title: The role of ribosylated-BSA in regulating PC12 cell viability.
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.
authors.affiliation: Department of Animal Science, College of Bioresources, National Ilan University, Ilan 260, Taiwan.
authors.forename: Tsun-Yung
authors.initials: TY
authors.lastname: Kuo
authors.forename: Chuen-Lin
authors.initials: CL
authors.lastname: Huang
authors.forename: Jung-Mou
authors.initials: JM
authors.lastname: Yang
authors.forename: Wei-Jung
authors.initials: WJ
authors.lastname: Huang
authors.forename: Nai-Kuei
authors.initials: NK
authors.lastname: Huang
authors.forename: Yue-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Ren-Jye
authors.initials: RJ
authors.lastname: Lin
authors.forename: Ying-Chen
authors.initials: YC
authors.lastname: Yang
mesh_terms: D000818:Animals; D002470:Cell Survival; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005632:Fructose / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D017127:Glycation End Products, Advanced / Q000138:chemical synthesis / Q000494:pharmacology / Q000502:physiology*; D006031:Glycosylation; D007093:Imidazoles / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008970:Molecular Weight; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D016716:PC12 Cells; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D012266:Ribose / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D000077154:Rosiglitazone; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D017127:Glycation End Products, Advanced; D007093:Imidazoles; C090663:N(6)-(1-iminoethyl)lysine; D047495:PPAR gamma; D011134:Polysaccharides; D011743:Pyrimidines; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D012710:Serum Albumin, Bovine; D005632:Fructose; D012266:Ribose; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063; D005947:Glucose; D008239:Lysine; D000077205:Pioglitazone