pCLE highlights distinctive vascular patterns in early gastric cancer and in gastric diseases with high risk of malignant complications.

Endoscopy is widely used to detect and diagnose precancerous lesions and gastric cancer (GC). The probe-based Confocal Laser Endomicroscopy (pCLE) is an endoscopic technique suitable for subcellular resolution and for microvasculature analyses. The aim of this study was to use pCLE to identify specific vascular patterns in high-risk and early stage GC. Mucosal architecture, vessel tortuosity, enlargements and leakage were assessed in patients with autoimmune gastritis and early gastric cancer (EGC). We were able to stratify gastritis patients by identifying distinct vascular profiles: gastritis was usually associated with increased vascularization characterized by a high number of tortuous vessels, which were also found in atrophic autoimmune disease. Leaky and tortuous vessels, distributed in a spatially irregular network, characterized the atrophic metaplastic mucosa. The mucosal vasculature of EGC patients displayed tortuous vessels, but unlike what detected in atrophic gastritis, they appeared patchy, as is in neoplastic gastric tissue. Very importantly, we detected vascular changes even in areas without lesions, supporting the contention that vascular alterations may provide a favorable microenvironment for carcinogenesis. This report confirms that pCLE is a valid endoscopic approach to improve the definition of patients with malignant lesions or at increased risk for GC by assessing vascular changes.

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.

Melatonin ameliorates aging-related impaired angiogenesis in gastric endothelial cells via local actions on mitochondria and VEGF-survivin signaling.

Tissue injury healing is impaired in aging, and this impairment is caused in part by reduced angiogenesis. Melatonin, a neuroendocrine hormone that regulates sleep and circadian rhythm, is also produced in the gastrointestinal tract. The expression of melatonin receptors MT1 and MT2 in gastric endothelial cells and their roles in aging-related impairment of gastric angiogenesis have not been examined. We hypothesized that MT1 and MT2 expression is reduced in gastric endothelial cells of aging rats and that melatonin treatment can upregulate their expression and improve angiogenesis. We examined the expression of MT1 and MT2 in gastric endothelial cells (GECs) isolated from young and aging rats. We also examined the effects of melatonin treatment on angiogenesis, GEC mitochondrial function, expression of vascular endothelial growth factor (VEGF), its signaling receptor (VEGFR-2), and the inhibitor of apoptosis protein, survivin. Young and aging GECs expressed MT1 (in the cytoplasm and mitochondria) and MT2 (in nucleus and mitochondria). In aging GECs, MT1 and MT2 levels, in vitro angiogenesis, and mitochondrial membrane potential were significantly reduced (by 1.5-fold, 1.9-fold, 3.1-fold, and 1.63-fold, respectively) compared with young GECs. Melatonin treatment of aging GECs significantly increased MT1 and MT2 expression compared with the controls, induced nuclear translocation of MT1, and significantly ameliorated the aging-related impairment of angiogenesis and mitochondrial function. Aging GECs have significantly reduced MT1 and MT2 expression, angiogenesis, and mitochondrial membrane potential compared with young GECs. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function.NEW & NOTEWORTHY This study showed reduced expression of melatonin receptors MT1 and MT2, angiogenesis, and mitochondrial function in gastric endothelial cells (GECs) isolated from aging rats. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function. These studies provide new insight into the mechanisms of the aging-related impairment of angiogenesis and delayed tissue injury healing and provide a rationale for melatonin treatment to reverse these abnormalities.

Novel Hydrogen Sulfide (H2S)-Releasing BW-HS-101 and Its Non-H2S Releasing Derivative in Modulation of Microscopic and Molecular Parameters of Gastric Mucosal Barrier.

Hydrogen sulfide (H2S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H2S-prodrug, BW-HS-101 with the ability to release H2S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5-50 µmol/kg) or its analogue without the ability to release H2S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE2 concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-γ, TNF-α, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 µmol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H2S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H2S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H2S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways.

Intra-mural distribution of the blood vessels in the stomach demonstrated by contrast medium injection: a cadaver study.

PURPOSE: With advances in diagnostic imaging techniques of gastric cancer screening with X-ray fluoroscopy, it has been suggested that mucosal projections induced by the vessels distributed in the submucosal layer of the stomach may be mistaken for abnormal mucosal folds. In this study, we aimed to describe the distribution of blood vessels in the submucosal layer of the stomach to improve the diagnostic accuracy of screening of gastric cancer. METHODS: Twenty-four stomachs from Japanese cadavers were used in this study. Uncolored or colored contrast agents were injected into arteries and/or veins for macroscopic analyses, X-ray imaging, and methyl salicylate clearing. In addition, histological analysis was performed to examine blood vessels distributed inside the stomach wall. RESULTS: Following contrast agent injection, thick blood vessels were distributed perpendicular to both curvature sides, and branches parallel to both curvature sides flowed from these thick blood vessels, and a vascular network was formed throughout the stomach wall. This vascular network had intra-mural anastomoses connecting both curvature sides. Moreover, in histological analyses, blood vessels depicted by injection were mainly distributed in the submucosal layer. CONCLUSION: This study strongly suggests that the mucosal projections induced by arteries and veins in the submucosal layer could be mistaken for abnormal mucosal folds. Therefore, a better understanding of the vascular distribution in the submucosal layer is important to improve diagnostic accuracy from imaging studies of the stomach. The information provided by this research may facilitate better accuracy in diagnosis and reduce the number of unnecessary invasive procedures.

Protective Effects of Wheat Peptides against Ethanol-Induced Gastric Mucosal Lesions in Rats: Vasodilation and Anti-Inflammation.

Alcohol consumption increases the risk of gastritis and gastric ulcer. Nutritional alternatives are considered for relieving the progression of gastric mucosal lesions instead of conventional drugs that produce side effects. This study was designed to evaluate the gastroprotective effects and investigate the defensive mechanisms of wheat peptides against ethanol-induced acute gastric mucosal injury in rats. Sixty male Sprague-Dawley rats were divided into six groups and orally treated with wheat peptides (0.1, 0.2, 0.4 g/kgbw) and omeprazole (20 mg/kgbw) for 4 weeks, following absolute ethanol administration for 1 h. Pretreatment with wheat peptides obviously enhanced the vasodilation of gastric mucosal blood vessels via improving the gastric mucosal blood flow and elevating the defensive factors nitric oxide (NO) and prostaglandin E2 (PGE2), and lowering the level of vasoconstrictor factor endothelin (ET)-1. Wheat peptides exhibited anti-inflammatory reaction through decreasing inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, and increasing trefoil factor 1 (TFF1) levels. Moreover, wheat peptides significantly down-regulated the expression of phosphorylated nuclear factor kappa-B (p-NF-κB) p65 proteins in the NF-κB signaling pathway. Altogether, wheat peptides protect gastric mucosa from ethanol-induced lesions in rats via improving the gastric microcirculation and inhibiting inflammation mediated by the NF-κB signaling transduction pathway.

Outcomes of Hemospray therapy in the treatment of intraprocedural upper gastrointestinal bleeding post-endoscopic therapy.

INTRODUCTION: With increasing advances in minimally invasive endoscopic therapies and endoscopic resection techniques for luminal disease, there is an increased risk of post-procedure bleeding. This can contribute to significant burden on patient's quality of life and health resources when reintervention is required. Hemospray (Cook Medical, North Carolina, USA) is a novel haemostatic powder licensed for gastrointestinal bleeding. The aim of this single-arm, prospective, non-randomised multicentre international study is to look at outcomes in patients with upper gastrointestinal bleeds following elective endoscopic therapy treated with Hemospray to achieve haemostasis. METHODS: Data was prospectively collected on the use of Hemospray from 16 centres (January 2016-November 2019). Hemospray was used during the presence of progressive intraprocedural bleeding post-endoscopic therapy as a monotherapy, dual therapy with standard haemostatic techniques or rescue therapy once standard methods had failed. Haemostasis was defined as the cessation of bleeding within 5 min of the application of Hemospray. Re-bleeding was defined as a sustained drop in haemoglobin (>2 g/l), haematemesis or melaena with haemodynamic instability after the index endoscopy. RESULTS: A total of 73 patients were analysed with bleeding post-endoscopic therapy. The median Blatchford score at baseline was five (interquartile range 0-9). The median Rockall score was six (interquartile range 5-7). Immediate haemostasis following the application of Hemospray was achieved in 73/73 (100%) of patients. Two out of 57 (4%) had a re-bleed post-Hemospray, one was following oesophageal endoscopic mucosal resection and the other post-duodenal endoscopic mucosal resection. Both patients had a repeat endoscopy and therapy within 24 h. Re-bleeding data was missing for 16 patients, and mortality data was missing for 14 patients. There were no adverse events recorded in association with the use of Hemospray. CONCLUSION: Hemospray is safe and effective in achieving immediate haemostasis following uncontrolled and progressive intraprocedural blood loss post-endoscopic therapy, with a low re-bleed rate.

Bleeding after endoscopic submucosal dissection of gastric lesions.

Endoscopic submucosal dissection (ESD) is generally used to treat gastric mucosal and submucosal lesions. Nevertheless, ESD is more difficult and complicated to perform than a traditional endoscopic mucosal resection, which can increase the incidence of various complications including hemorrhage, perforation and infection. Hemorrhage is a major post-ESD complication. Prevention and early diagnosis of post-ESD bleeding for gastric lesions are closely associated with the efficacy and safety of the operation. Many studies have reported the risks of and the preventative measures for hemorrhage after gastric ESD, but there remain some issues to be solved. We thus reviewed the risk factors, precautions and treatments for hemorrhage after ESD of gastric lesions.

A randomized-controlled trial of arginine infusion in severe sepsis on microcirculation and metabolism.

BACKGROUND & AIMS: Sepsis is hypothesized as an arginine deficient state, with lack of nitric oxide (NO) for adequate microcirculation and local perfusion. This study aimed to investigate if prolonged (72-h) intravenous l-arginine administration in sepsis patients improves microcirculation. Secondly, effects on arginine and protein metabolism, and organ function were studied. METHODS: Critically ill patients with a diagnosis of septic shock participated in a long-term (72 h) randomized double-blind placebo-controlled parallel-group study. l-arginine-HCl (1.2 µmol kg-1 min-1; n = 9) or l-alanine (isocaloric control: 2.4 µmol kg-1 min-1; n = 9) was continuously infused. Primary study outcome was microcirculation, assessed as gastric mucosal perfusion by gastric tonometry (Pr-aCO2 gap) and skin perfusion by Laser Doppler flowmetry. Secondary endpoints were whole body (WB) arginine and protein metabolism, organ function and clinical outcomes. We measured global hemodynamics continuously for safety monitoring. Statistical analyses were performed by mixed model for repeated measures with treatment by time interaction as estimate for between-group difference. RESULTS: Pr-aCO2 increased only in the l-arginine group (p = 0.006), without a significant between-group difference (p = 0.17). We found no significant differences in skin perfusion parameters. l-arginine infusion resulted in a larger increase of plasma arginine and ornithine concentrations (p < 0.01), WB (endogenous) arginine appearance (p < 0.001), WB NO synthesis (p = 0.027) and WB arginine to urea conversion (p < 0.001) than infusion of l-alanine. We found no effect on global hemodynamics, and protein metabolism by l-arginine infusion. Organ function parameters were unaffected, except for a significant difference between groups in intra-abdominal pressure over time (p = 0.029). CONCLUSIONS: Prolonged intravenous l-arginine administration does not improve local perfusion and organ function despite an increase in WB NO synthesis. Administration is safe with regard to global hemodynamics, but the observed increase in Pr-aCO2 and intra-abdominal pressure warrants careful application of l-arginine infusion and further research, especially in the early stage of septic shock.

Effect of Pravastatin Pretreatment and Hypercapnia on Intestinal Microvascular Oxygenation and Blood Flow During Sepsis.

INTRODUCTION: In septic patients, adequate microvascular oxygenation (µHBO2) of the intestine is vital for their outcome. Recent studies suggest that statins can ameliorate septic microcirculation in a variety of tissues. However, the effect on intestinal microvascular oxygenation and blood flow is largely unknown. Furthermore, there are indications that statin therapy might not be beneficial in the presence of hypercapnia, as observed in septic acute respiratory distress syndrome (ARDS) patients. Therefore, the present study explores the effect of pravastatin with and without additional moderate acute hypercapnia on intestinal microvascular oxygenation and blood flow in experimental sepsis. METHODS: Forty male Wistar rats were randomized into four groups. Half of the animals received 0.2 mg • kg pravastatin s.c., the other half received the same volume as vehicle (NaCl 0.9%). After 18 h, colon ascendens stent peritonitis surgery was conducted in all animals to induce sepsis. Twenty-four hours after surgery, baseline was established and the animals were subjected to either 120 min of normocapnic (pCO2 40 ±â€Š6 mm Hg) or moderate hypercapnic (pCO2 72 ±â€Š10 mm Hg) ventilation. Microcirculatory oxygenation (µHBO2) and perfusion (µflow) of the colon were continuously recorded using tissue reflectance spectrophotometry and laser Doppler, respectively. RESULTS: In normocapnic septic animals µHBO2 decreased over time (-8.4 ±â€Š8.7%; P < 0.05 vs. baseline), whereas after pravastatin pretreatment µHBO2 remained constant (-1.9 ±â€Š5.7% vs. baseline). However, in hypercapnic septic animals pretreated with pravastatin µHBO2 declined significantly over time (-8.9 ±â€Š11.8%; P < 0.05 vs. baseline) and was significantly lower compared with normocapnic pravastatin-pretreated animals. µflow did not change over time in any group. CONCLUSION: Pravastatin pretreatment ameliorates the intestinal microvascular oxygenation in sepsis and thus seems to prevent intestinal hypoxia. Furthermore, we demonstrated that additional hypercapnia abolishes this effect, indicating why septic ARDS patients might not benefit from pravastatin therapy.

Linked color imaging identifies important risk factors associated with gastric cancer after successful eradication of Helicobacter pylori.

BACKGROUND AND AIMS: Limited studies have evaluated the risk factors of gastric cancer (GC) after eradication of Helicobacter pylori (H pylori) using endoscopic findings. We aimed to investigate GC detection-related endoscopic findings after eradication of H pylori using linked color imaging (LCI), a novel image-enhanced endoscopy. METHODS: This single-center, cross-sectional study evaluated background mucosa-associated endoscopic findings described in the Kyoto classification of gastritis in patients with newly detected GC after eradication of H pylori (CA group, n = 109) and those without GC (NC group, n = 85) using white-light imaging (WLI) and LCI. RESULTS: Severe atrophy and map-like redness were significantly more frequent in the CA group than in the NC group using WLI (79.8% vs 63.5%, P = .01; 61.5% vs 37.7%, P = .001, respectively) and LCI (79.8% vs 63.5%, P = .01; 78.0% vs 45.9%, P < .0001, respectively). Regular arrangement of collecting venules (RAC) was significantly less frequent in the CA group than in the NC group using WLI (40.3% vs 64.7%, P = .0009) and LCI (37.6% vs 62.4%, P = .0006). Map-like redness was an independent positive risk factor (WLI: odds ratio [OR], 2.05; 95% confidence interval [CI], 1.09-3.87; P = .03; LCI: OR, 3.62; 95% CI, 1.88-6.97; P < .001), whereas RAC was an independent negative risk factor (WLI: OR, 0.42; 95% CI, 0.21-0.82; P = .01; LCI: OR, 0.46; 95% CI, 0.23-0.93, P = .03) for detection of GC after eradication of H pylori. CONCLUSIONS: Map-like redness, which was identified more frequently using LCI than WLI, and the absence of RAC were associated with detection of GC after eradication of H pylori.

The role of hydrogen sulfide in gastric mucosal damage.

Gastrointestinal disease is a major global threat to public health. In the past few decades, numerous studies have focuses on the application of small molecule gases in the disease treatment. Increasing evidence has shown that hydrogen sulfide (H2S) has anti-inflammatory and anti-oxidative effects, and can regulate gastric mucosal blood flow in the gastric mucosa. After gastric mucosa damage, the level of H2S in the stomach decreases. Administration of H2S can protect and repair the damaged gastric mucosa. Therefore, H2S is a new target for the repair and treatment of gastric mucosa damage. In this review, we introduce the roles of H2S in the treatment of gastric mucosa damage and provide the potential strategies for further clinical treatment.

Feasibility of gastric endoscopic submucosal dissection with continuous low-dose aspirin for patients receiving dual antiplatelet therapy.

BACKGROUND: Endoscopic submucosal dissection (ESD) for gastric neoplasms during continuous low-dose aspirin (LDA) administration is generally acceptable according to recent guidelines. This retrospective study aimed to investigate the effect of continuous LDA on the postoperative bleeding after gastric ESD in patients receiving dual antiplatelet therapy (DAPT). AIM: To investigate the feasibility of gastric ESD with continuous LDA in patients with DAPT. METHODS: A total of 597 patients with gastric neoplasms treated with ESD between January 2010 and June 2017 were enrolled. The patients were categorized according to type of antiplatelet therapy (APT). RESULTS: The postoperative bleeding rate was 6.9% (41/597) in all patients. Patients were divided into the following two groups: no APT (n = 443) and APT (n = 154). APT included single-LDA (n = 95) and DAPT (LDA plus clopidogrel, n = 59) subgroups. In the single-LDA and DAPT subgroups, 56 and 39 patients were received continuous LDA, respectively. The bleeding rate with continuous single-LDA (10.7%) was similar to that with discontinuous single-LDA (10.3%) (P > 0.99). Although the bleeding rate with continuous LDA in patients receiving DAPT (23.1%) was higher than that with discontinuous LDA in patients receiving DAPT (5.0%), no significant difference was observed (P = 0.141). CONCLUSION: The bleeding rate with continuous LDA in patients receiving DAPT was not statistically different from that with discontinuous LDA in patients receiving DAPT. Therefore, continuous LDA administration may be acceptable for ESD in patients receiving DAPT, although patients should be carefully monitored for possible bleeding.