NR0B2 Is a Key Factor for Gastric Diseases: A GEO Database Analysis Combined with Drug-Target Mendelian Randomization.

Small Heterodimer Partner (SHP; NR0B2) is an orphan receptor that acts as a transcriptional regulator, controlling various metabolic processes, and is a potential therapeutic target for cancer. Examining the correlation between the expression of NR0B2 and the risk of gastric diseases could open a new path for treatment and drug development. The Gene Expression Omnibus (GEO) database was utilized to explore NR0B2 gene expression profiles in gastric diseases. Co-expressed genes were identified through Weighted Correlation Network Analysis (WGCNA), and GO enrichment was performed to identify potential pathways. The Xcell method was employed to analyze immune infiltration relationships. To determine the potential causal relationship between NR0B2 expression and gastric diseases, we identified six single-nucleotide polymorphisms (SNPs) as a proxy for NR0B2 expression located within 100 kilobases of NR0B2 and which are associated with triglyceride homeostasis and performed drug-target Mendelian randomization (MR). Bioinformatics analysis revealed that NR0B2 expression levels were reduced in gastric cancer and increased in gastritis. GO analysis and Gene Set Enrichment Analysis (GSEA) showed that NR0B2 is widely involved in oxidation-related processes. Immune infiltration analyses found that NR0B2 was associated with Treg. Prognostic analyses showed that a low expression of NR0B2 is a risk factor for the poor prognoses of gastric cancer. MR analyses revealed that NR0B2 expression is associated with a risk of gastric diseases (NR0B2 vs. gastric cancer, p = 0.006, OR: 0.073, 95%CI: 0.011-0.478; NR0B2 vs. gastric ulcer, p = 0.03, OR: 0.991, 95%CI: 0.984-0.999; NR0B2 vs. other gastritis, p = 0.006, OR:3.82, 95%CI: 1.468-9.942). Our study confirms the causal relationship between the expression of NR0B2 and the risk of gastric diseases, and highlights its role in the progression of gastric cancer. The present study opens new avenues for exploring the potential of drugs that either activate or inhibit the NR0B2 receptor in the treatment of gastric diseases.

Liquid L-T4 therapy in hypothyroid patients with gastric diseases, an observational study.

Introduction: This is an observational and retrospective study, in which we have analyzed data from patients affected by gastric diseases (p) who have been treated with liquid L-T4 (L-LT4;84 p), or tablet L-T4 (T-LT4;120 p), for the replacement therapy of hypothyroidism. The aim of the study is to compare the stability of TSH [normal range, 0.3-3.5 µIU/ml] in these patients. Methods: All p assumed L-T4 30 minutes before breakfast. The types of gastric disease were: a) T-LT4 group: 74 chronic gastritis (CG); 4 gastrectomy for gastric cancer (GTx); 42 gastro-plastics (GP); b) L-LT4 group: 60 CG; 3 GTx; 21 GP (p>0.05). 66% p in T-LT4 group were chronically treated with proton pump inhibitors (PPI), against 51% in L-LT4 group (p>0.05). The frequency of Helicobacter Pylori infection was 17% in both T-LT4 and L-LT4 groups. The gender distribution, mean age and body weight were similar in the 2 groups (p>0.05). The mean L-T4 dosage in T-LT4 group at the basal evaluation was 1.22+/-0.27 µg/kg/die, in the L-LT4 group 1.36+/-0.22 µg/kg/die (p>0.05). Results: At the basal evaluation the prevalence of patients with a TSH>3.5 µIU/mL in T-LT4 group was 36%, in L-LT4 group 46% (p<0.05). After adjustment of the dosage of the LT-4 therapy, the p were re-evaluated in an interval range of 5-9 months, for 4 times, during an overall period ranging from 23 to 31 months. At the first re-evaluation, the prevalence of p with a TSH>3.5 µIU/mL was 13% in both groups. At the second re-evaluation, the prevalence of p with a TSH>3.5 µIU/mL in T-LT4 group was 26%, in L-LT4 group 13% (p>0.05). At the third re-evaluation, the prevalence of p with TSH<3.5 µIU/mL in T-LT4 group was 19%, in L-LT4 group 9% (p=0.05). At the fourth and last re-evaluation, the prevalence of patients with a TSH>3.5 µIU/mL in T-LT4 group was 18%, in L-LT4 group 5% (p<0.05). Mean FT4 and FT3 circulating levels were not significantly different in the two group at each visit. Discussion: These data suggest that the liquid L-T4 formulation therapy can result in a more stable control of TSH levels in hypothyroid patients with gastric disorders in the long-term follow-up.

Comparative pharmacokinetics of multi-components in normal and stomach cold syndrome rats after oral administration of Zingiberis Rhizoma - Jujubae Fructus herb pair and its single herb extracts by UHPLC-MS/MS.

The Zingiberis Rhizoma - Jujubae Fructus herb pair (ZJHP) is a classic herb pair in traditional Chinese medicine. The herb pair shows the effect of dispelling cold, harmonizing the middle and improving gastrointestinal function, and is widely used for patients with stomach cold syndrome (SCS), stomachache and anemofrigid cold. The gingerols, shogaols, flavonoids and triterpenic acids are the important bioactive ingredients of ZJHP. However, few pharmacokinetic studies have been investigated in vivo for the above compounds. To comprehend the kinetics of active components and promote their curative application, a fast and sensitive ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) method was established for simultaneous determination of 12 analytes in normal and SCS rats in this study. The results showed that the pharmacokinetic parameters (Cmax, Tmax, t1/2z, MRT0-t, AUC0-t and AUC0-∞) in SCS model were significantly different from those in normal rats. In addition, the pharmacokinetics of rats given ZJHP were also varied from single herb oral administration, especially in model condition. These results indicated that the in vivo processes of the above analytes changed under pathological conditions and the compatibility of the herb pair could significantly influence the absorption of active components, which might provide an insight and further supports for the clinical application of ZJHP.

LC-MS-Based Metabolomics Reveals the Mechanism of Protection of Berberine against Indomethacin-Induced Gastric Injury in Rats.

Berberine is a natural isoquinoline alkaloid with low toxicity, which exists in a wide variety of medicinal plants. Berberine has been demonstrated to exhibit potent prevention of indomethacin-induced gastric injury (GI) but the related mechanism remains unclear. In the present study, liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was applied for the first time to investigate the alteration of serum metabolites in the protection of berberine against indomethacin-induced gastric injury in rats. Subsequently, bioinformatics was utilized to analyze the potential metabolic pathway of the anti-GI effect of berberine. The pharmacodynamic data indicated that berberine could ameliorate gastric pathological damage, inhibit the level of proinflammatory factors in serum, and increase the level of antioxidant factors in serum. The LC-MS-based metabolomics analysis conducted in this study demonstrated the presence of 57 differential metabolites in the serum of rats with induced GI caused by indomethacin, which was associated with 29 metabolic pathways. Moreover, the study revealed that berberine showed a significant impact on the differential metabolites, with 45 differential metabolites being reported between the model group and the group treated with berberine. The differential metabolites were associated with 24 metabolic pathways, and berberine administration regulated 14 of the 57 differential metabolites, affecting 14 of the 29 metabolic pathways. The primary metabolic pathways affected were glutathione metabolism and arachidonic acid metabolism. Based on the results, it can be concluded that berberine has a gastroprotective effect on the GI. This study is particularly significant since it is the first to elucidate the mechanism of berberine's action on GI. The results suggest that berberine's action may be related to energy metabolism, oxidative stress, and inflammation regulation. These findings may pave the way for the development of new therapeutic interventions for the prevention and management of NSAID-induced GI disorders.

Analysis of Helicobacter pylori resistance in patients with different gastric diseases.

Helicobacter pylori (H. pylori) resistance is the most important risk factor for eradication failure. However, in most regions, antibiotic resistance rates of H. pylori in patients with different types of gastric mucosal lesions are still unclear. An 8-year clinical retrospective cohort study involving 2847 patients was performed. In this study, we first summarized and compared the resistance status of H. pylori in different years, ages, sexes, and gastric diseases. The resistance profiles of amoxicillin (AMX), clarithromycin (CLR), levofloxacin (LVX) and furazolidone (FR) and their changing trends in the clinic were described. Then, multiple antibiotic resistance in different gastric diseases and years were described and compared. The relationship between proton pump inhibitor (PPI) medication history and antibiotic resistance in H. pylori was also explored. Finally, an antibiotic resistance risk model was constructed for clinical resistance risk prediction. The overall resistance rates of AMX, CLR, LVX and FR in gastric diseases were 8.18%, 38.11%, 43.98%, and 13.73%, respectively. The mono resistance, double resistance, triple resistance, and quadruple resistance rates were 30.17%, 25.96%, 6.46%, and 0.63%, respectively. Compared with the period from 2014 to 2016, the rates of mono-resistance and multiple resistance all showed relatively downward trends in the past 5 years. Factors including age, sex, type of gastric lesions and recent PPI treatment history are associated with the antibiotic resistance rate of H. pylori. Atrophic gastritis is an important clinical feature of high-risk antibiotic resistance in H. pylori-infected patients. Patients with atrophic gastritis have higher risk of resistant strains infection. In this study, our data provide the association between antibiotic resistance of H. pylori and gastritis pattern, which indicate the higher risk of resistant strain infection if the patients with atrophic gastritis, PPI history and older age.

Xiaojianzhong decoction attenuates aspirin-induced gastric mucosal injury via the PI3K/AKT/mTOR/ULK1 and AMPK/ULK1 pathways.

CONTEXT: Xiaojianzhong decoction (XJZD), classically prescribed in Chinese medicine, has protective and healing effects on gastric mucosal injury. However, the exact mechanism behind this effect remains unclear. OBJECTIVE: To investigate the effect of XJZD on gastric mucosal injury and explore its underlying mechanisms. MATERIALS AND METHODS: C57BL/6 mice were randomized into six groups (n = 10): the control group receiving sterile water, the model (aspirin 300 mg/kg), the XJZD high-dose (12 g/kg), XJZD medium-dose (6 g/kg), XJZD low-dose (3 g/kg) and omeprazole (20 mg/kg) groups, by gavage daily for 14 days. The area of gastric mucosal injury, mucosal injury index and degree of histopathological damage were analysed. Gastric mucosal epithelial cell apoptosis was detected. Epithelial cell autophagy was observed. The expression levels of tight junction proteins and proteins related to apoptosis, autophagy and the pentose phosphate pathway were analysed. RESULTS: The results showed that after treatment with XJZD (12, 6 and 3 g/kg), the mucosal injury area was reduced (83.4%, 22.6% and 11.3%), the expression level of ZO-1 and occludin was up-regulated, the apoptosis rate of epithelial cells was reduced (40.8%, 25.4% and 8.7%), the expression of autophagy-related proteins LC3 and Beclin1 was decreased and the expression of p62 was increased, the PI3K/AKT/mTOR/ULK1(ser757) signalling pathway was activated, and the AMPK/ULK1(ser317) signalling pathway was inhibited. In addition, XJZD can antagonize the imbalance of redox homeostasis caused by aspirin and protect the gastric mucosa. DISCUSSION AND CONCLUSIONS: XJZD protects against aspirin-induced gastric mucosal injury, implying it to be a potential therapeutic agent.

Stomach perforation-induced general occlusion/occlusion-like syndrome and stable gastric pentadecapeptide BPC 157 therapy effect.

BACKGROUND: Using rat stomach perforation as a prototypic direct lesion applied in cytoprotection research, we focused on the first demonstration of the severe occlusion/ occlusion-like syndrome induced by stomach perforation. The revealed stomach-induced occlusion/occlusion-like syndrome corresponds to the previously described occlusion/occlusion-like syndromes in rats suffering multicausal pathology and shared severe vascular and multiorgan failure. This general point was particularly reviewed. As in all the described occlusion/occlusion-like syndromes with permanent occlusion of major vessels, peripheral and central, and other similar noxious procedures that severely affect endothelium function, the stable gastric pentadecapeptide BPC 157 was resolving therapy. AIM: To reveal the stomach perforation-induced general occlusion/occlusion-like syndrome and BPC 157 therapy effect. METHODS: The procedure included deeply anesthetized rats, complete calvariectomy, laparotomy at 15 min thereafter, and stomach perforation to rapidly induce vascular and multiorgan failure occlusion/occlusion-like syndrome. At 5 min post-perforation time, rats received therapy [BPC 157 (10 µg or 10 ng/kg) or saline (5 mL/kg, 1 mL/rat) (controls)] into the perforated defect in the stomach). Sacrifice was at 15 min or 60 min post-perforation time. Assessment (gross and microscopy; volume) included: Brain swelling, peripheral vessels (azygos vein, superior mesenteric vein, portal vein, inferior caval vein) and heart, other organs lesions (i.e., stomach, defect closing or widening); superior sagittal sinus, and peripherally the portal vein, inferior caval vein, and abdominal aorta blood pressures and clots; electrocardiograms; and bleeding time from the perforation(s). RESULTS: BPC 157 beneficial effects accord with those noted before in the healing of the perforated defect (raised vessel presentation; less bleeding, defect contraction) and occlusion/occlusion-like syndromes counteraction. BPC 157 therapy (into the perforated defect), induced immediate shrinking and contraction of the whole stomach (unlike considerable enlargement by saline application). Accordingly, BPC 157 therapy induced direct blood delivery via the azygos vein, and attenuated/eliminated the intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension. Thrombosis, peripherally (inferior caval vein, portal vein, abdominal aorta) and centrally (superior sagittal sinus) BPC 157 therapy markedly reduced/annihilated. Severe lesions in the brain (swelling, hemorrhage), heart (congestion and arrhythmias), lung (hemorrhage and congestion), and marked congestion in the liver, kidney, and gastrointestinal tract were markedly reduced. CONCLUSION: We revealed stomach perforation as a severe occlusion/occlusion-like syndrome, peripherally and centrally, and rapid counteraction by BPC 157 therapy. Thereby, further BPC 157 therapy may be warranted.

An aqueous extract from Artemisia capillaris inhibits acute gastric injury through mucosal stabilization.

BACKGROUND: Artemisia capillaris is among the most abundantly used traditional medicines, utilized in East Asia to treat diverse illnesses, including gastrointestinal tract diseases. We previously reported that an aqueous extract of A. capillaris (AEAC) inhibited gastric inflammation induced by HCl/ethanol via reactive oxygen species scavenging and NF-κB downregulation. To date, the pharmacological potential of AEAC for promoting mucosal integrity has not been studied. RESULTS: Here, we report that a single treatment with AEAC increased mucus production, and repeated administration of AEAC abolished HCl/ethanol-induced mucosal injury in vivo. Single- and multiple-dose AEAC treatments measurably increased the expression of mucosal stabilizing factors in vivo, including mucin (MUC) 5 AC, MUC6, and trefoil factor (TFF) 1 and TFF2 (but not TFF3). AEAC also induced mucosal stabilizing factors in both SNU-601 cells and RGM cells through phosphorylation of extracellular signal-regulated kinases. CONCLUSION: Taken together, our results suggest that AEAC protects against HCl/ethanol-induced gastritis by upregulating MUCs and TFFs and stabilizing the mucosal epithelium. © 2021 Society of Chemical Industry.

The effect of flunixin meglumine on eating and rumination variables in cows after omentopexy for correction of left displaced abomasum.

INTRODUCTION: Eating and rumination variables were recorded using a pressure sensor integrated into the noseband of a halter in 60 cows with left displaced abomasum (LDA) before and after postoperative administration of flunixin meglumine (FM). Group 1 comprised 9 healthy control cows that were used to establish reference intervals. Group 2 included 60 cows with LDA that received one of the following three treatments: intravenous saline solution (2A, n=20), 1.1 mg/kg FM (2B, n=20) or 2.2 mg/kg FM (2C, n=20) once daily for 3 days after right-flank omentopexy. Median eating times on the day before surgery were 93 (2A), 80 (2B) and 114 (2C) min, which were below the reference interval (246 to 381 min). On the day after surgery, eating times had increased significantly to 201 (2A), 172 (2B) and 216 (2C) min, after which time they continued to increase. Eating and rumination times, numbers of regurgitated feed boluses per day and chewing cycles per bolus did not differ among treated groups. Postoperative administration of FM did not affect eating and rumination variables in this study, and normalisation of these variables was attributable to surgical correction of LDA.

INTRODUCTION: Les variables d'alimentation et de rumination ont été enregistrées à l'aide d'un capteur de pression intégré à la muserolle d'un licol chez 60 vaches avec déplacement à gauche de la caillette (LDA) avant et après l'administration postopératoire de flunixine méglumine (FM). Le groupe 1 comprenait 9 vaches témoins en bonne santé qui ont été utilisées pour établir des intervalles de référence. Le groupe 2 comprenait 60 vaches avec LDA qui ont reçu l'un des trois traitements suivants : solution saline intraveineuse (2A, n=20), 1,1 mg/kg FM (2B, n=20) ou 2,2 mg/kg FM (2C, n= 20) une fois par jour pendant 3 jours après omentopexie par le flanc droit. La durée médiane des repas la veille de la chirurgie était de 93 (2A), 80 (2B) et 114 (2C) minutes, ce qui était inférieur à l'intervalle de référence (246 à 381 min). Le lendemain de la chirurgie, la durée des repas avait augmenté de manière significative à 201 (2A), 172 (2B) et 216 (2C) minutes, après quoi elle a continué à augmenter. Les temps de repas et de rumination, le nombre de bolus alimentaires régurgités par jour et les cycles de mastication par bolus ne différaient pas entre les groupes traités. L'administration postopératoire de FM n'a pas affecté les variables d'alimentation et de rumination dans cette étude et la normalisation de ces variables était attribuable à la correction chirurgicale de la LDA.

Role of the posterior mucosal defense barrier in portal hypertensive gastropathy.

Portal hypertensive gastropathy (PHG) is a complication of cirrhotic or noncirrhotic portal hypertension. PHG is very important in the clinic because it can cause acute or even massive blood loss, and its treatment efficacy and prognosis are poor. Currently, the incidence of PHG in patients with cirrhosis is 20-80%, but its pathogenesis is complicated and poorly understood. Studies have shown that portal hypertension can cause changes in gastric mucosal microcirculation hemodynamics, leading to changes in gastric mucosal histology and function and thereby weakening the mucosal defense barrier. However, no specific drug treatment plans are currently available. This article reviews the current literature to further our understanding of the mechanism underlying PHG and the relationship between PHG and the posterior mucosal defense barrier and to explore new therapeutic targets.

Investigating Helicobacter pylori-related pyloric hypomotility: functional, histological, and molecular alterations.

Multiple theories have been proposed describing the pathogenic mechanisms of Helicobacter pylori (H. pylori)-associated gastric motility disorders. We assessed ex vivo pyloric activity in H. pylori-infected rats, and tried to explore the associated ghrelin hormone alteration and pyloric fibrogenesis. In addition, miR-1 was assessed in pyloric tissue samples, being recently accused of having a role in smooth muscle dysfunction. Ninety adult male Wistar albino rats were assigned into nine groups: 1) control group, 2) sterile broth (vehicle group), 3) amoxicillin control, 4) omeperazole control, 5) clarithromycin control, 6) triple therapy control, 7) H. pylori- group, 8) H. pylori-clarithromycin group, and 9) H. pylori-triple therapy group. Urease enzyme activity was applied as an indicator of H. pylori infection. Ex vivo pyloric contractility was evaluated. Serum ghrelin was assessed, and histological tissue evaluation was performed. Besides, pyloric muscle miR-1 expression was measured. The immunological epithelial to mesenchymal transition (EMT) markers; transforming growth factor ß (TGFß), α-smooth muscle actin (α-SMA), and E-cadherin-3 were also evaluated. By H. pylori infection, a significant (P < 0.001) reduced pyloric contractility index was recorded. The miR-1 expression was decreased (P < 0.001) in the H. pylori-infected group, associated with reduced serum ghrelin, elevated TGFß, and α-SMA levels and reduced E-cadherin levels. Decreased miR-1 and disturbed molecular pattern were improved by treatment. In conclusion, H. pylori infection was associated with reduced miR-1, epithelial to mesenchymal transition, and pyloric hypomotility. The miR-1 may be a target for further studies to assess its possible involvement in H. pylori-associated pyloric dysfunction, which might help in the management of human H. pylori manifestations and complications.NEW & NOTEWORTHY This work is investigating functional, histopathological, and molecular changes underlying Helicobacter pylori hypomotility and is correlating these with miR-1, whose disturbance is supposed to be involved in smooth muscle dysfunction and cell proliferation according to literature. Epithelial to mesenchymal transition and reduced ghrelin hormone may contribute to H. pylori infection-associated hypomotility. H. pylori infection was associated with reduced pyloric miR-1 expression. Targeting miR-1 could be valuable in the clinical management of pyloric hypofunction.

ANKRD22 Drives Rapid Proliferation of Lgr5+ Cells and Acts as a Promising Therapeutic Target in Gastric Mucosal Injury.

BACKGROUND & AIMS: Rapid gastric epithelial progenitor cell (EPC) proliferation and inflammatory response inhibition play key roles in promoting the repair of gastric mucosal damage. However, specific targets inducing these effects are unknown. In this study, we explored the effects of a potential target, Ankyrin repeat domain 22 (ANKRD22). METHODS: An acute gastric mucosal injury model was established with Ankrd22-/- and Ankrd22+/+ mice by intragastric administration of acidified ethanol. Organoid culture and flow cytometry were performed to evaluate the effects of ANKRD22 on leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) gastric EPC proliferation. The mechanisms by which ANKRD22 affects gastric EPC proliferation and inflammatory responses were explored by mitochondrial Ca2+ influx and immunoblotting. Candidate ANKRD22 inhibitors then were screened virtually and validated in vitro and in vivo. RESULTS: After acute gastric mucosal injury, the number of Lgr5+ gastric EPCs was increased significantly in Ankrd22-/- mice compared with that in Ankrd22+/+ mice. Moreover, Ankrd22 knockout attenuated inflammatory cell infiltration into damaged gastric tissues. ANKRD22 deletion also reduced mitochondrial Ca2+ influx and cytoplasmic nuclear factor of activated T cells in gastric epithelial cells and macrophages, which further induced Lgr5+ gastric EPC proliferation and decreased macrophage release of tumor necrosis factor-α and interleukin 1α. In addition, a small molecule, AV023, was found to show similar effects to those produced by ANKRD22 deletion in vitro. Intraperitoneal injection of AV023 into the mouse model promoted the repair of gastric mucosal damage, with increased proliferation of Lgr5+ gastric EPCs and visible relief of inflammation. CONCLUSIONS: ANKRD22 inhibition is a potential target-based therapeutic approach for promoting the repair of gastric mucosal damage.

Proton-pump inhibitor vs. H2-receptor blocker use and overall risk of CKD progression.

BACKGROUND: The relationship between proton-pump inhibitor (PPI) use and chronic kidney disease (CKD) progression remains controversial. Specifically, there is a lack of data evaluating renal outcomes in established CKD patients. The aim of our study is to determine the risk of progression to end-stage kidney disease (ESKD) or death amongst CKD patients on PPI, histamine-2 receptor blocker (H2B), or no anti-acid therapy. METHODS: Using our CKD registry, we evaluated the relationship between PPI and H2B use and outcomes amongst patients with CKD (eGFR < 60), with at least 2 PCP visits in the year prior. A Cox proportional hazards model was used to evaluate the relationship between medication groups and overall mortality, while competing risks regression models were used to determine the risk of ESKD with death as a competing risk. RESULTS: 25,455 patients met inclusion criteria and were stratified according to medication group: no antacid therapy (15,961), PPI use (8646), or H2B use (848). At 4 years, the cumulative incidence of ESKD with death as a competing risk was 2.0% (95% CI: 1.7, 2.4), 1.5% (0.8, 2.8), and 1.6%(1.4, 1.9) among PPI, H2B, and no medication respectively (P = 0.22). The cumulative incidence of death with ESKD as a competing risk was 17.6% (95% CI: 16.6, 18.6), 16.7% (13.7, 19.8), and 17.3% (16.6, 18.0) (P = 0.71). CONCLUSIONS: Use of PPI in a CKD population was not associated with increased mortality or progression to ESKD when compared to H2 blocker and to no acid suppressing therapy.

Activation of AMPK/mTOR-driven autophagy and inhibition of NLRP3 inflammasome by saxagliptin ameliorate ethanol-induced gastric mucosal damage.

AIMS: Saxagliptin, a selective/potent dipeptidyl peptidase-4 inhibitor, has revealed remarkable anti-inflammatory features in murine models of nephrotoxicity, hepatic injury, and neuroinflammation. However, its potential effect on ethanol-induced gastric mucosal injury has not been examined. Hence, the present work investigated the prospect of saxagliptin to attenuate ethanol-evoked gastric injury, with emphasis on the AMPK/mTOR-driven autophagy and NLRP3/ASC/caspase-1 pathway. MATERIALS AND METHODS: In ethanol-induced gastropathy, the gastric tissues were examined by immunohistochemistry, immunoblotting, histopathology, and ELISA. KEY FINDINGS: The results demonstrated that saxagliptin (10 mg/kg; by gavage) suppressed the gastric pathological signs (area of gastric ulcer and ulcer index scores), histopathologic aberrations/damage scores, without provoking hypoglycemia in rats. These protective features were attributed to the enhancement of gastric mucosal autophagy flux, as proven with increased expression of LC3-II and Beclin 1, decreased accumulation of p62 SQSTM1, and activation of the autophagy-linked AMPK/mTOR pathway by increasing the expression of p-AMPK/AMPK and decreasing the expression of the autophagy suppressor p-mTOR/mTOR signal. In tandem, saxagliptin counteracted the ethanol-induced pro-apoptotic events by downregulating Bax, upregulating Bcl2 protein, and lowering the Bax/Bcl2 ratio. Equally important, saxagliptin suppressed the NLRP3 inflammasome in the gastric tissue by lowering the expression of NLRP3, ASC, and nuclear NF-κBp65, decreasing the activity of caspase-1, and diminishing the IL-1ß levels. In the same regard, saxagliptin suppressed the mucosal oxidative stress by lowering lipid peroxide levels, increasing GSH and GPx antioxidants, and activating Nrf2/HO-1 pathway. SIGNIFICANCE: Saxagliptin may be a promising intervention against ethanol-evoked gastropathy by activating AMPK/mTOR-driven autophagy and inhibiting NLRP3 inflammasome.

Zuojin Pill ameliorates inflammation in indomethacin-induced gastric injury via inhibition of MAPK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin Pill (ZJP) has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. But its effect on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury (GI) is still uncharted. AIM OF THE STUDY: This study aims to investigate the therapeutic effect and molecular mechanism of ZJP on indomethacin (IDO) induced gastric injury. MATERIALS AND METHODS: GI was induced in rat by oral administration of 5 mg/kg IDO. Then the rats were treated with ZJP (1.26, 2.52, 5.04 g/kg, ig). The changes of food intake, body weight, gastric pH and general state observation were carried out to determine the improvement of ZJP in IDO-induced GI: HE staining and AB-PAS staining was analyzed to characterize the thickness of gastric mucosa and micro mucosal injury; in order to elucidate the effect of ZJP on IDO-induced inflammatory injury, the inflammatory infiltration of gastric tissue was observed by MPO immunohistochemical method, and the contents of TNF-α, IL-6 and IL-10 were measured. Furthermore, the regulatory mechanism of ZJP in treating IDO-induced GI was predicted with the help of network pharmacology, and the expression levels of key proteins ERK, p-ERK, P38, p-P38, JNK, p-JNK were determined to elucidate the molecular mechanism of ZJP. RESULTS: Current data strongly demonstrated that ZJP alleviated food intake reduction, weight loss and gastric injury caused by IDO and made gastric pH and mucosal thickness return to normal. In addition, ZJP could reduce the level of MPO to alleviate the inflammatory infiltration of gastric tissue. Simultaneously, ZJP could down regulate the expression of TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage caused by inflammatory, and create a healing environment. Furthermore, ZJP could significantly inhibit the phosphorylation of ERK, p38 and JNK, which leaded to the increase of inflammatory factors and the damage of gastric mucosa. CONCLUSION: ZJP improved local inflammation by inhibiting MAPK signaling pathway, and had a good therapeutic effect on IDO-induced GI. This study has reference significance for the study of ZJP in the prevention and treatment of NSAID induced gastric injury. In addition, ZJP may be a new treatment option for the prevention and treatment of NSAID induced gastric disease.

The clinical efficacy of pentoxifylline and l-glutamine on ischemia and reperfusion injury in cattle with displaced abomasum: a longitudinal study.

This study aimed to assess the clinical efficacy of pentoxifylline (PTX) and L-glutamine (L-Gln) treatment on ischemia and reperfusion (I/R) injury in the abomasal tissue, acute phase response (APR), oxidative stress (OS), cytokine response, hemostatic, and coagulation disorders in the 96-h period before and after surgery in displaced abomasum (DA) cases. The study sample consisted of 48 dairy cows with DA that were categorized into four groups as group S (Sham group) (9 Left displaced abomasum (LDA)+3 Right displaced abomasum (RDA), group P (PTX) (10 LDA+2 RDA), group G (L-Gln) (10 LDA+2 RDA), and group P+G (PTX+L-Gln) (10 LDA+2 RDA). Acute-phase protein (Haptoglobin), oxidative stress indicators (malondialdehyde, nitric oxide, and glutathione), cytokines (tumor necrosis factor (TNF)-α and interleukin-1ß (IL-1ß), coagulation factors (D-Dimer, Antithrombin (ATIII), Thrombin-antithrombin complex, Plasminogen activator inhibitor-1), and enzyme activities (lactate dehydrogenase, gamma- -glutamyl transferase, sorbitol dehydrogenase, glutamate dehydrogenase, adenosine deaminase, myeloperoxidase, and creatine phosphokinase) in blood serum samples and coagulometric analyses of blood plasma were performed in samples taken before the operation and at 30 and 60 min and 2, 5, 10, 24, 48, 72, and 96 h after the operation. In DA cases, while post-operative treatment procedures with PTX and L-Gln were effective in decreasing APR and OS, these were ineffective in prohibiting the inflammatory response coordinated by cytokines. For the treatment and prevention of I/R injury in the DA cases, PTX and L-Gln procedures hold promise with their effects on APR, OS, and hemostatic dysfunction. Additional treatment procedures are required for the suppression of inflammatory response, and the effectiveness of preconditioning treatment may be evaluated.

Irsogladine maleate alters expression of a tight junction protein in portal hypertensive gastropathy.

BACKGROUND AND AIM: Portal hypertensive gastropathy (PHG) is characterized by noninflammatory edema and vasodilatation of the lamina propria of the mucosal epithelium. In addition, the alterations of intercellular junction proteins and dilatation of the endothelial gaps have been reported. In this study, we examined whether irsogladine maleate (IM), a gastric mucosal protective agent, has the potential to improve PHG by restoration of tight junctions (TJs). METHODS: Twenty-four patients with PHG were registered and randomly assigned into two groups: 12 patients in the IM-administration group and 12 patients in the non-administration group. In the administration group, IM (4 mg/day) was administered orally for 12 weeks. Gastric mucosa with a red color in patients with PHG were obtained endoscopically on the registration day and 12 weeks later. The endoscopic findings were evaluated, an immunohistochemical analysis of claudin-3 (a TJ protein) expression in gastric mucosal tissues by a laser microscope was performed, and claudin-3 expression was quantified by western blot analysis. RESULTS: Irsogladine maleate improved the degree of PHG in 2/12 patients endoscopically, in contrast to none of the 12 patients in the non-administration group. Immunohistochemical analysis showed that expression of claudin-3 increased in 8/12 patients in the IM-administration group and 2/12 patients in the non-administration group (P = 0.036). Western blot analysis revealed that the increase in claudin-3 after 12 weeks was significantly higher in the IM-administration group than in the non-administration group (P = 0.010). CONCLUSIONS: The present pilot study suggested that IM might improve the gastric mucosa in PHG through restoration of TJ-protein claudin-3.

Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching.

OBJECTIVE: The adverse effects of proton pump inhibitors (PPIs) have been documented for pneumonia; however, there is no consensus regarding whether the use of PPIs might be harmful regarding the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this regard, we aimed to measure the potential associations of the current use of PPIs with the infection rates of COVID-19 among patients who underwent SARS-CoV-2 testing. DESIGN: Data were derived from a Korean nationwide cohort study with propensity score matching. We included 132 316 patients older than 18 years who tested for SARS-CoV-2 between 1 January and 15 May 2020. Endpoints were SARS-CoV-2 positivity (primary) and severe clinical outcomes of COVID-19 (secondary: admission to intensive care unit, administration of invasive ventilation or death). RESULTS: In the entire cohort, there were 111 911 non-users, 14 163 current PPI users and 6242 past PPI users. After propensity score matching, the SARS-CoV-2 test positivity rate was not associated with the current or past use of PPIs. Among patients with confirmed COVID-19, the current use of PPIs conferred a 79% greater risk of severe clinical outcomes of COVID-19, while the relationship with the past use of PPIs remained insignificant. Current PPI use starting within the previous 30 days was associated with a 90% increased risk of severe clinical outcomes of COVID-19. CONCLUSION: Patients taking PPIs are at increased risk for severe clinical outcomes of COVID-19 but not susceptible to SARS-CoV-2 infection. This suggests that physicians need to assess benefit-risk assessments in the management of acid-related diseases amid the COVID-19 pandemic.