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...
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