More promising interstitial cystitis research by Susan Keay
Posted Mar 09 2011 1:52pm
IC Nerd Alert! Here’s another interesting study by Susan Keay, the reearcher who discovered the APF factor in the urine of IC patients. She and her colleagues have determined that they can inhibit the effect of apf by using an apf antagonist. Interesting stuff. Doncha just love science! – Jill
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 – Abstract
Tuesday, 08 March 2011
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland. Veterans Administration Maryland Health Care System, Baltimore, Maryland; Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
Interstitial cystitis/painful bladder syndrome (IC/PBS) 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 IC/PBS bladder epithelial cells make a glycopeptide antiproliferative factor or “APF” (Neu5Ac?2-3Gal?1-3GalNAc?-O-TVPAAVVVA) that induces abnormalities in normal cells similar to those in IC/PBS 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 IC/PBS cells. Only two of these derivatives [Gal?1-3GalNAc?-O-TV-(D-pipecolic acid)-AAVVVA and Gal?1-3GalNAc?-O-TV-(D-proline)-AAVVVA] blocked as-APF antiproliferative activity in normal cells (p< .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 IC/PBS cells by qRT-PCR; 2) normalized IC/PBS 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 IC/PBS epithelial cells on Transwell plates, suggesting that these potent APF antagonists may be useful for development as IC/PBS therapies.
Keay S, Kaczmarek P, Zhang CO, Koch K, Szekely Z, Barchi JJ Jr, Michejda C.