John B Furness

University of Melbourne, Melbourne, Victoria, Australia

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Publications (120)532.51 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: This study has investigated the patterns of colocalisation of the conventional K cell marker, glucagon-like insulinotropic peptide (GIP), and the L cell markers, glucagon like peptide-1 (GLP-1) and peptide YY (PYY), in enteroendocrine cells (EEC) of the small intestine and colon of mouse and pig. All combinations of the hormones, 3 in a cell, 2 in a cell and 1 at a time, were encountered. In both species, the three most common EEC types contained (1) both GLP-1 and PYY but not GIP, (2) GLP-1 alone or (3) GIP plus GLP-1 without PYY. Few GIP plus PYY cells and rare cells containing all 3 hormones were encountered. Gradients of cell types occurred along the intestine. For example, in mouse, there were no PYY cells in the duodenum and few in the jejunum, but >50 % of labelled EEC in the distal ileum and colon were PYY immunoreactive. By contrast, over 40 % of EEC in the pig duodenum contained PYY, and most also contained either GLP-1 or GIP. The gradient in pig was less pronounced. It is concluded that the traditional classification of K and L cells requires revision, and that there are major inter-species differences in the patterns of colocalisation of hormones that have been used to characterise K and L cells.
    Cell and Tissue Research 11/2014; · 3.68 Impact Factor
  • Brid Callaghan, John B Furness
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    ABSTRACT: The only molecularly identified ghrelin receptor is the growth hormone secretagogue receptor GHSR1a. Its natural ligand, ghrelin, is an acylated peptide whose unacylated counterpart (UAG) is almost inactive at GHSR1a. A truncated, nonfunctional receptor, GHSR1b, derives from the same gene. We have critically evaluated evidence for effects of ghrelin receptor ligands that are not consistent with actions at GHSR1a. Effects of ghrelin are observed in cells or tissues where the expression of GHSR1a is not detectable or after the Ghsr gene has been inactivated. In several, effects of ghrelin are mimicked by UAG, and ghrelin binding is competitively reduced by UAG. Effects in the absence of GHSR1a and sites at which ghrelin and UAG have similar potency suggest the presence of novel nonspecific ghrelin receptors (ghrelin receptor-like receptors [GRLRs]). A third class of receptor, the UAG receptors, at which UAG, but not ghrelin, is an agonist has been proposed. None of the novel receptors, with the exception of the glycoprotein CD36, which accounts for ghrelin action at a limited number of sites, have been identified. GHSR1a and GHSR1b combine with other G protein-coupled receptors to form heterodimers, whose pharmacologies differ from their components. Thus, it is feasible some GRLRs and some UAG receptors are heterodimers. Effects mediated through GRLRs or UAG receptors include adipocyte lipid accumulation, myoblast differentiation, osteoblast proliferation, insulin release, cardioprotection, coronary artery constriction, vascular endothelial cell proliferation, and tumor cell proliferation. The molecular identification and pharmacologic characterization of novel ghrelin receptors are thus important objectives.
    Pharmacological reviews. 10/2014; 66(4):984-1001.
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    ABSTRACT: Aromatase converts androgens into estrogens and its expression within adipose stromal cells (ASCs) is believed to be the major driver of estrogen-dependent cancers in older women. Ghrelin is a gut-hormone that is involved in the regulation of appetite and known to bind to and activate the cognate ghrelin receptor, GHSR1a. The unacylated form of ghrelin, des-acyl ghrelin, binds weakly to GHSR1a but has been shown to play an important role in regulating a number of physiological processes. The aim of this study was to determine the effect of ghrelin and des-acyl ghrelin on aromatase in primary human ASCs. Primary human ASCs were isolated from adipose tissue of women undergoing cosmetic surgery. Real-time PCR and tritiated water-release assays were performed to examine the effect of treatment on aromatase transcript expression and aromatase activity, respectively. Treatments included ghrelin, des-acyl ghrelin, obestatin, and capromorelin (GHSR1a agonist). GHSR1a protein expression was assessed by Western blot and effects of treatment on Ca(2+) and cAMP second messenger systems were examined using the Flexstation assay and the Lance Ultra cAMP kit, respectively. Results demonstrate that pM concentrations of ghrelin and des-acyl ghrelin inhibit aromatase transcript expression and activity in ASCs under basal conditions and in PGE2-stimulated cells. Moreover, the effects of ghrelin and des-acyl ghrelin are mediated via effects on aromatase promoter PII-specific transcripts. Neither the GHSR1a-specific agonist capromorelin nor obestatin had any effect on aromatase transcript expression or activity. Moreover, GHSR1a protein was undetectable by Western blot and neither ghrelin nor capromorelin elicited a calcium response in ASCs. Finally, ghrelin caused a significant decrease in basal and forskolin-stimulated cAMP in ASC. These findings suggest that ghrelin acts at alternate receptors in ASCs by decreasing intracellular cAMP levels. Ghrelin mimetics may be useful in the treatment of estrogen-dependent breast cancer.
    Breast Cancer Research and Treatment 07/2014; · 4.47 Impact Factor
  • John Furness
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    ABSTRACT: Abstract Text: The optimal utilisation of nutrients requires an integrated response of the gastrointestinal tract to ingested food. Broad mechanisms are similar in all mammals, and involve sensing food components through olfaction, taste and specialised receptors within the stomach and intestines. The sensing of food components leads to release of gut hormones and activation of nerves, which in turn modify digestive functions. Bacteria, viruses, fungi and potentially injurious substances in foods activate tissue defence mechanisms. While the responses to nutrients lead to broadly similar changes in appetite, satiety and food-seeking behaviour, gastrointestinal motility, release of digestive enzymes and induction of nutrient transporters, the requirements in different animals differ. To simplify discussion, we can divide species into ruminant foregut fermenters (such as cattle and sheep), non-ruminant foregut fermenters (e.g., kangaroo, colobus monkey), hind-gut fermenters (such as horse), and auto-enzyme dependent digesters (pig, human) that also gain nutrition from hind-gut fermentation. Ruminants are efficient digesters because the rumenal movements are able to stratify food into gas, fluid and particle components, retaining food to be digested in the forestomach and passing more fully digested material into the abomasum and duodenum, and also being able to return food from the forestomach to the mouth for mastication and limited enzyme exposure. Poultry have multiple stomachs that allow for storage, digestion and tituration, but not fermentation. Ruminants lose efficiency in that most carbohydrate is utilised by gastric bacteria and very little glucose reaches the small intestine. Thus glucose must be synthesised from short chain fatty acids produced by bacteria, whereas species such as pig and human convert carbohydrate to glucose enzymatically. Thus ruminants are more prone than other groups to enter into negative glucose balance, for example during post-partum lactation. Obligatory by-products of fermentation are carbon dioxide and methane. Foregut fermenters are also advantaged by being able to readily utilise vitamins produced by fermentation. It is thought that coprophagy by hind-gut fermenters, such as rabbits, provides access to such vitamins. Foregut fermentation also contributes to detoxification, for which hindgut fermenters and autoenzymic digesters rely primarily on the liver. With these differences in mind, it is necessary to closely consider what information can be readily extrapolated between species. Conversely, we can point to similarities in neural and hormonal signalling systems and products of digestion, achieved in different ways, that are available for energy utilisation and incorporation into tissues. Keywords: digestive physiology; fermentation; glucose; comparative
    2014 ADSA-ASAS-CSAS Joint Annual Meeting; 07/2014
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    ABSTRACT: Abstract Text: Intestinal L cells have key roles in the detection of the chemical environment in the gut lumen, to which they react by the release of hormones that influence appetite, proximal gut motility, insulin secretion and mucosal function (Furness et al, Nature Gastroenterology, 10, 729–740, 2013). Important amongst L cell hormones are glucagon-like peptide1 (GLP-1) and peptide tyrosine-tyrosine (PYY), which are products of separate genes. The conventional description of their localisation is that GLP-1 and PYY are in the same storage vesicles in the same cells. However, GLP-1 and PYY have different functions, particularly in relation to insulin secretion and mucosal function. We have used super-resolution (3D-SIM) microscopy and double-labelling immunohistochemistry to investigate the subcellular localisations of the hormones, and digital scanning microscopy to investigate cell populations. Super-resolution microscopy revealed that GLP-1 and PYY are in separate storage organelles in enteroendocrine cells from mouse, rat, pig and human. The majority of the organelles were 150-170 nm or less in diameter, and are concluded to be secretory vesicles. Only 10-20% of organelles had immunoreactivity for both hormones. Even this may be an overestimate, as touching or very close vesicles may not be effectively resolved, even with super-resolution microscopy. In investigating co-localisation at the cell level, we included glucagon-like insulinotropic peptide (GIP), an incretin of K cells, in the analysis. The work shows that there is a K/L cell gradient in the mouse intestine. From the duodenum to the distal colon, there are populations of cells with GIP alone, GLP alone, PYY alone and all combinations of the three hormones. Greatest numbers of GIP cells were in the doudenum and jejunum, where 30-40% contained only GIP and the remainder also contained GLP-1. A small proportion also contained PYY. Similar patterns of overlap occurred in the proximal and distal ileum, where GLP-1 was the dominant peptide, which was often alone, or co-localised with PYY. In the large intestine the majority of cells contained both GLP-1 and PYY, but cells with only one of these and cells with all three hormones were found. The findings reveal a structural basis for the separate or preferential control of GLP-1, PYY (and possibly GIP) release. A number of physiological studies imply that there can be differential release of GLP-1 and PYY. This should be investigated further. Keywords: enteroendocrine cells, incretins, glucagon like peptide, peptideYY
    2014 ADSA-ASAS-CSAS Joint Annual Meeting; 07/2014
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    ABSTRACT: Objective To analyse the temporal bones and implant of the first University of Melbourne's (UOM) patient (MC-1) to receive the multi-channel cochlear prosthesis. Methods The left cochlea was implanted with the prototype multi-channel cochlear prosthesis on 1 August 1978, and the Cochlear versions CI-22 and CI-24 on 22 June 1983 and 10 November 1998, respectively. MC-1 died in 2007. Results Plain X-rays of the temporal bones showed that after the CI-22 had been explanted seven electrode bands remained in situ. Micro-CT scans also revealed a partially united fracture transecting the left implanted and right control cochleae. Histology indicated a total loss of the organ of Corti on both sides, and a tear of the left basilar membrane. In addition, there was a dense fibrous capsule with heterotopic bone surrounding one proximal band of the CI-22 array that restricted its removal. This pathology was associated with dark particulate material within macrophages, probably due to the release of platinum from the electrode bands. Scanning electron microscopy (SEM) showed possible corrosion of platinum and surface roughening. Three-dimensional reconstruction of the cochlear histology demonstrated the position of the electrode tracts (C1-22 and CI-24) in relation to the spiral ganglion, which showed 85-90% loss of ganglion cells. Discussion and conclusions This study confirms our first histopathological findings that our first free-fitting banded electrode array produced moderate trauma to the cochlea when inserted around the scala tympani of the basal turn. The difficulty in extraction was most likely due to one band being surrounded by an unusually large amount of fibrous tissue and bone, with an electrode band caught due to surface irregularities. Some surface corrosion and a small degree of platinum deposition in the tissue may also help explain the outcome for this long-term cochlear implantation.
    Cochlear implants international. 06/2014;
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    ABSTRACT: A sub-group of enteroendocrine cells (L cells) release gastrointestinal hormones, GLP-1 and PYY, which have different but overlapping physiological effects, in response to intraluminal nutrients. Whilst their release profiles are not identical, how the plasma levels of these two hormones are differentially regulated is not well understood. We investigate the possibility that GLP-1 and PYY are in separate storage vesicles. In this study, the subcellular location of GLP-1 and PYY storage organelles is investigated using double-labelling immunohistochemistry, super resolution microscopy and high-resolution confocal microscopy. In all species tested, human, pig, rat and mouse, most cytoplasmic stores that exhibited GLP-1 or PYY immunofluorescence were distinct from each other. The volume occupancy, determined by 3D analysis, overlapped by only about 10∼20 %. At the lower resolution achieved by conventional confocal microscopy, there was also evidence of GLP-1 and PYY being in separate storage compartments but, in subcellular regions where there were many storage vesicles, separate storage could not be resolved. The results indicate that different storage vesicles in L cells contain predominantly GLP-1 or predominantly PYY. Whether GLP-1 and PYY storage vesicles are selectively mobilised and their products are selectively released needs to be determined.
    Cell and Tissue Research 05/2014; · 3.68 Impact Factor
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    ABSTRACT: Some agonists of ghrelin receptors cause rapid decreases in BP. The mechanisms by which they cause hypotension and the pharmacology of the receptors are unknown. The effects of ligands of ghrelin receptors were investigated in rats in vivo, on isolated blood vessels and on cells transfected with the only molecularly defined ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a). Three agonists of GHSR1a receptors, ulimorelin, capromorelin and CP464709, caused a rapid decrease in BP in the anaesthetized rat. The effect was not reduced by either of two GHSR1a antagonists, JMV2959 or YIL781, at doses that blocked effects on colorectal motility, in vivo. The rapid hypotension was not mimicked by ghrelin, unacylated ghrelin or the unacylated ghrelin receptor agonist, AZP531. The early hypotension preceded a decrease in sympathetic nerve activity. Early hypotension was not reduced by hexamethonium or by baroreceptor (sino-aortic) denervation. Ulimorelin also relaxed isolated segments of rat mesenteric artery, and, less potently, relaxed aorta segments. The vascular relaxation was not reduced by JMV2959 or YIL781. Ulimorelin, capromorelin and CP464709 activated GHSR1a in transfected HEK293 cells at nanomolar concentrations. JMV2959 and YIL781 both antagonized effects in these cells, with their pA2 values at the GHSR1a receptor being 6.55 and 7.84. Our results indicate a novel vascular receptor or receptors whose activation by ulimorelin, capromorelin and CP464709 lowered BP. This receptor is activated by low MW GHSR1a agonists, but is not activated by ghrelin.
    British Journal of Pharmacology 03/2014; 171(5):1275-86. · 5.07 Impact Factor
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    ABSTRACT: TRPA1 is an ion channel that detects specific chemicals in food and also transduces mechanical, cold and chemical stimulation. Its presence in sensory nerve endings is well known and recent evidence indicates that it is expressed by some gastrointestinal enteroendocrine cells (EEC). The purpose of the present work is to identify and quantify EEC that express TRPA1 in the mouse gastrointestinal tract. Combined in situ hybridisation histochemistry for TRPA1 and immunofluorescence for EEC hormones was used. TRPA1 expressing EEC were common in the duodenum and jejunum, were rare in the distal small intestine and were absent from the stomach and large intestine. In the duodenum and jejunum, TRPA1 occurred in EEC that contained both cholecystokinin (CCK) and 5-hydroxytryptamine (5HT) and in a small number of cells expressing 5HT but not CCK. TRPA1 was absent from CCK cells that did not express 5HT and from EEC containing glucagon-like insulinotropic peptide. Thus TRPA1 is contained in very specific EEC populations. It is suggested that foods such as garlic and cinnamon that contain TRPA1 stimulants may aid digestion by facilitating the release of CCK.
    Cell and Tissue Research 01/2014; · 3.68 Impact Factor
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    ABSTRACT: The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5-HT4 receptor agonist, 1 μM) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 μM in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 μM) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity.
    Frontiers in neuroscience. 01/2014; 8:301.
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    ABSTRACT: Dietary effects of organic Se supplementation in the form of Se-enriched Agaricus bisporus mushroom on ileal mucosal permeability and antioxidant selenoenzymes status in heat induced oxidative stress in rats were evaluated. Acute heat stress (40 °C, 21% relative humidity, 90 min exposure) increased ileum baseline short circuit current (Isc; 2.40-fold) and epithelial conductance (Ge; 2.74-fold). Dietary supplementation with Se-enriched A. bisporus (1 µg Se/g feed) reduced (p < 0.05) ileum Isc and Ge during heat stress to 1.74 and 1.91 fold, respectively, indicating protection from heat stress-induced mucosal permeability increase. The expression of ileum glutathione peroxidase (GPx-) 1 and 2 mRNAs were up-regulated (p < 0.05) by 1.90 and 1.87-fold, respectively, for non-heat stress rats on the Se-enriched diet relative to the control. The interplay between heat stress and dietary Se is complex. For rats on the control diet, heat stress alone increased ileum expression of GPx-1 (2.33-fold) and GPx-2 (2.23-fold) relative to thermoneutral conditions. For rats on the Se-enriched diet, heat stress increased (p < 0.05) GPx-1 expression only. Rats on Se-enriched + α-tocopherol diet exhibited increased expression of both genes (p < 0.05). Thus, dietary Se-enriched A. bisporus protected against increase in ileum permeability and up-regulated GPx-1 and GPx-2 expression, selenoenzymes relevant to mitigating oxidative stress.
    Nutrients. 01/2014; 6(6):2478-92.
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    ABSTRACT: The digestive system is innervated through its connections with the central nervous system (CNS) and by the enteric nervous system (ENS) within the wall of the gastrointestinal tract. The ENS works in concert with CNS reflex and command centers and with neural pathways that pass through sympathetic ganglia to control digestive function. There is bidirectional information flow between the ENS and CNS and between the ENS and sympathetic prevertebral ganglia.The ENS in human contains 200-600 million neurons, distributed in many thousands of small ganglia, the great majority of which are found in two plexuses, the myenteric and submucosal plexuses. The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter. Submucosal ganglia and connecting fiber bundles form plexuses in the small and large intestines, but not in the stomach and esophagus. The connections between the ENS and CNS are carried by the vagus and pelvic nerves and sympathetic pathways. Neurons also project from the ENS to prevertebral ganglia, the gallbladder, pancreas and trachea.The relative roles of the ENS and CNS differ considerably along the digestive tract. Movements of the striated muscle esophagus are determined by neural pattern generators in the CNS. Likewise the CNS has a major role in monitoring the state of the stomach and, in turn, controlling its contractile activity and acid secretion, through vago-vagal reflexes. In contrast, the ENS in the small intestine and colon contains full reflex circuits, including sensory neurons, interneurons and several classes of motor neuron, through which muscle activity, transmucosal fluid fluxes, local blood flow and other functions are controlled. The CNS has control of defecation, via the defecation centers in the lumbosacral spinal cord. The importance of the ENS is emphasized by the life-threatening effects of some ENS neuropathies. By contrast, removal of vagal or sympathetic connections with the gastrointestinal tract has minor effects on GI function. Voluntary control of defecation is exerted through pelvic connections, but cutting these connections is not life-threatening and other functions are little affected.
    Advances in experimental medicine and biology 01/2014; 817:39-71. · 1.83 Impact Factor
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    Brid Callaghan, John B Furness
    Digestive Diseases and Sciences 10/2013; · 2.26 Impact Factor
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    ABSTRACT: Mucosal-associated invariant T cells (MAIT cells) express a semi-invariant T cell receptor (TCR) α-chain, TRAV1-2-TRAJ33, and are activated by vitamin B metabolites bound by the major histocompatibility complex (MHC)-related class I-like molecule, MR1. Understanding MAIT cell biology has been restrained by the lack of reagents to specifically identify and characterize these cells. Furthermore, the use of surrogate markers may misrepresent the MAIT cell population. We show that modified human MR1 tetramers loaded with the potent MAIT cell ligand, reduced 6-hydroxymethyl-8-d-ribityllumazine (rRL-6-CH2OH), specifically detect all human MAIT cells. Tetramer(+) MAIT subsets were predominantly CD8(+) or CD4(-)CD8(-), although a small subset of CD4(+) MAIT cells was also detected. Notably, most human CD8(+) MAIT cells were CD8α(+)CD8β(-/lo), implying predominant expression of CD8αα homodimers. Tetramer-sorted MAIT cells displayed a TH1 cytokine phenotype upon antigen-specific activation. Similarly, mouse MR1-rRL-6-CH2OH tetramers detected CD4(+), CD4(-)CD8(-) and CD8(+) MAIT cells in Vα19 transgenic mice. Both human and mouse MAIT cells expressed a broad TCR-β repertoire, and although the majority of human MAIT cells expressed TRAV1-2-TRAJ33, some expressed TRAJ12 or TRAJ20 genes in conjunction with TRAV1-2. Accordingly, MR1 tetramers allow precise phenotypic characterization of human and mouse MAIT cells and revealed unanticipated TCR heterogeneity in this population.
    Journal of Experimental Medicine 10/2013; · 13.21 Impact Factor
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    ABSTRACT: The gastrointestinal tract presents the largest and most vulnerable surface to the outside world. Simultaneously, it must be accessible and permeable to nutrients and must defend against pathogens and potentially injurious chemicals. Integrated responses to these challenges require the gut to sense its environment, which it does through a range of detection systems for specific chemical entities, pathogenic organisms and their products (including toxins), as well as physicochemical properties of its contents. Sensory information is then communicated to four major effector systems: the enteroendocrine hormonal signalling system; the innervation of the gut, both intrinsic and extrinsic; the gut immune system; and the local tissue defence system. Extensive endocrine-neuro-immune-organ-defence interactions are demonstrable, but under-investigated. A major challenge is to develop a comprehensive understanding of the integrated responses of the gut to the sensory information it receives. A major therapeutic opportunity exists to develop agents that target the receptors facing the gut lumen.
    Nature Reviews Gastroenterology &#38 Hepatology 09/2013; · 10.43 Impact Factor
  • JAMA The Journal of the American Medical Association 09/2013; · 29.98 Impact Factor
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    ABSTRACT: Cell therapy has the potential to treat gastrointestinal motility disorders caused by diseases of the enteric nervous system. Many studies have demonstrated that various stem/progenitor cells can give rise to functional neurons in the embryonic gut; however, it is not yet known whether transplanted neural progenitor cells can migrate, proliferate, and generate functional neurons in the postnatal bowel in vivo. We transplanted neurospheres generated from fetal and postnatal intestinal neural crest-derived cells into the colon of postnatal mice. The neurosphere-derived cells migrated, proliferated, and generated neurons and glial cells that formed ganglion-like clusters within the recipient colon. Graft-derived neurons exhibited morphological, neurochemical, and electrophysiological characteristics similar to those of enteric neurons; they received synaptic inputs; and their neurites projected to muscle layers and the enteric ganglia of the recipient mice. These findings show that transplanted enteric neural progenitor cells can generate functional enteric neurons in the postnatal bowel and advances the notion that cell therapy is a promising strategy for enteric neuropathies.
    The Journal of clinical investigation 03/2013; 123(3):1182-91. · 15.39 Impact Factor
  • Romke Bron, Lei Yin, Domenico Russo, John B Furness
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    ABSTRACT: There is ambiguity concerning the distribution of neurons that express the ghrelin receptor (GHSR) in the medulla oblongata. In the current study we have used a sensitive non-radioactive method to investigate GHSR mRNA distribution by in situ hybridization. Strong expression of the GHSR gene was confirmed in neurons of the facial nucleus (FacN, 7), the dorsal vagal complex (DVC) and the semi-compact (but not compact) nucleus ambiguus (AmbSC and AmbC). In addition, expression of GHSR was found in other regions, where it had not been described before. GHSR-positive neurons were observed in the gustatory rostral nucleus tractus solitarius and in areas involved in vestibulo-ocular processing (such as the medial vestibular nucleus and the nucleus abducens). GHSR expression was also noted in ventral areas associated with cardio-respiratory control, including the gigantocellular reticular nucleus, the lateral paragigantocellular nucleus, the rostral and caudal ventrolateral medulla, the (pre)-Bötzinger complex and the rostral and caudal ventrolateral respiratory group. However, GHSR-positive neurons in ventrolateral areas did not express markers for cardiovascular presympathetic vasomotor neurons, respiratory propriobulbar rhythmogenic neurons or sensory interneurons. GHSR-positive cells were intermingled with catecholamine neurons in the dorsal vagal complex but these populations did not overlap. Thus, the ghrelin receptor occurs in the medulla oblongata in i) second order sensory neurons processing gustatory, vestibulo-ocular and visceral sensation; ii) cholinergic somatomotor neurons of the FacN and autonomic preganglionic neurons of the DMNX and AmbSC; iii) cardiovascular neurons in the DVC, Gi and LPGi; iv) neurons of as yet unknown function in the ventrolateral medulla. J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 01/2013; · 3.66 Impact Factor
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    ABSTRACT: Extracellular purines play important roles as neurotransmitters and paracrine mediators in the gastrointestinal (GI) tract. Inflammation of the GI tract causes marked changes in the release and extracellular catabolism of purines, and can modulate purinoceptor expression and/or signaling. The functional consequences of this include suppression of the purinergic component of inhibitory neuromuscular and neurovascular transmission, increased release of purines from immune and epithelial cells, loss of enteric neurons to damage through P2X(7) purinoceptors, and enhanced activation of pain fibres. The purinergic system represents an important target for drug therapies that may improve GI inflammation and its consequences.
    Current Opinion in Pharmacology 10/2012; · 5.44 Impact Factor
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    ABSTRACT: Circulating ghrelin reduces blood pressure, but the mechanism for this action is unknown. This study investigated whether ghrelin has direct vasodilator effects mediated through the growth hormone secretagogue receptor 1a (GHSR1a) and whether ghrelin reduces sympathetic nerve activity. Mice expressing enhanced green fluorescent protein under control of the promoter for growth hormone secretagogue receptor (GHSR) and RT-PCR were used to locate sites of receptor expression. Effects of ghrelin and the nonpeptide GHSR1a agonist capromorelin on rat arteries and on transmission in sympathetic ganglia were measured in vitro. In addition, rat blood pressure and sympathetic nerve activity responses to ghrelin were determined in vivo. In reporter mice, expression of GHSR was revealed at sites where it has been previously demonstrated (hypothalamic neurons, renal tubules, sympathetic preganglionic neurons) but not in any artery studied, including mesenteric, cerebral, and coronary arteries. In rat, RT-PCR detected GHSR1a mRNA expression in spinal cord and kidney but not in the aorta or in mesenteric arteries. Moreover, the aorta and mesenteric arteries from rats were not dilated by ghrelin or capromorelin at concentrations >100 times their EC(50) determined in cells transfected with human or rat GHSR1a. These agonists did not affect transmission from preganglionic sympathetic neurons that express GHSR1a. Intravenous application of ghrelin lowered blood pressure and decreased splanchnic nerve activity. It is concluded that the blood pressure reduction to ghrelin occurs concomitantly with a decrease in sympathetic nerve activity and is not caused by direct actions on blood vessels or by inhibition of transmission in sympathetic ganglia.
    AJP Heart and Circulatory Physiology 08/2012; 303(8):H1011-21. · 4.01 Impact Factor

Publication Stats

2k Citations
532.51 Total Impact Points


  • 1999–2014
    • University of Melbourne
      • • Department of Anatomy and Neuroscience
      • • Department of Medicine (Austin)
      • • Department of Pathology
      Melbourne, Victoria, Australia
  • 2007–2012
    • Victoria University Melbourne
      Melbourne, Victoria, Australia
  • 2008
    • Fundação Oswaldo Cruz
      Rio de Janeiro, Rio de Janeiro, Brazil
    • Universidade Federal de Uberlândia (UFU)
      • Institute of Biomedical Sciences (ICBIM)
      Uberlândia, Estado de Minas Gerais, Brazil
  • 2007–2008
    • Federal University of Minas Gerais
      • Instituto de Cîências Biológicas (ICB)
      Cidade de Minas, Minas Gerais, Brazil
  • 2004–2008
    • University of Bologna
      • School of Agriculture and Veterinary Medicine
      Bologna, Emilia-Romagna, Italy
  • 2006
    • GlaxoSmithKline plc.
      Londinium, England, United Kingdom