ABSTRACT
Glycation, one of the post-translational modifications, is known to influence protein structure and biological function. Advanced glycation end products (AGEs) have been shown to cause pathologies of diabetes. Glycation levels in patients with Alzheimer's disease (AD) are higher than in normal people. However, whether the glycation of susceptible proteins is a triggering event for cell damage or simply a result remains to be elucidated. In this study, we demonstrated that ribose-conjugated BSA (Rib-BSA) directly induces PC12 cell death in a dose- and time-dependent manner. The IC(50) is 4.6 µM. Unlike glucose-incubated BSA, Rib-BSA rapidly forms cytotoxic AGEs. PC12 is vulnerable to Rib-BSA. However, fructose can induce AGE formation, although no effect on cell survival was observed. This effect of Rib-BSA is reversed by pretreatment of pioglitazone and rosiglitazone, which belongs to thiazolidinediones (TZDs) and are peroxisome proliferator-activated receptor (PPAR-γ) ligands. Moreover, Rib-BSA upregulates inducible nitric oxide synthase (iNOS), cycloxygenase 2 (COX-2) expression, and p-38 phosphorylation and leaves extracellular regulated protein1/2 (ERK1/2) phosphorylation unchanged. The Rib-BSA-induced signaling changes are blocked by rosiglitazone and confirmed by PPAR-γ small-interfering RNA transfection. The reduction of cell survival by Rib-BSA is blocked by the iNOS inhibitor and p38 inhibitor. No effect on cell survival was observed using the COX-2 inhibitor. Consequently, these results show that Rib-BSA directly inducing PC12 cell death is a triggering event and TZDs protect PC12 cell from Rib-BSA damage. Signaling molecules, such as PPAR-γ, P38, and iNOS, are involved in Rib-BSA-mediated cytotoxicity.
Subject(s)
Cell Survival , Glycation End Products, Advanced/physiology , Polysaccharides/physiology , Ribose/physiology , Serum Albumin, Bovine/physiology , Animals , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Dose-Response Relationship, Drug , Extracellular Signal-Regulated MAP Kinases/metabolism , Fructose/chemistry , Glucose/chemistry , Glycation End Products, Advanced/chemical synthesis , Glycation End Products, Advanced/pharmacology , Glycosylation , Imidazoles/pharmacology , Lysine/analogs & derivatives , Lysine/pharmacology , Mice , Molecular Weight , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/metabolism , PC12 Cells , PPAR gamma/agonists , Pioglitazone , Polysaccharides/chemistry , Polysaccharides/pharmacology , Pyrimidines/pharmacology , Rats , Ribose/chemistry , Ribose/pharmacology , Rosiglitazone , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/pharmacology , Thiazolidinediones/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
BACKGROUND: The relationship between lower urinary tract symptoms and male sexual dysfunction remains controversial. In this study, we aimed to evaluate the relationship between voiding and erectile function (EF) using the American Urological Association Symptom Index (AUA-SI) and International Index of EF (IIEF-15) in patients with benign prostatic hyperplasia (BPH). METHODS: From March 2001 to January 2002, 50 men (aged 43-92 years) with symptomatic BPH were enrolled in the study. They completed the AUA-SI and IIEF-15 questionnaires. An additional question about subjective erectile dysfunction (ED) was also evaluated. AUA-SI scores were divided into 3 categories (irritative, obstructive, and total), and IIEF-15 scores were divided into 6 categories (EF, orgasmic function [OF], sexual desire [SD], intercourse satisfaction [IS], overall satisfaction [OS], and total). RESULTS: Irritative, obstructive and total AUA-SI scores were 7.8 +/- 3.7, 8.4 +/- 5.6 and 16.3 +/- 8.2, respectively. Scores in the 6 categories of the IIEF-15 questionnaire were as follows: EF, 12.1 +/- 10.1; OF, 3.7 +/- 3.8; SD, 4.4 +/- 2.0; IS, 4.5 +/- 4.4; OS, 4.4 +/- 2.6; and total, 29.4 +/- 22.2. No obvious correlation was noted between AUA-SI and IIEF-15 scores. Further, no statistical significance was noted, either between AUA-SI and IIEF-15 severity, or between AUA-SI and EF severity. Among 22 patients who self-reported the absence of ED, 17 (77%) had an EF-domain score less than 26. The mean age of patients with, versus those without, ED was significantly greater. CONCLUSION: Voiding and EF, assessed by the AUA-SI and IIEF-15 questionnaires, respectively, are not correlated in patients with BPH.
