Structural Elucidation of a Carnosine-Acrolein Adduct and its Quantification in Human Urine Samples

Bispo, Vanderson S.; Campos, Ivan P. de Arruda; Mascio, Paolo Di; Medeiros, Marisa H. G.

doi:10.1038/srep19348

Cited by 28 publications

(26 citation statements)

References 20 publications

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“…Although l-carnosine was not detected in serum, it was easily detectable in the urine as a conjugate with ACR (69). The in vivo RCS-scavenging capacity of l-carnosine was further confirmed by 2 independent studies reporting the presence of covalent adducts between carnosine and lipid peroxidation by-products (e.g., ACR, HNE, HHE) in the urine of human volunteers (70,71).…”

Section: Methodsmentioning

confidence: 79%

A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress

Anderson

Vistoli

Katunga

et al. 2018

Journal of Clinical Investigation

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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, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show 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 (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. 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.

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Section: Methodsmentioning

confidence: 79%

A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress

Anderson

Vistoli

Katunga

et al. 2018

Journal of Clinical Investigation

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“…Carnosine contains an amino group of the β-alanyl residue and the imidazole ring of L -histidine, and it also has been reported that it acts in quenching α, β-unsaturated aldehydes synergistically when bound as a dipeptide. Like carnosine, the sulfydryl of NAC provides acceptor site for alkylation, which is beneficial for the cyclization of PM [32] , [33] , [34] . Moreover, the pKa of the imidazole ring is 6.83, which means carnosine has the capacity to inhibit intracellular oxidation under physiological pH conditions [35] .…”

Section: Resultsmentioning

confidence: 99%

Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage

et al. 2018

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Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX). However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (β-alanyl-l-histidine), a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200 mg/kg, i.p.) significantly inhibited the generation of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-oxo-dG), and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20 mg/kg, i.v., 24 h). Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity.

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“…The recent identification of adducts of carnosine with by-products of aldehyde detoxification (e.g., acrolein) suggests that carnosine may be consumed by sub-products linked with the pathogenesis of diabetes complications, such as exacerbated lipoxidation (Bispo et al, 2016).…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Carnosine in health and disease

Artioli

Sale

Jones

2018

European Journal of Sport Science

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Carnosine was originally discovered in skeletal muscle, where it exists in larger amounts than in other tissues. The majority of research into the physiological roles of carnosine have been conducted on skeletal muscle. Given this and the potential for muscle carnosine content to be increased with supplementation, there is now a large body of research examining the ergogenic effects (or otherwise) of carnosine. More recent research, however, points towards a potential for carnosine to exert a wider range of physiological effects in other tissues, including the brain, heart, pancreas, kidney and cancer cells. Taken together, this is suggestive of a potential for carnosine to have therapeutic benefits in health and disease, although this is by no means without complication. Herein, we will provide a review of the current literature relating to the potential therapeutic effects of carnosine in health and disease.

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Structural Elucidation of a Carnosine-Acrolein Adduct and its Quantification in Human Urine Samples

Cited by 28 publications

References 20 publications

A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress

A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress

Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage

Carnosine in health and disease

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