgens exert overlapping effects to regulate gastric inflammation. Androgen signaling within ILC2s prevents their pathogenic activation by suppressing the transcription of proinflammatory cytokines. This work revealed a critical role for sex hormones in regulating gastric inflammation and metaplasia.