Total triterpenes from fruits of Chaenomeles speciosa(Sweet) Nakai protect against indomethacin-induced gastric mucosal injury: involvement of TFF1-mediated EGF/EGFR and apoptotic pathways

OBJECTIVE Gastric ulcers affect people of all ages and half of the world's population,which is being considered as the new"plague of the 21st century".As is well known,gastric mucosa is known as the first guard to protect the stomach from ulcer injury,while the aetiology of gastric ulcer is relative to imbalances between gastric mucosal protective and aggressive factors.Therefore,reducing or eliminating the aggressive factors,returning to the balance of between mucosal protective and aggressive factors,and then restoring the normal functional of gastric mucosal barrier could be crucial for treating the gastric ulcer.The fruits of Chaenomeles speciosa(TCS),also known as"mugua",might be processed into edible and health care derived products,and used as a commonly used traditional medicine in China for thousands of years.In China folk,there is a saying that"apricot one benefit,pear two benefits,mgua hundred benefits",so it has a"hundred-benefit"fruit reputation.Tujia nationality inhabitants in Southwestern China should have rheumatic diseases and peptic ulcers for living in the damp environments and bingeing on spicy and pungent foods.For the exis⁃tence of the fruit derived products of Chaenomeles speciosa as their complementary foods or snacks,the habit makes them rarely suffer from the two kinds of diseases.Enlightened by these,we had investigated the structure-activity rela⁃tionships,screened out CSTT with gastroprotective activity.Our previous studies demonstrated that TCS owned effec⁃tively therapeutic effects on gastric ulcer patients and animals,and further confirmed that TFF1 and apoptotic pathway were closely interrelated with its exerting gastroprotection.However,its underlying molecular mechanisms involved have not been fully elucidated.The current study was to further investigate its protective effect on indomethacin(IND)-damaged RGM-1 cells and rats and its underlying mechanisms through modulating TFF1-mediated EGF/EGFR and apoptotic pathways.METHODS The gastroprotection of TCS was evaluated with IND-induced gastric lesions model in RGM-1 cells and rats.In vitro,the proliferation,migration,mitochondrial viability and apoptosis were assessed,In vivo,ulcer index,ulcer inhibition rate,gastric juice acidity,gastric wall mucus(GWM),histopathology of gastric mucosa were detected.The gastroprotective effects of TCS through the TFF1-mediated EGFR/EGFR and apoptotic pathways were presented and measured by qRT-PCR and Western blotting assays.RESULTS TCS had gastroprotective function,which was related to the amelioration in promoting IND-damaged RGM-1 cell proliferation and migration,hoisting gastric juice acidity and GWM,improving ulcer index and ulcer inhibition rate,attenuating the hemorrhage,edema,epithelial cell loss and inflammatory cell infiltration of gastric mucosa,upregulating proliferation cell nuclear antigen,Bcl-2,Bcl-xl mRNA and TFF1,EGF,p-EGFR,p-Src,pro-caspase-3,pro-caspase-9 protein expressions,mitochondrial viability,mitochondrial cytochrome C concentration and p-EGFR/EGFR,p-Src/Src,Bcl-2/Bax,Bcl-xl/Bad ratioes,downregulating Bax,Bad,Apaf-1 mRNA and cleaved-caspase-3,cleaved-caspase-9,cleaved-PARP-1 protein expressions,cytosol cytochrome C concentration.CONCLUSION TCS′s gastroprotective effect was closely connected with boosting TFF1 expression,acti⁃vating TFF1-mediated EGF/EGFR pathway,thus restraining mitochondrial-dependent apoptosis,which provided new insights into interpreting its underlying mechanism and promised to act as a candidate drug to treat gastric mucosal injury.

Protective role of fruits of Rosa odorata var. gigantea against WIRSinduced gastric mucosal injury in rats by modulating pathway related to inflammation, oxidative stress and apoptosis

Objective:Rosa odorata var.gigantea is a popular medicinal plant.Some studies have demonstrated that ethanolic extract of the fruits of R.odorata var.gigantea(FOE)has gastroprotective properties.The aim of this study was to investigate the gastroprotective activity of FOE on water immersion restrained stress(WIRS)-induced gastric mucosal injury in a rat model and elucidate the possible molecular mechanisms involved.Methods:A rat stress ulcer model was established in this study using WIRS.After rats were treated with FOE orally for 7 d,the effect of FOE treatment was analyzed by hematoxylin and eosin(H&E)staining,and the changes of inflammatory factors,oxidative stress factors,and gastric-specific regulatory factors and pepsin in the blood and gastric tissues of rats were examined by ELISA assay.Molecular mechanism of FOE was investigated by immunohistochemical assay and Western blot.Results:Compared with the WIRS group,FOE could diminish both the macroscopic and microscopic pathological morphology of gastric mucosa.FOE significantly preserved the antioxidants glutathione peroxidase(GSH-PX),superoxide dismutase(SOD)and catalase(CAT)contents;anti-inflammatory cytokines interleukin-10(IL-10)and prostaglandin E2(PGE2)levels as well as regulatory factors tumor necrosis factor-a(TGF-a)and somatostatin(SS)contents,while decreasing malondialdehyde(MDA),nitric oxide synthase(iNOS),tumor necrosis factor(TNF-a),interleukin-1b(IL-1b),interleukin-6(IL-6),gastrin(GAS)and endothelin(ET)levels.Moreover,FOE distinctly upregulated the expression of Nrf2,HO-1,Bcl2 and proliferating cell nuclear antigen(PCNA).In addition,FOE activated the expression of p-EGFR and downregulated the expression of NF-jB,Bax,Cleaved-caspase-3,Cyto-C and Cleaved-PARP1,thus promoting gastric mucosal cell survival.Conclusion:The current work demonstrated that FOE exerted a gastroprotective activity against gastric mucosal injury induced by WIRS.The underlying mechanism might be associated with the improvement of anti-inflammatory,anti-oxidation and anti-apoptosis systems.

Effect of Weikang Capsule(胃康胶囊)on Aspirin-Related Gastric and Small Intestinal Mucosal Injury

Objective To investigate the effects of Weikang Capsule(胃康胶囊,WKC)on aspirin-related gastric and small intestinal mucosal injury by magnetically controlled capsule endoscopy(MCCE).Methods Patients taking enteric-coated aspirin aged 40-75 years were enrolled in Beijing Anzhen Hospital,Capital Medical University from January 2019 to December 2019.The patients continued taking aspirin Tablet(100 mg per day)and underwent MCCE before and after 1-month combined treatment with WKC(0.9 g per time orally,3 times per day).The gastrointestinal symptom score,gastric Lanza score,the duodenal,jejunal and ileal mucosal injury scores were used to evaluate the gastrointestinal injury before and after treatment.Adverse events including nausea,vomiting,abdominal pain,abdominal distension,abdominal discomfort,dizziness,or headache during MCCE and combined treatment were observed and recorded.Results Twenty-two patients(male/female,13/9)taking enteric-coated aspirin aged 59.5±11.3 years with a duration of aspirin use of 28.0(1.0,48.0)months were recruited.Compared with pre-treatment,the gastrointestinal symptom rating scale scores,gastric Lanza scores,and duodenal mucosal injury scores were significantly reduced after 1-month WKC treatment(P<0.05),and jejunal and ileal mucosal injury scores showed no obvious change.No adverse events occurred during the trial.Conclusions WKC can alleviate gastrointestinal symptoms,as well as gastric and duodenal mucosal injuries,in patients taking enteric-coated aspirin;it does not aggravate jejunal or ileal mucosal injury,which may be an effective alternative for these patients(Clinical trial registry No.ChiCTR1900025451).