Document Detail


Normalization of proliferation and tight junction formation in bladder epithelial cells from patients with interstitial cystitis/painful bladder syndrome by d-proline and d-pipecolic acid derivatives of antiproliferative factor.
MedLine Citation:
PMID:  21352500     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Interstitial cystitis/painful bladder syndrome is a chronic bladder disorder with epithelial thinning or ulceration, pain, urinary frequency and urgency, for which there is no reliably effective therapy. We previously reported that interstitial cystitis/painful bladder syndrome bladder epithelial cells make a glycopeptide antiproliferative factor or 'APF' (Neu5Acα2-3Galβ1-3GalNAcα-O-TVPAAVVVA) that induces abnormalities in normal cells similar to those in interstitial cystitis/painful bladder syndrome cells in vitro, including decreased proliferation, decreased tight junction formation, and increased paracellular permeability. We screened inactive APF derivatives for their ability to block antiproliferative activity of asialylated-APF ('as-APF') in normal bladder cells and determined the ability of as-APF-blocking derivatives to normalize tight junction protein expression, paracellular permeability, and/or proliferation of interstitial cystitis/painful bladder syndrome cells. Only two of these derivatives [Galβ1-3GalNAcα-O-TV-(d-pipecolic acid)-AAVVVA and Galβ1-3GalNAcα-O-TV-(d-proline)-AAVVVA] blocked as-APF antiproliferative activity in normal cells (p < 0.001 for both). Both of these antagonists also 1) significantly increased mRNA expression of ZO-1, occludin, and claudins 1, 4, 8, and 12 in interstitial cystitis/painful bladder syndrome cells by qRT-PCR; 2) normalized interstitial cystitis/painful bladder syndrome epithelial cell tight junction protein expression and tight junction formation by confocal immunofluorescence microscopy; and 3) decreased paracellular permeability of (14) C-mannitol and (3) H-inulin between confluent interstitial cystitis/painful bladder syndrome epithelial cells on Transwell plates, suggesting that these potent APF antagonists may be useful for the development as interstitial cystitis/painful bladder syndrome therapies.
Authors:
Susan Keay; Piotr Kaczmarek; Chen-Ou Zhang; Kristopher Koch; Zoltan Szekely; Joseph J Barchi; Christopher Michejda
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-04-27
Journal Detail:
Title:  Chemical biology & drug design     Volume:  77     ISSN:  1747-0285     ISO Abbreviation:  Chem Biol Drug Des     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-16     Completed Date:  2011-09-16     Revised Date:  2011-12-16    
Medline Journal Info:
Nlm Unique ID:  101262549     Medline TA:  Chem Biol Drug Des     Country:  England    
Other Details:
Languages:  eng     Pagination:  421-30     Citation Subset:  IM    
Copyright Information:
Published 2011. This article is a US Government work and is in the public domain in the USA.
Affiliation:
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA. skeay@medicine.umaryland.edu
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Carbohydrate Sequence
Cell Membrane Permeability / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Cystitis, Interstitial / drug therapy*,  metabolism,  pathology
Epithelial Cells / drug effects*,  metabolism,  pathology
Gene Expression Regulation / drug effects
Glycoproteins / antagonists & inhibitors,  chemistry*,  metabolism,  pharmacology*
Humans
Pipecolic Acids / chemistry
Proline / chemistry
Tight Junctions / drug effects*,  metabolism,  pathology
Urinary Bladder / cytology*
Grant Support
ID/Acronym/Agency:
R01 DK52596/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Glycoproteins; 0/Pipecolic Acids; 0/antiproliferative factor APF, human; 147-85-3/Proline; 535-75-1/pipecolic acid
Comments/Corrections
Comment In:
J Urol. 2011 Dec;186(6):2264-5   [PMID:  22078590 ]

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