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Wang Y.,China Agricultural University | Wang Y.,Childrens Nutrition Research Center | Guan X.,Childrens Nutrition Research Center | Guan X.,Baylor College of Medicine
American Journal of Physiology - Endocrinology and Metabolism | Year: 2010

Glucagon-like peptide-2 (GLP-2) is a neuropeptide secreted from endocrine cells in the gut and neurons in the brain. GLP-2 stimulates intestinal crypt cell proliferation and mucosal blood flow while decreasing gastric emptying and gut motility. However, a GLP-2-mediated signaling network has not been fully established in primary cells. Since the GLP-2 receptor mRNA and protein were highly expressed in the mouse hippocampus, we further characterized that human 125I-labeled GLP-2 1-33 specifically bound to cultured hippocampal neurons with Kd = 0.48 nM, and GLP-2 acutely induced subcellular translocalization of the early gene c-Fos. Using the whole cell patch clamp, we recorded barium currents (I Ba) flowing through voltage-gated Ca 2+ channels (VGCC) in those neurons in the presence of GLP-2 with and without inhibitors. We showed that GLP-2 (20 nM) enhanced the whole cell I Ba mediated by L-type VGCC that was defined using an L-type Ca 2+ channel blocker (nifedipine, 10 μM). Moreover, GLP-2-potentiation of L-type VGCC was abolished in neurons pretreated with a PKA inhibitor (PKI 14- 22, 1 μM). Finally, using a fluorescent nonmetabolized glucose analog (6-NBDG) tracing imaging, we showed that glucose was taken up directly by cultured neurons. GLP-2 increased 2-deoxy-D-[ 3H]glucose uptake that was dependent upon dosage, activation of PKA, and potentiation of L-type VGCC. We conclude that GLP-2 potentiates L-type VGCC activity through activating PKA signaling, partially stimulating glucose uptake by primary cultured hippocampal neurons. The potentiation of L-type VGCC may be physiologically relevant to GLP-2-induced neuroendocrine modulation of neurotransmitter release and hormone secretion. Copyright © 2010 the American Physiological Society. Source

Mayer E.A.,University of California at Los Angeles | Savidge T.,Baylor College of Medicine | Savidge T.,Texas Childrens Microbiome Center | Shulman R.J.,Baylor College of Medicine | Shulman R.J.,Childrens Nutrition Research Center
Gastroenterology | Year: 2014

Alterations in the bidirectional interactions between the intestine and the nervous system have important roles in the pathogenesis of irritable bowel syndrome (IBS). A body of largely preclinical evidence suggests that the gut microbiota can modulate these interactions. A small and poorly defined role for dysbiosis in the development of IBS symptoms has been established through characterization of altered intestinal microbiota in IBS patients and reported improvement of subjective symptoms after its manipulation with prebiotics, probiotics, or antibiotics. It remains to be determined whether IBS symptoms are caused by alterations in brain signaling from the intestine to the microbiota or primary disruption of the microbiota, and whether they are involved in altered interactions between the brain and intestine during development. We review the potential mechanisms involved in the pathogenesis of IBS in different groups of patients. Studies are needed to better characterize alterations to the intestinal microbiome in large cohorts of well-phenotyped patients, and to correlate intestinal metabolites with specific abnormalities in gut-brain interactions. © 2014 by the AGA Institute. Source

Shulman R.J.,Childrens Nutrition Research Center | Ou C.-N.,Baylor College of Medicine | Smith E.O.,Childrens Nutrition Research Center
Neonatology | Year: 2011

Background: The clinical measures of gastric residuals and abdominal distention are often used to guide feeding in preterm infants, but there are few data demonstrating their usefulness. Similarly, techniques are now available to investigate gastrointestinal (GI) function noninvasively and safely, but their ability to predict attainment of full gavage feedings and/or feeding volume in preterm infants is unclear. Objective: We sought to determine prospectively the potential relationships of attainment of full gavage feedings and feeding volume with clinical measures and noninvasive GI tests. Methods: Fifty preterm infants were followed prospectively. Daily tally was taken of gavage feeding intake, gastric residual volumes (GRVs; milliliters per day, number of GRVs >50% of the previous feeding volume, and number of GRVs >2 ml/kg), and abdominal distention. Infants underwent repeated measurement of lactase activity, GI permeability, fecal calprotectin concentration, and gastric emptying. Results: The number of GRVs >2 ml/kg tended to decrease with postnatal age (p = 0.06). Lactase activity and feeding volume in milliliters per kilogram per day prior to achieving full feedings were correlated (p = 0.007, β = 0.164). There was no correlation between feeding outcomes and GRV (ml/day), GRV >50%, GRV >2 ml/kg, small bowel, colonic, or whole bowel permeability, fecal calprotectin concentration, gastric emptying, or abdominal distention. Conclusions: GRV is unreliable in predicting attainment of full gavage feeding. Lactase activity is related to feeding volume. However, other noninvasive GI tests utilized were not predictive. These data cast doubt upon the utility of GRV in guiding feeding therapy. Randomized trials of different GRV management protocols are needed. Copyright © 2010 S. Karger AG, Basel. Source

Williams A.E.,Loyola University | Heitkemper M.,University of Washington | Self M.M.,Baylor College of Medicine | Czyzewski D.I.,Baylor College of Medicine | And 2 more authors.
Journal of Pain | Year: 2013

Endogenous pain inhibition is often deficient in adults with chronic pain conditions including irritable bowel syndrome (IBS). It is unclear whether deficiencies in pain inhibition are present in young children with IBS. The present study compared endogenous pain inhibition, somatic pain threshold, and psychosocial distress in young girls with IBS versus controls. Girls with IBS did not show significant endogenous pain inhibition of heat pain threshold during a cold-pressor task in contrast to controls, who had significant pain inhibition. Girls with IBS did not differ from peers on measures of somatic pain but had more symptoms of depression, somatization, and anxiety than controls. When psychological variables were included as covariates, the difference in pain inhibition was no longer significant, although poor achieved power limits interpretation of these results. Higher-order cognitive processes including psychological variables may be contributing to observed pain inhibition. In girls with IBS, pain inhibition was positively related to the number of days without a bowel movement. To our knowledge, this is the first study to demonstrate deficiencies of endogenous pain inhibition in young children with IBS. Findings have implications for better understanding of onset and maintenance of IBS and other chronic pain conditions. Perspective: This study found that young girls with IBS have deficient endogenous pain inhibition compared to healthy girls, which is consistent with the literature on adults. This information can facilitate clinicians in identification of risk factors for onset/maintenance of IBS and other chronic pain conditions. © 2013 by the American Pain Society. Source

Salama S.A.,Baylor College of Medicine | Mohammad M.A.,Childrens Nutrition Research Center | Diaz-Arrastia C.R.,Baylor College of Medicine | Kamel M.W.,Cairo University | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Objectives: Our objectives were to study whether E2 induces reprogramming of glucose metabolism in hESCs and to investigate the potential roles of PKM2 in E2-induced metabolic reprogramming and proliferation of these cells.Context: Proliferating cells reprogram their cellular glucose metabolism to meet the bioenergetic and biosynthetic demands and to maintain cellular redox homeostasis. Pyruvate kinase M (PKM) is a critical regulator of this metabolic reprogramming. However, whether estradiol-17β (E2) reprograms cellular metabolism to support proliferation of human primary endometrial stromal cells (hESCs) and the molecular basis of this reprogramming are not well understood.Methods: The oxygen consumption rate and extracellular acidification rate were assessed by a Seahorse XF24 analyzer. PKM2 expression was assessed by real-time RT-PCR and immunoblotting.Results: E2 induces a Warburg-like glucose metabolism in hESCs by inducing the expression of PKM. E2 also enhanced PKM splicing into the PKM2 isoform by upregulating the c-Myc-hnRNP axis. Furthermore, E2 induces PKM2 oxidation, phosphorylation, and nucleartranslocation. In addition to its glycolytic function, PKM2 physically interacted with estrogen receptor-α (ERα) and functioned as an ERα coactivator. Small-molecule PKM2 activators ameliorated ERa transcriptional activity and abrogated the E2-induced hESC proliferation.Conclusions: We show for the first time that E2-induced hESC proliferation is associated with a shift in glucose metabolism toward aerobic glycolysis, and the molecular basis for this metabolic shift is linked to the effects of E2 on PKM2. In addition, PKM2 acts as a transcriptional coactivator for ERa and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation. Copyright © 2014 by the Endocrine Society. Source

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