Influence of gastric inhibitory polypeptide on pentagastrinstimulated gastric acid secretion in patients with type 2 diabetes and healthy controls

AIM： Gastric inhibitory polypeptide is secreted from intestinal K-cells in response to nutrient ingestion and acts as an incretin hormone in human physiology. While animal experiments suggested a role for GIP as an inhibitor of gastric secretion, the GIP effects on gastric acid output in humans are still controversial. METHODS： Pentagastrin was administered at an infusion rate of 1 μg . kg^-1 . h^-1 over 300 min in 8 patients with type 2 diabetes （2 female, 6 male, 54± 10 years, BMI 30.5 ± 2.2 kg/m^2; no history of autonomic neuropathy） and 8 healthy subjects （2/6, 46 ± 6 years., 28.9 ± 5.3 kg/ m^2）. A hyperglycaemic clamp （140 mg/dl） was performed over 240 min. Placebo, GIP at a physiological dose （1 pmol . kg^-1 . min^-1）, and GIP at a pharmacological dose （4 mol . kg^-1 . min^-1） were administered over 60 min each. Boluses of placebo, 20 pmol GIP/kg, and 80 pmol GIP/kg were injected intravenously at the beginning of each infusion period, respectively. Gastric volume, acid and chloride output were analysed in 15-min intervals. Capillary and venous blood samples were drawn for the determination of glucose and total GIP. Statistics were carried out by repeated-measures ANOVA and one-way ANOVA. RESULTS： Plasma glucose concentrations during the hyperglycaemic clamp experiments were not different between patients with type 2 diabetes and controls. Steady-state GIP plasma levels were 61 ±8 and 79 ± 12 pmol/I during the low-dose and 327±35 and 327± 17 pmol/I during the high-dose infusion of GIP, in healthy control subjects and in patients with type 2 diabetes, respectively （P= 0.23 and p 0.99）. Pentagastrin markedly increased gastric acid and chloride secretion （P〈 0.001）. There were no significant differences in the rates of gastric acid or chloride output between the experimental periods with placebo or any dose of GIP. The temporal patterns of gastric acid and chloride secretion were similar in patients with type 2 diabetes and healthy controls （P= 0.86 and P= 0.61, respectively）. CONCLUSION： Pentagastrin-stimulated gastric acid secretion is similar in patients with type 2 diabetes and healthy controls. GIP administration does not influence gastric acid secretion at physiological or pharmacological plasma levels. Therefore, GIP appears to act as an incretin rather than as an enterogastrone in human physiology.

Ghrelin and gastric acid secretion

Ghrelin, a novel growth hormone-releasing peptide, was originally isolated from rat and human stomach. Ghrelin has been known to increase the secretion of growth hormone (GH), food intake, and body weight gain when administered peripherally or centrally. Ghrelin is also known to stimulate the gastric motility and the secretion of gastric acid. In the previous studies, the action of ghrelin on acid secretion was shown to be as strong as that of histamine and gastrin in in-vivo experiment. In the studies, the mechanism for the action of ghrelin was also investigated. It was shown that vagotomy completely inhibited the action of ghrelin on the secretion of gastric acid suggesting that vagal nerve is involved in the mechanism for the action of ghrelin on acid secretion. As famotidine did not inhibit ghrelin-in-duced acid secretion in the study by Masuda et al, they concluded that histamine was not involved in the action of ghrelin on acid secretion. However, we have shown that famotidine completely inhibited ghrelin-induced acid secretion and histidine decarboxylase (HDC) mRNA was increased in gastric mucosa by ghrelin injection which is inhibited by vagotomy Our results indicate that histamine is involved in the action of ghrelin on acid secretion. Furthermore synergistic action of gastrin and ghrelin on gastric acid secretion was shown. Although gastrin has important roles in postprandial secretion of gastric acid, ghrelin may be related to acid secretion during fasting period or at night. However, further studies are needed to elucidate the physiological role of ghrelin in acid secretion.

Effect of Lanthanum on Acid Secretion from Isolated Mouse Stomach in Vitro

To explore the effect and the mechanism of La^(3+) on gastric acid secretion (GAS) of isolated mouse stomach with perfused lumen, 12 cm H_2O column intragastric pressure-provided, whole stomach preparations from mice were incubated in buffer at 37 ℃ in vitro, and perfusate was measured for pH with a pHS-3 type pH meter. The results show that La^(3+) (0.41～820×10^(-6) mol·L^(-1)) significantly promotes GAS in a concentration-dependant manner. Proglutamine, a blocker of gastrin receptor, potently inhibits GAS, and it may block the promotive effect of La^(3+) on GAS, and this effect increases with the increase of proglutamin concentration. Cimetidine, a blocker of histamine H_2 receptor, also potently inhibits GAS, and blocks the promotive effect of La^(3+) on GAS in the same manner with proglutamine. These results suggest that La^(3+) promotes GAS in isolated stomach possibly by stimulating the releases of gastrin from G cell and Histamine from ECL cell or by activating the gastrin receptors and Histamine H_2 receptors on the parietal cell, thereby accelerating the acid secretion of parietal cells in stomach.

Gastric Mucosal Blood Flow and Acid Secretion in Rats

The relationship between gastric mucosal blood flow (GMBF) and gastric acid secretionwere studied in rats by using secretory stimulant (pentagastrin)and inhibitor(cimetidine). GMBFwas measured by Laser Doppler flowmetry (LDF) and gastric mucosal pH determined by microglasspH electrode. GMBF increased and gastric mucosal pH decreased significantly after intravenous injec-tion of 6μg/kg of pentagastrin; nevertheless GMBF decreased and gastric mucosal pH increasedmarkedly after intravenous administration of 100mg/kg of cimetidine. This indicates that pentagastrincan increase GMBF and gastric acid secretion, and cimetidine can decrease GMBF and gastric acidsecretion in rats, proving the close relationship between GMBF and gastric acid secretion in rats.

Construction and Expression of Recombinant Ghrelin Plasmid and Effects on Growth Performance and Gastric Acid Secretion of Rats

The paper was to study construction and expression of rGhrelin （pcDNA3 -Ghrelin） and its effect on growth performance and gastric acid secretion of rats. Ghrelin amplified from gastric mucosa of weaned piglets was cloned into the expression vector pcDNA3 to get recombinant plasmid pcDNA3 - Ghrelin. Twelve weaning rats were randomly divided into two groups, six rats each group. The rats in each treatment group were individually injected with 100pg of naked plasmid pcDNA3 -Ghrelin, and the rats in control group were injected with empty plasmid. The weights and feed consumption of rats were measured after injection for 7, 14 and 29 d, respectively. The rats were sacrificed at the end of the experiment, and their stomach was separated and weighed, the pH value of gastric juice was measured as well. The results showed that the average daily gain of rats at 7 and 29 d were significantly higher than that in control group, respectively （P〈0.05）, and feed consumption did not have significant chan- ges; the feed meat ratio of rats in the treatment groups was significantly lower than that in control group （ P 〈0.05） ; the gastric relative weight and gastric weight did not change significantly, while the pH value of gastric juice of rats in treatment groups was significantly lower than that in control group （P 〈 0.05）. This indicated that after transfected expression of muscle tissue, ghrelin played an important regulatory role in growth and gastric acid secretion of rats.

CHANGES OF GASTRIC ACID SECRETION AND SOMATOSTATIN AFTER ROUX-EN-Y CHOLANGIOJEJUNOSTOMY

The authors studied the changes of gastric acid secretion and determined the levels of somatostatin(SS) and gastrin (Gn)in blood, gastric jujce and

Peripheral mechanism of inhibitory effect of centrally administrated histamine on gastric acid secretion

AIM To study the peripheral mechanism of the inhibitory effect of intra third ventricular administration (icv) of histamine (HA) on gastric acid secretion in rats. METHODS Gastric acid was continuously washed with 37℃ saline by a perfusion pump in male adrenalectomized SD rats. Drugs were injected intravenously (iv) by a syringe pump and their effect on pentagastrin induced (10μg·kg·h, iv) gastric acid secretion was observed. RESULTS The inhibitory effect of HA (1μg, icv) on gastric acid secretion was blocked by subdiaphragmatic vagotomy, and pretreatment with atropine (0 005mg·kg·h, iv). Pretreatment with somatostatin antagonist, cyclo [7 aminoheptanoyl Phe D Trp Lys Thr(Bzl)], ( 2μg - 4μg ·kg· 100min , iv) could also block the inhibitory effect of HA on gastric acid secretion in a dose dependent manner. CONCLUSION The inhibitory effect of centrally administrated HA on gastric acid secretion may be mediated by vagi, acetylcholine M receptor and somatostatin.

Organic Acids Secreted from Plant Roots under Soil Stress and Their Effects on Ecological Adaptability of Plants

[Objective] In this study,the secretion of organic acids from plant roots under soil nutrient and water stress and the effects of organic acids on ecological adaptability of plants were investigated,which provided theoretical basis for improving the adaptability of plants to a variety of stress conditions.The results showed that,under nutrient and water stress,the content of organic acids secreted from plant roots increased significantly as a common active adaptive response.Organic acids could improve the activities of a variety of antioxidant enzymes,contents of osmotic regulatory substances,contents of chlorophyll and photosynthesis levels,promote nutrient absorption and transportation in plants,and ultimately contribute to plant growth and biomass accumulation,reduce the toxicity of stress conditions to plants and improve the stress resistance and adaptability of plants.

Gastric cancer:Animal studies on the risk of hypoacidity and hypergastrinemia

Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy.Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients.Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis.In this report,we briefly review findings from relevant animal studies on this topic.Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings.In all species where sufficient hypoacidity and hypergastrinaemia have been induced,a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.

Aberrant methylation of secreted protein acidic and rich in cysteine gene and its significance in gastric cancer

BACKGROUND Aberrant methylation in DNA regulatory regions could downregulate tumor suppressor genes without changing the sequences.However,our knowledge of secreted protein acidic and rich in cysteine(SPARC)and its aberrant methylation in gastric cancer(GC)is still inadequate.In the present research,we performed fundamental research to clarify the precise function of methylation on SPARC and its significance in GC.AIM To investigate promoter methylation and the effects of the SPARC gene in GC cells and tissues and to evaluate its clinical significance.METHODS Plasmids that overexpressed the SPARC gene were transfected into human GC BGC-823 cells;non-transfected cells were used as a control group(NC group).Quantitative real-time polymerase chain reaction and western blotting(WB)were then used to detect the expression of SPARC.Methylation-specific polymerase chain reaction was executed to analyze the gene promoter methylation status.Cell viability was measured by the cell counting kit-8 assay.The migration and invasion ability of cells were detected by scratch assays and transwell chamber assays,respectively.Cell cycle events and apoptosis were observed with a flow cytometer.RESULTS The expression of SPARC mRNA in GC tissues and cells was significantly lower and showed differing degrees of hypermethylation,respectively,than that in normal adjacent tissues and control cells.Treatment with 5-Aza-2’-deoxycytidine(5-Aza-Cdr)was able to restore the expression of SPARC and reverse promoter hypermethylation.Overexpression of the SPARC gene significantly inhibited proliferation,migration,and invasion of GC cells,while also causing cell cycle arrest and apoptosis;the NC group exhibited the opposite effects.CONCLUSION This study demonstrated that SPARC could function as a tumor suppressor and might be silenced by promoter hypermethylation.Furthermore,in GC cells,SPARC inhibited migration,invasion,and proliferation,caused cell cycle arrest at the G0/G1 phase,and promoted apoptosis.

Diagnostic and prognostic value of secreted protein acidic and rich in cysteine in the diffuse large B-cell lymphoma

BACKGROUND Secreted protein acidic and rich in cysteine(SPARC)is an extracellular matrixassociated protein.Studies have revealed that SPARC is involved in the cell interaction and function including proliferation,differentiation,and apoptosis.However,the role of SPARC in cancer is controversial,as it was reported as the promoter or suppressor in different cancers.Further,the role of SPARC in lymphoma is unclear.AIM To identify the expression and significance of SPARC in lymphoma,especially in diffuse large B-cell lymphoma(DLBCL).METHODS The expression analysis of SPARC in different cancers was evaluated with Oncomine.The Brune,Eckerle,Piccaluga,Basso,Compagno,Alizadeh,and Rosenwald datasets were included to evaluate the mRNA expression of SPARC in lymphoma.The Cancer Genome Atlas(TCGA)-DLBCL was used to analyze the diagnostic value of SPARC in DLBCL.The Compagno and Brune DLBCL datasets were used for validation.Then,the diagnostic value was evaluated with the receiver operating characteristic(ROC)curve.The Kaplan-Meier plot was conducted with TCGA-DLBCL,and the ROC analysis was performed based on the survival time.Further,the overall survival analysis based on the level of SPARC expression was performed with the GSE4475 and E-TABM-346.The Gene Set Enrichment Analyses(GSEA)was performed to make the underlying mechanism-regulatory networks.RESULTS The pan-cancer analysis of SPARC showed that SPARC was highly expressed in the brain and central nervous system,breast,colon,esophagus,stomach,head and neck,pancreas,and sarcoma,especially in lymphoma.The overexpression of SPARC in lymphoma,especially DLBCL,was confirmed in several datasets.The ROC analysis revealed that SPARC was a valuable diagnostic biomarker.More importantly,compared with DLBCL patients with low SPARC expression,those with higher SPARC expression represented a higher overall survival rate.The ROC analysis showed that SPARC was a favorable prognostic biomarker for DLBCL.Results of the GSEA confirmed that the high expression of SPARC was closely associated with focal adhesion,extracellular matrix receptor interaction,and leukocyte transendothelial migration,which suggested that SPARC may be involved in the regulation of epithelial-mesenchymal transition,KRAS,and myogenesis in DLBCL.CONCLUSION SPARC was highly expressed in DLBCL,and the overexpression of SPARC showed sound diagnostic value.More interestingly,the overexpression of SPARC might be a favorable prognostic biomarker for DLBCL,suggesting that SPARC might be an inducible factor in the development of DLBCL,and inducible SPARC was negative in some oncogenic pathways.All the evidence suggested that inducible SPARC might be a good diagnostic and prognostic biomarker for DLBCL.

Chronic spinal cord compression associated with intervertebral disc degeneration in SPARC-null mice

Chronic spinal cord compression(CSCC)is induced by disc herniation and other reasons,leading to movement and sensation dysfunction,with a serious impact on quality of life.Spontaneous disc herniation rarely occurs in rodents,and therefore establishing a chronic spinal cord compression(CSCC)animal model is of crucial importance to explore the pathogenesis and treatment of CSCC.The absence of secreted protein,acidic,and rich in cysteine(SPARC)leads to spontaneous intervertebral disc degeneration in mice,which resembles human disc degeneration.In this study,we evaluated whether SPARC-null mice may serve as an animal model for CSCC.We performed rod rotation test,pain threshold test,gait analysis,and Basso Mouse Scale score.Our results showed that the motor function of SPARC-null mice was weakened,and magnetic resonance images revealed compression at different spinal cord levels,particularly in the lumbar segments.Immunofluorescence staining and western blot assay showed that the absence of SPARC induced apoptosis of neurons and oligodendrocytes,activation of microglia/macrophages with M1/M2 phenotype and astrocytes with A1/A2 phenotype;it also activated the expression of the NOD-like receptor protein 3 inflammasome and inhibited brain-derived neurotrophic factor/tyrosine kinase B signaling pathway.Notably,these findings are characteristics of CSCC.Therefore,we propose that SPARC-null mice may be an animal model for studying CSCC caused by disc herniation.

Vultures as a model for testing molecular adaptations of dietary specialization in birds

Vultures are the only obligate scavengers among extant vertebrates.They provide valuable ecological services in ecosystems through removing carcasses,thus preventing the growth of other scavenger populations and the spread of pathogens.Moreover,their specific diets expose them to various deadly pathogens,which makes them potential candidates for studying molecular adaptations required to survive this extremely specialized scavenging habit.In this review,we summarize the morphological characteristics and behavioral habits,origin and phylogeny,and molecular adaptations to scavenging in both Old and New World vultures.The two groups of vultures share a similar appearance,indicative of convergent evolution.Vultures have experienced different degrees of specialization in their sensory organs;Old World vultures depend on sight,while New World ones depend on both smell and sight.Combined fossil records and molecular data suggest that vultures evolved independently,with distinct phylogenetic positions.We also explored their adaptation to scavenging in facial and intestinal microbiomes,gastric acid secretion and immunity.Compared with the facial microbiome,the intestinal microbiome had a lower diversity,dominated by Fusobacteria and Clostridia.The phages and single invertebrate species Adineta vaga,which feeds on dead bacteria and protozoa,present in the gut suggest a possible alternative defense mechanism.Several genes involved in gastric acidic secretion(including ATP4B,SLC26A7 and SST)and immunity(including BCL6,STING,and TLRs) undergoing positive selection likely have essential roles in eliminating invasive pathogens and initiating an innate immune response.Taken together,this review presents the current research status of vultures and highlights the use of vultures as a model for exploring molecular adaptations of dietary specialization in birds.It also provides a theoretical basis for the study of the genetic mechanisms of vultures to scavenging,and contributes to the formulation of vulture conservation strategies.

Direct measurement of gastric H^+/K^+-ATPase activities in patients with or without Helicobacter pylori-associated chronic gastritis

AIM:The role of Helicobacter pylori (H pylori) infection in gastric acid secretion of patients with chronic gastritis remains controversial. This study was designed to elucidate the effect of H pylori on H+/K+-ATPase activities in gastric biopsy specimens. METHODS: Eighty-two patients with chronic gastritis who had undergone upper endoscopy were included in this study. H pylori infection was confirmed by rapid urease test and histology. Gastric H+/K+-ATPase activities and serum gastrin concentrations were measured by an enzymatic method and radioimmunoassay, respectively. For those patients who received triple therapy for eradicating H pylori, changes in the activity of gastric H+/K+-ATPase and serum gastrin levels were also measured. RESULTS: The mean gastric H+/K+-ATPase activity in Hpylori-positive group (42 patients) was slightly higher than that in Hpylori-negative group (29 patients) (169.65±52.9 and 161.38±43.85nmol P/(mg·h),respectively, P=0.301). After eradication of H pylori, the gastric H+/K+-ATPase activities slightly decreased compared to prior therapy (165.03±59.50 and 158.42±38.93 nmol P/(mg·h), respectively, P=0.805). The mean basal gastrin concentration was slightly higher in H pylori-positive patients than in H pylori-negative patients (87.92±39.65 pg/mL vs75.04±42.57 pg/mL, P= 0.228). The gastrin levels fell significantly after the eradication of H pylori. (Before treatment 87.00±30.78 pg/mL, after treatment 64.73±18.96 pg/mL, P=0.015). CONCLUSION: Gastric H+/K+-ATPase activities are not associated with H pylori status in patients with chronic gastritis.

Two-Dimensional pH Mapping of a Histamine-Stimulated Gastric Mucosa by Using an Ion Image Sensor in the Guinea Pig

In order to examine the hydronium ion （proton）-releasing functions in cells, [pH]out （extracellular pH） was measured using an ion image sensor composed of a 2D （two-dimensional） array of potential sensitive pixels. Using gastric tissues prepared from the stomach, pH distribution was observed during the histamine stimulation. The 2D distribution of [pH]out in the gastric tissues showed clear differences between the mucosal sides and the serous side. Even before the histamine stimulation, the mucosal side of the gastric mucosa showed a slightly lower pH than that of serous side. In the mucosal side, [pH]out decreased after the onset of the stimulation. The ion image sensor was capable of visualizing [pH]out in the gastric tissues. The present chemical-sensing technique realized a label-free microscopic assessment of the 2D distributions of biologically interesting substances, and consequently, [pH] out imaging via chemical microscopy has a future potential in medical fields for endoscopic analysis of gastric ulcers.

Pathogenetic factors affecting gastroesophageal refluxin patients with esophagitis and concomitant duodenal ulcer:a multivariate analysis

AIM To assess the relationship between gastric acid output (GAO) and both pattern of gastroesophageal reflux (GER) and esophageal lesions, and to evaluate the role of GAO and other potential pathogenetic factors in the development of esophagitis. METHODS Gastric acid secretory testing and 24 h intraesophageal pH monitoring were performed in 31 patients with esophagitis and concomitant duodenal ulcer (E+DU) and compared with those of 72 patients with esophagitis (E) alone. RESULTS The GAO in patients with E+DU was significantly higher than in patients with E ( P <0 05). There was no significant difference between the two groups of patients as to endoscopicl findings and parameters of GER ( P >0 05). A multiple regression analysis with stepwise deletion showed that the pre sence of hiatal hernia (HH), GER in upright position and age appeared to correlate significantly with the presence of esophagitis. CONCLUSIONS No parallel relationship between GAO and severity of GER or esophageal lesions exists in patients with E+DU, and that GAO is not a major pathogenetic factor in GER disease.

Change of SPARC expression after chemotherapy in gastric cancer

Objective： The expression of tumor biomarkers may change after chemotherapy. However, whether secreted protein acidic and rich in cysteine （SPARC） expression changes after chemotherapy in gastric cancer （GC） is unclear, qqais study investigated the influence of chemotherapy on SPARC expression in GC. Methods： Immunohistochemistry was used to analyze SPARC expression in 132 GC cases （including 54 cases with preoperative chemotherapy and 78 cases without preoperative chemotherapy）. SPARC expression of postoperative specimens with and without preoperative chemotherapy was assessed to analyze the influence of chemotherapy on SPARC expression. Results： SPARC was highly expressed in GC compared with the desmoplastic stroma surrounding tumor cells and noncancerous tissues. High SPAKC expression was correlated with invasion depth, lymph node, and TNM stage. After chemotherapy, a lower proportion of high SPARC expression was observed in patients with preoperative chemotherapy than in the controls. For 54 patients with preoperative chemotherapy; gross type, histology, depth of invasion, lymph node, TNM stage, and SPARC expression were related to overall survival. Further multivariate analysis showed that lymph node, histology, and SPARC expression after chemotherapy were independent prognostic factors. Conclusiou： SPARC expression may change after chemotherapy in GC. SPARC expression should be reassessed for patients with GC after chemotherapy.