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2-Oxo-imidazole-containing dipeptides (2-oxo-IDPs), novel imidazole-containing dipeptide (IDP) derivatives, exhibit a much higher antioxidant capacity than that of IDPs. However, quantitative methods have only been developed for IDPs, and methods for the quantitative analysis of 2-oxo-IDPs are needed. In this study, we developed methods for the quantitative analysis of 2-oxo-IDPs by high-performance liquid chromatography with online electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) coupled with a stable isotope dilution method. First, we prepared stable isotope-labeled IDP and 2-oxo-IDP standards for MS analyses. Next, using these standards, we established highly sensitive, selective, and absolute quantitative analysis methods for five IDPs and five 2-oxo-IDPs by HPLC-ESI-MS/MS, achieving a limit of detection in the fmol range. Finally, we applied the method to various types of meat, such as beef, pork, chicken, and whale meat, demonstrating the detection of both IDPs and 2-oxo-IDPs. Furthermore, we provide the first evidence for the endogenous production of 2-oxo-balenine in meats. The methods developed in this study enable the detection of trace levels of 2-oxo-IDPs in biological samples and could be helpful for understanding the biological relevance of 2-oxo-IDPs.

Histidine is an amino acid which plays a critical role in protein synthesis, muscle buffering during anaerobic exercise, and antioxidation. It also acts as a precursor to carnosine, a dipeptide that enhances physical performance by being present in fast-contracting muscle fibers and contributing to buffering capacity. Recent studies have examined other histidine-containing compounds, such as anserine, balenine, and ergothioneine, to assess their potential benefits for physical activity. This narrative review focuses on the literature about the effects of dietary supplementation with these histidine-containing compounds on exercise capacity in animals and humans. The findings indicate that anserine may improve physical performance and reduce fatigue, particularly in quick, repetitive activities. Although balenine has been less extensively studied, it has shown promise in enhancing muscle regeneration and antioxidative defense in animal models. Ergothioneine, a sulfur-containing histidine derivative, displayed antioxidant and anti-inflammatory properties in both animal and human studies, suggesting its potential role in reducing exercise-induced oxidative stress and aiding recovery. The diversity of the presented studies and their limitations do not provide an opportunity to confirm the ergogenic properties of the histidine-containing compounds studied. Nevertheless, supplementation with anserine and ergothioneine shows promise for enhancing physical performance and recovery, though further research is required to better understand their mechanisms and optimize their use in sports and exercise.

Balenine is one of the endogenous imidazole dipeptides derived from marine products. It is composed of beta-alanine and 3-methyl-L-histidine, which exist mainly in the muscles of marine organisms. The physiological functions of dietary balenine are not well-known. In this study, we investigated whether the supplementation of dietary balenine was associated with muscle function in a cardiotoxin-indued muscle degeneration/regeneration model. Through morphological observation, we found that the supplementation of balenine-enriched extract promoted the regeneration stage. In addition, the expression of regeneration-related myogenic marker genes, such as paired box protein 7, MyoD1, myogenin, and Myh3, in a group of mice fed a balenine-enriched extract diet was higher than that in a group fed a normal diet. Moreover, the supplementation of balenine-enriched extract promoted the expression of anti-inflammatory cytokines as well as pro-inflammatory cytokines at the degeneration stage. Interestingly, phagocytic activity in the balenine group was significantly higher than that in the control group in vitro. These results suggest that balenine may promote the progress of muscle regeneration by increasing the phagocytic activity of macrophages.

Balenine is one of the endogenous imidazole dipeptides. It is composed of beta-alanine and 3-methyl-l-histidine, which exist mainly in the muscles and the brain. The exact biological properties of balenine are still not well known, although the antioxidant activity of carnosine, another imidazole dipeptide, is known. In this study we investigated whether balenine exhibits antioxidant activity. It was found to decrease the superoxide anion (O2−) and increased hydrogen peroxide (H2O2) generation. We found that SOD activity increased in balenine-treated C2C12 myotubes, although balenine did not increase expression of SOD mRNA. On the other hand, there were no changes in other antioxidant enzymes, CAT and GPX activity, and mRNA levels. In an in vitro assay, the direct activation of SOD treated by balenine was significantly higher than with carnosine treatment. Moreover, balenine constituent amino acids did not have the ability to activate SOD. Our results suggest that balenine contributes to antioxidant effects through activation of SOD.

Imidazole dipeptides (IDPs) such as carnosine (CAR), anserine (ANS), and balenine (BAL) are widely distributed in the skeletal muscle of vertebrates. Recently, several studies have revealed that CAR plays an important role in the detoxification of cytotoxic aldehydes arising from the peroxide of unsaturated fatty acids and carbohydrate metabolite. Although intensive studies on the detoxification of aldehydes by CAR have been performed, few studies have focused on the effects of detoxification by ANS and BAL. To determine the potential of minor IDPs such as ANS and BAL to react with cytotoxic aldehydes, the present study was established to investigate the consumption of IDP after co-incubation with cytotoxic aldehydes using high-performance liquid chromatography (HPLC). In the case of unsaturated fatty acid-derived aldehydes such as 4-hydroxy-2-trans-nonenal (from n-6 fatty acid) and 4-hydroxy-2-trans-hexenal (from n-3 fatty acid), ANS and CAR decreased considerably after co-incubation, but BAL did not. In the case of 3-deoxyglucosone and methylglyoxal as carbohydrate metabolites, no IDPs decreased after co-incubation; however, the absorbance at 336 nm of the CAR and BAL mixtures increased dramatically in a time-dependent manner. In the case of glyceraldehyde, which is also a carbohydrate metabolite, all IDPs, especially BAL, decreased after co-incubation and a new peak, surmised to represent an IDP-glyceraldehyde adduct, appeared on the HPLC chromatogram. These results can help explain the unique function and behavior of ANS and BAL in specific species.

Balenine is one of the endogenous imidazole dipeptides, mainly found in the muscle of marine animals. In this study we focused on the safety evaluation and physiological function of dietary balenine derived from opah Lampris guttatus in skeletal muscle of mice. There were no significant differences among different concentrations (0–1%) of balenine diet in the basic data included the weight of body weight, food intake, skeletal muscle and some organs, indicating that less than 1% dietary balenine showed no side effects. The cross-sectional area of myofibers in the group fed a balenine diet was similar to that observed in the group fed a normal diet. In physiological function, supplementation of balenine significantly induced the expression of peroxisome proliferator-activated receptor-γ coactivator-1α and pyruvate dehydrogenase kinase 4, which are related to mitochondrial biogenesis and lipid metabolism. Moreover, the activity of superoxide dismutase (SOD) in the skeletal muscle of the group fed a balenine diet was significantly increased, compared with that of the group fed a normal diet, whereas the supplementation of balenine did not affect the mRNA transcription of SODs in skeletal muscle. Our results suggest that dietary balenine contributes to the regulation of mitochondrial biogenesis and metabolism, and SOD activity in skeletal muscle of mice.

We examined the absorption of balenine (Bal) in mouse blood after the administration of a high-purity Bal prepared from opah muscle. Using HPLC with phenyl isothiocyanate pre-column derivatization, we successfully isolated imidazole peptides and their constituents. We detected Bal and 3-methylhistidine (3-Me-His) in mouse blood 1 h after the administration of opah-derived Bal. The concentrations of Bal and 3-Me-His significantly increased to 128.27 and 69.09 nmol/mL in plasma, respectively, but were undetectable in control and carnosine (Car)-administrated mice. In contrast, β-alanine and histidine did not increase in mouse plasma 1 h after the administration of Car and opah-derived Bal. The present study is the first report on the absorption of food-derived Bal in mouse blood and serves as a pilot study for future clinical trials.

The quantification of histidine-containing dipeptides (anserine, carnosine, and balenine) in serum might be a diagnostic tool to assess the health condition of animals. In this study, an existing reversed-phase ion-pair high-performance liquid chromatography (HPLC)–ultraviolet detection method was improved and validated to quantify serum anserine, carnosine, and balenine levels in the dolphin. The serum was deproteinized with trichloroacetic acid and directly injected into the HPLC system. Chromatographic separation of the three histidine-containing dipeptides was achieved on a TSK–gel ODS-80Ts (4.6 mm × 150 mm, 5 µm) analytical column using a mobile phase of 50 mmol/L potassium dihydrogen phosphate (pH 3.4) containing 6 mmol/L 1-heptanesulfonic acid and acetonitrile (96:4). The standard curve ranged from 0.1 µmol/L to 250 µmol/L. The average accuracy of the intra- and inter-analysis of anserine, carnosine, and balenine was 97–106%. The relative standard deviations of total precision (RSDr) of anserine, carnosine, and balenine in dolphin serum were 5.9%, 4.1%, and 2.6%, respectively. The lower limit of quantification of these compounds was 0.11–0.21 µmol/L. These results indicate that the improved method is reliable and concise for the simultaneous determination of anserine, carnosine, and balenine in dolphin serum, and may be useful for evaluation of health conditions in dolphins. Furthermore, this method can also be applied to other biological samples.

This review article gives a brief survey of principal pathways that lead to the biosynthesis of most important peptides occurring in foods. Glutathione, selected plant gamma-glutamyl peptides, and animal histidine dipeptides are included in this review.