Function and regulation of apelin/APJ system in digestive physiology and pathology

Apelin is an endogenous ligand of seven-transmembrane G-protein-coupled receptor APJ. Apelin and APJ are distributed in various tissues, including the heart, lung, liver, kidney, and gastrointestinal tract and even in tumor tissues. Studies show that apelin messenger RNA is widely expressed in gastrointestinal (GI) tissues, including stomach and small intestine, which is closely correlated with GI function. Thus, the apelin/APJ system may exert a broad range of activities in the digestive system. In this paper, we review the role of the apelin/APJ system in the digestive system in physiological conditions, such as gastric acid secretion, control of appetite and food intake, cell proliferation, cholecystokinin secretion and histamine release, gut–brain axis, GI motility, and others. In pathological conditions, the apelin/APJ system plays an important role in the healing process of stress gastric injury, the clinical features and prognosis of patients with gastric cancers, the reduction of inflammatory response to enteritis and pancreatitis, the mediation of liver fibrogenesis, the promotion of liver damage, the inhibition of liver regeneration, the contribution of splanchnic neovascularization in portal hypertension, the treatment of colon cancer, and GI oxidative damage. Overall, the apelin/APJ system plays diversified functions and regulatory roles in digestive physiology and pathology. Further exploration of the relationship between the apelin/APJ system and the digestive system will help to find new and effective drugs for treating and alleviating the pain of digestive diseases.     

The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies

The gastrointestinal (GI) peptide gastrin is an important regulator of the release of gastric acid from the stomach parietal cells and it also plays an important role in growth of the gastrointestinal tract. It has become apparent that gastrin and its related peptide cholecystokinin (CCK) are also significantly involved with growth of GI cancers as well as other malignancies through activation of the cholecystokinin-B (CCK-B) receptor. Of interest, gastrin is expressed in the embryologic pancreas but not in the adult pancreas; however, gastrin becomes re-expressed in pancreatic cancer where it stimulates growth of this malignancy by an autocrine mechanism. Strategies to down-regulate gastrin or interfere with its interface with the CCK receptor with selective antibodies or receptor antagonists hold promise for the treatment of pancreatic cancer and other gastrin - responsive tumors.     

Effect of protein, fat, carbohydrate and fibre on gastrointestinal peptide release in humans

Short-term regulation of food intake controls what, when and how much we eat within a single day or a meal. This regulation results from an integrated response to neural and humoral signals that originate from the brain, gastrointestinal (GI) tract and adipose tissue. In the GI tract, multiple sites including the stomach, duodenum, distal small intestine, colon, and pancreas are involved in this process. Ingested food evokes satiety by mechanical stimulation and by release of peptides in the GI tract. The intestine in particular plays a key role in satiety through various peptides secreted in response to food. Many of the intestinal peptides inhibit also gastric emptying thus enhancing gastric mechanoreceptor stimulation. In this review, the current knowledge about the effects of different macronutrients and fibre on the release of GI satiety-related peptides in humans is discussed.     

Bacterial Community Mapping of the Mouse Gastrointestinal Tract

Keeping mammalian gastrointestinal (GI) tract communities in balance is crucial for host health maintenance. However, our understanding of microbial communities in the GI tract is still very limited. In this study, samples taken from the GI tracts of C57BL/6 mice were subjected to 16S rRNA gene sequence-based analysis to examine the characteristic bacterial communities along the mouse GI tract, including those present in the stomach, duodenum, jejunum, ileum, cecum, colon and feces. Further analyses of the 283,234 valid sequences obtained from pyrosequencing revealed that the gastric, duodenal, large intestinal and fecal samples had higher phylogenetic diversity than the jejunum and ileum samples did. The microbial communities found in the small intestine and stomach were different from those seen in the large intestine and fecal samples. A greater proportion of Lactobacillaceae were found in the stomach and small intestine, while a larger proportion of anaerobes such as Bacteroidaceae, Prevotellaceae, Rikenellaceae, Lachnospiraceae, and Ruminococcaceae were found in the large intestine and feces. In addition, inter-mouse variations of microbiota were observed between the large intestinal and fecal samples, which were much smaller than those between the gastric and small intestinal samples. As far as we can ascertain, ours is the first study to systematically characterize bacterial communities from the GI tracts of C57BL/6 mice.     

Persistent gastric colonization with Burkholderia pseudomallei and dissemination from the gastrointestinal tract following mucosal inoculation of mice

Melioidosis is a disease of humans caused by opportunistic infection with the soil and water bacterium Burkholderia pseudomallei. Melioidosis can manifest as an acute, overwhelming infection or as a chronic, recurrent infection. At present, it is not clear where B. pseudomallei resides in the mammalian host during the chronic, recurrent phase of infection. To address this question, we developed a mouse low-dose mucosal challenge model of chronic B. pseudomallei infection and investigated sites of bacterial persistence over 60 days. Sensitive culture techniques and selective media were used to quantitate bacterial burden in major organs, including the gastrointestinal (GI) tract. We found that the GI tract was the primary site of bacterial persistence during the chronic infection phase, and was the only site from which the organism could be consistently cultured during a 60-day infection period. The organism could be repeatedly recovered from all levels of the GI tract, and chronic infection was accompanied by sustained low-level fecal shedding. The stomach was identified as the primary site of GI colonization as determined by fluorescent in situ hybridization. Organisms in the stomach were associated with the gastric mucosal surface, and the propensity to colonize the gastric mucosa was observed with 4 different B. pseudomallei isolates. In contrast, B. pseudomallei organisms were present at low numbers within luminal contents in the small and large intestine and cecum relative to the stomach. Notably, inflammatory lesions were not detected in any GI tissue examined in chronically-infected mice. Only low-dose oral or intranasal inoculation led to GI colonization and development of chronic infection of the spleen and liver. Thus, we concluded that in a mouse model of melioidosis B. pseudomallei preferentially colonizes the stomach following oral inoculation, and that the chronically colonized GI tract likely serves as a reservoir for dissemination of infection to extra-intestinal sites.     

Magnetic resonance imaging in the diagnosis of gastric cancer: X-ray versus MRI anatomic findings

The paper assesses the present-day role of MRI in the diagnosis of gastric cancer. The authors consider the major prerequisites for the main aim of their study to be: 1) a dramatic incidence of diffuse (endophytic) gastric carcinoma, which requires significant correction of today's approaches to its diagnosis and 2) a rather biased and, in the authors' opinion, present-day mainly negative attitude towards MRI of the stomach as a diagnostic method for its tumor lesions. By applying the X-ray-MRI anatomic principle to the comparative study of MRI findings in 50 patients with predominantly gastric intramural carcinoma and in 25 patients without gastric tumors (controls), the authors present their methods for gastric MRI, the MRI semiotics of gastric cancer by concurrently touching upon a variety of problems that characterize the potentialities of MRI of the stomach in the diagnosis of its tumor lesions, including their differential diagnosis. As a result, the authors highly appreciate gastric MRI and consider this method to be included into the diagnostic algorithm of radiation techniques used in the diagnosis of gastric cancer, which should occupy its definite diagnostic place.     

Gastric magnetic resonance study (methods,semiotics)

The paper shows the potentialities of gastric study by magnetic resonance imaging (MRI). The methodic aspects of gastric study have been worked out. The MRI-semiotics of the unchanged and tumor-affected wall of the stomach and techniques in examining patients with gastric cancer of various sites are described. Using the developed procedure, MRI was performed in 199 patients, including 154 patients with gastric pathology and 45 control individuals who had no altered gastric wall. Great emphasis is placed on the role of MRI in the diagnosis of endophytic (diffuse) gastric cancer that is of priority value in its morphological structure. MRI was found to play a role in the diagnosis of the spread of a tumorous process both along the walls of the stomach and to its adjacent anatomic structures.     

Gastric tuft cells express DCLK1 and are expanded in hyperplasia

Epithelial tuft cells are named after their characteristic microtubule bundles located at the cell apex where these are exposed to the luminal environment. As such, tuft cells are found in multiple organs, including the gastrointestinal (GI) tract where the apical “tuft” is hypothesized to detect and transmit environmental signals. Thus, the goal of our study was to characterize gastric tuft cells during GI tract development, then subsequently in the normal and metaplastic adult stomach. GI tracts from mouse embryos, and newborn and postnatal mice were analyzed. Tuft cells were identified by immunohistochemistry using acetylated-α-tubulin (acTub) antibody to detect the microtubule bundle. Additional tuft cell markers, e.g., doublecortin-like kinase 1 (DCLK1), were used to co-localize with acTub. Tuft cells were quantified in human gastric tissue arrays and in mouse stomachs with or without inflammation. In the developing intestine, tuft cells in both the crypts and villi expressed all markers by E18.5. In the stomach, acTub co-localized with DCLK1 and other established tuft cell markers by E18.5 in the antrum, but not until postnatal day 7 in the corpus, with the highest density of tuft cells clustered at the forestomach ridge. Tuft cell numbers increased in hyperplastic human and mouse stomachs. In the adult GI tract, the tuft cell marker acTub co-expressed with DCKL1 and chemosensory markers, e.g.,TRPM5. In summary, tuft cells appear in the gastric antrum and intestine at E18.5, but their maximal numbers in the corpus are not achieved until after weaning. Tuft cell numbers increase with inflammation, hyperplasia, and metaplasia.     

Coordination of motilin and ghrelin regulates the migrating motor complex of gastrointestinal motility in Suncus murinus

Motilin and ghrelin are the gastrointestinal (GI) hormones released in a fasting state to stimulate the GI motility of the migrating motor complex (MMC). We focused on coordination of the ghrelin/motilin family in gastric contraction in vivo and in vitro using the house musk shrew (Suncus murinus), a ghrelin- and motilin-producing mammal. To measure the contractile activity of the stomach in vivo, we recorded GI contractions either in the free-moving conscious or anesthetized S. murinus and examined the effects of administration of motilin and/or ghrelin on spontaneous MMC in the fasting state. In the in vitro study, we also studied the coordinative effect of these hormones on the isolated stomach using an organ bath. In the fasting state, phase I, II, and III contractions were clearly recorded in the gastric body (as observed in humans and dogs). Intravenous infusion of ghrelin stimulated gastric contraction in the latter half of phase I and in the phase II in a dose-dependent manner. Continuous intravenous infusion of ghrelin antagonist (d-Lys3-GHRP6) significantly suppressed spontaneous phase II contractions and prolonged the time of occurrence of the peak of phase III contractions. However, intravenous infusion of motilin antagonist (MA-2029) did not inhibit phase II contractions but delayed the occurrence of phase III contractions of the MMC. In the in vitro study, even though a high dose of ghrelin did not stimulate contraction of stomach preparations, ghrelin administration (10(-10)-10(-7) M) with pretreatment of a low dose of motilin (10(-10) M) induced gastric contraction in a dose-dependent manner. Pretreatment with 10(-8) M ghrelin enhanced motilin-stimulated gastric contractions by 10 times. The interrelation of these peptides was also demonstrated in the anesthetized S. murinus. The results suggest that ghrelin is important for the phase II contraction and that coordination of motilin and ghrelin are necessary to initiate phase III contraction of the MMC.     

Characterization of bacterial community in the stomach of yellow catfish (<Emphasis Type="Italic">Pelteobagrus fulvidraco</Emphasis>)

In this study, the traditional culture-based technique and the 16S rDNA sequencing method were used to investigate the characterization of bacterial community in the stomach contents and mucus of yellow catfish (Pelteobagrus fulvidraco). The culture-based technique disclosed that the average bacterial numbers in the gastric contents and mucus were 5.79 × 10⁷ cfu/g (cfu: colony forming unit) and 1.89 × 10⁵ cfu/g, respectively. Several different bacteria were obtained from gastric contents, including species from genera Bradyrhizobium, Phyllobacterium, Plesiomonas, Hafnia, Edwardsiella, Pseudomonas, and Bacillus. However, only two species were isolated from the gastric mucus, including species from genera Plesiomonas and Aeromonas. Forty-five phylotypes were observed from the 65 positive clones from the stomach contents (library SC); nineteen phylotypes were detected from the 45 clones from the stomach mucus (library SM). Further analyses revealed that the fish stomach harbored characteristic microbiota, where Firmicutes was dominant, followed by Proteobacteria and Bacteroidetes and Fusobacteria. This characterization of bacterial community is markedly different from that of the fish intestine, where Proteobacteria is predominant, followed by Fusobacteria and Firmicutes. Chloroflexi (1.5%) was only found in the library SC, while Actinobacteria (4.4%) was only found in the library SM, suggesting that microbiota of GI contents was quite different from that of GI mucus. In addition, several species of bacteria found in the stomach may be potentially opportunistic pathogens, indicating that fish digestive tract is a reservoir for many nosocomial pathogens.     

Roles of cancer stem cells in gastrointestinal cancers

Cancer stem cells (CSCs) are the main cause of tumor growth, invasion, metastasis and recurrence. Recently, CSCs have been extensively studied to identify CSC-specific surface markers as well as signaling pathways that play key roles in CSCs self-renewal. The involvement of CSCs in the pathogenesis of gastrointestinal (GI) cancers also highlights these cells as a priority target for therapy. The diagnosis, prognosis and treatment of GI cancer have always been a focus of attention. Therefore, the potential application of CSCs in GI cancers is receiving increasing attention. This review summarizes the role of CSCs in GI cancers, focusing on esophageal cancer, gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer. In addition, we propose CSCs as potential targets and therapeutic strategies for the effective treatment of GI cancers, which may provide better guidance for clinical treatment of GI cancers.     

Apelin cells in the rat stomach

Apelin is a recently discovered peptide that is the endogenous ligand for the APJ receptor. Apelin is produced in the central nervous system, heart, lung, mammary gland and gastrointestinal (GI) tract. The aim of this study was to identify by immunohistochemistry (IHC) cell types in the rat stomach that produce apelin peptide. IHC revealed abundant apelin-positive cells, primarily in the neck and upper base regions of the gastric glands in the mucosal epithelium. Apelin is not detected in the muscle layer. Apelin-positive cells were identified as mucous neck, parietal cells, and chief cells. Apelin is also identified in gastric epithelial cells that produce chromogranin A (CGA), a marker of enteroendocrine cells. The findings that apelin is expressed in gastric exocrine and endocrine cells agrees with and extends other data showing that apelin peptide is measurable in the gut lumen and in the systemic circulation by immunoassay.     

Gastrointestinal flora of cotton rats

The gastrointestinal (GI) flora of cotton rats was examined. No lactobacilli were detected in any part of the GI tract. Anaerobes, including Peptococcaceae, Bacteroidaceae, bifidobacteria and eubacteria, were the predominant bacteria in the stomach, small intestine, caecum and faeces. Aerobes and facultative anaerobes, including Enterobacteriaceae and streptococci, were detected at low numbers and very low frequency of occurrence in all parts of the GI tract. Sixty-one isolates of bifidobacteria were recovered from the stomach, small intestine, caecum and faeces of cotton rats. They were identified as Bifidobacterium animalis, B. pseudolongum biovar a and b. The study showed that the GI flora of cotton rats seem to be very different from the GI flora in other rodents.     

Chronic injury as a major factor in susceptibility to gastric cancer

The etiology of gastric cancer is still unclear. The lesser curvature of stomach is more susceptible to chronic injury due to the anatomical characteristics. Many previous studies demonstrated that the lesser curvature is the most frequent tumor site in gastric cancer. And, precancerous gastric lesions, such as atrophic and intestinal metaplasia were also typically located in the lesser curvature. The lesser curvature is the first part of the stomach to be infected with Helicobacter pylori (H. pylori) infection which was associated with precancerous gastric lesions and gastric cancer. So, chronic injury of the stomach may lead to gastric cancer have hypothesized.     

血清胃蛋白酶原Ⅰ/Ⅱ、铁蛋白及肿瘤坏死因子-alpha对胃癌的诊断价值

目的：探讨血清胃蛋白酶原Ⅰ/Ⅱ(PGⅠ/Ⅱ)、铁蛋白、肿瘤坏死因子-alpha联合检查诊断胃癌的临床意义。方法：选择2013 年5 月至2014 年10 月收治的胃病住院患者及健康体检者,根据胃镜及病理组织学结果,将其分良性胃病组、胃癌组以及健康组,比 较三组血清胃蛋白酶原Ⅰ/Ⅱ、铁蛋白及肿瘤坏死因子-alpha水平,分析血清胃蛋白酶原Ⅰ/Ⅱ(PGⅠ/Ⅱ)、铁蛋白、肿瘤坏死因子-alpha单 独和联合诊断胃癌的敏感性、特异性和准确性。结果：与健康组比较,良性胃病组以及胃癌组的血清PGⅠ/Ⅱ水平较低(P＜0.05), 与良性胃病组比较,胃癌组血清PGⅠ/Ⅱ水平较低(P＜0.05);与健康组比较,良性胃病组以及胃癌组的血清铁蛋白以及TNF-alpha水 平较高(P＜0.05),与良性胃病组比较,胃癌组血清铁蛋白以及TNF-alpha水平较高(P＜0.05)。PGⅠ/Ⅱ、铁蛋白以及TNF-alpha联合检测 诊断胃癌的敏感度以及准确度分别为88.4％以及83.1％,高于单一检测。结论：血清PGⅠ/Ⅱ、血清铁蛋白、肿瘤坏死因子-alpha联合 检测诊断胃癌的效能优于单一检测。     

Protein-tyrosine kinase and protein-serine/threonine kinase expression in human gastric cancer cell lines

Protein kinases play key roles in cellular functions. They are involved in many cellular functions including; signal transduction, cell cycle regulation, cell division, and cell differentiation. Alterations of protein kinase by gene amplification, mutation or viral factors often induce tumor formation and tumor progression toward malignancy. The identification and cloning of kinase genes can provide a better understanding of the mechanisms of tumorigenesis as well as diagnostic tools for tumor staging. In this study, we have used degenerated polymerase-chain-reaction primers according to the consensus catalytic domain motifs to amplify protein kinase genes (protein-tyrosine kinase, PTK, and protein-serine/threonine kinase, PSK) from human stomach cancer cells. Following amplification, the protein kinase molecules expressed in the gastric cancer cells were cloned into plasmid vectors for cloning and sequencing. Sequence analysis of polymerase-chain-reaction products resulted in the identification of 25 protein kinases, including two novel ones. Expression of several relevant PTK/PSK genes in gastric cancer cells and tissues was further substantiated by RT-PCR using gene-specific primers. The identification of protein kinases expressed or activated in the gastric cancer cells provide the framework to understand the oncogenic process of stomach cancer.     

Satiety: the roles of peptides from the stomach and the intestine

Rats were surgically prepared to allow perfusions of anatomically limited portions of the gastrointestinal (GI) surface during test meals. The results demonstrated that at least one potent satiety signal was generated when ingested food accumulated in the stomach and did not enter the small intestine. This gastric satiety signal did not require the vagus nerve for its operation. In addition, at least one other potent satiety signal was generated when food perfused the small intestine. This intestinal satiety signal did not require gastric distension for its operation. We tested a variety of GI peptides to determine whether any met the criteria imposed by this evidence for regionally specific satiety signals. Bombesin (BBS), a peptide present in high concentration in the stomach, was a potent and behaviorally specific inhibitor of food intake. Its satiating effect was not altered by subdiaphragmatic vagotomy. Cholecystokinin (CCK), a peptide hormone that is released from the small intestine by food, was also a potent and behaviorally specific inhibitor of food intake; its satiating effect did not require gastric distension for its expression, but its satiating effect was markedly reduced or abolished by subdiaphragmatic vagotomy. Thus, BBS and CCK may mediate at least part of the satiating effect of food acting in the stomach and in the small intestine, respectively.