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  1. Article ; Online: Protective actions of a luminally acting 5-HT

    Hurd, Molly / Haag, Melody M / Kwasnik, Matthew J / Wykosky, Jill / Lavoie, Brigitte / Mawe, Gary M

    Neurogastroenterology and motility

    2023  Volume 35, Issue 11, Page(s) e14673

    Abstract: Background: 5-hydroxytryptamine 4 receptors (5-HT: Methods: The dextran sodium sulfate (DSS), trinitrobenzene sulfonic acid (TNBS), and interleukin 10 knockout (IL-10KO) models of colitis were used to test the protective effects of the luminally ... ...

    Abstract Background: 5-hydroxytryptamine 4 receptors (5-HT
    Methods: The dextran sodium sulfate (DSS), trinitrobenzene sulfonic acid (TNBS), and interleukin 10 knockout (IL-10KO) models of colitis were used to test the protective effects of the luminally acting 5-HT
    Key results: Daily enema of 5HT4-LA1 attenuated the development of, and accelerated recovery from, active colitis. Enema administration of 5HT4-LA1 did not attenuate the development of colitis in 5-HT
    Conclusions and inferences: Luminally restricted 5-HT
    MeSH term(s) Humans ; Mice ; Animals ; Serotonin ; Caco-2 Cells ; Colitis/chemically induced ; Colitis/drug therapy ; Colitis/pathology ; Mice, Knockout ; Water
    Chemical Substances Serotonin (333DO1RDJY) ; Water (059QF0KO0R)
    Language English
    Publishing date 2023-10-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 1186328-6
    ISSN 1365-2982 ; 1350-1925
    ISSN (online) 1365-2982
    ISSN 1350-1925
    DOI 10.1111/nmo.14673
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  2. Article: Stratification of enterochromaffin cells by single-cell expression analysis.

    Song, Yan / Fothergill, Linda J / Lee, Kari S / Liu, Brandon Y / Koo, Ada / Perelis, Mark / Diwakarla, Shanti / Callaghan, Brid / Huang, Jie / Wykosky, Jill / Furness, John B / Yeo, Gene W

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine (5-HT) to mediate disparate ... ...

    Abstract Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine (5-HT) to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify fourteen EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A
    Language English
    Publishing date 2023-08-25
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.08.24.554649
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  3. Article ; Online: Development of the aganglionic colon following surgical rescue in a cell therapy model of Hirschsprung disease in rat.

    Furness, John B / Lei, Enie / Hunne, Billie / Adams, Cameron D / Burns, Alan J / Wykosky, Jill / Fazio Coles, Therese E / Fothergill, Linda J / Molero, Juan C / Pustovit, Ruslan V / Stamp, Lincon A

    Disease models & mechanisms

    2023  Volume 16, Issue 6

    Abstract: Patients with Hirschsprung disease lack enteric ganglia in the distal colon and propulsion of colorectal content is substantially impaired. Proposed stem cell therapies to replace neurons require surgical bypass of the aganglionic bowel during re- ... ...

    Abstract Patients with Hirschsprung disease lack enteric ganglia in the distal colon and propulsion of colorectal content is substantially impaired. Proposed stem cell therapies to replace neurons require surgical bypass of the aganglionic bowel during re-colonization, but there is inadequate knowledge of the consequences of bypass. We performed bypass surgery in Ednrb-/- Hirschsprung rat pups. Surgically rescued rats failed to thrive, an outcome reversed by supplying electrolyte- and glucose-enriched drinking water. Histologically, the bypassed colon had normal structure, but grew substantially less in diameter than the functional region proximal to the bypass. Extrinsic sympathetic and spinal afferent neurons projected to their normal targets, including arteries and the circular muscle, in aganglionic regions. However, although axons of intrinsic excitatory and inhibitory neurons grew into the aganglionic region, their normally dense innervation of circular muscle was not restored. Large nerve trunks that contained tyrosine hydroxylase (TH)-, calcitonin gene-related peptide (CGRP, encoded by Calca or Calcb)-, neuronal nitric oxide synthase (nNOS or NOS1)-, vasoactive intestinal peptide (VIP)- and tachykinin (encoded by Tac1)-immunoreactive axons occurred in the distal aganglionic region. We conclude that the rescued Ednrb-/- rat provides a good model for the development of cell therapies for the treatment of Hirschsprung disease.
    MeSH term(s) Rats ; Animals ; Hirschsprung Disease/therapy ; Hirschsprung Disease/pathology ; Colon/pathology ; Neurons/pathology ; Intestines/pathology ; Cell- and Tissue-Based Therapy
    Language English
    Publishing date 2023-04-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2451104-3
    ISSN 1754-8411 ; 1754-8403
    ISSN (online) 1754-8411
    ISSN 1754-8403
    DOI 10.1242/dmm.050055
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  4. Article ; Online: Development of the aganglionic colon following surgical rescue in a cell therapy model of Hirschsprung disease in rat

    John B. Furness / Enie Lei / Billie Hunne / Cameron D. Adams / Alan J. Burns / Jill Wykosky / Therese E. Fazio Coles / Linda J. Fothergill / Juan C. Molero / Ruslan V. Pustovit / Lincon A. Stamp

    Disease Models & Mechanisms, Vol 16, Iss

    2023  Volume 6

    Keywords hirschsprung disease ; stem cell therapy ; colon ; intestinal bypass ; enteric neurons ; enteric nervous system ; Medicine ; R ; Pathology ; RB1-214
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Mfge8 attenuates human gastric antrum smooth muscle contractions.

    Li, Wen / Olseen, Ashley / Xie, Yeming / Alexandru, Cristina / Outland, Andrew / Herrera, Angela F / Syder, Andrew J / Wykosky, Jill / Perrino, Brian A

    Journal of muscle research and cell motility

    2021  Volume 42, Issue 2, Page(s) 219–231

    Abstract: Coordinated gastric smooth muscle contraction is critical for proper digestion and is adversely affected by a number of gastric motility disorders. In this study we report that the secreted protein Mfge8 (milk fat globule-EGF factor 8) inhibits the ... ...

    Abstract Coordinated gastric smooth muscle contraction is critical for proper digestion and is adversely affected by a number of gastric motility disorders. In this study we report that the secreted protein Mfge8 (milk fat globule-EGF factor 8) inhibits the contractile responses of human gastric antrum muscles to cholinergic stimuli by reducing the inhibitory phosphorylation of the MYPT1 (myosin phosphatase-targeting subunit (1) subunit of MLCP (myosin light chain phosphatase), resulting in reduced LC20 (smooth muscle myosin regulatory light chain (2) phosphorylation. Mfge8 reduced the agonist-induced increase in the F-actin/G-actin ratios of β-actin and γ-actin1. We show that endogenous Mfge8 is bound to its receptor, α8β1 integrin, in human gastric antrum muscles, suggesting that human gastric antrum muscle mechanical responses are regulated by Mfge8. The regulation of gastric antrum smooth muscles by Mfge8 and α8 integrin functions as a brake on gastric antrum mechanical activities. Further studies of the role of Mfge8 and α8 integrin in regulating gastric antrum function will likely reveal additional novel aspects of gastric smooth muscle motility mechanisms.
    MeSH term(s) Antigens, Surface/metabolism ; Humans ; Milk Proteins/metabolism ; Muscle Contraction ; Muscle, Smooth ; Myosin Light Chains/metabolism ; Myosin-Light-Chain Phosphatase/metabolism ; Phosphorylation ; Pyloric Antrum/metabolism
    Chemical Substances Antigens, Surface ; MFGE8 protein, human ; Milk Proteins ; Myosin Light Chains ; Myosin-Light-Chain Phosphatase (EC 3.1.3.53)
    Language English
    Publishing date 2021-06-03
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 283053-x
    ISSN 1573-2657 ; 0142-4319
    ISSN (online) 1573-2657
    ISSN 0142-4319
    DOI 10.1007/s10974-021-09604-y
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    Zs.MO 298: Show issues

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  6. Article: The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting.

    Wykosky, Jill / Debinski, Waldemar

    Molecular cancer research : MCR

    2008  Volume 6, Issue 12, Page(s) 1795–1806

    Abstract: The Eph receptor tyrosine kinases and ephrin ligands have been studied extensively for their roles in developmental processes. In recent years, Eph receptors and ephrins have been found to be integral players in cancer formation and progression. Among ... ...

    Abstract The Eph receptor tyrosine kinases and ephrin ligands have been studied extensively for their roles in developmental processes. In recent years, Eph receptors and ephrins have been found to be integral players in cancer formation and progression. Among these are EphA2 and ephrinA1, which are involved in the development and maintenance of many different types of solid tumors. The function of EphA2 and ephrinA1 in tumorigenesis and tumor progression is complex and seems to be dependent on cell type and microenvironment. These variables affect the expression of the EphA2 and ephrinA1 proteins, the pathways through which they induce signaling, and the functional consequences of that signaling on the behavior of tumor cells and tumor-associated cells. This review will specifically focus on the roles that EphA2 and ephrinA1 play in the different cell types that contribute to the malignancy of solid tumors, with emphasis on the opportunities for therapeutic targeting.
    MeSH term(s) Ephrin-A1/antagonists & inhibitors ; Ephrin-A1/genetics ; Ephrin-A1/metabolism ; Humans ; Neoplasms/metabolism ; Neoplasms/therapy ; Receptor, EphA2/antagonists & inhibitors ; Receptor, EphA2/genetics ; Receptor, EphA2/metabolism ; Signal Transduction/physiology
    Chemical Substances Ephrin-A1 ; Receptor, EphA2 (EC 2.7.10.1)
    Language English
    Publishing date 2008-12-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2098788-2
    ISSN 1557-3125 ; 1541-7786
    ISSN (online) 1557-3125
    ISSN 1541-7786
    DOI 10.1158/1541-7786.MCR-08-0244
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    Zs.A 5744: Show issues Location:
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  7. Article ; Online: Dopamine and ghrelin receptor co-expression and interaction in the spinal defecation centers.

    Furness, John B / Pustovit, Ruslan V / Syder, Andrew J / Ringuet, Mitchell T / Yoo, Eun Ji / Fanjul, Andrea / Wykosky, Jill / Fothergill, Linda J / Whitfield, Emily A / Furness, Sebastian G B

    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

    2020  Volume 33, Issue 5, Page(s) e14051

    Abstract: Background: Dopamine receptor 2 (DRD2) and ghrelin receptor (GHSR1a) agonists both stimulate defecation by actions at the lumbosacral defecation center. Dopamine is in nerve terminals surrounding autonomic neurons of the defecation center, whereas ... ...

    Abstract Background: Dopamine receptor 2 (DRD2) and ghrelin receptor (GHSR1a) agonists both stimulate defecation by actions at the lumbosacral defecation center. Dopamine is in nerve terminals surrounding autonomic neurons of the defecation center, whereas ghrelin is not present in the spinal cord. Dopamine at D2 receptors generally inhibits neurons, but at the defecation center, its effect is excitatory.
    Methods: In vivo recording of defecation and colorectal propulsion was used to investigate interaction between DRD2 and GHSR1a. Localization studies were used to determine sites of receptor expression in rat and human spinal cord.
    Key results: Dopamine, and the DRD2 agonist, quinpirole, directly applied to the lumbosacral cord, caused defecation. The effect of intrathecal dopamine was inhibited by the GHSR1a antagonist, YIL781, given systemically, but YIL781 was not an antagonist at DRD2. The DRD2 agonist, pramipexole, administered systemically caused colorectal propulsion that was prevented when the pelvic nerves were cut. Drd2 and Ghsr were expressed together in autonomic preganglionic neurons at the level of the defecation centers in rat and human. Behaviorally induced defecation (caused by water avoidance stress) was reduced by the DRD2 antagonist, sulpiride. We had previously shown it is reduced by YIL781.
    Conclusions and inferences: Our observations imply that dopamine is a transmitter of the defecation pathways whose actions are exerted through interacting dopamine (D2) and ghrelin receptors on lumbosacral autonomic neurons that project to the colorectum. The results explain the excitation by dopamine agonists and the conservation of GHSR1a in the absence of ghrelin.
    MeSH term(s) Animals ; Defecation/drug effects ; Defecation/physiology ; Dopamine/pharmacology ; Dopamine Agonists/pharmacology ; Dopamine Antagonists/pharmacology ; Gastrointestinal Motility/drug effects ; Gastrointestinal Motility/physiology ; Ghrelin/metabolism ; Humans ; Piperidines/pharmacology ; Pramipexole/pharmacology ; Quinazolinones/pharmacology ; Quinpirole/pharmacology ; Rats ; Receptors, Dopamine D2/metabolism ; Receptors, Ghrelin/antagonists & inhibitors ; Receptors, Ghrelin/metabolism ; Spinal Cord/drug effects ; Spinal Cord/metabolism ; Spinal Cord/physiology ; Spinal Cord Lateral Horn/metabolism ; Sulpiride/pharmacology
    Chemical Substances DRD2 protein, human ; DRD2 protein, rat ; Dopamine Agonists ; Dopamine Antagonists ; Ghrelin ; Ghsr1a protein, human ; Ghsr1a protein, rat ; Piperidines ; Quinazolinones ; Receptors, Dopamine D2 ; Receptors, Ghrelin ; YIL 781 ; Quinpirole (20OP60125T) ; Sulpiride (7MNE9M8287) ; Pramipexole (83619PEU5T) ; Dopamine (VTD58H1Z2X)
    Language English
    Publishing date 2020-12-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1186328-6
    ISSN 1365-2982 ; 1350-1925
    ISSN (online) 1365-2982
    ISSN 1350-1925
    DOI 10.1111/nmo.14051
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  8. Article ; Online: A quantitative systems pharmacology model of colonic motility with applications in drug development.

    Das, Raibatak / Wille, Lucia / Zhang, Liming / Chen, Chunlin / Winchester, Wendy / Selimkhanov, Jangir / Wykosky, Jill / Apgar, Joshua F / Burke, John M / Rogge, Mark / Hua, Fei / Vakilynejad, Majid

    Journal of pharmacokinetics and pharmacodynamics

    2019  Volume 46, Issue 5, Page(s) 485–498

    Abstract: We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was ... ...

    Abstract We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT
    MeSH term(s) Colon/physiology ; Constipation/complications ; Constipation/drug therapy ; Constipation/physiopathology ; Drug Development/methods ; Gastrointestinal Motility/physiology ; Humans ; Models, Biological ; Multiple Sclerosis/complications ; Multiple Sclerosis/drug therapy ; Serotonin Receptor Agonists/pharmacokinetics ; Serotonin Receptor Agonists/therapeutic use
    Chemical Substances Serotonin Receptor Agonists
    Language English
    Publishing date 2019-08-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2041601-5
    ISSN 1573-8744 ; 1567-567X
    ISSN (online) 1573-8744
    ISSN 1567-567X
    DOI 10.1007/s10928-019-09651-6
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    Zs.A 980: Show issues Location:
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  9. Article ; Online: Prokinetic actions of luminally acting 5-HT

    Konen, John R / Haag, Melody M / Guseva, Daria / Hurd, Molly / Linton, Alisha A / Lavoie, Brigitte / Kerrigan, Colleen B / Joyce, Emily / Bischoff, Stephan C / Swann, Steve / Griffin, Luana / Matsukawa, Jun / Falk, Matthew D / Gibson, Tony S / Hennig, Grant W / Wykosky, Jill / Mawe, Gary M

    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

    2020  Volume 33, Issue 4, Page(s) e14026

    Abstract: Background: 5-HT: Methods: Non-absorbed 5-HT: Key results: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT: Conclusions and inferences: These findings demonstrated that stimulation of epithelial 5- ... ...

    Abstract Background: 5-HT
    Methods: Non-absorbed 5-HT
    Key results: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT
    Conclusions and inferences: These findings demonstrated that stimulation of epithelial 5-HT
    MeSH term(s) Animals ; CHO Cells ; Colon/drug effects ; Colon/physiology ; Constipation/drug therapy ; Constipation/physiopathology ; Cricetinae ; Cricetulus ; Gastrointestinal Motility/drug effects ; Gastrointestinal Motility/physiology ; Humans ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Receptors, Serotonin, 5-HT4/physiology ; Serotonin 5-HT4 Receptor Agonists/pharmacology ; Serotonin 5-HT4 Receptor Agonists/therapeutic use
    Chemical Substances Serotonin 5-HT4 Receptor Agonists ; Receptors, Serotonin, 5-HT4 (158165-40-3)
    Language English
    Publishing date 2020-11-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1186328-6
    ISSN 1365-2982 ; 1350-1925
    ISSN (online) 1365-2982
    ISSN 1350-1925
    DOI 10.1111/nmo.14026
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  10. Article ; Online: Escape from targeted inhibition: the dark side of kinase inhibitor therapy.

    Wykosky, Jill / Mukasa, Akitake / Furnari, Frank / Cavenee, Webster K

    Cell cycle (Georgetown, Tex.)

    2010  Volume 9, Issue 9, Page(s) 1661–1662

    MeSH term(s) Antineoplastic Agents/therapeutic use ; Cell Cycle Proteins/metabolism ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/metabolism ; Humans ; Neoplasms/drug therapy ; Protein Kinase Inhibitors/therapeutic use
    Chemical Substances Antineoplastic Agents ; Cell Cycle Proteins ; Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1)
    Language English
    Publishing date 2010-05-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.9.9.11592
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