We previously demonstrated that polymorphisms in the carnosinase-1 gene (CNDP1) determine the risk of nephropathy in type 2 diabetic patients. Carnosine, the substrate of the enzyme encoded by this gene, is considered renoprotective and could possibly be used to treat diabetic nephropathy (DN). In this study, we examined the effect of carnosine treatment in vivo in BTBR (Black and Tan, BRachyuric) ob/ob mice, a type 2 diabetes model which develops a phenotype that closely resembles advanced human DN. Treatment of BTBR ob/ob mice with 4 mM carnosine for 18 weeks reduced plasma glucose and HbA1c, concomitant with elevated insulin and C-peptide levels. Also, albuminuria and kidney weights were reduced in carnosine-treated mice, which showed less glomerular hypertrophy due to a decrease in the surface area of Bowman’s capsule and space. Carnosine treatment restored the glomerular ultrastructure without affecting podocyte number, resulted in a modified molecular composition of the expanded mesangial matrix and led to the formation of carnosine-acrolein adducts. Our results demonstrate that treatment with carnosine improves glucose metabolism, albuminuria and pathology in BTBR ob/ob mice. Hence, carnosine could be a novel therapeutic strategy to treat patients with DN and/or be used to prevent DN in patients with diabetes.

Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, due in part to their highly diffuse and broad reactivity, and to lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) possess RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here we present the rational design, characterization and pharmacological evaluation of ‘carnosinol’ (i.e. (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol) a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g. 4-hydroxynonenal, HNE, acrolein) among all others so far reported. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE-adduct formation in liver and skeletal muscle while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders, and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.

Several studies have shown that fresh grape and its derivatives contain phenolic compounds exhibiting antioxidant and health promoting effects, particularly in relation to the cardiovascular system. In this study, two methods were developed to characterize sixteen varieties of table and wine grapes: (1) a LC-MS method to identify major and minor phenolic compounds; and (2) a HPLC-DAD method to quantify the most representative compounds. Sixty-seven molecules belonging to different classes of phenolic compounds were identified: anthocyanins, flavan-3-ols, flavonols, stilbenes and organic acids. In parallel, the free radical scavenging activity and anti-inflammatory activities of the 16 grape varieties were evaluated. The results showed a good correlation between the total phenolic content and the biological activity. Extracts from Exalta and Albarossa grape varieties were the most active in reducing IL-8 release by gastric epithelial cells (IC₅₀ = 8.48 μg mL⁻¹ and 6.68 μg mL⁻¹, respectively), a biomarker of inflammatory processes. The observed biological activities were mainly associated with skin and seed extracts/portions. The interest in studying table grapes and their non-fermented derivatives as sources of healthy compounds has increased in the last few years and our findings suggest that table grapes and their fresh derivatives, in addition to wine, could be involved in the health promoting effects of the Mediterranean diet.