Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy.

Background/aims: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus.

Methods: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy.

Therapeutic potential of breakers of advanced glycation end product-protein crosslinks.

Long-lived structural proteins, collagen and elastin, undergo continual non-enzymatic crosslinking during aging and in diabetic individuals. This abnormal protein crosslinking is mediated by advanced glycation end products (AGEs) generated by non-enzymatic glycosylation of proteins by glucose. The AGE-derived protein crosslinking of structural proteins contributes to the complications of long-term diabetes such as nephropathy, retinopathy, and neuropathy.

Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links.

Glucose and other reducing sugars react non-enzymatically with proteins leading to the formation of advanced glycosylation end products (AGEs) and AGE-derived protein cross-linking. Formation of AGEs is a normal physiological process, which is accelerated under the hyperglycaemic condition in diabetes. Under normal conditions, AGEs build up slowly and accumulate as one ages.

Evidence for an important role of DNA pyridyloxobutylation in rat lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: effects of dose and phenethyl isothiocyanate.

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), selectively induces lung tumors in F344 rats. NNK is metabolically activated to intermediates that methylate and pyridyloxobutylate DNA. To explore the importance of pyridyloxobutyl DNA adducts in NNK-induced rat lung tumorigenesis, the first study in this report examined levels of these adducts in whole lung and pulmonary cells of F344 rats treated with different doses of NNK (0.

The relationship between N-nitrosodimethylamine metabolism and DNA methylation in isolated rat hepatocytes.

The metabolism of N-nitrosodimethylamine (NDMA) and its methylation of DNA were simultaneously determined in hepatocytes isolated from untreated and saline- and pyrazole-treated male Sprague-Dawley rats. Metabolism of NDMA was directly measured by monitoring its disappearance via gas chromatography coupled with a sensitive and specific detector for N-nitrosamines. DNA methylation was determined in the same cells employed in the metabolism studies using a monoclonal antibody-based competitive ELISA procedure specific for O6-methyldeoxyguanosine (6-Me-dG).