A physics-based model for maintenance of the pH gradient in the gastric mucus layer
It is generally accepted that the gastric mucus layer provides a protective barrier between the lumen and the mucosa, shielding the mucosa from acid and digestive enzymes and preventing autodigestion of the stomach epithelium. However, the precise mechanisms that contribute to this protective function are still up for debate. In particular, it is not clear what physical processes are responsible for transporting hydrogen protons, secreted within the gastric pits, across the mucus layer to the lumen without acidifying the environment adjacent to the epithelium. One hypothesis is that hydrogen may be bound to the mucin polym...
Source: AJP: Gastrointestinal and Liver Physiology - December 1, 2017 Category: Gastroenterology Authors: Lewis, O. L., Keener, J. P., Fogelson, A. L. Tags: RESEARCH ARTICLE Source Type: research

Role of MicroRNA-423-5p in posttranscriptional regulation of the intestinal riboflavin transporter-3
Riboflavin (RF) is essential for normal cellular functions and health. Humans obtain RF from exogenous sources via intestinal absorption that involves a highly specific carrier-mediated process. We have recently established that the riboflavin transporter-3 (RFVT3) is vital for the normal intestinal RF uptake process and have characterized certain aspects of its transcriptional regulation. Little is known, however, about how this transporter is regulated at the posttranscriptional level. We address this issue by focusing on the role of microRNAs. Using bioinformatics, we identified two potential interacting miRNAs with the...
Source: AJP: Gastrointestinal and Liver Physiology - December 1, 2017 Category: Gastroenterology Authors: Lakhan, R., Subramanian, V. S., Said, H. M. Tags: RESEARCH ARTICLE Source Type: research

Age-related external anal sphincter muscle dysfunction and fibrosis: possible role of Wnt/{beta}-catenin signaling pathways
Studies show an age-related increase in the prevalence of anal incontinence and sphincter muscle atrophy. The Wnt/β-catenin signaling pathway has been recently recognized as the major molecular pathway involved in age-related skeletal muscle atrophy and fibrosis. The goals of our study were to 1) evaluate the impact of normal aging on external anal sphincter (EAS) muscle length-tension (L-T) function and morphology and 2) specifically examine the role of Wnt signaling pathways in anal sphincter muscle fibrosis. New Zealand White female rabbits [6 young (6 mo of age) and 6 old (36 mo of age)] were anesthetized, and ana...
Source: AJP: Gastrointestinal and Liver Physiology - December 1, 2017 Category: Gastroenterology Authors: Rajasekaran, M. R., Kanoo, S., Fu, J., Nguyen, M.-U., Bhargava, V., Mittal, R. K. Tags: RESEARCH ARTICLE Source Type: research

Ammonia modifies enteric neuromuscular transmission through glial {gamma}-aminobutyric acid signaling
Impaired gut motility may contribute, at least in part, to the development of systemic hyperammonemia and systemic neurological disorders in inherited metabolic disorders, or in severe liver and renal disease. It is not known whether enteric neurotransmission regulates intestinal luminal and hence systemic ammonia levels by induced changes in motility. Here, we propose and test the hypothesis that ammonia acts through specific enteric circuits to influence gut motility. We tested our hypothesis by recording the effects of ammonia on neuromuscular transmission in tissue samples from mice, pigs, and humans and investigated s...
Source: AJP: Gastrointestinal and Liver Physiology - December 1, 2017 Category: Gastroenterology Authors: Fried, D. E., Watson, R. E., Robson, S. C., Gulbransen, B. D. Tags: RESEARCH ARTICLE Source Type: research

Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling
In conclusion, we determined that alcohol-induced microtubule acetylation and associated defects in microtubule-dependent trafficking are mediated by ADH metabolism whereas impaired microtubule-independent Jak2/STAT5B activation is mediated by CYP2E1 activity. NEW & NOTEWORTHY Impaired growth hormone-mediated signaling is observed in ethanol-exposed hepatocytes and is explained by differential effects of alcohol dehydrogenase (ADH)- and cytochrome P450 2E1 (CYP2E1)-mediated ethanol metabolism on the Jak2/STAT5B pathway. (Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - December 1, 2017 Category: Gastroenterology Authors: Doody, E. E., Groebner, J. L., Walker, J. R., Frizol, B. M., Tuma, D. J., Fernandez, D. J., Tuma, P. L. Tags: RESEARCH ARTICLE Source Type: research

Targeting palmitoyl acyltransferase ZDHHC21 improves gut epithelial barrier dysfunction resulting from burn-induced systemic inflammation
In this study, we identified a significant function of a particular palmitoyl acyltransferase, zinc finger DHHC domain-containing protein-21 (ZDHHC21), in mediating signaling events required for gut hyperpermeability induced by inflammation. Using quantitative PCR, we show that ZDHHC21 mRNA production was enhanced twofold when intestinal epithelial cells were treated with TNF-α-IFN- in vitro. In addition, pharmacological targeting of palmitoyl acyltransferases with 2-bromopalmitate (2-BP) showed significant improvement in TNF-α-IFN--mediated epithelial barrier dysfunction by using electric cell-substrate impeda...
Source: AJP: Gastrointestinal and Liver Physiology - December 1, 2017 Category: Gastroenterology Authors: Haines, R. J., Wang, C. Y., Yang, C. G. Y., Eitnier, R. A., Wang, F., Wu, M. H. Tags: RESEARCH ARTICLE Source Type: research

Zinc strengthens the jejunal barrier by reversibly tightening the paracellular route
During the postweaning period, piglets are prone to gastrointestinal infections. The resulting impairment of intestinal barrier function may cause diarrhea associated with growth retardation or even death of piglets. Orally applied Zn is commonly used to prevent and treat diarrhea, but its mode of action still needs to be elucidated. To analyze the molecular mechanism whereby Zn acts on porcine intestinal barrier function, ex vivo studies on piglet jejunum and accompanying in vitro studies on a porcine jejunal epithelial cell line, IPEC-J2/PS, were performed with electrophysiological tools. Feeding pharmacological Zn doses...
Source: AJP: Gastrointestinal and Liver Physiology - December 1, 2017 Category: Gastroenterology Authors: Zakrzewski, S. S., Fromm, M., Schulzke, J. D., Günzel, D. Tags: RESEARCH ARTICLE Source Type: research

Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges
This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism. (Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - November 2, 2017 Category: Gastroenterology Authors: Maertin, S., Elperin, J. M., Lotshaw, E., Sendler, M., Speakman, S. D., Takakura, K., Reicher, B. M., Mareninova, O. A., Grippo, P. J., Mayerle, J., Lerch, M. M., Gukovskaya, A. S. Tags: RESEARCH ARTICLE Source Type: research

Hamp1 mRNA and plasma hepcidin levels are influenced by sex and strain but do not predict tissue iron levels in inbred mice
Iron homeostasis is tightly regulated, and the peptide hormone hepcidin is considered to be a principal regulator of iron metabolism. Previous studies in a limited number of mouse strains found equivocal sex- and strain-dependent differences in mRNA and serum levels of hepcidin and reported conflicting data on the relationship between hepcidin (Hamp1) mRNA levels and iron status. Our aim was to clarify the relationships between strain, sex, and hepcidin expression by examining multiple tissues and the effects of different dietary conditions in multiple inbred strains. Two studies were done: first, Hamp1 mRNA, liver iron, a...
Source: AJP: Gastrointestinal and Liver Physiology - November 2, 2017 Category: Gastroenterology Authors: McLachlan, S., Page, K. E., Lee, S.-M., Loguinov, A., Valore, E., Hui, S. T., Jung, G., Zhou, J., Lusis, A. J., Fuqua, B., Ganz, T., Nemeth, E., Vulpe, C. D. Tags: RESEARCH ARTICLE Source Type: research

Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant
Aprepitant, an NK1 receptor antagonist, is approved for the treatment of chemotherapy-induced or postoperative emesis by blocking NK1 receptors in the brain stem vomiting center. The effects of NK1 receptors on gastric functions and postprandial symptoms in humans are unclear; a single, crossover study did not show a significant effect of aprepitant on gastrointestinal transit. Our aim was to compare, in a randomized, double-blind, placebo-controlled, parallel-group study (12 healthy volunteers per group), the effects of aprepitant vs. placebo on gastric emptying of solids (by scintigraphy) with a 320-kcal meal, gastric vo...
Source: AJP: Gastrointestinal and Liver Physiology - November 2, 2017 Category: Gastroenterology Authors: Jacob, D., Busciglio, I., Burton, D., Halawi, H., Oduyebo, I., Rhoten, D., Ryks, M., Harmsen, W. S., Camilleri, M. Tags: RESEARCH ARTICLE Source Type: research

A small population of liver endothelial cells undergoes endothelial-to-mesenchymal transition in response to chronic liver injury
Rising evidence points to endothelial-to-mesenchymal transition (EndMT) as a significant source of the mesenchymal cell population in fibrotic diseases. In this context, we hypothesized that liver endothelial cells undergo EndMT during fibrosis progression. Cirrhosis in mice was induced by CCl4. A transgenic mouse expressing a red fluorescent protein reporter under the control of Tie2 promoter (Tie2-tdTomato) was used to trace the acquisition of EndMT. Sinusoidal vascular connectivity was evaluated by intravital microscopy and high-resolution three-dimensional confocal microscopy. A modest but significant fraction of liver...
Source: AJP: Gastrointestinal and Liver Physiology - November 2, 2017 Category: Gastroenterology Authors: Ribera, J., Pauta, M., Melgar-Lesmes, P., Cordoba, B., Bosch, A., Calvo, M., Rodrigo-Torres, D., Sancho-Bru, P., Mira, A., Jimenez, W., Morales-Ruiz, M. Tags: RESEARCH ARTICLE Source Type: research

Krüppel-like factor 5 is essential for maintenance of barrier function in mouse colon
Krüppel-like factor 5 (KLF5) is a member of the zinc finger family of transcription factors that regulates homeostasis of the intestinal epithelium. Previous studies suggested an indispensable role of KLF5 in maintaining intestinal barrier function. In the current study, we investigated the mechanisms by which KLF5 regulates colonic barrier function in vivo and in vitro. We used an inducible and a constitutive intestine-specific Klf5 knockout mouse models (Villin-CreERT2;Klf5fl/fl designated as Klf5IND and Villin-Cre;Klf5fl/fl as Klf5IS) and studied an inducible KLF5 knockdown in Caco-2 BBe cells using a lentiviral Tet-o...
Source: AJP: Gastrointestinal and Liver Physiology - November 2, 2017 Category: Gastroenterology Authors: Liu, Y., Chidgey, M., Yang, V. W., Bialkowska, A. B. Tags: RESEARCH ARTICLE Source Type: research

KLF-5 extends its fingers to desmosomes: the next frontier for enteric epithelial research?
(Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - November 2, 2017 Category: Gastroenterology Authors: Israelyan, N., Margolis, K. G. Tags: EDITORIAL FOCUS Source Type: research

A simple, cost-effective method for generating murine colonic 3D enteroids and 2D monolayers for studies of primary epithelial cell function
We describe, in detail, the protocols required to maintain three-dimensional cultures of murine colonoids and passage these primary epithelial cells to confluent monolayers in a standardized, high-yield and cost-effective manner. (Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Fernando, E. H., Dicay, M., Stahl, M., Gordon, M. H., Vegso, A., Baggio, C., Alston, L., Lopes, F., Baker, K., Hirota, S., McKay, D. M., Vallance, B., MacNaughton, W. K. Tags: INNOVATIVE METHODOLOGY Source Type: research

A novel mouse model of radiation-induced cancer survivorship diseases of the gut
A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Bull, C., Malipatlolla, D., Kalm, M., Sjöberg, F., Alevronta, E., Grander, R., Sultanian, P., Persson, L., Boström, M., Eriksson, Y., Swanpalmer, J., Wold, A. E., Blomgren, K., Björk-Eriksson, T., Steineck, G. Tags: RESEARCH ARTICLE Source Type: research

Adaptive regulation of pancreatic acinar mitochondrial thiamin pyrophosphate uptake process: possible involvement of epigenetic mechanism(s)
The essentiality of thiamin stems from its roles as a cofactor [mainly in the form of thiamin pyrophosphate (TPP)] in critical metabolic reactions including oxidative energy metabolism and reduction of cellular oxidative stress. Like other mammalian cells, pancreatic acinar cells (PAC) obtain thiamin from their surroundings and convert it to TPP; mitochondria then take up TPP by a carrier-mediated process that involves the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). Previous studies have characterized different physiological/biological aspects of the MTPP uptake process, but little is known abou...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Sabui, S., Subramanian, V. S., Kapadia, R., Said, H. M. Tags: RESEARCH ARTICLE Source Type: research

Relationship of gastric emptying or accommodation with satiation, satiety, and postprandial symptoms in health
The contributions of gastric emptying (GE) and gastric accommodation (GA) to satiation, satiety, and postprandial symptoms remain unclear. We aimed to evaluate the relationships between GA or GE with satiation, satiety, and postprandial symptoms in healthy overweight or obese volunteers (total n = 285, 73% women, mean BMI 33.5 kg/m2): 26 prospectively studied obese, otherwise healthy participants and 259 healthy subjects with previous similar GI testing. We assessed GE of solids, gastric volumes, calorie intake at buffet meal, and satiation by measuring volume to comfortable fullness (VTF) and maximum tolerated volume (MTV...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Halawi, H., Camilleri, M., Acosta, A., Vazquez-Roque, M., Oduyebo, I., Burton, D., Busciglio, I., Zinsmeister, A. R. Tags: RESEARCH ARTICLE Source Type: research

Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat
Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1) assess the gastric effects of brain stem DA application, 2) identify the DA receptor subtype, and, 3) ident...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Anselmi, L., Toti, L., Bove, C., Travagli, R. A. Tags: RESEARCH ARTICLE Source Type: research

Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal
Regulation of colonic motility depends on the integrity of enteric inhibitory neurotransmission mediated by nitric oxide (NO), purine neurotransmitters, and neuropeptides. Intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor-α-positive (PDGFRα+) cells are involved in generating responses to NO and purine neurotransmitters, respectively. Previous studies have suggested a decreased nitrergic and increased purinergic neurotransmission in KitW/KitW-v (W/Wv) mice that display lesions in ICC-IM along the gastrointestinal tract. However, contributions of NO to these phenotypes...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Durnin, L., Lees, A., Manzoor, S., Sasse, K. C., Sanders, K. M., Mutafova-Yambolieva, V. N. Tags: RESEARCH ARTICLE Source Type: research

Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats
This study expands these findings by investigating neural GnRH regulation by melatonin during BDL-induced cholestasis by infusing melatonin into the brain. Melatonin infusion reduced cholangiocyte proliferation and fibrosis, and these effects are due to GNRH receptor 1-dependent paracrine signaling between cholangiocytes and hepatic stellate cells. (Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: McMillin, M., DeMorrow, S., Glaser, S., Venter, J., Kyritsi, K., Zhou, T., Grant, S., Giang, T., Greene, J. F., Wu, N., Jefferson, B., Meng, F., Alpini, G. Tags: RESEARCH ARTICLE Source Type: research

PARP2 deficiency affects invariant-NKT-cell maturation and protects mice from concanavalin A-induced liver injury
In conclusion, our results suggest that the defect of T-lymphocyte maturation in Parp2 knockout mice leads to a systemic reduction of iNKT cells, reducing hepatocyte death during ConA-mediated liver damage, thus protecting the mice from hepatitis. NEW & NOTEWORTHY The genetic inactivation of Parp2, but not Parp1, protects mice from concanavalin A hepatitis. Immune cell populations are lower in the thymus, but not in the spleen, liver, or bone marrow of Parp2-deficient mice compared with wild-type mice. Spleen and liver invariant natural killer T (NKT) lymphocytes, as well as thymic T and NKT lymphocytes, are reduced in...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Filliol, A., Piquet-Pellorce, C., Dion, S., Genet, V., Lucas-Clerc, C., Dantzer, F., Samson, M. Tags: RESEARCH ARTICLE Source Type: research

Enteric serotonin and oxytocin: endogenous regulation of severity in a murine model of necrotizing enterocolitis
Necrotizing enterocolitis (NEC), a gastrointestinal inflammatory disease of unknown etiology that may also affect the liver, causes a great deal of morbidity and mortality in premature infants. We tested the hypothesis that signaling molecules, which are endogenous to the bowel, regulate the severity of intestinal and hepatic damage in an established murine NEC model. Specifically, we postulated that mucosal serotonin (5-HT), which is proinflammatory, would exacerbate experimental NEC and that oxytocin (OT), which is present in enteric neurons and is anti-inflammatory, would oppose it. Genetic deletion of the 5-HT transpor...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Gross Margolis, K., Vittorio, J., Talavera, M., Gluck, K., Li, Z., Iuga, A., Stevanovic, K., Saurman, V., Israelyan, N., Welch, M. G., Gershon, M. D. Tags: RESEARCH ARTICLE Source Type: research

Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis
Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver that may progress to hepatic fibrosis and nonalcoholic steatohepatitis (NASH). Mechanisms underlying NAFLD and NASH are not yet fully understood. Dietary cholesterol was recently shown to be a risk factor for the development of NASH, suggesting a role for intestinal handling of cholesterol. One important regulator of cholesterol homeostasis is the sterol response element-binding protein-2 (SREBP-2) transcription factor. We tested the hypothesis that the overactivation of intestinal SREBP-2 increases the susceptibility to diet-induc...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Malhotra, P., Aloman, C., Ankireddy, A., Khadra, H., Ooka, K., Gill, R. K., Saksena, S., Dudeja, P. K., Alrefai, W. A. Tags: RESEARCH ARTICLE Source Type: research

Impact of prevailing thiamin levels on thiamin pyrophosphate uptake in pancreatic acinar cells: do the shuttle!
(Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Kennedy, L., Francis, H., Alpini, G. Tags: EDITORIAL FOCUS Source Type: research

Role of G protein-coupled receptors-microRNA interactions in gastrointestinal pathophysiology
G protein-coupled receptors (GPCRs) make up the largest transmembrane receptor superfamily in the human genome and are expressed in nearly all gastrointestinal cell types. Coupling of GPCRs and their respective ligands activates various phosphotransferases in the cytoplasm, and, thus, activation of GPCR signaling in intestine regulates many cellular and physiological processes. Studies in microRNAs (miRNAs) demonstrate that they represent critical epigenetic regulators of different pathophysiological responses in different organs and cell types in humans and animals. Here, we reviewed recent research on GPCR-miRNA interact...
Source: AJP: Gastrointestinal and Liver Physiology - November 1, 2017 Category: Gastroenterology Authors: Law, I. K. M., Padua, D. M., Iliopoulos, D., Pothoulakis, C. Tags: REVIEW Source Type: research

Consumption of a high-iron diet disrupts homeostatic regulation of intestinal copper absorption in adolescent mice
High-iron feeding of rodents has been commonly used to model human iron-overload disorders. We recently noted that high-iron consumption impaired growth and caused severe systemic copper deficiency in growing rats, but the mechanism by which this occurred could not be determined due to technical limitations. In the current investigation, we thus utilized mice; first to determine if the same phenomenon occurred in another mammalian species, and second since we could assess in vivo copper absorption in mice. We hypothesized that excessive dietary iron impaired intestinal copper absorption. Weanling, male mice were thus fed A...
Source: AJP: Gastrointestinal and Liver Physiology - October 1, 2017 Category: Gastroenterology Authors: Ha, J.-H., Doguer, C., Collins, J. F. Tags: RESEARCH ARTICLE Source Type: research

Validation and characterization of a novel method for selective vagal deafferentation of the gut
We report that CCK-SAP ablates a subpopulation of VAN in culture. In vivo, CCK-SAP injection into the NG reduces VAN innervating the mucosal and muscular layers of the stomach and small intestine but not the colon, while leaving vagal efferent neurons intact. CCK-SAP abolishes feeding-induced c-Fos in the NTS, as well as satiation by CCK or glucagon like peptide-1 (GLP-1). CCK-SAP in the NG of mice also abolishes CCK-induced satiation. Therefore, we provide multiple lines of evidence that injection of CCK-SAP in NG is a novel selective vagal deafferentation technique of the upper GI tract that works in multiple vertebrate ...
Source: AJP: Gastrointestinal and Liver Physiology - October 1, 2017 Category: Gastroenterology Authors: Diepenbroek, C., Quinn, D., Stephens, R., Zollinger, B., Anderson, S., Pan, A., de Lartigue, G. Tags: RESEARCH ARTICLE Source Type: research

Augmentation of cGMP/PKG pathway and colonic motility by hydrogen sulfide
Hydrogen sulfide (H2S), like nitric oxide (NO), causes smooth muscle relaxation, but unlike NO, does not stimulate soluble guanylyl cyclase (sGC) activity and generate cyclic guanosine 5'-monophosphate (cGMP). The aim of this study was to investigate the interplay between NO and H2S in colonic smooth muscle. In colonic smooth muscle from rabbit, mouse, and human, l-cysteine, substrate of cystathionine--lyase (CSE), or NaHS, an H2S donor, inhibited phosphodiesterase 5 (PDE5) activity and augmented the increase in cGMP levels, IP3 receptor phosphorylation at Ser1756 (measured as a proxy for PKG activation), and muscle relaxa...
Source: AJP: Gastrointestinal and Liver Physiology - October 1, 2017 Category: Gastroenterology Authors: Nalli, A. D., Bhattacharya, S., Wang, H., Kendig, D. M., Grider, J. R., Murthy, K. S. Tags: RESEARCH ARTICLE Source Type: research

Abdominal surgery induced gastric ileus and activation of M1-like macrophages in the gastric myenteric plexus: prevention by central vagal activation in rats
Inflammation plays a role in abdominal surgery (AS)-induced intestinal ileus that is alleviated by electrical vagal stimulation. Intracisternal injection of RX-77368, the stable thyrotropin-releasing hormone agonist, activates dorsal motor nucleus neurons and gastric vagal efferent discharges. We investigated the gastric inflammation induced by AS and the modulation by intracisternal RX-77368 in rats. RX-77368 (50 ng/rat) or saline was injected followed, 1 h later, by laparotomy and small intestinal/cecal manipulation. The sham group had anesthesia alone. After 6 h, gastric emptying (GE) and the inflammation in gastric cor...
Source: AJP: Gastrointestinal and Liver Physiology - October 1, 2017 Category: Gastroenterology Authors: Yuan, P.-Q., Tache, Y. Tags: RESEARCH ARTICLE Source Type: research

Does acid-base equilibrium correlate with remnant liver volume during stepwise liver resection?
Small for size and flow syndrome (SFSF) is one of the most challenging complications following extended hepatectomy (EH). After EH, hepatic artery flow decreases and portal vein flow increases per 100 g of remnant liver volume (RLV). This causes hypoxia followed by metabolic acidosis. A correlation between acidosis and posthepatectomy liver failure has been postulated but not studied systematically in a large animal model or clinical setting. In our study, we performed stepwise liver resections on nine pigs to defined SFSF limits as follows: step 1: segment II/III resection, step 2: segment IV resection, step 3: segment V/...
Source: AJP: Gastrointestinal and Liver Physiology - October 1, 2017 Category: Gastroenterology Authors: Golriz, M., Abbasi, S., Fathi, P., Majlesara, A., Brenner, T., Mehrabi, A. Tags: RESEARCH ARTICLE Source Type: research

Determinants of postprandial plasma bile acid kinetics in human volunteers
Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women (n = 72, 62 ± 8 yr, mean ± SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed-meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography-tandem mass spectrometry comb...
Source: AJP: Gastrointestinal and Liver Physiology - October 1, 2017 Category: Gastroenterology Authors: Fiamoncini, J., Yiorkas, A. M., Gedrich, K., Rundle, M., Alsters, S. I., Roeselers, G., van den Broek, T. J., Clavel, T., Lagkouvardos, I., Wopereis, S., Frost, G., van Ommen, B., Blakemore, A. I., Daniel, H. Tags: RESEARCH ARTICLE Source Type: research

Dclk1-expressing tuft cells: critical modulators of the intestinal niche?
Dclk1-expressing tuft cells constitute a unique intestinal epithelial lineage that is distinct from enterocytes, Paneth cells, goblet cells, and enteroendocrine cells. Tuft cells express taste-related receptors and distinct transcription factors and interact closely with the enteric nervous system, suggesting a chemosensory cell lineage. In addition, recent work has shown that tuft cells interact closely with cells of the immune system, with a critical role in the cellular regulatory network governing responses to luminal parasites. Importantly, ablation of tuft cells severely impairs epithelial proliferation and tissue re...
Source: AJP: Gastrointestinal and Liver Physiology - October 1, 2017 Category: Gastroenterology Authors: Middelhoff, M., Westphalen, C. B., Hayakawa, Y., Yan, K. S., Gershon, M. D., Wang, T. C., Quante, M. Tags: REVIEW Source Type: research

RNA-seq implicates deregulation of the immune system in the pathogenesis of diverticulitis
Individuals with diverticula or outpouchings of the colonic mucosa and submucosa through the colonic wall have diverticulosis, which is usually asymptomatic. In 10-25% of individuals, the diverticula become inflamed, resulting in diverticulitis. Very little is known about the pathophysiology or gene regulatory pathways involved in the development of diverticulitis. To identify these pathways, we deep sequenced RNAs isolated from full-thickness sections of sigmoid colon from diverticulitis patients and control individuals. Specifically for diverticulitis cases, we analyzed tissue adjacent to areas affected by chronic diseas...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Schieffer, K. M., Choi, C. S., Emrich, S., Harris, L., Deiling, S., Karamchandani, D. M., Salzberg, A., Kawasawa, Y. I., Yochum, G. S., Koltun, W. A. Tags: RAPID REPORT Source Type: research

High-resolution mapping of gastric slow-wave recovery profiles: biophysical model, methodology, and demonstration of applications
Slow waves play a central role in coordinating gastric motor activity. High-resolution mapping of extracellular potentials from the stomach provides spatiotemporal detail on normal and dysrhythmic slow-wave patterns. All mapping studies to date have focused exclusively on tissue activation; however, the recovery phase contains vital information on repolarization heterogeneity, the excitable gap, and refractory tail interactions but has not been investigated. Here, we report a method to identify the recovery phase in slow-wave mapping data. We first developed a mathematical model of unipolar extracellular potentials that re...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Paskaranandavadivel, N., Cheng, L. K., Du, P., Rogers, J. M., OGrady, G. Tags: INNOVATIVE METHODOLOGY Source Type: research

CDX2 upregulates SLC26A3 gene expression in intestinal epithelial cells
SLC26A3 [downregulated in adenoma (DRA)] plays a key role in mammalian intestinal NaCl absorption, in that it mediates apical membrane Cl–/HCO3– exchange. DRA function and expression are significantly decreased in diarrhea associated with inflammatory bowel disease. DRA is also considered to be a marker of cellular differentiation and is predominantly expressed in differentiated epithelial cells. Caudal-type homeobox protein-2 (CDX2) is known to regulate genes involved in intestinal epithelial differentiation and proliferation. Reduced expression of both DRA and CDX2 in intestinal inflammation prompted us to st...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Chatterjee, I., Kumar, A., Castilla-Madrigal, R. M., Pellon-Cardenas, O., Gill, R. K., Alrefai, W. A., Borthakur, A., Verzi, M., Dudeja, P. K. Tags: RESEARCH ARTICLE Source Type: research

Activated Notch signaling cascade is correlated with stem cell differentiation toward absorptive progenitors after massive small bowel resection in a rat
In conclusion, 2 wk after bowel resection in rats, stimulated Notch signaling directs the crypt cell population toward absorptive progenitors. NEW & NOTEWORTHY This study provides novel insight into the mechanisms of cell proliferation following massive small bowel resection. We show that 2 wk after bowel resection in rats, enhanced stem cell activity was associated with stimulated Notch signaling pathway. We demonstrate that activated Notch signaling cascade directs the crypt cell population toward absorptive progenitors. (Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Sukhotnik, I., Coran, A. G., Pollak, Y., Kuhnreich, E., Berkowitz, D., Saxena, A. K. Tags: RESEARCH ARTICLE Source Type: research

Oatmeal particle size alters glycemic index but not as a function of gastric emptying rate
The aim of this study was to determine the extent to which oat particle size in a porridge could alter glucose absorption, gastric emptying, gastrointestinal hormone response, and subjective feelings of appetite and satiety. Porridge was prepared from either oat flakes or oat flour with the same protein, fat, carbohydrate, and mass. These were fed to eight volunteers on separate days in a crossover study, and subjective appetite ratings, gastric contents, and plasma glucose, insulin, and gastrointestinal hormones were determined over a period of 3 h. The flake porridge gave a lower glucose response than the flour porridge,...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Mackie, A. R., Bajka, B. H., Rigby, N. M., Wilde, P. J., Alves-Pereira, F., Mosleth, E. F., Rieder, A., Kirkhus, B., Salt, L. J. Tags: RESEARCH ARTICLE Source Type: research

Disease activity in eosinophilic esophagitis is associated with impaired esophageal barrier integrity
In eosinophilic esophagitis (EoE), the esophageal barrier integrity is impaired. Integrity can be assessed with different techniques. To assess the correlations between esophageal eosinophilia and various measures of mucosal integrity and to evaluate whether endoscopic impedance measurements can predict disease activity, endoscopies and mucosal integrity measurements were performed in adult EoE patients with active disease (≥15 eosinophils/high-power field) at baseline (n = 32) and after fluticasone (n = 15) and elemental dietary treatment (n = 14) and in controls (n = 19). Mucosal integrity was evaluated during endosco...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Warners, M. J., van Rhijn, B. D., Verheij, J., Smout, A. J. P. M., Bredenoord, A. J. Tags: RESEARCH ARTICLE Source Type: research

Characterization and mechanisms of the supragastric belch in the cat
A response in which a belch occurs without gastric involvement, i.e., the supragastric belch (SGB), has been characterized in humans. The aims of this study were to determine whether animals have an SGB and, if so, to determine its mechanisms. Studies were conducted in decerebrate cats (n = 30) with electromyographic electrodes on hyoid, pharyngeal, esophageal, and diaphragm muscles. The effects of distending different regions of the esophagus in different manners using a balloon were quantified to determine the most appropriate stimulus for activating the cat SGB. The effects of esophageal perfusion of lidocaine (n = 3), ...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Lang, I. M., Medda, B. K., Shaker, R. Tags: RESEARCH ARTICLE Source Type: research

Functional morphology of the lower esophageal sphincter and crural diaphragm determined by three-dimensional high-resolution esophago-gastric junction pressure profile and CT imaging
The smooth muscles of the lower esophageal sphincter (LES) and skeletal muscles of the crural diaphragm (CD) provide a closure/antireflux barrier mechanism at the esophago-gastric junction (EGJ). A number of questions in regard to the pressure profile of the LES and CD remain unclear, e.g., 1) Why is the LES pressure profile circumferentially asymmetric, 2) Is the crural diaphragm (CD) contraction also circumferentially asymmetric, and 3) Where is the LES and CD pressure profile located in the anatomy of the esophagus and stomach? The three-dimensional (3-D) high-resolution esophageal manometry (HRM) catheter can record a ...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Mittal, R. K., Zifan, A., Kumar, D., Ledgerwood-Lee, M., Ruppert, E., Ghahremani, G. Tags: RESEARCH ARTICLE Source Type: research

Dysfunctional neutrophil effector organelle mobilization and microbicidal protein release in alcohol-related cirrhosis
Patients with alcohol-related cirrhosis (ALD) are prone to infection. Circulating neutrophils in ALD are dysfunctional and predict development of sepsis, organ dysfunction, and survival. Neutrophil granules are important effector organelles containing a toxic array of microbicidal proteins, whose controlled release is required to kill microorganisms while minimizing inflammation and damage to host tissue. We investigated the role of these granular responses in contributing to immune disarray in ALD. Neutrophil granular content and mobilization were measured by flow cytometric quantitation of cell-surface/intracellular mark...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Tranah, T. H., Vijay, G. K. M., Ryan, J. M., Abeles, R. D., Middleton, P. K., Shawcross, D. L. Tags: RESEARCH ARTICLE Source Type: research

Anti-inflammatory effects and mechanisms of vagal nerve stimulation combined with electroacupuncture in a rodent model of TNBS-induced colitis
The purpose of this study was to determine the effects and mechanisms of vagal nerve stimulation (VNS) and additive effects of electroacupuncture (EA) on colonic inflammation in a rodent model of IBD. Chronic inflammation in rats was induced by intrarectal TNBS (2,4,6-trinitrobenzenesulfonic acid). The rats were then treated with sham ES (electrical stimulation), VNS, or VNS + EA for 3 wk. Inflammatory responses were assessed by disease activity index (DAI), macroscopic scores and histological scores of colonic tissues, plasma levels of TNFα, IL-1β, and IL-6, and myeloperoxidase (MPO) activity of colonic tissues...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Jin, H., Guo, J., Liu, J., Lyu, B., Foreman, R. D., Yin, J., Shi, Z., Chen, J. D. Z. Tags: RESEARCH ARTICLE Source Type: research

Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair
Esophageal injury is a risk factor for diseases such as Barrett’s esophagus (BE) and esophageal adenocarcinoma. To improve understanding of signaling pathways associated with both normal and abnormal repair, animal models are needed. Traditional rodent models of esophageal repair are limited by the absence of esophageal submucosal glands (ESMGs), which are present in the human esophagus. Previously, we identified acinar ductal metaplasia in human ESMGs in association with both esophageal injury and cancer. In addition, the SOX9 transcription factor has been associated with generation of columnar epithelium and the pa...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Krüger, L., Gonzalez, L. M., Pridgen, T. A., McCall, S. J., von Furstenberg, R. J., Harnden, I., Carnighan, G. E., Cox, A. M., Blikslager, A. T., Garman, K. S. Tags: RESEARCH ARTICLE Source Type: research

Loss of the anion exchanger DRA (Slc26a3), or PAT1 (Slc26a6), alters sulfate transport by the distal ileum and overall sulfate homeostasis
The ileum is considered the primary site of inorganic sulfate (SO42–) absorption. In the present study, we explored the contributions of the apical chloride/bicarbonate (Cl–/HCO3–) exchangers downregulated in adenoma (DRA; Slc26a3), and putative anion transporter 1 (PAT1; Slc26a6), to the underlying transport mechanism. Transepithelial 35SO42– and 36Cl– fluxes were determined across isolated, short-circuited segments of the distal ileum from wild-type (WT), DRA-knockout (KO), and PAT1-KO mice, together with measurements of urine and plasma sulfate. The WT distal ileum supported net sulfate abs...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Whittamore, J. M., Hatch, M. Tags: RESEARCH ARTICLE Source Type: research

The liver in regulation of iron homeostasis
The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the bod...
Source: AJP: Gastrointestinal and Liver Physiology - September 1, 2017 Category: Gastroenterology Authors: Rishi, G., Subramaniam, V. N. Tags: REVIEW Source Type: research

Long non-coding RNA NEAT1 promotes hepatocellular carcinoma cell proliferation through the regulation of miR-129-5p-VCP-I{kappa}B
This study provides new insights into the pathogenesis of HCC, as well as identifying new target genes for diagnosis and treatment. NEW & NOTEWORTHY The results provide strong evidence that upregulated NEAT1 promotes the proliferation of cancer cells in hepatocellular carcinoma (HCC) and this regulatory mechanism depends on the microRNA (miR)-129-5p-valosin-containing protein-IB axis. The study also indicates that NEAT1 could be a potential therapeutic target for HCC. (Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - August 1, 2017 Category: Gastroenterology Authors: Fang, L., Sun, J., Pan, Z., Song, Y., Zhong, L., Zhang, Y., Liu, Y., Zheng, X., Huang, P. Tags: RESEARCH ARTICLE Source Type: research

CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma
CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor m...
Source: AJP: Gastrointestinal and Liver Physiology - August 1, 2017 Category: Gastroenterology Authors: Wadkin, J. C. R., Patten, D. A., Kamarajah, S. K., Shepherd, E. L., Novitskaya, V., Berditchevski, F., Adams, D. H., Weston, C. J., Shetty, S. Tags: RESEARCH ARTICLE Source Type: research

A common NHE3 single-nucleotide polymorphism has normal function and sensitivity to regulatory ligands
This study reports results on the functional significance of human NHE3-799C under basal conditions and in response to regulatory ligands, including a novel NHE3 inhibitor called tenapanor. We demonstrate that NHE3-799C is a common variant of NHE3 that is enriched in Asian populations; however, in contrast to our previous studies using rabbit NHE3, its presence seems to have limited clinical significance in humans and is not associated with compromised function or abnormal transport regulation. (Source: AJP: Gastrointestinal and Liver Physiology)
Source: AJP: Gastrointestinal and Liver Physiology - August 1, 2017 Category: Gastroenterology Authors: Yin, J., Tse, C.-M., Cha, B., Sarker, R., Zhu, X. C., Walentinsson, A., Greasley, P. J., Donowitz, M. Tags: RESEARCH ARTICLE Source Type: research

FFA2 activation combined with ulcerogenic COX inhibition induces duodenal mucosal injury via the 5-HT pathway in rats
Serotonin (5-HT), predominantly synthesized and released by enterochromaffin cells, is implicated in gastrointestinal symptoms such as emesis, abdominal pain, and diarrhea. Because luminal short-chain fatty acids (SCFAs) release 5-HT from enterochromaffin cells, which express the SCFA receptor free fatty acid receptor 2 (FFA2) in rat duodenum, we examined the effects of the selective FFA2 agonist phenylacetamide-1 (PA1) on duodenal 5-HT release with consequent bicarbonate secretion [duodenal bicarbonate secretion (DBS)] and on indomethacin (IND)-induced enteropathy. Intestinal injury was induced by IND (10 mg/kg sc) with o...
Source: AJP: Gastrointestinal and Liver Physiology - August 1, 2017 Category: Gastroenterology Authors: Akiba, Y., Maruta, K., Narimatsu, K., Said, H., Kaji, I., Kuri, A., Iwamoto, K.-i., Kuwahara, A., Kaunitz, J. D. Tags: RESEARCH ARTICLE Source Type: research

Emerging concepts in biliary repair and fibrosis
Chronic diseases of the biliary tree (cholangiopathies) represent one of the major unmet needs in clinical hepatology and a significant knowledge gap in liver pathophysiology. The common theme in cholangiopathies is that the target of the disease is the biliary tree. After damage to the biliary epithelium, inflammatory changes stimulate a reparative response with proliferation of cholangiocytes and restoration of the biliary architecture, owing to the reactivation of a variety of morphogenetic signals. Chronic damage and inflammation will ultimately result in pathological repair with generation of biliary fibrosis and clin...
Source: AJP: Gastrointestinal and Liver Physiology - August 1, 2017 Category: Gastroenterology Authors: Fabris, L., Spirli, C., Cadamuro, M., Fiorotto, R., Strazzabosco, M. Tags: REVIEW Source Type: research