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PubMed Central (PMC3 - NLM DTD) (2,805,745 recursos)
Archive of life sciences journal literature at the U.S. National Institutes of Health (NIH), developed and managed by NIH's National Center for Biotechnology Information (NCBI) in the National Library of Medicine (NLM).

American Journal of Physiology - Gastrointestinal and Liver Physiology

Mostrando recursos 1 - 20 de 852

1. Src-mediated caveolin-1 phosphorylation regulates intestinal epithelial restitution by altering Ca2+ influx after wounding - Rathor, Navneeta; Zhuang, Ran; Wang, Jian-Ying; Donahue, James M.; Turner, Douglas J.; Rao, Jaladanki N.
Early mucosal restitution occurs as a consequence of intestinal epithelial cell (IEC) migration to reseal superficial wounds, but its exact mechanism remains largely unknown. Caveolin-1 (Cav1), a major component associated with caveolar lipid rafts in the plasma membrane, is implicated in many aspects of cellular functions. This study determined if c-Src kinase (Src)-induced Cav1 phosphorylation promotes intestinal epithelial restitution after wounding by activating Cav1-mediated Ca2+ signaling. Src directly interacted with Cav1, formed Cav1-Src complexes, and phosphorylated Cav1 in IECs. Inhibition of Src activity by its chemical inhibitor PP2 or suppression of the functional caveolin scaffolding domain by caveolin-scaffolding domain peptides...

2. Role of peripheral reflexes in the initiation of the esophageal phase of swallowing - Lang, Ivan M.; Medda, Bidyut K.; Babaei, Arash; Shaker, Reza
The aim of this study was to determine the role of peripheral reflexes in initiation of the esophageal phase of swallowing. In 10 decerebrate cats, we recorded electromyographic responses from the pharynx, larynx, and esophagus and manometric data from the esophagus. Water (1–5 ml) was injected into the nasopharynx to stimulate swallowing, and the timing of the pharyngeal and esophageal phases of swallowing was quantified. The effects of transection or stimulation of nerves innervating the esophagus on swallowing and esophageal motility were tested. We found that the percent occurrence of the esophageal phase was significantly related to the bolus size....

3. Computational modeling of anoctamin 1 calcium-activated chloride channels as pacemaker channels in interstitial cells of Cajal - Lees-Green, Rachel; Gibbons, Simon J.; Farrugia, Gianrico; Sneyd, James; Cheng, Leo K.
Interstitial cells of Cajal (ICC) act as pacemaker cells in the gastrointestinal tract by generating electrical slow waves to regulate rhythmic smooth muscle contractions. Intrinsic Ca2+ oscillations in ICC appear to produce the slow waves by activating pacemaker currents, currently thought to be carried by the Ca2+-activated Cl− channel anoctamin 1 (Ano1). In this article we present a novel model of small intestinal ICC pacemaker activity that incorporates store-operated Ca2+ entry and a new model of Ano1 current. A series of simulations were carried out with the ICC model to investigate current controversies about the reversal potential of the Ano1...

4. Altered expression and function of canalicular transporters during early development of cholestatic liver injury in Abcb4-deficient mice - Cai, Shi-Ying; Mennone, Albert; Soroka, Carol J.; Boyer, James L.
Deficiency of ABCB4 is associated with several forms of cholestasis in humans. Abcb4−/− mice also develop cholestasis, but it remains uncertain what role other canalicular transporters play in the development of this disease. We examined the expression of these transporters in Abcb4−/− mice compared with their wild-type littermate controls at ages of 10 days and 3, 6, and 12 wk. Elevated plasma bile acid levels were already detected at 10 days and at all ages thereafter in Abcb4−/− mice. The expression of Bsep, Mrp2, Atp8b1, Abcg5, and Abcg8 liver proteins did not change at 10 days, but Bsep, Mrp2, and...

5. Feeding-dependent activation of enteric cells and sensory neurons by lymphatic fluid: evidence for a neurolymphocrine system - Poole, Daniel P.; Lee, Mike; Tso, Patrick; Bunnett, Nigel W.; Yo, Sek Jin; Lieu, TinaMarie; Shiu, Amy; Wang, Jen-Chywan; Nomura, Daniel K.; Aponte, Gregory W.
Lymphatic fluid is a plasma filtrate that can be viewed as having biological activity through the passive accumulation of molecules from the interstitial fluid. The possibility that lymphatic fluid is part of an active self-contained signaling process that parallels the endocrine system, through the activation of G-protein coupled receptors (GPCR), has remained unexplored. We show that the GPCR lysophosphatidic acid 5 (LPA5) is found in sensory nerve fibers expressing calcitonin gene-related peptide (CGRP) that innervate the lumen of lymphatic lacteals and enteric nerves. Using LPA5 as a model for nutrient-responsive GPCRs present on sensory nerves, we demonstrate that dietary protein...

6. Myosin IIB and F-actin control apical vacuolar morphology and histamine-induced trafficking of H-K-ATPase-containing tubulovesicles in gastric parietal cells - Natarajan, Paramasivam; Crothers, James M.; Rosen, Jared E.; Nakada, Stephanie L.; Rakholia, Milap; Okamoto, Curtis T.; Forte, John G.; Machen, Terry E.
Selective inhibitors of myosin or actin function and confocal microscopy were used to test the role of an actomyosin complex in controlling morphology, trafficking, and fusion of tubulovesicles (TV) containing H-K-ATPase with the apical secretory canaliculus (ASC) of primary-cultured rabbit gastric parietal cells. In resting cells, myosin IIB and IIC, ezrin, and F-actin were associated with ASC, whereas H-K-ATPase localized to intracellular TV. Histamine caused fusion of TV with ASC and subsequent expansion resulting from HCl and water secretion; F-actin and ezrin remained associated with ASC whereas myosin IIB and IIC appeared to dissociate from ASC and relocalize to the...

7. Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase α-subunit gene expression by miRNA - Zhang, Yong-Mei; Noto, Jennifer M.; Hammond, Charles E.; Barth, Jeremy L.; Argraves, W. Scott; Backert, Steffen; Peek, Richard M.; Smolka, Adam J.
Acute Helicobacter pylori infection of gastric epithelial cells induces CagA oncoprotein- and peptidoglycan (SLT)-dependent mobilization of NF-κB p50 homodimers that bind to H-K-ATPase α-subunit (HKα) promoter and repress HKα gene transcription. This process may facilitate gastric H. pylori colonization by induction of transient hypochlorhydria. We hypothesized that H. pylori also regulates HKα expression posttranscriptionally by miRNA interaction with HKα mRNA. In silico analysis of the HKα 3′ untranslated region (UTR) identified miR-1289 as a highly conserved putative HKα-regulatory miRNA. H. pylori infection of AGS cells transfected with HKα 3′ UTR-Luc reporter construct repressed luciferase activity by 70%, whereas ΔcagA or...

8. Mechanisms involved in the inhibitory effect of chronic alcohol exposure on pancreatic acinar thiamin uptake - Srinivasan, Padmanabhan; Subramanian, Veedamali S.; Said, Hamid M.
Pancreatic acinar cells (PAC) obtain thiamin from the circulation via a carrier-mediated process that involves thiamin transporters 1 and 2 (THTR-1 and THTR-2; products of SLC19A2 and SLC19A3, respectively). Chronic alcohol exposure of PAC inhibits thiamin uptake, and, on the basis of in vitro studies, this inhibition appears to be transcriptionally mediated. The aim of this study was to confirm the involvement of a transcriptional mechanism in mediating the chronic alcohol effect in in vivo settings and to delineate the molecular mechanisms involved. Using transgenic mice carrying full-length SLC19A2 and SLC19A3 promoters, we found that chronic alcohol feeding led to...

9. Dickkopf-1, the Wnt antagonist, is induced by acidic pH and mediates epithelial cellular senescence in human reflux esophagitis - Lyros, Orestis; Rafiee, Parvaneh; Nie, Linghui; Medda, Rituparna; Jovanovic, Nebojsa; Schmidt, Jamie; Mackinnon, Alexander; Venu, Nanda; Shaker, Reza
Squamous esophageal epithelium adapts to acid reflux-mediated injury by proliferation and differentiation via signal transduction pathways. Induction of the Wnt antagonist Dickkopf-1 (Dkk1) is involved in tissue repair during inflammation and cellular injury. In this study, we aimed to identify the biological role of Dkk1 in human reflux esophagitis with respect to cell growth and regulation of Wnt signaling. Esophageal biopsies from reflux-esophagitis patients (n = 15) and healthy individuals (n = 10) were characterized in terms of Dkk1 expression. The role of Dkk1 in response to acid-mediated epithelial injury was analyzed by cellular assays in vitro utilizing squamous esophageal...

10. Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa - Woodland, Philip; Aktar, Rubina; Mthunzi, Engelbert; Lee, Chung; Peiris, Madusha; Preston, Sean L.; Blackshaw, L. Ashley; Sifrim, Daniel
Little is known about the mucosal phenotype of the proximal human esophagus. There is evidence to suggest that the proximal esophagus is more sensitive to chemical and mechanical stimulation compared with the distal. This may have physiological relevance (e.g., in prevention of aspiration of gastroesophageal refluxate), but also pathological relevance (e.g., in reflux perception or dysphagia). Reasons for this increased sensitivity are unclear but may include impairment in mucosal barrier integrity or changes in sensory innervation. We assessed mucosal barrier integrity and afferent nerve distribution in the proximal and distal esophagus of healthy human volunteers. In 10 healthy volunteers baseline...

11. Importance of apical membrane delivery of 1,25-dihydroxyvitamin D3 to vitamin D-responsive gene expression in the colon - Koszewski, Nicholas J.; Horst, Ronald L.; Goff, Jesse P.
Synthetic conjugation of a glucuronide to 1,25-dihydroxyvitamin D3 (1,25D3) to produce β-25-monoglucuronide-1,25D3 (βGluc-1,25D3) renders the hormone biologically inactive and resistant to mammalian digestive enzymes. However, β-glucuronidase produced by bacteria in the lower intestinal tract can cleave off the glucuronide, releasing the active hormone. In mice given a single oral dose of 1,25D3, 24-hydroxylase (Cyp24a1) gene expression was strongly enhanced in the duodenum, but not in the colon, despite circulating concentrations of 1,25D3 that peaked at ∼3.0 nmol/l. In contrast, in mice treated with an equimolar dose of βGluc-1,25D3, Cyp24a1 gene expression increased 700-fold in the colon but was significantly weaker...

12. EpCAM and the biology of hepatic stem/progenitor cells - Dollé, Laurent; Theise, Neil D.; Schmelzer, Eva; Boulter, Luke; Gires, Olivier; van Grunsven, Leo A.
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is frequently and highly expressed on carcinomas, tumor-initiating cells, selected tissue progenitors, and embryonic and adult stem cells. During liver development, EpCAM demonstrates a dynamic expression, since it can be detected in fetal liver, including cells of the parenchyma, whereas mature hepatocytes are devoid of EpCAM. Liver regeneration is associated with a population of EpCAM-positive cells within ductular reactions, which gradually lose the expression of EpCAM along with maturation into hepatocytes. EpCAM can be switched on and off through a wide panel of strategies to fine-tune EpCAM-dependent functional and differentiative...

13. Purse-string morphology of external anal sphincter revealed by novel imaging techniques - Mittal, Ravinder K.; Bhargava, Valmik; Sheean, Geoff; Ledgerwood, Melissa; Sinha, Shantanu
The external anal sphincter (EAS) may be injured in 25–35% of women during the first and subsequent vaginal childbirths and is likely the most common cause of anal incontinence. Since its first description almost 300 years ago, the EAS was believed to be a circular or a “donut-shaped” structure. Using three-dimensional transperineal ultrasound imaging, MRI, diffusion tensor imaging, and muscle fiber tracking, we delineated various components of the EAS and their muscle fiber directions. These novel imaging techniques suggest “purse-string” morphology, with “EAS muscles” crossing contralaterally in the perineal body to the contralateral transverse perineal (TP) and bulbospongiosus (BS) muscles,...

14. Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis - Németh, Balázs Csaba; Sahin-Tóth, Miklós
Variations in the serine protease 1 (PRSS1) gene encoding human cationic trypsinogen have been conclusively associated with autosomal dominant hereditary pancreatitis and sporadic nonalcoholic chronic pancreatitis. Most high-penetrance PRSS1 variants increase intrapancreatic trypsin activity by stimulating trypsinogen autoactivation and/or by inhibiting chymotrypsin C-dependent trypsinogen degradation. Alternatively, some PRSS1 variants can cause trypsinogen misfolding, which results in intracellular retention and degradation with consequent endoplasmic reticulum stress. However, not all PRSS1 variants are pathogenic, and clinical relevance of rare variants is often difficult to ascertain. Here we review the PRSS1 variants published since 1996 and discuss their functional properties and role in...

15. Glial cell line-derived neurotrophic factor protects against high-fat diet-induced obesity - Mwangi, Simon Musyoka; Nezami, Behtash Ghazi; Obukwelu, Blessing; Anitha, Mallappa; Marri, Smitha; Fu, Ping; Epperson, Monica F.; Le, Ngoc-Anh; Shanmugam, Malathy; Sitaraman, Shanthi V.; Tseng, Yu-Hua; Anania, Frank A.; Srinivasan, Shanthi
Obesity is a growing epidemic with limited effective treatments. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) was recently shown to enhance β-cell mass and improve glucose control in rodents. Its role in obesity is, however, not well characterized. In this study, we investigated the ability of GDNF to protect against high-fat diet (HFD)-induced obesity. GDNF transgenic (Tg) mice that overexpress GDNF under the control of the glial fibrillary acidic protein promoter and wild-type (WT) littermates were maintained on a HFD or regular rodent diet for 11 wk, and weight gain, energy expenditure, and insulin sensitivity were monitored. Differentiated...

16. Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium - Aronson, Boaz E.; Stapleton, Kelly A.; Krasinski, Stephen D.
The small intestinal epithelium develops from embryonic endoderm into a highly specialized layer of cells perfectly suited for the digestion and absorption of nutrients. The development, differentiation, and regeneration of the small intestinal epithelium require complex gene regulatory networks involving multiple context-specific transcription factors. The evolutionarily conserved GATA family of transcription factors, well known for its role in hematopoiesis, is essential for the development of endoderm during embryogenesis and the renewal of the differentiated epithelium in the mature gut. We review the role of GATA factors in the evolution and development of endoderm and summarize our current understanding of the...

17. Inhibitory signaling by CB1 receptors in smooth muscle mediated by GRK5/β-arrestin activation of ERK1/2 and Src kinase - Mahavadi, Sunila; Sriwai, Wimolpak; Huang, Jiean; Grider, John R.; Murthy, Karnam S.
We examined whether CB1 receptors in smooth muscle conform to the signaling pattern observed with other Gi-coupled receptors that stimulate contraction via two Gβγ-dependent pathways (PLC-β3 and phosphatidylinositol 3-kinase/integrin-linked kinase). Here we show that the anticipated Gβγ-dependent signaling was abrogated. Except for inhibition of adenylyl cyclase via Gαi, signaling resulted from Gβγ-independent phosphorylation of CB1 receptors by GRK5, recruitment of β-arrestin1/2, and activation of ERK1/2 and Src kinase. Neither uncoupling of CB1 receptors from Gi by pertussis toxin (PTx) or Gi minigene nor expression of a Gβγ-scavenging peptide had any effect on ERK1/2 activity. The latter was abolished in muscle...

18. Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice - Asai, Akihiro; Chou, Pauline M.; Bu, Heng-Fu; Wang, Xiao; Rao, M. Sambasiva; Jiang, Anthony; DiDonato, Christine J.; Tan, Xiao-Di
Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 wk old) were fed a high-fat and high-carbohydrate (HFHC) or control diet for 16 wk followed by the application of a combination of classic physiological, biochemical, and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level,...

19. Rab1a regulates sorting of early endocytic vesicles - Mukhopadhyay, Aparna; Quiroz, Jose A.; Wolkoff, Allan W.
We previously reported that Rab1a is associated with asialoorosomucoid (ASOR)-containing early endocytic vesicles, where it is required for their microtubule-based motility. In Rab1a knockdown (KD) cell lines, ASOR failed to segregate from its receptor and, consequently, did not reach lysosomes for degradation, indicating a defect in early endosome sorting. Although Rab1 is required for Golgi/endoplasmic reticulum trafficking, this process was unaffected, likely due to retained expression of Rab1b in these cells. The present study shows that Rab1a has a more general role in endocytic vesicle processing that extends to EGF and transferrin (Tfn) trafficking. Compared with results in control Huh7...

20. Role of innate immunity and altered intestinal motility in LPS- and MnCl2-induced intestinal intussusception in mice - Killoran, Kristin E.; Miller, Amber D.; Uray, Karen S.; Weisbrodt, Norman W.; Pautler, Robia G.; Goyert, Sanna M.; van Rooijen, Nico; Conner, Margaret E.
Intestinal intussusception (ISS) commonly causes intestinal obstruction in children. One mechanism that has been proposed to cause ISS is inflammation-induced alteration of intestinal motility. We investigated whether innate inflammatory factors or altered motility is required for induction of ISS by LPS. We compared rates of ISS among BALB/c and C57BL/6 mice, mice lacking lymphocytes or depleted of phagocytes, or mice with defects in the Toll-like receptor 4 (TLR4) signaling pathway following administration of LPS or the Ca2+ analog MnCl2. At 6 or 2 h after administration of LPS or MnCl2, respectively, mice underwent image analysis to assess intestinal contraction rate...

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