Cystic fibrosis (CF), an inherited disease characterized by defective epithelial Cl − transport, damages lungs via chronic inflammation and oxidative stress. Glutathione, a major antioxidant in the epithelial lung lining fluid, is decreased in the apical fluid of CF airway epithelia due to reduced glutathione efflux (Gao L, Kim KJ, Yankaskas JR, and Forman HJ. Am J Physiol Lung Cell Mol Physiol 277: L113–L118, 1999). The present study examined the question of whether restoration of chloride transport would also restore glutathione secretion. We found that a Cl − channel-forming peptide (N-K 4 -M2GlyR) and a K + channel activator (chlorzoxazone) increased Cl − secretion, measured as bumetanide-sensitive short-circuit current, and glutathione efflux, measured by high-performance liquid chromatography, in a human CF airway epithelial cell line (CFT1). Addition of the peptide alone increased glutathione secretion (181 ± 8% of the control value), whereas chlorzoxazone alone did not significantly affect glutathione efflux; however, chlorzoxazone potentiated the effect of the peptide on glutathione release (359 ± 16% of the control value). These studies demonstrate that glutathione efflux is associated with apical chloride secretion, not with the CF transmembrane conductance regulator per se, and the defect of glutathione efflux in CF can be overcome pharmacologically.
e18093 Background: Prostate cancer patients face several treatment options which vary in their impact on sexual function: active surveillance (least), radiotherapy, and radical prostatectomy (most). In a population-based, prospective cohort of men with newly-diagnosed prostate cancer, we examined whether patient preference for sexual function preservation and baseline sexual function status were associated with treatment choice. Methods: In collaboration with the North Carolina Cancer Registry, 1147 patients were enrolled before treatment from 2011 to 2013 from across the state and followed prospectively. Study staff collected patient-reported treatment preferences (including “preserving your sexual function is…very important, somewhat important, not important”) and pre-treatment quality of life using the validated Prostate Cancer Symptom Indices (PCSI). Per PCSI, each patient was categorized as having normal, intermediate, or poor baseline sexual function. Treatment received was abstracted from medical records. Multivariable logistic regression adjusted for age, race, cancer risk group, marital status, insurance, education and income. Results: Median age was 67 years. 53% of patients indicated preserving sexual function was “very important” – this varied significantly by baseline function: normal (67%), intermediate (58%), and poor (40%). In each group, treatments for patients who indicated “very important” to preserve sexual function were no different than those who indicated this to be somewhat/not important (Table, p = .23). Multivariable analysis showed no association between patient preference and treatment (p = .88). Conclusions: Patient preference to preserve sexual function has little impact on treatment choice in localized prostate cancer. Percentage of patients receiving each treatment modality based on baseline function and preference. Baseline Sexual Function Very important to preserve sexual function Active Surveillance (%) Radiotherapy (%) Radical Prostatectomy (%) Other Treatments (%) Normal Yes (N = 226) 26 24 49 1 No (N = 112) 31 22 46 1 Intermediate Yes (N = 177) 31 25 43 1 No (N = 129) 17 33 47 4 Poor Yes (N = 202) 24 38 35 3 No (N = 301) 30 36 29 5
NC-1059, a synthetic channel-forming peptide, transiently increases transepithelial electrical conductance (g(TE)) and ion transport (as indicated by short-circuit current) across Madin-Darby canine kidney (MDCK) cell monolayers in a time- and concentration-dependent manner when apically exposed. g(TE) increases from <2 to >40 mS/cm(2) over the low to middle micromolar range. Dextran polymer (9.5 but not 77 kDa) permeates the monolayer following apical NC-1059 exposure, suggesting that modulation of the paracellular pathway accounts for changes in g(TE). However, concomitant alterations in junctional protein localization (zonula occludens-1, occludin) and cellular morphology are not observed. Effects of NC-1059 on MDCK g(TE) occur in nominally Cl(-)- and Na(+)-free apical media, indicating that permeation by these ions is not required for effects on g(TE), although two-electrode voltage-clamp assays with Xenopus oocytes suggest that both Cl(-) and Na(+) permeate NC-1059 channels with a modest Cl(-) permselectivity (P(Cl):P(Na) = 1.3). MDCK monolayers can be exposed to multiple NC-1059 treatments over days to weeks without diminution of response, alteration in the time course, or loss of responsiveness to physiological and pharmacological secretagogues. Together, these results suggest that NC-1059 represents a valuable tool to investigate tight junction regulation and may be a lead compound for therapeutic interventions.
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