Prolongation of the gastric residence time of caffeine after administration in fed state: Comparison of effervescent granules with an extended release tablet.

The aim of the present study was to investigate the gastroretentive capacity of different formulation principles. This was indirectly determined by the absorption behavior of caffeine from the dosage forms. A slow and continuous appearance of caffeine in the saliva of healthy volunteers was used as a parameter for a prolonged gastric retention time. For this purpose, a four-way study was conducted with twelve healthy volunteers using the following test procedures: (1) Effervescent granules with 240 mL of still water administered in fed state, (2) effervescent granules with 20 mL of still water in fed state, (3) extended release (ER) tablet with 240 mL of still water in fed state, and (4) effervescent granules with 240 mL of still water in fasted state. The initial rise of the caffeine concentrations was more pronounced after the intake of the effervescent granules in the fed state compared to that of the ER tablets. However, tmax tended to be shorter in the fed study arms following administration of the ER tablet compared to the granules. Overall, the application of active pharmaceutical ingredients formulated as effervescent granules seems to be a promising approach to increase their gastric residence time after intake in fed state.

Impact of Physicochemical Modifications in Casein Promoted by UV-C on the Peptide Profile of Gastric Digestion and the Transepithelial Transport of Peptides.

Caseins are the main proteins in milk, and their structure and spatial conformation are responsible for their slow digestion rate. The release of bioactive and ß-casomorphin peptides from casein digestion may induce allergic responses during consumption. Spectroscopic techniques were used to observe the structural changes in casein conformation induced by Ultraviolet light irradiation (UV-C). Raman spectroscopy results showed more pronounced peaks at 618 and 640 cm-1 for phenylalanine and tyrosine moieties of the photolyzed micellar casein, respectively, suggesting changes in the micelle structure. The decrease in the intensity of Raman signals for tryptophan and tyrosine corroborates to the UV-C-induced modifications of the micelle structure. Particle size distribution showed a decrease in the average micelle size after 15 min of UV-C exposure, while low-temperature, long-time (LTLT) pasteurization led to the formation of large aggregates, as observed by atomic force microscopy. UV-C did not impact the formation or transport of peptides, as observed by using the Caco-2 cell as a model for peptide absorption. However, the absence of the opioid peptide SRYPSY from κ-casein and only 20% of the concentration of opioid peptide RYLGY were noted. This work demonstrated that UV-C can be utilized to induce the physicochemical modification of dairy products, promoting a higher digestion rate and reducing allergenicity.

The Effect of Dried Ginger (Gan Jiang) on Stomach Energy Metabolism and the Related Mechanism in Rats Based on Metabonomics.

Dried ginger is a commonly used stomachic. Dried ginger is often used as a gastric protector to treat stomach-related diseases. However, the effect of dried ginger on energy metabolism in stomach tissue of rats under physiological condition has not been studied. In this study, different doses of water extract of dried ginger were given to rats for 4 weeks. The activity of Na+ -K+ -ATPase, Ca2+ -Mg2+ -ATPase, SDH (succinate dehydrogenase) enzyme, ATP content, mitochondrial metabolic rate and mitochondrial number in stomach tissue of rats were measured. Analysis of potential biomarkers related to the effect of dried ginger on energy metabolism in stomach tissue of rats by metabonomics, and their metabolic pathways were also analyzed. The results revealed that there was no significant difference in Na+ -K+ -ATPase in high-dose group (GJH), medium-dose group (GJM) and low-dose group (GJL) compared to the Control group. The Ca2+ -Mg2+ -ATPase activity was significantly increased in stomach tissue of GJH group and GJM group, but there were no significant changes in stomach tissue of GJL group. The SDH activity and the ATP levels were significantly increased in stomach tissue of GJH group, GJM group and GJL group. The mitochondrial metabolic rate was significantly increased in GJL group, but there was no significant change in GJM group and was inhibited in GJH group. These effects might be mediated by arginine biosynthesis, glutathione metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, arginine and proline metabolism, purine metabolism pathway.

Fucoidan from Sargassum hemiphyllum inhibits infection and inflammation of Helicobacter pylori.

Having infected by Helicobacter pylori, the infection often leads to gastritis, gastric ulcer, or even gastric cancer. The disease is typically treated with antibiotics as they used to effectively inhibit or kill H. pylori, thus reducing the incidence of gastric adenoma and cancer to significant extent. H. pylori, however, has developed drug resistance to many clinically used antibiotics over the years, highlighting the crisis of antibiotic failure during the H. pylori treatment. We report here that the fucoidan from Sargassum hemiphyllum can significantly reduce the infection of H. pylori without developing to drug resistance. Fucoidan appears to be a strong anti-inflammation agent as manifested by the RAW264.7 cell model examination. Fucoidan can prohibit H. pylori adhesion to host cells, thereby reducing the infection rate by 60%, especially in post treatment in the AGS cell model assay. Mechanistically, fucoidan intervenes the adhesion of BabA and AlpA of H. pylori significantly lowering the total count of H. pylori and the level of IL-6 and TNF-α in vivo. These results all converge on the same fact that fucoidan is an effective agent in a position to protect the stomach from the H. pylori infection by reducing both the total count and induced inflammation.

Zuojin Pill attenuates Helicobacter pylori-induced chronic atrophic gastritis in rats and improves gastric epithelial cells function in GES-1 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin pill (ZJP), a classical Chinese medicine formula, has been widely applied in Chinese clinical practice for the treatment of gastric injury such as acute gastric lesion, acute gastric mucosal injury, chronic unpredictable mild stress, gastroesophageal reflux disease, etc, thereby exerting anti-chronic atrophic gastritis (CAG) effects in traditional Chinese herbal medicine. AIM OF THE STUDY: This study was aimed to explore the therapeutic effects and molecular mechanisms of ZJP on Helicobacter pylori (H. pylori)-induced CAG based on the comprehensive approaches. MATERIALS AND METHODS: Sprague-Dawley rats were infected with H. pylori for 8 weeks to establish CAG model. Then, rats in the ZJP groups received doses of 0.63, 1.26, and 2.52 g/kg ZJP for 4 weeks. Therapeutic effects of ZJP on serum indices and the histopathology of the gastric were analyzed in vivo. Moreover, GES-1 cells were infected with H. pylori to establish gastric epithelial cell injury model in vitro. Cell viability and gastric epithelial cell morphology were detected by a high-content screening (HCS) assay. Furthermore, the relative mRNA and protein expression of JMJD2B/COX-2/VEGF axis and HMGB1/NF-κB signaling pathway in vivo and in vitro were determined by RT-PCR and Western Blotting, respectively. RESULTS: The results showed that the therapeutic effects of ZJP on CAG rats were presented in down-regulation serum biochemical indices and alleviating histological damage of gastric tissue. ZJP could dose-dependently decrease the serum IL-6, MCP-1, PGE2, TNF-α, and VEGF level and significantly improved gastric tissue inflammatory lesions. Besides, ZJP has an effect on increasing cell proliferation of GES-1 cells, ameliorating H. pylori-induced gastric epithelial cell damage. It was found that ZJP has a down-regulating effect on inflammatory reaction and could inhibit the relative mRNA and protein expression of JMJD2B/COX-2/VEGF axis and HMGB1/NF-κB signaling pathway in vivo and in vitro, including JMJD2B, COX-2, VEGF, VEGFR1, and VEGFR2, which in turn reduced the damage of gastric mucosal cells. CONCLUSIONS: The results suggested that ZJP exerts therapeutic effects on H. pylori-induced CAG by inhibiting the JMJD2B/COX-2/VEGF axis and HMGB1/NF-κB signaling pathway. These findings deeply explained why ZJP could be used to treat CAG clinically and clarified its pharmacological effect and potential mechanism in the treatment of CAG.

Formulation of stomach-specific floating microparticles of nizatidine and their radiographic evaluation

Nizatidine is an anti-secretogogue and a gastroprotective drug with a half-life of 1-2 h and is well absorbed in the stomach. This study aimed to optimize the process and develop floating microparticles of nizatidine that are based on low methoxyl pectin. Oil-in-oil dispersion method and Taguchi orthogonal array design were employed, and the prolonged residence time of the microparticles in the stomach was demonstrated. The constraints for independent variables, viz. A-polymer, B-internal solvent volume, C-surfactant, D-stirring rate and E-stirring time were set to generate the experimental runs. Particle size, percentage yield, micromeritic properties, entrapment efficiency, in vitro buoyancy and in vitro release were characterized. Surface morphology, zeta potential, in vitro release kinetics and in vivo floating performance of the optimized formulation was examined. The microparticles were free-flowing, irregular in shape and had a mean particle size distribution of 73-187 µ. Low methoxyl pectin played a predominant role in achieving buoyancy and optimum gastric retention for the modified release of the drug, suggesting Korsmeyer-Peppas model as the possible release mechanism. In vivo radiographic study in rabbits revealed that the drug was retained in the stomach for a period of 6 h. These results indicate that nizatidine floating microparticulate system provides modified drug release for the effective treatment of gastric ulcer

Comparative stomach tissue distribution profiles of four major bio-active components of Radix Astragali in normal and gastric ulcer mice

Numerous studies have demonstrated that Radix Astragali can inhibit gastric ulcers in mice. Anhydrous ethanol (0.01 mL/g) administered to mice by intragastric infusion can induce gastric ulcer injury. This study was performed to compare the stomach tissue distribution profiles of four major bioactive constituents of Radix Astragali(calycosin-7-O-ß-d-glucoside, calycosin, ononin and formononetin) after oral administration of extract of Radix Astragali (ERA)in normal and gastric ulcer mice. The abundance of Radix Astragali constituents was determined using an ultra-pressure liquid chromatograph with a photodiode array detector (UPLC-PDA), after which histograms were drawn. In comparison with normal mice, the contents of calycosin- 7-O-ß-d-glucoside, calycosin, ononin and formononetin in the stomach tissue samples of gastric ulcer mice showed significant differences at the selected time points (P < 0.05).The abundance of each of the four tested constituents in the normal groups was higher than that of the gastric ulcer groups. This study provides an empirical foundation for future studies focused on developing clinical applications of Radix Astragali

Efficacy and safety of a thermosensitive hydrogel for endoscopic submucosal dissection: An in vivo swine study.

Injectable thermo-sensitive chitosan hydrogels have recently been developed for the use of submucosal fluids in endoscopic submucosal dissections (ESD). This study aimed to investigate the efficacy and safety of chitosan hydrogels during ESD. Submucosal fluids were administered as follows: 0.9% normal saline (NS), 0.4% hyaluronic acid (HA) and chitosan/ß-glycerophosphate (CS/GP) hydrogel. Each solution was administered twice into the stomach and colon of a pig, with a total of 72 ESD procedures performed on 12 pigs. The injected volume and procedure-related parameters were recorded and analyzed. ESDs that created ulcers after 7 days were histologically compared. All ESD specimens were resected en bloc. The total injected volumes during ESD of the stomach (NS, 16.09±3.27 vs. HA, 11.17±2.32 vs. CS/GP, 9.44±2.33; p<0.001) and colon (NS, 9.17±1.80 vs. HA, 6.67±1.50 vs. CS/GP, 6.75±1.57; p = 0.001) were significantly different. Hydrogel showed significant differences from normal saline in terms of fluid power (mm2/vol; NS, 35.70±9.00 vs. CS/GP 57.48±20.77; p = 0.001) and consumption rate (vol/min; NS, 2.59±0.86 vs. CS/GP, 1.62±0.65; p = 0.013) in the stomach. Histological examination revealed preserved muscularis propria, although the chitosan hydrogel resulted in a partial inflammatory response, with a hypertrophied submucosal layer. Chitosan hydrogel was found to be superior to normal saline, with an efficacy similar to that of hyaluronic acid. Nonetheless, long-term histological changes should be evaluated before clinical implementation.

Multiplexed imaging reveals an IFN-γ-driven inflammatory state in nivolumab-associated gastritis.

Immune checkpoint blockade using PD-1 inhibition is an effective approach for treating a wide variety of cancer subtypes. While lower gastrointestinal (GI) side effects are more common, upper gastrointestinal adverse events are rarely reported. Here, we present a case of nivolumab-associated autoimmune gastritis. To elucidate the immunology underlying this condition, we leverage multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to identify the presence and proportion of infiltrating immune cells from a single section of biopsy specimen. Using MIBI-TOF, we analyze formalin-fixed, paraffin-embedded human gastric tissue with 28 labels simultaneously. Our analyses reveal a gastritis characterized by severe mucosal injury, interferon gamma (IFN-γ)-producing gastric epithelial cells, and mixed inflammation that includes CD8 and CD4 T cell infiltrates with reduced expression of granzyme B and FOXP3, respectively. Here, we provide a comprehensive multiplexed histopathological mapping of gastric tissue, which identifies IFN-γ-producing epithelial cells as possible contributors to the nivolumab-associated gastritis.

Metaplasia of respiratory and digestive tissues in the eastern oyster Crassostrea virginica associated with the Deepwater Horizon oil spill.

Metaplasia is a well documented and deleterious effect of crude oil components on oysters. This reversible transformation of one cell type to another is a common response to petroleum-product exposure in molluscs. It has been shown experimentally in previous work that eastern oysters (Crassostrea virginica) exposed to petroleum products will exhibit metaplasia of digestive tissues. Here we document for the first time that wild adult oysters inhabiting coastal waters in the northern Gulf of Mexico during and in the aftermath of the Deepwater Horizon oil spill (2010) exhibited metaplasia in both ctenidial (respiratory and suspension feeding) and digestive tract tissues at significantly higher frequencies than geographic controls of C. virginica from Chesapeake Bay. Metaplasia included the loss of epithelial cilia, transformations of columnar epithelia, hyperplasia and reduction of ctenidial branches, and vacuolization of digestive tissues. Evidence for a reduction of metaplasia following the oil spill (2010-2013) is suggestive but equivocal.

Protocol for chemically induced murine gastric tumor model.

N-Methyl-N-nitrosourea, an N-nitroso compound converted from dietary nitrite by Helicobacter pylori, causes somatic mutations in epithelial cells and induces gastric premalignancy. Here, we describe a detailed protocol for induction of gastric tumor and analysis of tumor phenotypes in mice. This model can be widely used for studying the initiation and growth of gastric cancer. For complete details on the use and execution of this protocol, please refer to Li et al. (2021).

The suppressive effect of REVERBs on ghrelin and GOAT transcription in gastric ghrelin-producing cells.

Ghrelin is a multifunctional gut peptide with a unique structure, which is modified by a medium chain fatty acid at the third serine by ghrelin O-acyl transferase (GOAT). It is well known that the major source of plasma ghrelin is the stomach, but the transcriptional regulation of gastric ghrelin and GOAT is incompletely understood. Here, we studied the involvement of the nuclear receptors REV-ERBα and REV-ERBß on ghrelin and GOAT gene expression in vivo and in vitro. Reverse-transcriptase polymerase chain reaction analysis showed that REV-ERBα and REV-ERBß mRNAs were expressed in the stomach and a stomach-derived ghrelin cell line (SG-1 cells). In vivo experiments with mice revealed the circadian rhythm of ghrelin, GOAT, and REV-ERBs. The peak expression of ghrelin and GOAT mRNAs occurred at Zeitgeber time (ZT) 4, whereas that of REV-ERBα and REV-ERBß was observed at ZT8 and ZT12, respectively. Treatment of SG-1 cells with SR9009, a REV-ERB agonist, led to a significant reduction in ghrelin and GOAT mRNA levels. Overexpression of REV-ERBα and REV-ERBß decreased ghrelin and GOAT mRNA levels in SG-1 cells. In contrast, small-interfering RNA (siRNA)-mediated double-knockdown of REV-ERBα and REV-ERBß in SG-1 cells led to the upregulation in the expression of ghrelin and GOAT mRNAs. These results suggest that REV-ERBs suppress ghrelin and GOAT mRNA expression.

Montelukast potentiates the antiinflammatory effect of NSAIDs in the rat paw formalin model and simultaneously minimizes the risk of gastric damage.

OBJECTIVE AND DESIGN: Montelukast, a cysteinyl leukotriene receptor antagonist, exhibits antiinflammatory action. We tested whether exposure to montelukast plus nonsteroidal antiinflammatory drugs (NSAIDs) elicits better control of paw inflammation in the rat formalin test and improves associated gastric damage. MATERIALS: A total of 46 adult male rats were used in the study. TREATMENTS: We evaluated separate and combined effects of montelukast (20 mg/kg), celecoxib (COX2 inhibitor, 10 mg/kg), and diclofenac (nonselective COX1/COX2 inhibitor, 10 mg/kg) on paw and gastric damage in the rat formalin test. RESULTS: Individual pretreatments of rats with montelukast, diclofenac, or celecoxib partly reduced formalin-induced increases in (i) paw edema, fibrosis, and inflammatory cells, (iii) serum interleukin-6 (IL-6) and leukotrienes (LTB4 and LTD4), and (iv) paw expressions of inducible nitric oxide synthase (iNOS) and COX2. These effects were accentuated in rats treated with montelukast plus diclofenac or montelukast plus celecoxib. Alternatively, montelukast or celecoxib, but not diclofenac, alleviated formalin-evoked gastric damage and increments in tumor necrosis factor-α and decrements in prostaglandin-E2. These advantageous gastric influences were potentiated in rats treated with montelukast plus celecoxib. CONCLUSIONS: While montelukast equally enhances antiinflammatory action of diclofenac or celecoxib via downregulating iNOS/COX2/LTs/IL-6 signaling, its gastroprotective action is preferentially potentiated by celecoxib.

Effects of acute oral exposure to acrylamide on histological structures of the stomach in Wistar rats / Efectos de la exposición oral aguda a la acrilamida sobre las estructuras histológicas del estómago en ratas Wistar

SUMMARY: Acrylamide is a toxic chemical substance with wide implementation in chemical industry. In 2002 the presence of acrylamide was discovered in foods rich in starch which are prepared at high temperatures. The aim of this study was to investigate the histopathological changes in the gastric tissue in Wistar rats induced with injection of oral acrylamide. The research was carried out 6 groups of 5 animals (Wistar rats), two control groups and four experimental groups. Histological changes in the stomach tissue of Wistar rats are seen as a direct slight damage of the surface epithelium, accompanynig inflammatory reaction and renewal of the epithelium. Examined inflammatory and degenerative parameters show a positive correlation with respect to dose and time of exposition to acrylamide. Knowing the mechanism of action of these toxic substances, allows to apply adequate prevention in nutrition and make an appropriate choice of therapeutic methods.

RESUMEN: La acrilamida es una sustancia química tóxica con amplia aplicación en la industria química. En el año 2002 se determinó la presencia de acrilamida en alimentos ricos en almidón preparados a altas temperaturas. El objetivo de este estudio fue investigar los cambios histopatológicos en el tejido gástrico en ratas Wistar inducidos con inyección de acrilamida oral. La investigación se llevó a cabo en 6 grupos de 5 animales, dos grupos control y cuatro grupos experimentales. Los cambios histológicos en el tejido del estómago de las ratas Wistar se ven como un ligero daño directo del epitelio superficial, que acompaña a la reacción inflamatoria y la renovación del epitelio. Los parámetros inflamatorios y degenerativos examinados muestran una correlación positiva con respecto a la dosis y el tiempo de exposición a la acrilamida. El conocimiento del mecanismo de acción de estas sustancias tóxicas permite aplicar una prevención adecuada en nutrición y hacer una elección oportuna de los métodos terapéuticos.

Clinical Perspectives on the Use of Subcutaneous and Oral Formulations of Semaglutide.

Early and effective glycemic control can prevent or delay the complications associated with type 2 diabetes (T2D). The benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly recognized and they now feature prominently in international T2D treatment recommendations and guidelines across the disease continuum. However, despite providing effective glycemic control, weight loss, and a low risk of hypoglycemia, GLP-1RAs are currently underutilized in clinical practice. The long-acting GLP-1RA, semaglutide, is available for once-weekly injection and in a new once-daily oral formulation. Semaglutide is an advantageous choice for the treatment of T2D since it has greater efficacy in reducing glycated hemoglobin and body weight compared with other GLP-1RAs, has demonstrated benefits in reducing major adverse cardiovascular events, and has a favorable profile in special populations (e.g., patients with hepatic impairment or renal impairment). The oral formulation represents a useful option to help improve acceptance and adherence compared with injectable formulations for patients with a preference for oral therapy, and may lead to earlier and broader use of GLP-1RAs in the T2D treatment trajectory. Oral semaglutide should be taken on an empty stomach, which may influence the choice of formulation. As with most GLP-1RAs, initial dose escalation of semaglutide is required for both formulations to mitigate gastrointestinal adverse events. There are also specific dose instructions to follow with oral semaglutide to ensure sufficient gastric absorption. The evidence base surrounding the clinical use of semaglutide is being further expanded with trials investigating effects on diabetic retinopathy, cardiovascular outcomes, and on the common T2D comorbidities of obesity, chronic kidney disease, and non-alcoholic steatohepatitis. These will provide further information about whether the benefits of semaglutide extend to these other indications.

Circular RNA PLEC acts as a sponge of microRNA-198 to promote gastric carcinoma cell resistance to paclitaxel and tumorigenesis.

Gastric carcinoma (GC) is one of the most frequent types of malignancy worldwide. Resistance to paclitaxel (PTX) has become an obstacle to the prognosis of GC, and the underlying mechanism is not clear. A previous study identified GC-related circRNAs via microarray analysis and bioinformatics analysis, and we discovered that circPLEC (hsa_circ_104722) was markedly upregulated in GC tissues and cells. The molecular mechanism of circPLEC in PTX-resistant GC cells still needs to be explored. In the present study, qRT-PCR demonstrated that circPLEC was upregulated in PTX-resistant GC tissues and cells, indicating that circPLEC boosts the PTX resistance of GC. circPLEC downregulation weakened GC resistance to PTX and tumorigenesis, migration and invasion and promoted the apoptosis of PTX-resistant GC cells. MiR-198 inhibitor reversed the effect of circPLEC downreguAlation in PTX-resistant GC cells, and MUC19 downregulation weakened GC resistance to PTX and tumorigenesis and improved the apoptosis of PTX-resistant GC cells. In summary, circPLEC acts as a sponge of miR-198 to promote the PTX resistance and tumorigenesis of GC cells by regulating MUC19 expression.

Clinical Significance of PLA2G2A Expression in Gastric Cancer Patients who Receive Gastrectomy and Adjuvant S-1.

BACKGROUND/AIM: This study aimed to evaluate the prognostic significance of PLA2G2A expression in patients with locally advanced gastric cancer (GC). PATIENTS AND METHODS: PLA2G2A expression levels in cancerous tissue specimens and adjacent normal mucosa obtained from 134 patients with stage II/III GC who received adjuvant chemotherapy with S-1 after curative resection were measured using real-time quantitative polymerase chain reaction. Subsequently, the associations of PLA2G2A expression with clinicopathological features and survival were evaluated. RESULTS: No association was observed between clinicopathological features and PLA2G2A expression levels. Overall survival was significantly longer in patients with high PLA2G2A expression levels (p=0.022). Multivariate analysis revealed that PLA2G2A expression was a significant, independent prognostic factor (hazard ratio=0.136; 95% confidence interval=0.0185-0.992; p=0.049). CONCLUSION: PLA2G2A mRNA expression may serve as a useful prognostic marker in patients with locally advanced GC who receive curative surgery and adjuvant chemotherapy with S-1.

Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil.

Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer metabolism, including the Warburg effect, a preference for glycolysis rather than oxidative phosphorylation for energy production, has been accepted as a pivotal mechanism regulating resistance to chemotherapy. Thus, we investigated the detailed mechanism and possible usefulness of antiglycolytic agents in ameliorating 5FU resistance using established gastric cancer cell lines, SNU620 and SNU620/5FU. SNU620/5FU, a gastric cancer cell harboring resistance to 5FU, showed much higher lactate production and expression of glycolysis-related enzymes, such as lactate dehydrogenase A (LDHA), than those of the parent SNU620 cells. To limit glycolysis, we examined catechin and its derivatives, which are known anti-inflammatory and anticancer natural products because epigallocatechin gallate has been previously reported as a suppressor of LDHA expression. Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity. In addition, the combination of 5FU and catechin showed additional cytotoxicity and induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells. Thus, based on these results, we suggest catechin as a candidate for the development of a novel adjuvant drug that reduces chemoresistance to 5FU by restricting LDHA.

Gastric Serotonin Biosynthesis and Its Functional Role in L-Arginine-Induced Gastric Proton Secretion.

Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach, vascular serotonin release induced by gastric distension is thought to chiefly contribute to satiation after food intake. However, little information is available on the capability of gastric cells to synthesize, release and respond to serotonin by functional changes of mechanisms regulating gastric acid secretion. We investigated whether human gastric cells are capable of serotonin synthesis and release. First, HGT-1 cells, derived from a human adenocarcinoma of the stomach, and human stomach specimens were immunostained positive for serotonin. In HGT-1 cells, incubation with the tryptophan hydroxylase inhibitor p-chlorophenylalanine reduced the mean serotonin-induced fluorescence signal intensity by 27%. Serotonin release of 147 ± 18%, compared to control HGT-1 cells (set to 100%) was demonstrated after treatment with 30 mM of the satiating amino acid L-Arg. Granisetron, a 5-HT3 receptor antagonist, reduced this L-Arg-induced serotonin release, as well as L-Arg-induced proton secretion. Similarly to the in vitro experiment, human antrum samples released serotonin upon incubation with 10 mM L-Arg. Overall, our data suggest that human parietal cells in culture, as well as from the gastric antrum, synthesize serotonin and release it after treatment with L-Arg via an HTR3-related mechanism. Moreover, we suggest not only gastric distension but also gastric acid secretion to result in peripheral serotonin release.

Methods to improve efficacy of orally administered bioactive peptides using bovine colostrum as an exemplar.

BACKGROUND: Oral administration of bioactive peptides has potential clinical advantages, but its applicability is limited due to gastric and pancreatic enzyme proteolysis. OBJECTIVE: To examine whether the co-packaging of bovine colostrum (BC), a rich source of IgG, immune and growth factors, with the food additives trehalose (carbohydrate), stearine (fat), casein (protein present in BC) or soy flour (plant based with high protease inhibitory activity) enhances the stability of BC against digestion. DESIGN: Samples alone and in combination (BC+ 10% wt/wt trehalose, stearine, casein or soy) were exposed to HCl/pepsin, followed by trypsin and chymotrypsin ("CT"). Assessment of proliferation used gastric AGS cells (Alamar blue), IgG function measured bovine IgG anti-E.coli binding and ELISAs quantified growth factor constituents. In vivo bioassay assessed ability of BC alone or with soy to reduce injury caused by dextran sodium sulphate (DSS, 4% in drinking water, 7 days, test products started 2 days prior to DSS). RESULTS: Proliferative activity of BC reduced 61% following HCl/pepsin and CT exposure. This was truncated 50% if soy was co-present, and also protected against loss of total IgG, IgG E.coli binding, TGFß, lactoferrin and EGF (all P<0.01 vs BC alone). Co-packaging with trehalose was ineffective in preventing digestion whereas casein or stearine provided some intermediate protective effects. Rats given BC alone showed beneficial effects on weight gain, disease activity index, tissue histology and colonic MPO. Soy alone was ineffective. BC+ soy combination showed the greatest benefit with a dose of 7 mg/kg (6.4 BC + 0.6 soy flour) having the same degree of benefit as using 20 mg/kg BC alone. CONCLUSION: Soy, and to a lesser extent casein, enhanced the biostability of BC against digestive enzymes. Co-packaging of BC with other food products such as soy flour could result in a decreased dose being required, improving cost-effectiveness and patient compliance.