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PubMed Central (PMC3 - NLM DTD) (2,823,233 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 863

1. Substance P is essential for maintaining gut muscle contractility: a novel role for coneurotransmission revealed by botulinum toxin - Li, Cuiping; Micci, Maria-Adelaide; Murthy, Karnam S.; Pasricha, Pankaj Jay
Substance P (SP) is commonly coexpressed with ACh in enteric motor neurons, and, according to the classical paradigm, both these neurotransmitters excite smooth muscle via parallel pathways. We hypothesized that, in addition, SP was responsible for maintaining the muscular responsiveness to ACh. We tested this hypothesis by using botulinum toxin (BoNT/A), a known blocker of vesicular release of neurotransmitters including ACh and neuropeptides. BoNT/A was injected into rat pyloric sphincter in different doses; as control we used boiled BoNT/A. At the desired time point, pylorus was dissected out and pyloric contractility was measured ex vivo in an organ bath and...

2. Animals Models of Gastrointestinal and Liver Diseases. Animal models of alcohol-induced liver disease: pathophysiology, translational relevance, and challenges - Mathews, Stephanie; Xu, Mingjiang; Wang, Hua; Bertola, Adeline; Gao, Bin
Over the last four decades, chronic ethanol feeding studies in rodents using either ad libitum feeding or intragastric infusion models have significantly enhanced our understanding of the pathogenesis of alcoholic liver disease (ALD). Recently, we developed a chronic plus binge alcohol feeding model in mice that is similar to the drinking patterns of many alcoholic hepatitis patients: a history of chronic drinking and recent excessive alcohol consumption. Chronic+binge ethanol feeding synergistically induced steatosis, liver injury, and neutrophil infiltration in mice, which may be useful for the study of early alcoholic liver injury and inflammation. Using this chronic+binge model, researchers have...

3. Epithelial VEGF signaling is required in the mouse liver for proper sinusoid endothelial cell identity and hepatocyte zonation in vivo - Walter, Teagan J.; Cast, Ashley E.; Huppert, Kari A.; Huppert, Stacey S.
Vascular endothelial growth factor (VEGF) is crucial for vascular development in several organs. However, the specific contribution of epithelial-VEGF signaling in the liver has not been tested. We used a mouse model to specifically delete Vegf from the liver epithelial lineages during midgestational development and assessed the cell identities and architectures of epithelial and endothelial tissues. We find that without epithelial-derived VEGF, the zonal endothelial and hepatocyte cell identities are altered. We also find decreased portal vein and hepatic artery branching coincident with an increase in hepatic hypoxia postnatally. Together, these data indicate that VEGF secreted from the hepatic epithelium...

4. Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates - Malo, Madhu S.; Moaven, Omeed; Muhammad, Nur; Biswas, Brishti; Alam, Sayeda N.; Economopoulos, Konstantinos P.; Gul, Sarah Shireen; Hamarneh, Sulaiman R.; Malo, Nondita S.; Teshager, Abeba; Mohamed, Mussa M. Rafat; Tao, Qingsong; Narisawa, Sonoko; Millán, José Luis; Hohmann, Elizabeth L.; Warren, H. Shaw; Robson, Simon C.; Hodin, Richard A.
The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a...

5. Role of intracellular calcium and NADPH oxidase NOX5-S in acid-induced DNA damage in Barrett's cells and Barrett's esophageal adenocarcinoma cells - Li, Dan; Cao, Weibiao
Mechanisms whereby acid reflux may accelerate the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. Acid and reactive oxygen species (ROS) have been reported to cause DNA damage in Barrett's cells. We have previously shown that NADPH oxidase NOX5-S is responsible for acid-induced H2O2 production in Barrett's cells and in EA cells. In this study we examined the role of intracellular calcium and NADPH oxidase NOX5-S in acid-induced DNA damage in a Barrett's EA cell line FLO and a Barrett's cell line CP-A. We found that pulsed acid treatment significantly increased tail moment in FLO...

6. Regulation of hepatic insulin receptor activity following injury - Jiang, Shaoning; Gavrikova, Tatyana A.; Messina, Joseph L.
Impaired insulin receptor (IR) activity has been found in various models of insulin resistance, including models of injury or critical illness and Type 2 diabetes. However, mechanisms that modulate IR function remain unclear. With an animal model of critical-illness diabetes, we found insulin-induced IR tyrosine phosphorylation in the liver was impaired as early as 15 min following trauma and hemorrhage. Possible mechanisms for this defect were examined, including IR protein levels and IR posttranslational modifications. The total amounts of hepatic IRα and IRβ subunits and the membrane localization of the IR were not altered by trauma and hemorrhage, and, likewise,...

7. Fibroblast growth factor 15 deficiency impairs liver regeneration in mice - Kong, Bo; Huang, Jiansheng; Zhu, Yan; Li, Guodong; Williams, Jessica; Shen, Steven; Aleksunes, Lauren M.; Richardson, Jason R.; Apte, Udayan; Rudnick, David A.; Guo, Grace L.
Fibroblast growth factor (FGF) 15 (human homolog, FGF19) is an endocrine FGF highly expressed in the small intestine of mice. Emerging evidence suggests that FGF15 is critical for regulating hepatic functions; however, the role of FGF15 in liver regeneration is unclear. This study assessed whether liver regeneration is altered in FGF15 knockout (KO) mice following 2/3 partial hepatectomy (PHx). The results showed that FGF15 KO mice had marked mortality, with the survival rate influenced by genetic background. Compared with wild-type mice, the KO mice displayed extensive liver necrosis and marked elevation of serum bile acids and bilirubin. Furthermore, hepatocyte proliferation...

8. Disruption of retinoblastoma protein expression in the intestinal epithelium impairs lipid absorption - Choi, Pamela M.; Guo, Jun; Erwin, Christopher R.; Wandu, Wambui S.; Leinicke, Jennifer A.; Xie, Yan; Davidson, Nicholas O.; Warner, Brad W.
We previously demonstrated increased villus height following genetic deletion, or knockout, of retinoblastoma protein (Rb) in the intestinal epithelium (Rb-IKO). Here we determined the functional consequences of augmented mucosal growth on intestinal fat absorption and following a 50% small bowel resection (SBR). Mice with constitutively disrupted Rb expression in the intestinal epithelium (Rb-IKO) along with their floxed (wild-type, WT) littermates were placed on a high-fat diet (HFD, 42% kcal fat) for 54 wk. Mice were weighed weekly, and fat absorption, indirect calorimetry, and MRI body composition were measured. Rb-IKO mice were also subjected to a 50% SBR, followed by HFD...

9. Conditioned medium from Bifidobacteria infantis protects against Cronobacter sakazakii-induced intestinal inflammation in newborn mice - Weng, Meiqian; Ganguli, Kriston; Zhu, Weishu; Shi, Hai Ning; Walker, W. Allan
Necrotizing enterocolitis (NEC) is associated with a high morbidity and mortality in very low birth weight infants. Several hypotheses regarding the pathogenesis of NEC have been proposed but to date no effective treatment is available. Previous studies suggest that probiotic supplementation is protective. We recently reported that probiotic (Bifidobacterium infantis) conditioned medium (PCM) has an anti-inflammatory effect in cultured fetal human intestinal cells (H4) and fetal intestine explants. In this study, we tested in vivo whether PCM protects neonatal mice from developing intestinal inflammation induced by exposure to Cronobacter sakazakii (C. sakazakii), an opportunistic pathogen associated with NEC. We found...

10. Overexpression of membrane metalloendopeptidase inhibits substance P stimulation of cholangiocarcinoma growth - Meng, Fanyin; DeMorrow, Sharon; Venter, Julie; Frampton, Gabriel; Han, Yuyan; Francis, Heather; Standeford, Holly; Avila, Shanika; McDaniel, Kelly; McMillin, Matthew; Afroze, Syeda; Guerrier, Micheleine; Quezada, Morgan; Ray, Debolina; Kennedy, Lindsey; Hargrove, Laura; Glaser, Shannon; Alpini, Gianfranco
Substance P (SP) promotes cholangiocyte growth during cholestasis by activating its receptor, NK1R. SP is a proteolytic product of tachykinin (Tac1) and is deactivated by membrane metalloendopeptidase (MME). This study aimed to evaluate the functional role of SP in the regulation of cholangiocarcinoma (CCA) growth. NK1R, Tac1, and MME expression and SP secretion were assessed in human CCA cells and nonmalignant cholangiocytes. The proliferative effects of SP (in the absence/presence of the NK1R inhibitor, L-733,060) and of L-733,060 were evaluated. In vivo, the effect of L-733,060 treatment or MME overexpression on tumor growth was evaluated by using a xenograft model...

11. Inhibition of Gαi activity by Gβγ is mediated by PI 3-kinase-γ- and cSrc-dependent tyrosine phosphorylation of Gαi and recruitment of RGS12 - Huang, Jiean; Nalli, Ancy D.; Mahavadi, Sunila; Kumar, Divya P.; Murthy, Karnam S.
Others and we have characterized several Gβγ-dependent effectors in smooth muscle, including G protein-coupled receptor kinase 2 (GRK2), PLCβ3, and phosphatidylinositol (PI) 3-kinase-γ, and have identified various signaling targets downstream of PI 3-kinase-γ, including cSrc, integrin-linked kinase, and Rac1-Cdc42/p21-activated kinase/p38 MAP kinase. This study identified a novel mechanism whereby Gβγ acting via PI 3-kinase-γ and cSrc exerts an inhibitory influence on Gαi activity. The Gi2-coupled δ-opioid receptor agonist d-penicillamine (2,5)-enkephalin (DPDPE) activated cSrc, stimulated tyrosine phosphorylation of Gαi2, and induced regulator of G protein signaling 12 (RGS12) association; all three events were blocked by PI 3-kinase (LY294002) and cSrc (PP2)...

12. 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...

13. 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....

14. 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...

15. 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...

16. 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...

17. 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...

18. 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...

19. 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...

20. 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...

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