RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Characterized by inflammation of the gastric mucosa, atrophy of gastric gland cells, and intestinal metaplasia, Chronic Atrophic Gastritis (CAG) is a precancerous lesion disease. In traditional Chinese medicine, Rhizoma Coptidis (RC) is extensively used for treating gastrointestinal disorders, mainly because RC alkaloids-based extracts are the main active pharmaceutical ingredients. Total Rhizoma Coptidis extracts (TRCE) is a mixture of Rhizoma Coptidis extracts from Rhizoma Coptidis with alkaloids as the main components. However, the efficacy and mechanism of TRCE on CAG need further study. AIM OF THE STUDY: To explore the therapeutic effect and underlying mechanisms of action of TRCE on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced chronic atrophic gastritis (CAG) using network pharmacological analysis. MATERIALS AND METHODS: The amelioration effect of TRCE on CAG was evaluated in MNNG-induced CAG mice. The pathological severity of the mice was evaluated through H&E staining. Detection of gastric mucosal parietal cell loss was conducted using immunofluorescence staining, and serum indices were measured using ELISA. Additionally, the active compounds and drug targets of Rhizoma Coptidis were curated from the STP, SEA, and TCMSP databases, alongside disease targets of CAG sourced from PharmGkb, OMIM, and GeneCards databases. By mapping drug targets to disease targets, overlapping targets were identified. A shared protein-protein interaction (PPI) and drug target network were constructed for the overlapping targets and analyzed for KEGG enrichment. RESULTS: The results of animal experiments demonstrate that TRCE has the potential to improve the CAG process in mice. In conjunction with disease characteristics, cyberpharmacology analysis has identified nine core compounds, 151 targets, 10 core targets, and five significant inflammatory pathways within the compound-target-pathway network. Furthermore, there is a remarkable coincidence rate of 98% between the core compound targets of TRCE and the targets present in the CAG disease database. The accurate search and calculation of literature reports indicate that the coverage rate for 121 predicted core targets related to CAG reaches 81%. The primary characteristic of CAG lies in its inflammatory process. Both predicted and experimental findings confirm that TRCE can regulate ten key inflammation-associated targets (TP53, STAT3, AKT1, HSP90AA1, TNF, IL-6, MAPK3, SRC, JUN, and HSP90AA1) as well as inflammation-related pathways (MAPK, HIF-1, Toll-Like Receptor, IL-17, TNF, and other signaling pathways). These mechanisms mitigate inflammation and reduce gastric mucosal damage in CAG mice. CONCLUSIONS: In conclusion, TRCE was shown to alleviate CAG by modulating TP53, STAT3, AKT1, HSP90AA1, TNF, IL-6, MAPK3, SRC, JUN, and EGFR, as demonstrated by combined network pharmacology and biological experiments. In conclusion, our study provides a robust foundation for future clinical trials evaluating the efficacy of RC in treating CAG.
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Medicamentos Herbarios Chinos , Gastritis Atrófica , Metilnitronitrosoguanidina , Animales , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/inducido químicamente , Gastritis Atrófica/patología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Ratones , Masculino , Farmacología en Red , Coptis chinensis , Mapas de Interacción de Proteínas , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Enfermedad Crónica , Modelos Animales de EnfermedadRESUMEN
The prevention and treatment of gastrointestinal mucosal injury caused by a plateau hypoxic environment is a clinical conundrum due to the unclear mechanism of this syndrome; however, oxidative stress and microbiota dysbiosis may be involved. The Robinia pseudoacacia L. flower, homologous to a functional food, exhibits various pharmacological effects, such as antioxidant, antibacterial, and hemostatic activities. An increasing number of studies have revealed that plant exosome-like nanoparticles (PELNs) can improve the intestinal microbiota and exert antioxidant effects. In this study, the oral administration of Robinia pseudoacacia L. flower exosome-like nanoparticles (RFELNs) significantly ameliorated hypoxia-induced gastric and small intestinal mucosal injury in mice by downregulating hypoxia-inducible factor-1α (HIF-1α) and HIF-2α expression and inhibiting hypoxia-mediated ferroptosis. In addition, oral RFELNs partially improved hypoxia-induced microbial and metabolic disorders of the stomach and small intestine. Notably, RFELNs displayed specific targeting to the gastrointestinal tract. In vitro experiments using gastric and small intestinal epithelial cell lines showed that cell death caused by elevated HIF-1α and HIF-2α under 1% O2 mainly occurred via ferroptosis. RFELNs obviously inhibited HIF-1α and HIF-2α expression and downregulated the expression of NOX4 and ALOX5, which drive reactive oxygen species production and lipid peroxidation, respectively, suppressing ferroptosis under hypoxia. In conclusion, our findings underscore the potential of oral RFELNs as novel, naturally derived agents targeting the gastrointestinal tract, providing a promising therapeutic approach for hypoxia-induced gastric and small intestinal mucosal ferroptosis.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Exosomas , Ferroptosis , Flores , Mucosa Gástrica , Subunidad alfa del Factor 1 Inducible por Hipoxia , Mucosa Intestinal , Intestino Delgado , Peroxidación de Lípido , Nanopartículas , Animales , Ferroptosis/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Exosomas/metabolismo , Exosomas/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patología , Administración Oral , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Flores/química , Nanopartículas/química , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Humanos , Ratones Endogámicos C57BLRESUMEN
We studied the effect of enteral administration of GABA on the gastric mucosa in male Wistar rats (n=47) with modeled metabolic stress (food deprivation for 9 days with free access to water). The relative weights of the adrenal glands and thymus were determined, and histological examination of the stomach was performed. In control rats, modeling the metabolic stress was accompanied by the development of erosive damage to the gastric mucosa related to blood supply disturbances. Administration of GABA prevented erosions and exhibited a pronounced gastroprotective effect. Thus, administration of GABA can be a promising method for the prevention and treatment of erosive gastric lesions associated with metabolic stress.
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Mucosa Gástrica , Ratas Wistar , Estrés Fisiológico , Ácido gamma-Aminobutírico , Animales , Masculino , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacología , Ratas , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Estrés Fisiológico/efectos de los fármacos , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Timo/efectos de los fármacos , Timo/patología , Timo/metabolismo , Privación de Alimentos , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patología , Úlcera Gástrica/prevención & control , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológicoRESUMEN
The pathogenesis mechanism of acute gastric mucosal lesions (AGML) is still unclear; further exploration is urgently needed to find a new therapeutic target. This study aimed to investigate whether morphine might regulate the expression and function of transient receptor potential ankyrin 1 (TRPA1) through a cyclic adenosine monophosphate/protein kinase A (cAMP/PKA)-dependent pathway, thereby alleviating gastric mucosal lesions caused by water-immersion restraint stress (WIRS). Rats were administered with intrathecal morphine, TRPA1 antagonist (HC-030031), µ-opioid receptor antagonist, or protein kinase A inhibitor (H-89), respectively, before WIRS. After 6 hours of WIRS, microscopic lesions, hematoxylin and eosin staining, and transmission electron microscopy were applied to assess the damage of the gastric mucosa. Real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay were conducted to detect the levels of TRPA1 and substance P (SP) in the dorsal root ganglia (DRG) and gastric tissues. In addition, immunofluorescence was used to explore the possible co-expression of TRPA1 and µ-opioid receptors in the DRG. The results indicated that WIRS upregulated TRPA1 and SP in gastric mucosa, and HC-030031 or H-89 could alleviate gastric mucosal lesions caused by WIRS (P < .0001). Morphine was found to suppress both WIRS-induced gastric mucosal lesions (P < .0001) and the upregulation of TRPA1 (P = .0086) and SP (P = .0013). Both TRPA1 and SP play important roles in the pathogenesis of WIRS-induced AGML. Exogenous gastroprotective strategies reduce elevated levels of TRPA1 via the cAMP/PKA-dependent pathway. Inhibition of TRPA1 upregulation in the DRG is critical for intrathecal morphine preconditioning-induced gastric protection.
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Ganglios Espinales , Mucosa Gástrica , Isoquinolinas , Morfina , Ratas Sprague-Dawley , Restricción Física , Canal Catiónico TRPA1 , Regulación hacia Arriba , Animales , Morfina/farmacología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Canal Catiónico TRPA1/metabolismo , Masculino , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Restricción Física/efectos adversos , Ratas , Isoquinolinas/farmacología , Acetanilidas/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Purinas/farmacología , Estrés Psicológico/complicaciones , Inmersión , Receptores Opioides mu/metabolismo , AMP Cíclico/metabolismo , SulfonamidasRESUMEN
Ochratoxin A (OTA), as one of the most important and harmful mycotoxins, is classed as possible human carcinogen (group 2B). As we all know, DNA damage may cause genomic instability, cell cycle disorder, activation of DNA damage pathway, and stimulation of DNA repair system. To explore the roles of DNA damage repair protein (hMLH1) on OTA-induced G2 arrest, the DNA damage, chromosome aberration, cell cycle distribution and p53-p21 signaling pathway were evaluatd after different time OTA exposure (6, 12, 24, 48â¯h) in immortalized human gastric epithelial cells (GES-1). Our results demonstrated that OTA exposure could trigger genomic instability, DNA damage and G2 phase arrest of GES-1 cells. At the same time, OTA treatment could increase the expression of hMLH1, and induce phosphorylation of the p53 protein, as well as p21, in response to DNA damage. Finally, inhibition of hMLH1 by siRNA effectively prevented the activation of p53-p21 signaling pathway and rescued the G2 arrest elicited by OTA. This study demonstrated that hMLH1-p53-p21 signaling pathway played an important role in DNA damage and G2 cell cycle arrest the mediated by OTA in GES-1 cells.
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Daño del ADN , Puntos de Control de la Fase G2 del Ciclo Celular , Mucosa Gástrica , Homólogo 1 de la Proteína MutL , Ocratoxinas , Transducción de Señal , Proteína p53 Supresora de Tumor , Ocratoxinas/toxicidad , Humanos , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Transducción de Señal/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Línea Celular , Inestabilidad Genómica/efectos de los fármacos , FosforilaciónRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Galangin, a bioactive compound extracted from Alpinia officinarum Hance (Zingiberaceae), a plant with significant ethnopharmacological importance, has been used for thousands of years as a spice, condiment, and medicinal agent for various conditions, including gastrointestinal disorders. Although there is evidence suggesting its potential to improve gastric ulcers, the molecular mechanisms underlying its anti-ulcer properties are not fully understood. OBJECTIVE: of the Study: This study aimed to investigate the effects of galangin on ethanol-induced acute gastric mucosal injury (AGMI) in mice and elucidate its molecular mechanisms. MATERIALS AND METHODS: Sixty BALB/c mice were randomly assigned into two main groups: a normal control group (n = 10) and an ethanol-induced group (n = 50). After establishing the AGMI model in mice using a combination of 40% ethanol and anhydrous ethanol, the ethanol-induced group was further subdivided into five subgroups (n = 10): an omeprazole control group (20 mg/kg), an untreated ethanol group, and three treatment groups receiving high-dose (50 mg/kg) or low-dose (25 mg/kg) galangin or capsazepine (CPZ, 2 mg/kg). The protective effects of galangin were evaluated through mucosal injury indices, hematoxylin and eosin staining, and quantification of inflammatory markers (IL-1ß, IL-6, IL-8, and TNF-α). Oxidative stress levels and matrix metalloproteinase activity were measured using specific assay kits. Molecular docking was conducted to assess the binding affinity of galangin to key proteins within the transient receptor potential vanilloid 1 (TRPV1) pathway. Real-time fluorescence quantitative PCR (qPCR) was used to determine mRNA expression levels of TRPV1, calmodulin (CaM), substance P (SP), and CGRP in gastric tissues. Protein expression levels of TRPV1, nerve growth factor (NGF), tropomyosin receptor kinase A (TRKA), transforming growth factor beta (TGF-ß), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) were assessed through Western blot analysis. In cellular experiments, Culture of Human Gastric Epithelial Cells (GES-1) were treated with various concentrations of galangin after 7% ethanol induction. Cell proliferation, apoptosis, and migration were evaluated using Hoechst 33258 staining and transwell migration assays. TRPV1 protein expression was detected using immunofluorescence, and the expression levels of Bcl-2, BCL2-Associated X (BAX), and Caspase-3 were quantified by qPCR. Additionally, specific probe kits were used to measure intracellular calcium ions (Ca2+) and mitochondrial membrane potential. RESULTS: The findings indicate that galangin significantly improved mucosal pathology by reducing ulcer indices and inflammatory levels, while enhancing superoxide dismutase (SOD) activity and decreasing malondialdehyde (MDA) concentration. Galangin also reduced matrix metalloproteinase-2 (MMP-2), m metalloproteinase-9 (MMP-9) levels, promoting mucosal repair. At the cellular level, galangin decreased intracellular calcium ion concentration and mitigated the decline in mitochondrial membrane potential, enhance the restoration of mucosal cells, increased migration and proliferation, and reduced apoptosis. Molecularly, galangin demonstrated favorable binding to TRPV1, NGF, TRKA, TGF-ß, COX-2, and NF-κB, and reversed the elevated expression of these proteins. Additionally, galangin downregulated the mRNA expression of TRPV1, CaM, SP, CGRP, BAX, and Caspase-3 in gastric tissues/cells, while upregulating Bcl-2 mRNA expression. CONCLUSION: Galangin mitigates AGMI by inhibiting the overactivation of the TRPV1 pathway, thereby blocking aberrant signal transduction. This study suggests that galangin has therapeutic potential against ethanol-induced AGMI and may be a viable alternative for the treatment of alcohol-induced gastric mucosal injuries.
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Etanol , Flavonoides , Mucosa Gástrica , Ratones Endogámicos BALB C , Transducción de Señal , Úlcera Gástrica , Canales Catiónicos TRPV , Animales , Flavonoides/farmacología , Canales Catiónicos TRPV/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Mucosa Gástrica/lesiones , Transducción de Señal/efectos de los fármacos , Masculino , Ratones , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Simulación del Acoplamiento Molecular , Antiulcerosos/farmacología , Línea Celular , Estrés Oxidativo/efectos de los fármacos , Humanos , Apoptosis/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Peucedanum praeruptorum Dunn (PPD) was used to treat gastrointestinal disease in China before the Tang Dynasty, and it was considered a "Top-grade" herb in Shennong Bencaojing, known for its ability to relieve the stomach Qi and indigestion. AIM OF THE STUDY: Alcohol consumption can induce severe gastric mucosal injury that lacks effective and safe interventions. We aimed to investigate the gastroprotective effects of Peucedanum praeruptorum Dunn leaf (PPL) after bolting in alcohol-induced gastric damage in mice. MATERIALS AND METHODS: Mice were orally administered PPL aqueous extract at doses of 2.5, 5, and 10 g/kg for 5 consecutive days prior to the induction of gastric damage model with ethanol. Gastric tissue was stained by hematoxylin and eosin (H&E), and the levels of pro-inflammatory cytokines and oxidative stress indicators were determined using ELISA and RT-qPCR. RNA-seq was used to detect differentially expressed genes (DEGs) in the gastric tissue, while Western blotting was employed to measure the expressions of IL-17, TNF-a, and AKT pathways. RESULTS: Treatment with PPL alleviated alcohol-induced gastric damage in mice, whereas dried root (PPD) and stem (PPS) of Peucedanum praeruptorum Dunn had no gastroprotective function. The content of peucedanocoumarin I was higher in the dried PPL compared to PPD and PPS, with an increase in peucedanocoumarin I content in PPL after boiling. Additionally, PPL administration (5, 10 g/kg) decreased pro-inflammatory factors, such as interleukin-6 (IL-6), IL-8, IL-4, IL-1ß, IL-18, and tumor necrosis factor (TNF-a) in alcohol-induced gastric injury mice (p < 0.05), and improved oxidative stress markers, including superoxide dismutase enzymes (SOD), catalase (CAT), and malondialdehyde (MDA) (p < 0.05). RNA-seq data revealed that PPL treatment inhibited alcohol-induced inflammation-related signals, including IL-17 and TNF pathways, and restored alcohol-inhibited gastric digestive and metabolic functions, such as xenobiotics metabolism of cytochrome P450, and protein digestion and absorption pathways. Notably, treatment with PPL downregulated the expressions of IL-17 A, TNF-a, monocyte chemoattractant protein-1 (MCP-1), and AKT-phosphorylation induced by ethanol exposure (p < 0.05). Thus, the aqueous extract of PPL provided protection against alcohol-induced gastric injury by mitigating inflammation and oxidative stress in mice, suggesting a potential novel therapeutic approach for alcohol-induced gastric damage.
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Apiaceae , Etanol , Estrés Oxidativo , Extractos Vegetales , Hojas de la Planta , Animales , Estrés Oxidativo/efectos de los fármacos , Hojas de la Planta/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ratones , Etanol/química , Masculino , Apiaceae/química , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/prevención & controlRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Eucalyptus genus has been used for a very long time in conventional treatment as an anti-ulcer remedy. AIM OF THE STUDY: The study aimed to explore the gastroprotective potential of 7-O-methyl aromadendrin (7-OMA), and sakuranetin (SKN) in comparison with omeprazole. The study tackled the contribution of their anti-inflammatory, antioxidant, and antiapoptotic capabilities to their anti-gastric ulcer effects. MATERIALS AND METHODS: An ethanol-induced gastric ulcer model in rats was adopted and the consequences were confirmed by a molecular docking study. RESULTS: The oral pretreatment of rats 1 h before ethanol using omeprazole (20 mg/kg) or 7-OMA (20 or 40 mg/kg) or SKN (20 or 40 mg/kg) exhibited gastroprotective and anti-inflammatory properties to different extents. These amendments witnessed as restorations in the stomach histological architecture in H and E-stained sections, mucus content in periodic acid-Schiff (PAS) stained sections with increased cellular proliferation, as demonstrated by increased immunohistochemical staining of PCNA, and increments in stomach COX-1 activity and eNOS. The highest dose of SKN showed the best corrections to reach 4.8, 1.8, and 2.1 folds increase in PAS, COX-1 and eNOS, respectively as compared to the untreated ethanol-induced gastric ulcer group; effects that were comparable to that of omeprazole. Moreover, reductions in COX-2 activity, and the protein expression of NF-κB, IL-6, TNF-α and NOx, in addition to the gene expression of inducible iNOS were also noted. Moreover, the antioxidant and antiapoptotic capabilities of omeprazole, 7-OMA, and SKN were perceived. SKN (40 mg/kg) succeeded to show the unsurpassed results to reach 293.6%, 237.1%, 274.7%, 248.2%, and 175.4% in total and reduced GSH, catalase, SOD, and Bcl2, respectively, as well as 50.0%, 46.8%, and 52.1 % in oxidized GSSG, TBARS and caspase-3, respectively. The gastroprotective potential of the tested compounds can be assigned to their anti-inflammatory, antioxidant and antiapoptotic properties.7-OMA and SKN were studied using molecular docking into the binding sites of the most significant inflammatory targets, including COX-2, TNF-α, iNOS, and NF-κB. Pharmacokinetic and physicochemical parameters in silico were appropriate. CONCLUSION: The prophylactic use of 7-OMA and SKN could be considered as an add-on to recurrent gastric ulcers and might influence its therapeutic approaches.
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Antiinflamatorios , Antiulcerosos , Antioxidantes , Etanol , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Úlcera Gástrica , Animales , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patología , Estrés Oxidativo/efectos de los fármacos , Antiulcerosos/farmacología , Masculino , Antiinflamatorios/farmacología , Etanol/química , Ratas , Antioxidantes/farmacología , Ratas Wistar , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Flavonoides/farmacología , Omeprazol/farmacología , Apoptosis/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , FitoalexinasRESUMEN
Excessive alcohol consumption has led to the prevalence of gastrointestinal ailments. Alleviating gastric disorders attributed to alcohol-induced thinning of the mucus layer has centered on enhancing mucin secretion as a pivotal approach. In this study, foxtail millet bran polyphenol BPIS was divided into two components with MW < 200 D and MW > 200 D by molecular interception technology. Combined with MTT, cell morphology observation, and trypan blue staining, isoferulic acid (IFA) within the MW < 200 D fraction was determined as the effective constituent to mitigate ethanol-induced damage of gastric epithelial cells. Furthermore, a Wistar rat model with similar clinical features to alcohol-induced gastric mucosal injury was established. Then, gastric morphological observation, H&E staining, and assessments of changes in gastric hexosamine content and gastric wall binding mucus levels were carried out, and the results revealed that IFA (10 mg/Kg) significantly ameliorated alcohol-induced gastric mucosal damage. Finally, we applied techniques including Co-IP, molecular docking, and fluorescence spectroscopy and found that IFA inhibited the alcohol-induced downregulation of N-acetylgalactosamintransferase 2 (GALNT2) activity related to mucus synthesis through direct interaction with GALNT2 in gastric epithelial cells, thus promoting mucin synthesis. Our study lays a foundation for whole grain dietary intervention tailored to individuals suffering from alcoholic gastric mucosal injury.
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Etanol , Mucosa Gástrica , Ratas Wistar , Animales , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Ratas , Masculino , Setaria (Planta) , Extractos Vegetales/farmacología , Humanos , Células Epiteliales/efectos de los fármacos , Simulación del Acoplamiento Molecular , Modelos Animales de EnfermedadRESUMEN
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
Anisomeles indica (L.) Kuntze is a traditional herb with multiple medicinal properties and with potential for preventing or treating various diseases. Acteoside, one of the active ingredients in A. indica, is prepared into commercially available products of A. indica HP813 powder. In this study, the gastroprotective effects of A. indica HP813 powder were evaluated. Wistar rats were treated with A. indica HP813 powder at doses of 0, 207.5, 415, and 830 mg/kg body weight for 28 days. Then, gastric ulcers were induced by the oral administration of 70% ethanol (10 mL/kg body weight) on day 28. The rats were sacrificed at the end of the trial, and stomach tissues were collected. These stomach tissues were then used for macroscopic, microscopic, and immunohistochemical analyses. The results indicated that the area of gastric ulcer was 48.61%, 35.30%, and 27.16% in the ethanol-induced group, 415 mg/kg A. indica HP813 powder group, and 830 mg/kg A. indica HP813 powder group, respectively. In addition, the lesion scores were 2.9, 2.4, and 2.3 in the ethanol-induced group, 415 mg/kg A. indica HP813 powder group, and 830 mg/kg A. indica HP813 powder group, respectively. The immunochemical staining of the gastric tissue revealed that A. indica HP813 powder reduced the expressions of TNF-α and NF-κB proteins in the gastric tissue, which had been induced by ethanol. Finally, A. indica HP813 powder protected the gastric ulcer from ethanol damage through IκB-α induction. The present results demonstrated that A. indica HP813 powder has protective effects against ethanol-induced gastric ulcer.
Asunto(s)
Antiulcerosos , Etanol , Inhibidor NF-kappaB alfa , FN-kappa B , Úlcera Gástrica , Animales , Masculino , Ratas , Antiulcerosos/farmacología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , FN-kappa B/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Extractos Vegetales/farmacología , Polvos , Ratas Wistar , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/prevención & control , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/metabolismoRESUMEN
BACKGROUND: Gastric ulcer (GU) is a common gastrointestinal disease with high morbidity that may be caused by various pathogenic factors. Dan-Shen-Yin (DSY), a traditional prescription, improves myocardial and gastrointestinal functions; however, its effect on GU and the underlying mechanisms requires further research. PURPOSE: We aimed to evaluate the pharmacodynamics of DSY granules in GU using three different animal models and explore their potential mechanisms. METHODS: DSY granules were manufactured and subjected to quality control by high-performance liquid chromatography (HPLC). Three GU models were established using ethanol, aspirin, or water immersion restraint combined with aspirin and examined using the Guth method and hematoxylin and eosin (H&E) staining. The effects of DSY granules on gastric mucosal glycoproteins and the release of defensive and aggressive factors in ethanol-induced GU were measured using periodic acid-Schiff (PAS) staining and ELISA. TUNEL staining and detection of apoptosis-related proteins were used to evaluate the role of DSY granules on apoptosis. Potential mechanisms were predicted using network pharmacology, molecular docking, and western blot to verify the related targets and pathways. RESULTS: DSY granules were prepared for the first time and quality control standard was established. Pharmacodynamic evaluation indicated that DSY granules significantly reduced the GU index and gastric mucosal injury in the three GU models, and the GU inhibition rate of DSY granules was superior to omeprazole in ethanol-induced GU model (60.32 % vs. 21.96 %). Further studies in ethanol-induced GU model revealed that DSY granules increased the levels of the defensive factors (PGE2, NO, SOD, CAT, TAOC, and GSH) and decreased the levels of aggressive factors (MDA, TNF-α, and IL-1ß), thereby inhibiting oxidative stress and inflammation, attenuating gastric mucosal injury. Moreover, the results of TUNEL staining and western blot showed that DSY granules suppressed apoptosis by reducing the ratios of Bax/Bcl-2 and cleaved-Caspase-3/Caspase-3. In addition, the results of network pharmacology and molecular docking suggested that the mechanisms of DSY granules against GU may be related to the Akt-related signaling pathway. Further study confirmed that DSY granules significantly reduced the ratio of p-Akt/Akt and promoted the expression of Nrf2 and NQO1, protecting the gastric mucosa. CONCLUSIONS: Our results indicated that DSY granules had protective effects on GU caused by different mechanisms, especially ethanol-induced GU. DSY granules alleviated gastric mucosal damage by inhibiting oxidative stress, inflammation, and apoptosis, which may be associated with the regulation of Akt/Nrf2 signaling pathway. Therefore, DSY granules may be a promising drug for the treatment of GU.
Asunto(s)
Apoptosis , Medicamentos Herbarios Chinos , Etanol , Mucosa Gástrica , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Úlcera Gástrica , Animales , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ratas , Modelos Animales de Enfermedad , Simulación del Acoplamiento MolecularRESUMEN
Mycobacterium bovis (M. bovis) Bacillus Calmette-Guerin (BCG) strain used in immunotherapy of bladder cancer (onco-BCG) due to its acid tolerance can be a candidate for prevention or reversion of deleterious effects towards gastric cell barrier initiated by gastric pathogen Helicobacter pylori (Hp) with high resistance to commonly used antibiotics. Colonization of gastric mucosa by Hp promotes oxidative stress, apoptosis resulting in the gastric barrier damage. The aim of this study was to examine the ability of onco-BCG bacilli to control the Hp driven gastric damage using the model of Cavia porcellus primary gastric epithelial cells or fibroblasts in vitro. These cells were treated with Hp surface antigens (glycine acid extract-GE or lipopolysaccharide-LPS) alone or with onco-BCG bacilli and evaluated for cell apoptosis and proliferation in conjunction with the level of soluble lipid peroxidation marker (s4HNE). The cell migration was determined by "wound healing assay", while cytokine response of cells, including interleukin (IL)-33, IL-1ß, IL-8 and tumor necrosis factor alpha (TNF-α), by the ELISA. The apoptosis of cells pulsed in vitro with Hp surface components present in GE or with LPS was reduced after exposure of cells to mycobacteria. Similarly, the cell regeneration which was diminished by Hp LPS has been improved in response to mycobacteria. This study reveals that vaccine mycobacteria may reduce gastric barrier damage induced by Hp infection.
Asunto(s)
Apoptosis , Mucosa Gástrica , Helicobacter pylori , Mycobacterium bovis , Helicobacter pylori/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Lipopolisacáridos , Citocinas/metabolismo , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/microbiología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Peroxidación de Lípido/efectos de los fármacos , Fibroblastos/efectos de los fármacosRESUMEN
INTRODUCTION: Gastric ulcer is one of the most common and serious conditions in the gastrointestinal tract. One of the main causes of gastric ulcers is using of non-steroidal anti-inflammatory drugs (NSAIDs) which have limited their use in clinical practice. Several studies have revealed that metformin and Vitamin C (Vit C) exhibit protective effects against gastric mucosal damage in different animal models. However, no studies indicate their combination's effect on gastric ulcer models. Therefore, this study aims to investigate the protective effects of metformin and Vit C combination on indomethacin-induced gastric ulcers. MATERIAL AND METHODS: In total, thirty rats were divided into six groups, including the control group, rats received indomethacin (50 mg/kg, i.p.), rats received indomethacin and pretreated with ranitidine (100 mg/kg), metformin (100 mg/kg, i.p.), Vit C (100 mg/kg), or metformin combined with Vit C. Four hours after indomethacin administration, rats were euthanized, and gastric tissues were removed for macroscopic, histopathologic, and biochemical examinations. RESULTS: All therapeutics used in this study were found to alleviate gastric mucosal injury caused by indomethacin, as observed in histopathologic and macroscopic evaluations. Both Vit C and metformin were observed to significantly decrease lipid peroxidation and enhance the activity of anti-oxidative enzymes, SOD, GPx, and catalase. However, a more significant effectiveness was observed in catalase and GPx activities when Vit C was co-administered with metformin. CONCLUSIONS: In conclusion, the present study revealed that metformin and Vit C combination therapy could potentially treat gastric ulcers associated with indomethacin.
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Antiinflamatorios no Esteroideos , Ácido Ascórbico , Mucosa Gástrica , Indometacina , Metformina , Úlcera Gástrica , Animales , Metformina/farmacología , Indometacina/toxicidad , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/patología , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Ratas , Masculino , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Peroxidación de Lípido/efectos de los fármacos , Antioxidantes/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Ratas Wistar , Antiulcerosos/farmacologíaRESUMEN
Acid-related diseases (ARD) are the most common among digestive diseases. The main goals of therapy of ARD are to reduce the influence of aggression factors (production of HCl, pepsin) and increase the protective properties of the mucous membrane of the upper digestive tract. Also currently in medicine, one of the therapeutic and preventive methods is the use of chloride-hydrocarbonate sodium boron mineral waters. In this study, we compared the efficacy of table mineral waters in the therapy of induced gastropathy in Wistar rats. The study of the effect of mineral waters on the gastric mucosa of Wistar rats has provided valuable information that can be applied in medical practice for the treatment and prevention of various diseases of the gastrointestinal tract in humans. Careful analysis of the data obtained has shown that certain types of mineral waters can significantly reduce inflammatory processes and promote regeneration of the gastric mucosa, which makes them a useful addition to traditional treatment methods such as pharmacotherapy.
Asunto(s)
Mucosa Gástrica , Aguas Minerales , Ratas Wistar , Animales , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Ratas , Masculino , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/prevención & controlRESUMEN
This study aims to explore the protective effect of Albizia chinensis saponin on ethanol-induced acute gastric ulcer in rats and elucidate its mechanisms. SD rats were deprived of water for 24 hours before the experiment. The control group and model group were administered water by gavage, and the positive drug group received rabeprazole sodium solution(40 mg·kg~(-1)) by gavage. The experimental groups were given different doses of Albizia chinensis saponin solution(3, 10, and 30 mg·kg~(-1)). After 30 minutes, the control group received 1.5 mL of water by gavage, while the other groups were administered an equal volume of 95% ethanol for modeling. After six hours, the rats were killed by cervical dislocation, and the stomachs were collected. The ulcer area was measured, and the ulcer index was calculated. Hematoxylin-eosin(HE) staining was performed to assess histopathological changes in gastric tissue. Periodic acid-Schiff(PAS) staining was used to evaluate the distribution of gastric mucosal surface mucus. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of phospholipids and aminohexose in the gastric mucosa. Western blot was performed to determine the expression levels of the bicarbonate transporter, matrix metalloproteinase, and tight junction-associated proteins in gastric tissue. Immunohistochemistry(IHC) staining was conducted to quantify the number of positive cells for secreted mucin and tight junction-associated proteins. The results showed that the gastric tissue surface of rats in the control group was smooth without ulceration, and the gastric ulcer index of rats in the model group was 35±11. Albizia chinensis saponin at doses of 3, 10, and 30 mg·kg~(-1) resulted in inhibition rates of gastric ulcer of 46%(P<0.01), 85%(P<0.001), and 100%(P<0.001), respectively. Severe disruption of gastric mucosal structure and absence of the mucus layer were observed in the model group. Compared with the model group, the Albizia chinensis saponin group showed intact gastric mucosal surface mucus layer, significantly increased levels of phospholipids and aminohexose in the mucus, increased number of MUC5AC positive cells, and upregulated expression levels of the bicarbonate transporter SLC26A3 and CFTR. It also showed decreased phosphorylation of JNK and c-Jun, reduced expression levels of MMP-8, elevated expression of TIMP-1, and increased expression levels of Occludin and ZO-1. In conclusion, Albizia chinensis saponin enhances the function of the mucus-bicarbonate barrier by upregulating the content of MUC5AC, phospholipids, and aminohexose and increasing the expression levels of the bicarbonate transporter SLC26A3 and CFTR. Moreover, Albizia chinensis saponin exerts its protective effects on gastric ulcers by inhibiting the JNK signaling pathway to prevent excessive activation of MMP-8, thereby reducing the degradation of Occludin and ZO-1 and enhancing the mucosal barrier function. In summary, Albizia chinensis saponin exerts its anti-gastric ulcer effects by simultaneously enhancing the mucus barrier and the mucosal barrier.
Asunto(s)
Albizzia , Medicamentos Herbarios Chinos , Etanol , Mucosa Gástrica , Moco , Ratas Sprague-Dawley , Saponinas , Úlcera Gástrica , Animales , Saponinas/farmacología , Ratas , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Etanol/efectos adversos , Masculino , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/metabolismo , Úlcera Gástrica/prevención & control , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Albizzia/química , Moco/metabolismo , Sustancias Protectoras/farmacología , Sustancias Protectoras/administración & dosificación , HumanosRESUMEN
The Helicobacter pylori infection in the stomach is the key reason for gastric mucosal bleeding. Eliminating gastric Helicobacter pylori by oral treatment remains difficult due to the presence of the gastric mucosal layer, which acts as a physical barrier to drugs via oral administration. In this study, a magnetic-navigable microneedle drug delivery platform (MNsD) for oral administration, featuring differential dual-mode drug release rate, was designed to fulfil rapid gastric hemostasis and overcome the gastric barriers for long-lasting Helicobacter pylori inhibition in stomach. MNs-D was created by rationally loading the carrier substrate, which was composed of silk fibroin with variable solubility, with antibiotics and hemostats. In vitro experiments showed MNs-D may sustainably eradicate Helicobacter pylori in stimulated gastric juices with long-lasting drug release (79 % in 24 h) and quickly establish hemostasis with instant drug release (92 % within 60 s). Most importantly, in vivo studies demonstrated MNs-D overcame the unsettling gastric mucosal barrier in traditional therapies of oral administration by insertion into the GML under magnetic navigation, resulting in sustained antibiotic release for long-lasting Helicobacter pylori eradiation (99 %). For differential dual-mode medication release against gastric Helicobacter pylori infections, this study may have firstly examined the effects of magnetic navigated microneedles administered orally.
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Antibacterianos , Sistemas de Liberación de Medicamentos , Fibroínas , Mucosa Gástrica , Infecciones por Helicobacter , Helicobacter pylori , Agujas , Helicobacter pylori/efectos de los fármacos , Animales , Fibroínas/química , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Administración Oral , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/química , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Mucosa Gástrica/efectos de los fármacos , Liberación de Fármacos , Hemostasis/efectos de los fármacos , Estómago/microbiología , Estómago/efectos de los fármacos , Masculino , RatonesRESUMEN
Helicobacter pylori is a highly prevalent human gastric pathogen that causes gastritis, ulcer disease, and gastric cancer. It is not yet fully understood how H. pylori injures the gastric epithelium. The Na,K-ATPase, an essential transporter found in virtually all mammalian cells, has been shown to be important for maintaining the barrier function of lung and kidney epithelia. H. pylori decreases levels of Na,K-ATPase in the plasma membrane of gastric epithelial cells, and the aim of this study was to demonstrate that this reduction led to gastric injury by impairing the epithelial barrier. Similar to H. pylori infection, the inhibition of Na,K-ATPase with ouabain decreased transepithelial electrical resistance and increased paracellular permeability in cell monolayers of human gastric cultured cells, 2D human gastric organoids, and gastric epithelium isolated from gerbils. Similar effects were caused by a partial shRNA silencing of Na,K-ATPase in human gastric organoids. Both H. pylori infection and ouabain exposure disrupted organization of adherens junctions in human gastric epithelia as demonstrated by E-cadherin immunofluorescence. Functional and structural impairment of epithelial integrity with a decrease in Na,K-ATPase amount or activity provides evidence that the H. pylori-induced downregulation of Na,K-ATPase plays a role in the complex mechanism of gastric disease induced by the bacteria.
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Mucosa Gástrica , Infecciones por Helicobacter , Helicobacter pylori , Ouabaína , ATPasa Intercambiadora de Sodio-Potasio , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética , Humanos , Animales , Ouabaína/farmacología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Mucosa Gástrica/efectos de los fármacos , Gerbillinae , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/efectos de los fármacos , Organoides/metabolismo , Organoides/microbiologíaRESUMEN
Indole-3-lactic acid (ILA) has exhibited antimicrobial properties. However, its role in inhibiting Helicobacter pylori infection remains elusive. This study investigated the inhibitory effect of ILA produced by Lacticaseibacillus paracasei on H. pylori, which was further confirmed by cell and animal experiments. 5 mg/mL ILA was sufficient to directly inhibit the growth of H. pylori in vitro, with a urease inhibitory activity reaching 60.94 ± 1.03%, and the cell morphology and structure were destroyed. ILA inhibited 56.5% adhesion of H. pylori to GES-1 and significantly reduced the number of apoptotic cells. Furthermore, ILA suppresses H. pylori colonization by approximately 38% to 63%, reduced inflammation and oxidative stress in H. pylori-infected mice, and enhanced the enrichment and variety of gut microbiota, notably fostering the growth of beneficial bacteria such as Lactobacillus and Bifidobacterium strains. The results support that ILA derived from Lactobacillus can be applicated as a novel prebiotic in anti-H. pylori functional foods.
Asunto(s)
Células Epiteliales , Mucosa Gástrica , Infecciones por Helicobacter , Helicobacter pylori , Indoles , Lacticaseibacillus paracasei , Helicobacter pylori/efectos de los fármacos , Animales , Ratones , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Humanos , Mucosa Gástrica/microbiología , Mucosa Gástrica/efectos de los fármacos , Indoles/farmacología , Indoles/química , Lacticaseibacillus paracasei/química , Células Epiteliales/efectos de los fármacos , Células Epiteliales/microbiología , Antibacterianos/farmacología , Antibacterianos/química , Inflamación/prevención & control , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Adhesión Bacteriana/efectos de los fármacosRESUMEN
Non-steroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, cause gastric mucosal damage, including ulcers, directly or indirectly, by which the development of GI-safer (-sparing) NSAIDs relates to unmet medical needs. This study aimed to document the preventive effects of walnut polyphenol extracts (WPEs) against NSAID-induced gastric damage along with the molecular mechanisms. RGM-1 gastric mucosal cells were administered with indomethacin, and the expressions of the inflammatory mediators between indomethacin alone or a combination with WPEs were compared. The expressions of the inflammatory mediators, including COX-1 and COX-2, prostaglandin E2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and antioxidant capacity, were analyzed by Western blot analysis, RT-PCR, and ELISA, respectively. HO-1, Nrf-2, and keap1 were investigated. The in vivo animal models were followed with in vitro investigations. The NSAIDs increased the expression of COX-2 and decreased COX-1 and 15-PGDH, but the WPEs significantly attenuated the NSAID-induced COX-2 expression. Interestingly, the WPEs induced the expression of 15-PGDH. By using the deletion constructs of the 15-PGDH promoter, we found that c-Jun is the most essential determinant of the WPE-induced up-regulation of 15-PGDH expression. We confirmed that the knockdown of c-Jun abolished the ability of the WPEs to up-regulate the 15-PGDH expression. In addition, the WPEs significantly increased the HO-1 expression. The WPEs increased the nuclear translocation of Nrf2 by Keap-1 degradation, and silencing Nrf2 markedly reduced the WPE-induced HO-1 expression. We found that the WPE-induced HO-1 up-regulation was attenuated in the cells harboring the mutant Keap1, in which the cysteine 151 residue was replaced by serine. These in vitro findings were exactly validated in indomethacin-induced gastric rat models. Daily walnut intake can be a promising nutritional supplement providing potent anti-inflammatory, antioxidative, and mucosa-protective effects against NSAID-induced GI damage.