title: Decreased O-GlcNAcylation of the key proteins in kinase and redox signalling pathways is a novel mechanism of the beneficial effect of α-lipoic acid in diabetic liver.
abstract: The present study aimed to investigate the effects of the treatment with a-lipoic acid (LA), a naturally occurring compound possessing antioxidant activity, on liver oxidant stress in a rat model of streptozotocin (STZ)-induced diabetes by examining potential mechanistic points that influence changes in the expression of antioxidant enzymes such as catalase (CAT) and CuZn/Mn superoxide dismutase(s) (SOD). LA was administered for 4 weeks by daily intraperitoneal injections (10 mg/kg) to STZ-induced diabetic rats, starting from the last STZ treatment. LA administration practically normalised the activities of the indicators of hepatocellular injury, alanine and aspartate aminotransferases, and lowered oxidative stress, as observed by the thiobarbituric acid-reactive substance assay, restored the reduced glutathione:glutathione disulphide ratio and increased the protein sulfhydryl group content. The lower level of DNA damage detected by the comet assay revealed that LA reduced cytotoxic signalling, exerting a hepatoprotective effect. The LA-treated diabetic rats displayed restored specific enzymatic activities of CAT, CuZnSOD and MnSOD. Quantitative real-time PCR analysis showed that LA restored CAT gene expression to its physiological level and increased CuZnSOD gene expression, but the gene expression of MnSOD remained at the diabetic level. Although the amounts of CAT and CuZnSOD protein expression returned to the control levels, the protein expression of MnSOD was elevated. These results suggested that LA administration affected CAT and CuZnSOD expression mainly at the transcriptional level, and MnSOD expression at the post-transcriptional level. The observed LA-promoted decrease in the O-GlcNAcylation of extracellular signal-regulated kinase, protein 38 kinase, NF-kB, CCAAT/enhancer-binding protein and the antioxidative enzymes themselves in diabetic rats suggests that the regulatory mechanisms that supported the changes in antioxidative enzyme expression were also influenced by post-translational mechanisms.
authors: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
authors: Svetlana
authors: S
authors: Dinić
authors: Jelena
authors: J
authors: Arambašić
authors: Mirjana
authors: M
authors: Mihailović
authors: Aleksandra
authors: A
authors: Uskoković
authors: Nevena
authors: N
authors: Grdović
authors: Jelena
authors: J
authors: Marković
authors: Borivoje
authors: B
authors: Karadžić
authors: Goran
authors: G
authors: Poznanović
authors: Melita
authors: M
authors: Vidaković
mesh_terms: D049148:Aminoacylation; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D023081:CCAAT-Binding Factor; D002374:Catalase / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D000637:Transaminases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000975:Antioxidants; D023081:CCAAT-Binding Factor; D016328:NF-kappa B; D013438:Sulfhydryl Compounds; D008063:Thioctic Acid; D002374:Catalase; D013482:Superoxide Dismutase; D000637:Transaminases; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; D019803:Glutathione Disulfide