ArticleLiterature Review

Physiology and Pathophysiology of Carnosine

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Abstract

Carnosine (β-alanyl-l-histidine) was discovered in 1900 as an abundant non-protein nitrogen-containing compound of meat. The dipeptide is not only found in skeletal muscle, but also in other excitable tissues. Most animals, except humans, also possess a methylated variant of carnosine, either anserine or ophidine/balenine, collectively called the histidine-containing dipeptides. This review aims to decipher the physiological roles of carnosine, based on its biochemical properties. The latter include pH-buffering, metal-ion chelation, and antioxidant capacity as well as the capacity to protect against formation of advanced glycation and lipoxidation end-products. For these reasons, the therapeutic potential of carnosine supplementation has been tested in numerous diseases in which ischemic or oxidative stress are involved. For several pathologies, such as diabetes and its complications, ocular disease, aging, and neurological disorders, promising preclinical and clinical results have been obtained. Also the pathophysiological relevance of serum carnosinase, the enzyme actively degrading carnosine into l-histidine and β-alanine, is discussed. The carnosine system has evolved as a pluripotent solution to a number of homeostatic challenges. l-Histidine, and more specifically its imidazole moiety, appears to be the prime bioactive component, whereas β-alanine is mainly regulating the synthesis of the dipeptide. This paper summarizes a century of scientific exploration on the (patho)physiological role of carnosine and related compounds. However, far more experiments in the fields of physiology and related disciplines (biology, pharmacology, genetics, molecular biology, etc.) are required to gain a full understanding of the function and applications of this intriguing molecule.

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... Carnosine derivatives reported in the literature have been obtained through different approaches: (i) the substitution of L-histidine with D-histidine [31][32][33]; (ii) the modification of the carboxylic function of the histidine by reduction [19,34], esterification [31,33], or conversion to substituted amides [35,36]; (iii) the modification of the amino group at the peptide N-terminus [37][38][39][40]; (iv) the introduction of side chains in β-alanine [41]; (v) the modification of the imidazole ring [42,43] or; (vi) a combination of some of these approaches. The possibility to modify the primary amine function has not been fully exploited, since it plays a crucial role for binding to active transporters responsible for carnosine absorption, besides being important also for carnosine activity [44][45][46]. For instance, N-acetilcarnosine, as well as di-methyl-balenine, are inactive against HNE, while other derivatives reported in the literature obtained from the conjugation of carnosine to salicylic acid or sugars were not tested for their binding activity toward RCS [40,47]. ...
... This also suggests that the modification of the amino group of carnosine is possibly not a good strategy for the design of inhibitors of human serum carnosinase. Such a hypothesis is consistent with data suggesting the importance of N-terminus amino group for substrate recognition [44][45][46]. The effect of the substituent on the nucleophilicity of L-carnosine is exhibited in the following order: ...
... This also suggests that the modification of the amino group of carnosine is possibly not a good strategy for the design of inhibitors of human serum carnosinase. Such a hypothesis is consistent with data suggesting the importance of N-terminus amino group for substrate recognition [44][45][46]. ...
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Carnosine is a naturally occurring dipeptide that has been advocated by some authors as an interesting scaffold for the development of potential therapeutic agents in view of the positive outcomes of its supplementation in animal models of human diseases. Its mode of action seems to depend on the quenching of toxic electrophiles, such as 4–hydroxynonenal (HNE). However, carnosine’s bioavailability in humans is lower than that in other mammals. The main reason for such an unfavorable pharmacokinetic profile is the activity of the enzyme human serum carnosinase (E.C. 3.4.13.20), which rapidly hydrolyzes carnosine upon absorption. Therefore, some studies have focused on the design of carnosinase-resistant derivatives that retain binding activity toward toxic electrophiles. Nevertheless, the structural modification of the N-terminus amino group of carnosine has rarely been considered, possibly because of its key role in the electrophile scavenging mechanism. This was proven, since some carnosine N-terminus modification generated inactive compounds, despite some derivatives retaining oral bioavailability and gaining resistance to carnosinase hydrolysis. Herein, we therefore report a study aimed at exploring whether the amino group of carnosine can be conveniently modified to develop carnosinase-resistant derivatives retaining the dipeptide activity toward toxic electrophiles.
... Its action may be related to a beneficial effect on oxidative and nitroactive stress (Kohen etal., 1988;Hipkiss et al., 1998;Trombley et al., 2000;Boldyrev et al., 2004;Boldyrev et al., 2013), helping to preserve cellular homeostasis against the deleterious effects of these reactive oxygen and nitrogen species (Boldyrev et al., 2013;Guiotto et al., 2005) apparently by reducing the activity of enzymes inducible nitric oxide synthase and glucose oxidase (Trombley et al., 2000). ...
... Its action may be related to a beneficial effect on oxidative and nitroactive stress (Kohen etal., 1988;Hipkiss et al., 1998;Trombley et al., 2000;Boldyrev et al., 2004;Boldyrev et al., 2013), helping to preserve cellular homeostasis against the deleterious effects of these reactive oxygen and nitrogen species (Boldyrev et al., 2013;Guiotto et al., 2005) apparently by reducing the activity of enzymes inducible nitric oxide synthase and glucose oxidase (Trombley et al., 2000). ...
... Of the six studies that analyzed the effects after exercise, in half, a statistically Test evaluation after a bicycle exhaustion test, and Varanoske et al. (2018) observed improvement in the Dynavision test during and after a simulated military exercise. As carnosine has an antioxidant effect, for there to be any effect from this supplementation, a factor that generates oxidative stress could be necessary (Boldyrev et al., 2013;Guiotto et al., 2005;Bellia et al., 2011). ...
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This study aimed to review the effects of beta-alanine supplementation on cognitive performance in adult individuals. This review was carried out according to the PRISMA guidelines, using PubMed, Google Scholar, and Scopus databases, retrieving articles published between 2014 and 2024. Eligibility criteria followed the PICOS tool: healthy adult individuals of both sexes, isolated supplementation of beta-alanine, use of intervention and control groups, results of validated tests to assess cognitive capacity, and randomized controlled studies with parallel or crossover designs. Seven studies were included in this work, totaling 86 participants and using seven cognitive tests. The methodological quality and risk of bias were assessed using the PEDro and Cochrane Risk of Bias 2.0 scales, respectively. Most studies were considered good quality and had a low risk of bias. The analysis and interpretation of the studies demonstrated contradictory results of beta-alanine supplementation on cognitive performance regardless of the test protocols used. In four studies, this supplementation did not produce a significant effect, and in another three, an improvement was observed in cognitive tests after supplementation. It can be concluded that there is still 2 CUADERNOS DE EDUCACIÓN Y DESARROLLO, Portugal, v.16, n.10, p. 01-23, 2024 insufficient evidence to guarantee that beta-alanine supplementation can improve the cognitive performance of adult individuals. RESUMO Este estudo teve como objetivo revisar os efeitos da suplementação de beta-alanina no desempenho cognitivo em indivíduos adultos. Esta revisão foi realizada de acordo com as diretrizes PRISMA, utilizando as bases de dados PubMed, Google Scholar e Scopus, recuperando artigos publicados entre 2014 e 2024. Os critérios de elegibilidade seguiram a ferramenta PICOS: indivíduos adultos saudáveis de ambos os sexos, suplementação isolada de beta-alanina, utilização de grupos de intervenção e controle, resultados de testes validados para avaliação da capacidade cognitiva e estudos randomizados controlados com desenhos paralelos ou cruzados. Sete estudos foram incluídos neste trabalho, totalizando 86 participantes e utilizando sete testes cognitivos. A qualidade metodológica e o risco de viés foram avaliados pelas escalas PEDro e Cochrane Risk of Bias 2.0, respectivamente. A maioria dos estudos foi considerada de boa qualidade e apresentava baixo risco de viés. A análise e interpretação dos estudos demonstraram resultados contraditórios da suplementação de beta-alanina no desempenho cognitivo, independentemente dos protocolos de teste utilizados. Em quatro estudos esta suplementação não produziu efeito significativo e em outros três foi observada melhora nos testes cognitivos após a suplementação. Pode-se concluir que ainda não existem evidências suficientes para garantir que a suplementação de beta-alanina possa melhorar o desempenho cognitivo de indivíduos adultos. Palavras-chave: aminoácidos, stroop test, suplementação alimentar, testes cognitivos. RESUMEN Este estudio tuvo como objetivo revisar los efectos de la suplementación con beta-alanina sobre el rendimiento cognitivo en individuos adultos. Esta revisión se realizó según las guías PRISMA, utilizando las bases de datos PubMed, Google Scholar y Scopus, recuperando artículos publicados entre 2014 y 2024. Los criterios de elegibilidad siguieron la herramienta PICOS: individuos adultos sanos de ambos sexos, suplementación aislada de beta-alanina, uso de grupos de intervención y control, resultados de pruebas validadas para evaluar la capacidad cognitiva y estudios controlados aleatorios con diseños paralelos o cruzados. En este trabajo se incluyeron siete estudios, con un total de 86 participantes y que utilizaron siete pruebas cognitivas. La calidad metodológica y el riesgo de sesgo se evaluaron mediante las escalas PEDro y Cochrane Risk of Bias 2.0, respectivamente. La mayoría de los estudios se consideraron de buena calidad y tuvieron un riesgo bajo de sesgo. El análisis y la interpretación de los estudios demostraron resultados contradictorios de la suplementación con beta-alanina sobre el rendimiento cognitivo, independientemente de los protocolos de prueba utilizados. En cuatro estudios esta suplementación no 3 CUADERNOS DE EDUCACIÓN Y DESARROLLO, Portugal, v.16, n.10, p. 01-23, 2024 produjo un efecto significativo y en otros tres se observó una mejora en las pruebas cognitivas después de la suplementación. Se puede concluir que aún no hay evidencia suficiente para garantizar que la suplementación con beta-alanina pueda mejorar el rendimiento cognitivo de los individuos adultos. Palabras clave: aminoácidos, test de stroop, suplementación alimentaria, tests cognitivos.
... Carnosinases hydrolyse carnosine, a compound with pHbuffering and anti-oxidant capabilities, and were discovered in porcine kidneys in 1949 [18,19]. In 2003, genes encoding two human carnosinases (CN1 and CN2) were discovered [20]. ...
... In 2003, genes encoding two human carnosinases (CN1 and CN2) were discovered [20]. CN1 (now called CNDP1) codes for the carnosinase isoform found in serum while CN2 (now known as CNDP2) codes for the tissue carnosinase [19]. CNDP1 and CNDP2 are both located on chromosome 18 [19]. ...
... CN1 (now called CNDP1) codes for the carnosinase isoform found in serum while CN2 (now known as CNDP2) codes for the tissue carnosinase [19]. CNDP1 and CNDP2 are both located on chromosome 18 [19]. ...
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The heart requires a substantial amount of energy to function, utilising various substrates including lipids, glucose and lactate as energy sources. In times of increased stress, lactate becomes the primary energy source of the heart, but persistently elevated lactate levels are linked to poor patient outcomes and increased mortality. Recently, carnosine dipeptidase II (CNDP2) was discovered to catalyse the formation of Lac-Phe, an exercise-induced metabolite derived from lactate, which has been shown to suppress appetite in mice and reduce adipose tissue in humans. This review discusses CNDP2, including its role in lactate clearance, carnosine hydrolysis, oxidative stress regulation, and involvement in metabolite regulation. The association between CNDP2 and cardiometabolic and renal diseases is also explored, and knowledge gaps are highlighted. CNDP2 appears to be a complex participant in human physiological processes and disease, necessitating additional research to unveil its functions and potential therapeutic applications. Graphical Abstract
... Carnosine is a naturally occurring dipeptide histidine present in the body and is synthesized from a combination of β-alanine and L-histidine using the enzyme carnosine synthase [3]. Carnosine is only available in foods derived from animal products, which are mainly found in high concentrations in skeletal muscles [4]. ...
... Generally, muscles can function when cells are in homeostasis [30]; however, anaerobic glycolysis during high-intensity muscle contraction leads to a decline in intracellular pH [31] and denaturation, misfolding, and malfunction of proteins [32]. Carnosine acts as a buffer when anaerobic glycolysis occurs in muscles [33] and inhibits free radical activity by providing an electron to a radical molecule, leading to intracellular pH homeostasis [3]. This research finding pointed out that carnosine may be synthesized to restrain environmental extremes as a consequence of glycolytic activity in muscle. ...
... Maintenances of pH, temperature, oxygen concentration, and energy supply homeostasis in living animals are important processes that are deactivated quickly after death, influencing water-holding, tenderness, and meat color [34]. This association explains that carnosine acts as a buffer to maintain intracellular pH homeostasis in early postmortem muscle [3]. Hence, pH 45 min was not considerably low, and under the intracellular pH homeostasis, stability of protein structure represented by the high secondary structure of proteins (β-turn and α-helix) was found [35]. ...
Article
Objective: This study aimed to find global mechanisms related to carnosine synthesis in slow-growing Korat chickens (KRC) using a proteomic approach.Methods: M. pectoralis major samples were collected from 10-week-old female KRC including low-carnosine (LC, 2,756.6±82.88 μg/g; n = 5) and high-carnosine (HC, 4,212.5 ±82.88 μg/g; n = 5).Results: We identified 152 common proteins, and 8 of these proteins showed differential expression between the LC and HC groups (p<0.05). Heat shock 70 kDa protein 8, Heat shock 70 kDa protein 2, protein disulfide isomerase family A, member 6, and endoplasmic reticulum resident protein 29 were significantly involved in protein processing in the endoplasmic reticulum pathway (false discovery rate<0.05), suggesting that the pathway is related to differential carnosine concentration in the M. pectoralis major of KRC. A high concentration of carnosine in the meat is mainly involved in low abundances of Titin isoform Ch12 and Connectin and high abundances of M-protein to maintain homeostasis during muscle contraction. These consequences improve meat characteristics, which were confirmed by the principal component analysis.Conclusion: Carnosine synthesis may occur when muscle cells need to recover homeostasis after being interfered with carnosine synthesis precursors, leading to improved muscle function. To the best of our knowledge, this is the first study to describe in detail the global molecular mechanisms in divergent carnosine contents in meat based on the proteomic approach.
... Previous studies have also suggested that intramuscular carnosine can increase muscle force production due to the higher Ca +2 /H + exchanger in the fibre, increased H + binding to carnosine and Ca +2 unloading at the sarcomere, subsequently increasing cross-bridge formation and force production [9,10]. Moreover, the antioxidant, antiglycating and ion-chelating effects of carnosine have been reported [11][12][13]. This suggests the possible beneficial effect of β-alanine supplementation in the recovery process and subsequent exercise performance [7]. ...
... Meanwhile, the PLA group showed the opposite effect, reporting lower values of blood lactate concentration. This finding may be related to the antioxidant, and antiglycating and ion-chelating effect of carnosine [11][12][13]. Although this theory is not confirmed in humans yet, evidence suggests the possible beneficial effect of β-alanine supplementation in the recovery process [7]. ...
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Scientists and coaches seek effective ergogenic aids for performance improvement. Cyclists commonly use β-Alanine, which may enhance post-exercise recovery and physical performance. High-dose β-Alanine supplementation’s impact on World Tour cyclists during a 7-day camp remains unstudied. This study aimed to analyse the effect of a high dose of β-alanine in World Tour cyclist during a 7-day camp. A double-blinded, randomised controlled trial was conducted. 11 cyclists were included in the final analysis: β-alanine supplementation (n = 5; VO2max: 67.6±1.6 ml/kg/min) and a placebo group (n = 6; VO2max: 68.0±2.4 ml/kg/min). The duration of the supplementation protocol was seven days with four daily intakes. The subjects commenced supplementation after the physical tests (immediately following the snack) and consumed the final intake after breakfast on the day of the final test (a total of 7 days and 3 additional doses, 31 servings in total; 5g per dosage; 155g the total cumulative amount). Before and after seven days of supplementation, the cyclists performed an uphill time trial. Blood lactate, heart rate and rating of perceived exertion were measured during test. β-alanine supplementation improved the relative mean power attained during the time-trial compared with the control group (Z = -2.008; p = 0.045; Δ = 0.060), as well as the time needed to complete this trial (Z = -2.373; p = 0.018). As for physiological and metabolic variables, no significant change was found. In conclusion, the present study supports the effectiveness of one-week high dose of β-alanine during a cycling training in World Tour cyclists to improve their uphill time-trial performance. In addition, it is important to highlight the potential role of β-alanine in improving recovery power. This aspect is particularly relevant in the context of a training camp, where fatigue levels can increase alongside training intensity. Trial registration: This study was registered in ClinicalTrials.gov: (identifier: NCT04427319).
... Naturally occurring histidyl dipeptides such as carnosine (β-alanine-L-histidine) are present in high concentrations in glycolytically active tissues of humans, including skeletal muscle (8-10 mM), and the brain (1-2 mM) (Boldyrev et al. 2013;Hoetker et al. 2018;Zhao et al. 2020;Posa et al. 2023). These dipeptides have a unique chemical structure, allowing them to buffer intracellular pH ([pH] i ), neutralize lipid peroxidation products Baba et al. 2013), chelate transition metals , and quench reactive oxygen species (Ihara et al. 2019). ...
... Although previous studies have shown that levels of skeletal muscle carnosine could be increased by oral ingestion of carnosine or its precursor β-alanine (Boldyrev et al. 2013), a systematic evaluation of carnosine accumulation and distribution following supplementation, particularly in non-muscle tissues, is lacking. In this study we found that a ~ 6-week supplementation with 2 g/day carnosine was sufficient to increase its level in RBCs and extending the supplementation to ~ 12 weeks did not lead to further increases. ...
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Carnosine is an endogenous dipeptide that buffers intracellular pH and quenches toxic products of lipid peroxidation. Used as a dietary supplement, it also supports exercise endurance. However, the accumulation and distribution of carnosine after supplementation has not been rigorously evaluated. To do this, we randomized a cohort to receive daily supplements of either placebo or carnosine (2 g/day). Blood and urine samples were collected twice over the subsequent 12 week supplementation period and we measured levels of red blood cell (RBC) carnosine, urinary carnosine, and urinary carnosine-propanol and carnosine-propanal conjugates by LC/MS–MS. We found that, when compared with placebo, supplementation with carnosine for 6 or 12 weeks led to an approximate twofold increase in RBC carnosine, while levels of urinary carnosine increased nearly sevenfold. Although there were no changes in the urinary levels of carnosine propanol, carnosine propanal increased nearly twofold. RBC carnosine levels were positively associated with urinary carnosine and carnosine propanal levels. No adverse reactions were reported by those in the carnosine or placebo arms, nor did carnosine supplementation have any effect on kidney, liver, and cardiac function or blood electrolytes. In conclusion, irrespective of age, sex, or BMI, oral carnosine supplementation in humans leads to its increase in RBC and urine, as well as an increase in urinary carnosine-propanal. RBC carnosine may be a readily accessible pool to estimate carnosine levels. Clinical trial registration: This study is registered with ClinicalTrials.gov (Nucleophilic Defense Against PM Toxicity (NEAT Trial)—Full Text View—ClinicalTrials.gov), under the registration: NCT03314987.
... Importantly, there are already examples of the successful use of natural dicarbonyl scavengers in clinical trials [99,100]. Now positive examples are available, which demonstrate the effective inhibition of FRO intensity by the scavengers of dicarbonyls such as biguanides [41,101] and imidazole-containing peptides [93,102,103]. There are also positive examples which demonstrate the effective inhibition of FRO intensity with dicarbonyl scavengers such as biguanides [41,99,100] and imidazole-containing peptides in clinical investigations [102,103]. ...
... Now positive examples are available, which demonstrate the effective inhibition of FRO intensity by the scavengers of dicarbonyls such as biguanides [41,101] and imidazole-containing peptides [93,102,103]. There are also positive examples which demonstrate the effective inhibition of FRO intensity with dicarbonyl scavengers such as biguanides [41,99,100] and imidazole-containing peptides in clinical investigations [102,103]. Specifically, the use of biguanides pronouncedly suppresses the symptoms of oxidative and carbonyl stresses in patients with diabetes mellitus, even without intake of any antioxidants (so-called "quasi-antioxidant effect") [41]. There are data that hypolipidemic therapy with inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), which activates utilization of cholesterol-rich LDL in the liver, simultaneously lowering the level of MDA-modified LDL in blood plasma [104]. ...
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This review summarises the data from long-term experimental studies and literature data on the role of oxidatively modified low-density lipoproteins (LDL) in atherogenesis and diabetogenesis. It was shown that not “oxidized” (lipoperoxide-containing) LDL, but dicarbonyl-modified LDL are atherogenic (actively captured by cultured macrophages with the help of scavenger receptors), and also cause expression of lectin like oxidized low density lipoprotein receptor 1 (LOX-1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX-1) genes in endotheliocytes, which stimulate apoptosis and endothelial dysfunction. The obtained data allowed us to justify new approaches to pharmacotherapy of atherosclerosis and diabetes mellitus.
... Increasing the dietary intake of carnosine enhances its concentrations in, mostly, skeletal muscle, the brain, and the heart [3]. For that reason, it is essential to investigate its food sources, and we thank you for raising this issue. ...
... White mushrooms contain beta-glucans, ergosterol, ergothioneine, vitamin D, and an antioxidant compound usually reported as flavonoids [6]. Many sources [3], as well as your comment, do mention histidine dipeptides never having been found in plants. I find it beneficial to bring attention to a breakthrough paper by Kukreti et al. (2023), published a few months after our narrative review [7]. ...
... The dipeptide CAR is selected as the molecular target due to its high biological relevance acting as intra-/extracellular nonenzymatic free radical scavenger, 30 antioxidant, divalent metal ion chelating agent, 31,32 and proton buffering system. 32,33 Also, CAR is investigated as a specific metabolic tool against neurotoxic effects 34−36 in patients affected by neurodegenerative pathologies, such as Alzheimer's and Parkinson's disease. 35 In addition, considering CAR species-specific levels in muscle tissues of vertebrates, monitoring its concentration allows the investigation of adulteration/counterfeiting of meat-based food and feed products. ...
... We also evaluated specificity of the interaction between Cu 2+ -modified PSiO 2 scaffold and CAR using three interference molecules, namely, β-alanine, which is one of the two amino acid components of CAR dipeptide, anserine (β-alanyl-3-methylhistidine), a natural CAR-like derivative, 33,43 and glycyl-proline, as structural dipeptide analogues of CAR. Figure 2F summarizes the results of the experiments. In all cases the presence of interfering molecules does not dramatically affect the sensor response to CAR, with a maximum response of about 20% measured for anserine, reasonably ascribed to the copper chelating ability of this molecule 33,44 that differs from CAR only for the methyl group in position 1 of the imidazole ring of the histidine moiety. ...
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Reconfiguration of chemical sensors, intended as the capacity of the sensor to adapt to novel operational scenarios, e.g., new target analytes, is potentially game changing and would enable rapid and cost-effective reaction to dynamic changes occurring at healthcare, environmental, and industrial levels. Yet, it is still a challenge, and rare examples of sensor reconfiguration have been reported to date. Here, we report on a reconfigurable label-free optical sensor leveraging the versatile immobilization of metal ions through a chelating agent on a nanostructured porous silica (PSiO2) optical transducer for the detection of different biomolecules. First, we show the reversible grafting of different metal ions on the PSiO2 surface, namely, Ni²⁺, Cu²⁺, Zn²⁺, and Fe³⁺, which can mediate the interaction with different biomolecules and be switched under mild conditions. Then, we demonstrate reconfiguration of the sensor at two levels: 1) switching of the metal ions on the PSiO2 surface from Cu²⁺ to Zn²⁺ and testing the ability of Cu²⁺-functionalized and Zn²⁺-reconfigured devices for the sensing of the dipeptide carnosine (CAR), leveraging the well-known chelating ability of CAR toward divalent metal ions; and 2) reconfiguration of the Cu²⁺-functionalized PSiO2 sensor for a different target analyte, namely, the nucleotide adenosine triphosphate (ATP), switching Cu²⁺ with Fe³⁺ ions to exploit the interaction with ATP through phosphate groups. The Cu²⁺-functionalized and Zn²⁺-reconfigured sensors show effective sensing performance in CAR detection, also evaluated in tissue samples from murine brain, and so does the Fe³⁺-reconfigured sensor toward ATP, thus demonstrating effective reconfiguration of the sensor with the proposed surface chemistry.
... L-carnosine, a dipeptide, is found in excitable tissues such as skeletal muscles, the brain, myocardium and is made up of two amino acids, β-alanine and L-histidine [8]. It is a well-known nutraceutical proposed to be useful in brain disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, regulation of type 2 diabetes, ocular disorders, acute kidney failure, and cancer due to its antioxidant, anti-inflammatory, carbonyl scavenging, glycation inhibitory, anti-ischemic, anti-aging, pH buffering activity, heavy metal chelating activity, and neuroprotective properties [9][10][11][12][13][14]. Carnosine synthase (CARNS) produces L-carnosine, which is then degraded by carnosinase [15]. The two isoforms of the carnosinase enzyme, i.e., serum carnosinase (CN1 or CNDP1), are highly active and abundant and degrade carnosine and homocarnosine, whereas tissue carnosinase (CN2 or CNDP2) is known as "cytosol non-specific dipeptidase" [16]. ...
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Background Literature indicates that L-carnosine may be deficient in autism spectrum disorder (ASD) children. The aim of the present study was to estimate the level of L-carnosine in plasma and correlate it with the Autism Treatment Evaluation Checklist (ATEC) and Childhood Autism Rating Scale 2nd Edition, Standard Version (CARS2-ST) scores. To measure L-carnosine level, a bio-analytical method was developed using reverse phase high- liquid chromatography and validated as per International Conference on Harmonization guidelines. Method Children were supplemented with L-carnosine (10–15 mg/kg) along with standard care therapies for 2 months. Before and after supplementation, scores on the ATEC, CARS2-ST, BEARS sleep screening tool, 6-item Gastrointestinal Severity Index, and Parental Stress Scale were evaluated, and L-carnosine was measured at the end of the trial. Results The calibration curve was linear in the range of 100–600 ng/mL (R² = 0.998). The level of L-carnosine quantified was 33.7 ± 0.2 ng/mL. There was no significant difference found in any of the outcome measures (p > 0.05). Conclusions Despite the fact that L-carnosine is detectable in the blood, it was found to be ineffective in the management of ASD in children. Clinical Trial Registration The study was registered in the Clinical Trial Registry-India, registration number: CTRI/2019/07/020102.
... Histidyl dipeptides exhibit unique chemistry, where the amino group of the β-alanine can bind with reactive aldehydes via Michael adducts or Schiff 's base. They also exhibit the ability to quench reactive oxygen species, buffer the intracellular pH and chelate first transition metals [75,76]. Among all the nucleophiles present in skeletal muscle, only histidyl dipeptide levels can be increased either by exercise or by supplementation with the precursor amino acid β-alanine [40]. ...
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Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways. Whether the formation of lipid peroxidation products and metabolic pathways that remove these toxic products are affected during heart failure-associated skeletal muscle wasting has never been studied. Male C57BL/6J mice were subjected to sham and transverse aortic constriction (TAC) surgeries for 4, 8 or 14 weeks. Different skeletal muscle beds were weighed, and the total cross-sectional area of the gastrocnemius muscle was measured via immunohistochemistry. Muscle function and muscle stiffness were measured by a grip strength meter and atomic force microscope, respectively. Atrophic and inflammatory marker levels were measured via qRT‒PCR. The levels of acrolein and HNE-protein adducts, aldehyde-removing enzymes, the histidyl dipeptide-synthesizing enzyme carnosine synthase (CARNS), and amino acid transporters in the gastrocnemius muscle were measured via Western blotting and qRT‒PCR. Histidyl dipeptides and histidyl dipeptide aldehyde conjugates in the Gastrocnemius and soleus muscles were analyzed by LC/MS–MS. Body weight, gastrocnemius muscle and soleus muscle weights and the total cross-sectional area of the gastrocnemius muscle were decreased after 14 weeks of TAC. Heart weight, cardiac function, grip strength and muscle stiffness were decreased in the TAC-operated mice. Expression of the atrophic and inflammatory markers Atrogin1 and TNF-α, respectively, was increased ~ 1.5–2fold in the gastrocnemius muscle after 14 weeks of TAC (p < 0.05 and p = 0.004 vs sham). The formation of HNE and acrolein protein adducts was increased, and the expression of the aldehyde-removing enzyme aldehyde dehydrogenase (ALDH2) was decreased in the gastrocnemius muscle of TAC mice. Carnosine (sham: 5.76 ± 1.3 vs TAC: 4.72 ± 0.7 nmol/mg tissue, p = 0.04) and total histidyl dipeptide levels (carnosine and anserine; sham: 11.97 ± 1.5 vs TAC: 10.13 ± 1.4 nmol/mg tissue, p < 0.05) were decreased in the gastrocnemius muscle of TAC mice. Depletion of histidyl dipeptides diminished the aldehyde removal capacity of the atrophic gastrocnemius muscle. Furthermore, CARNS and TAUT protein expression were decreased in the atrophic gastrocnemius muscle. Our data reveals that reduced expression of ALDH2 and depletion of histidyl dipeptides in the gastrocnemius muscle during heart failure leads to the accumulation of toxic aldehydes and might contribute to muscle wasting.
... Carnosine, an animal-specific metabolite, is recognized as an important antioxidant, pH buffer, and neuromodulator [66]. We identified 49 metabolites, including eight annotated metabolites, such as carnosine, anserine, and histidine carnosine, as well as 31 unknown metabolites that were significantly associated with the expression of the GADL1 and CARNMT2 genes [67]. ...
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The duck (Anas platyrhynchos) is not only a vital farm animal but also an excellent model for genetic dissection of economic traits. The integration of multiomics data provides a powerful approach to elucidate the genetic basis of domestication and phenotype variation. Since its inception in 2014, the Duck 1000 Genomes Project has aimed to uncover the genetic foundation of key economic traits in ducks by combining multiomics data including genomic, transcriptomic, and metabolomic from various natural and segregating populations. This paper summarizes the strategies and achievements of the Duck 1000 Genomes Project, highlighting the reference genome assembly, genome evolution analysis, and the identification of genes and causative mutations responsible for key economic traits in ducks. We also discuss perspectives and potential challenges in functional genomic studies that could further accelerate duck molecular breeding.
... Previous research in murine models has demonstrated that elevations in brain carnosine were associated with a reduction in anxiety and an improvement in memory in animals exposed to predator scent stress (Hoffman et al., 2015) and low-pressure blast waves . It has been suggested that the increased resiliency to these stressors is related to carnosine's role as an antioxidant (Boldyrev et al., 2013). ...
... The change in lightness over storage time for all three species meat samples was not significant (p > 0.05). The lightness of meat is influenced by the water-holding capacity and moisture content on the surface of the meat, as well as the intramuscular lipid content (Bekhit et al., 2019). Neethling et al. (2016) reported that the L* value for venison peaked after the first day of storage (p < 0.05) and decreased (p < 0.05) by day 6. ...
... Multiple tissues in the body report the presence of carnosine like the brain, heart, and gastrointestinal tissues; with the highest amount in the skeletal muscle which is established to be around 20 mM. (Boldyrev et al. 2013). Carnosine, an existing dipeptide exhibiting pleiotropic effects is protective in nature. ...
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Carnosine, a compound with plethora of benefits, was originally discovered in 1900 and is formed by the amide linkage of β-alanine and L-histidine. Carnosine production is limited by β-alanine whereas the imidazole ring of histidine moiety makes it a suitable buffer in physiological pH range. It is reported to be found in the skeletal muscle, brain, heart, and gastrointestinal tissues of humans. This review focuses on the biological properties of carnosine including pH buffering ability, antioxidant activity, anti-inflammatory activity, anti-aging effect, enhancement of cognitive function, and immunomodulation. The relevance of carnosine in muscle function attributing to enhancement of physical performance has also been highlighted. Studies spanning several years have proved the preclinical effectiveness of carnosine in treating diverse pathological diseases. A complete summary of all key activities of carnosine from in vivo investigations and clinical trials has been compiled. Considering its numerous advantages, carnosine may be a promising option for the development of a nutraceutical.
... The differential metabolite pathway enrichment analysis showed that histidine metabolism and alanine, aspartate and glutamate metabolism were enriched in both KEGG and MetabolAnalyst pathway analysis. Histidine is an important substrate for the synthesis of carnosine, which is located mainly in skeletal muscle and plays a pivotal role in the muscle contraction process through calcium regulation and pH buffering [34]. Alanine, aspartate and glutamate, which are derived from intermediates of the citric acid cycle, are closely related to the energy metabolism of soleus. ...
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Background Skeletal muscle atrophy, which is induced by factors such as disuse, spaceflight, certain medications, neurological disorders and malnutrition, is a global health issue with clinical manifestations mainly being a reduction in muscle mass and muscle weakness. Currently there is a lack of effective treatment for muscle atrophy. Hindlimb unloading is currently a commonly used model for muscle atrophy. However, the underlying mechanism of muscle atrophy induced by hindlimb unloading remains unclear, particular from the perspective of myocyte proteome and metabolism. Methods We first conducted proteomic sequencing based on mass spectrometry to explore the protein abundance changes of soleus muscles from rats exposed to hindlimb unloading. Then untargeted metabolomics analysis was performed, followed by the combined analysis of proteomic and metabolomic profiles. Results In our study, 1052 differentially expressed proteins and 377 differentially abundant metabolites were revealed in HU group compared to CON group. These differentially expressed proteins included some proteins which are mainly expressed in the fast-twitch muscle such as ACTN3, MYH4, MYBPC2 and MYOZ1. Some metabolism-related proteins such as GLUL, GSTM4 and NDUFS4 were screened out. Some differentially abundant metabolites including arachidylcarnitine and 7,8-dihydrobiopterin, along with pathways such as histidine metabolism, taurine and hypotaurine metabolism might be related to muscle atrophy. Protein and metabolism joint analysis revealed that some pathways such as glutathione metabolism, ferroptosis and lysosome pathways were likely to be involved in soleus atrophy. Conclusion In this study, we have applied integrated deep proteomic and metabolomic analysis. The upregulation of proteins which are expressed in fast-twitch fibers indicated the conversion of slow-twitch fibers to fast-twitch fibers under HU. Some metabolism-related proteins have been screened out. Besides, some differentially abundant metabolites and pathways revealed the important role of metabolism in the muscle atrophy of soleus. Our study provides insights into the pathogenesis and treatment of muscle atrophy that results from unloading by integrating the proteomics and metabolomics of soleus muscles.
... Histidine and β-alanine are precursors of carnosine (β-alanyl-L-histidine) and its derivatives (e.g., anserine), which act as powerful buffers to attenuate the deleterious effects of H+ ions in skeletal muscle cells, produced during high-intensity anaerobic exercise [8]. Much higher levels of carnosine are observed in fast glycolytic (Type IIX) muscle fibers, typical of sprinters, than in oxidative (Type I) muscle fibers, and there is a significant positive correlation between muscle carnosine concentration and power output during maximal sprinting [45,46]. Increased muscle carnosine levels are thought to have an ergogenic effect and reduce fatigue during high-intensity exercise [47]. ...
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Background/Objectives: Free amino acids substantially contribute to energy metabolism. Also, their profile may identify (over)training status and effectiveness. The long-term effects of speed-power training on plasma free amino acid (PFAA) profiles are not known. We aimed to observe variations in PFAA levels in high-performance sprinters in a six-month training cycle. Methods: Ten male athletes (24.6 ± 3.3 years) were examined during four training phases: transition (1 month), general preparation (2 months), specific preparation (1 month), and pre-competition/competition (2 months). Venous blood was collected at rest, after exhaustive exercise, and recovery. Forty-two PFAAs were analyzed by the LC-ESI-MS/MS method. Results: Significant decreases in resting concentrations were observed between the transition and competition phases for glutamine (762 ± 117 vs. 623 ± 53 μmol∙L⁻¹; p < 0.001, η² = 0.47) and histidine (89 ± 15 vs. 75 ± 10 μmol∙L⁻¹; p = 0.010, η² = 0.27), whereas β-alanine (30 ± 7 vs. 41 ± 9 μmol∙L⁻¹; p = 0.024, η² = 016) and sarcosine (3.6 ± 0.4 vs. 4.8 ± 0.6 μmol∙L⁻¹; p = 0.006, η² = 0.188) levels increased. Between the specific and competition phases, significant decreases in the resting levels of 1-methylhistidine (22.1 ± 19.4 vs. 9.6 ± 8.8 μmol∙L⁻¹; p = 0.14, η² = 0.19), 3-methylhistidine (7.1 ± 1.5 vs. 6.5 ± 1.6 μmol∙L⁻¹; p = 0.009, η² = 0.18), citrulline (40 ± 10 vs. 29 ± 4 μmol∙L⁻¹; p = 0.05, η² = 0.29), and ornithine (74 ± 15 vs. 56 ± 10 μmol∙L⁻¹; p = 0.015, η² = 185) were noticed. Also, for β-alanine and sarcosine, the pattern of response to exercise strongly changed between the training phases. Blood ammonia levels at exhaustion decreased between the transition and competition phases (32 ± 4 vs. 23 ± 5 μmol∙L⁻¹; p < 0.001, η² = 0.67), while lactate, the phenylalanine–tyrosine ratio, the glutamine–glutamate ratio, hematological parameters, and cardiorespiratory indices remained at similar levels. Conclusions: Speed-power training seems to affect PFAAs involved in skeletal muscle metabolic pathways responsible for neutralizing toxic ammonia (glutamine, arginine, citrulline, ornithine), attenuating the deleterious effects of H⁺ ions (histidine, β-alanine), and reducing exercise-induced protein breakdown (1- and 3-methylhistidine). Our findings suggest that sprint-oriented training supports metabolic pathways that are responsible for the removal of harmful metabolites produced during exercise.
... The muscle content of carnosine depends on its synthesis from histidine and β-alanine, the latter mainly produced in the liver and available in the extracellular environment via the circulatory system [48]. A markedly higher carnosine content is observed in glycolytic than in oxidative muscle fibers and, consequently, in sprint-than endurancetrained athletes, however, there is no evidence of elevated plasma carnosine levels [49]. Our results, i.e. the lack of detectable amounts of carnosine in plasma, may indicate that carnosine, even if released from muscle, is degraded already in the intercellular space and may only enter the bloodstream in the form of its metabolites. ...
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Circulating blood is an important plasma free amino acids (PFAAs) reservoir and a pivotal link between metabolic pathways. No comparisons are available between athletes with opposite training adaptations that include a broader spectrum of both proteinogenic and non-proteinogenic amino acids, and that take into account skeletal muscle mass. We hypothesized that the levels of the exercise-induced PFAAs concentration are related to the type of training-related metabolic adaptation. We compared highly trained endurance athletes (n = 11) and sprinters (n = 10) aged 20‒35 years who performed incremental exercise until exhaustion. Venous blood was collected before and during the test and 30-min recovery (12 samples). Forty-two PFAAs were assayed using LC-ESI-MS/MS technique. Skeletal muscle mass was estimated using dual X-ray absorptiometry method. Glutamine and alanine were dominant PFAAs throughout the whole exercise and recovery period (~350‒650 μmol∙L⁻¹). Total, combined proteinogenic, non-essential, and non-proteinogenic PFAAs levels were significantly higher in endurance athletes than sprinters (ANOVA group effects: p = 0.007, η² = 0.321; p = 0.011, η² = 0.294; p = 0.003, η² = 0.376; p = 0.001, η² = 0.471, respectively). The exercise response was more pronounced in endurance athletes, especially for non-proteinogenic PFAAs (ANOVA interaction effect: p = 0.038, η² = 0.123). Significant between-group differences were observed for 19 of 33 PFAAs detected, including 4 essential, 7 non-essential, and 8 non-proteinogenic ones. We demonstrated that the PFAAs response to incremental aerobic exercise is associated with the type of training-related metabolic adaptation. A greater turnover and availability of circulating PFAAs for skeletal muscles and other body tissues is observed in endurance- than in sprint-trained individuals. Non-proteinogenic PFAAs, despite low concentrations, also respond to exercise loads, indicating their important, though less understood role in exercise metabolism. Our study provides additional insight into the exercise-induced physiological response of PFAAs, and may also provide a rationale in discussions regarding dietary amino acid requirements in high-performance athletes with respect to sports specialization.
... These include antiinflammation, antioxidation, anti-glycosylation, metal ion chelation, and promotion of wound healing (Alhamdani et al., 2007;Jukic et al., 2021;Schwank-Xu et al., 2021). Previous studies have revealed the potential of CARN in regulating blood glucose levels, as it protects the cells responsible for controlling blood glucose, enhances their sensitivity to glucose, and promotes insulin secretion (Boldyrev and AldiniW Derave, 2013;Liu et al., 2020), while CARN supplementation can reduce fasting blood glucose, serum triglyceride levels, advanced glycation end products, and TNF-a in T2D patients (Houjeghani et al., 2018), and inhibit the production of extracellular matrix components and transforming growth factor-b in a high glucose environment to protect against diabetic nephropathy (Janssen et al., 2005). Meanwhile, CARN restricts the migration and activation of the inflammatory cells, decreases the production of pro-inflammatory cytokines (such as TNF-a and IL-6) and the reactive oxygen species (Abdin et al., 2010), while peroxidation can damage the vascular endothelial cell and exacerbate the progression of the diabetic complications (Da Ros et al., 2004). ...
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Objective This study aims to investigate the pathogenesis of hyperglycemia and its associated vasculopathy using multiomics analyses in diabetes and impaired glucose tolerance, and validate the mechanism using the cell experiments. Methods In this study, we conducted a comprehensive analysis of the metagenomic sequencing data of diabetes to explore the key genera related to its occurrence. Subsequently, participants diagnosed with impaired glucose tolerance (IGT), and healthy subjects, were recruited for fecal and blood sample collection. The dysbiosis of the gut microbiota (GM) and its associated metabolites were analyzed using 16S rDNA sequencing and liquid chromatograph mass spectrometry, respectively. The regulation of gene and protein expression was evaluated through mRNA sequencing and data-independent acquisition technology, respectively. The specific mechanism by which GM dysbiosis affects hyperglycemia and its related vasculopathy was investigated using real-time qPCR, Western blotting, and enzyme-linked immunosorbent assay techniques in HepG2 cells and neutrophils. Results Based on the published data, the key alterable genera in the GM associated with diabetes were identified as Blautia, Lactobacillus, Bacteroides, Prevotella, Faecalibacterium, Bifidobacterium, Ruminococcus, Clostridium, and Lachnoclostridium. The related metabolic pathways were identified as cholate degradation and L-histidine biosynthesis. Noteworthy, Blautia and Faecalibacterium displayed similar alterations in patients with IGT compared to those observed in patients with diabetes, and the GM metabolites, tauroursodeoxycholic acid (TUDCA) and carnosine (CARN, a downstream metabolite of histidine and alanine) were both found to be decreased, which in turn regulated the expression of proteins in plasma and mRNAs in neutrophils. Subsequent experiments focused on insulin-like growth factor-binding protein 3 and interleukin-6 due to their impact on blood glucose regulation and associated vascular inflammation. Both proteins were found to be suppressed by TUDCA and CARN in HepG2 cells and neutrophils. Conclusion Dysbiosis of the GM occurred throughout the entire progression from IGT to diabetes, characterized by an increase in Blautia and a decrease in Faecalibacterium, leading to reduced levels of TUDCA and CARN, which alleviated their inhibition on the expression of insulin-like growth factor-binding protein 3 and interleukin-6, contributing to the development of hyperglycemia and associated vasculopathy.
... In contrast, plants and fungi use very different intracellular systems to counter the challenges of low pH [5,6]. Even though the imidazole group of the amino acid histidine facilitates intracellular pH regulation in plants [5,7], in 2013 it was reported that histidine dipetides (which include carnosine) had never been detected in plants, fungi or other eukaryotes [8]. In light of this, could Cesak et al. provide a reference demonstrating the presence of carnosine in asparagus, green peas and white mushrooms? ...
... Carnosine has been identified in the muscles of some invertebrates such as crabs (Cameron, 1989). While no previous report on the CNS of invertebrates is available, in the mouse brain carnosine concentration is usually ∼.1 mM or lower (Boldyrev et al., 2013;Jain et al., 2020). ...
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Carnosine is a naturally occurring endogenous dipeptide with well‐recognized anti‐inflammatory, antioxidant, and neuroprotective effects at the central nervous system level. To date, very few studies have been focused on the ability of carnosine to rescue and/or enhance memory. Here, we used a well‐known invertebrate model system, the pond snail Lymnaea stagnalis , and a well‐studied associative learning procedure, operant conditioning of aerial respiration, to investigate the ability of carnosine to enhance long‐term memory (LTM) formation and reverse memory obstruction caused by an immune challenge (i.e., lipopolysaccharide [LPS] injection). Exposing snails to 1 mM carnosine for 1 h before training in addition to enhancing memory formation resulted in a significant upregulation of the expression levels of key neuroplasticity genes (i.e., glutamate ionotropic receptor N ‐methyl‐ d ‐aspartate [NMDA]‐type subunit 1—LymGRIN1, and the transcription factor cAMP‐response element‐binding protein 1—LymCREB1) in snails' central ring ganglia. Moreover, pre‐exposure to 1 mM carnosine before an LPS injection reversed the memory deficit brought about by inflammation, by preventing the upregulation of key targets for immune and stress response (i.e., Toll‐like receptor 4—LymTLR4, molluscan defense molecule—LymMDM, heat shock protein 70—LymHSP70). Our data are thus consistent with the hypothesis that carnosine can have positive benefits on cognitive ability and be able to reverse memory aversive states induced by neuroinflammation.
... G3P is a precursor in biosynthetic pathways (nucleotides, amino acids, lipids, and glycogen) essential for cell growth and function [48,49]. N-acetylbeta-alanine is a product of the beta-alanine metabolism, which is involved in the synthesis of carnosine, predominantly found in the muscles [50], and has been reported to exhibit antioxidant activities in several animal models [51]. Threonine is an essential amino acid [52] which is involved in the formation of proteins, including collagen, elastin, etc., and is a precursor for the synthesis of isoleucine and methionine. ...
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Essential oils are natural feed additives that improve animal health and enhance their performance. This study investigated the effects of the rumen infusion of five essential oil blends (EOBs) on greenhouse gas (GHG) emissions, rumen fermentation parameters, and rumen metabolome and metabolic pathways in Black Angus cows. Using a 6 × 6 Latin Square experimental design, a 90-day study was conducted with six cattle. A daily dosage of 4 mL of EOBs was administered during each infusion. Volcano plot analyses between the control (CON) and each of the EOBs (EOB1, EOB2, EOB3, EOB4, and EOB5) revealed several differentially abundant (p ≤ 0.05; absolute fold change ≥1.5) metabolites. The EOB5 treatment exhibited the most significant impact, with 26 differentially abundant metabolites, including elevated valine and reduced gallic acid. Volatile fatty acids (VFAs), including valerate, isobutyrate, and isovalerate, were significantly increased (p < 0.05). GHG emissions were not significantly affected, but a numerical decrease was observed in the animals infused with the EOB5 treatment. Ammonia nitrogen concentrations remained within the suitable range for rumen microbes’ growth, indicating a normal internal environment for microbial crude protein synthesis. In conclusion, the study has demonstrated that the direct infusion of EOBs significantly improved the generation of VFAs and impacted the energy production, protein synthesis, and microbial activity of the animals.
... L-carnosine is a dipeptide alkaloid composed of β-alanine and L-histidine, mainly extracted from mammalian muscle and also found in high levels in some marine fish. L-carnosine is also found in the olfactory receptor neurons in the brain [17], and is hypothesized to be involved in the modulation of neurotransmission and maintenance of homeostasis mainly through the antioxidant, metal-chelating, and antiglycative properties in certain brain structures [18]. Zinc exists in structural or labile forms in the CNS, which is crucial to the control of the physiological and pathophysiological brain function [19,20]. ...
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Neuroinflammation is one of the main mechanisms involved in the progression of neurodegenerative diseases (NDs), and microglial activation is the main feature of neuroinflammation. Polaprezinc (Pol), a chelator of L-carnosine and zinc, is widely used as a clinical drug for gastric ulcers. However, its potential effects on NDs remain unexplored. In LPS-induced BV-2 microglia, we found that Pol reduced the generation of NO and ROS and revealed inhibited expression of iNOS, COX-2, and inflammatory factors such as IL-6, TNF-α, and 1L-1β by Pol using qRT-PCR and Western blotting. These effects were found to be associated with the suppression of the NF-κB signaling pathway. Moreover, we evaluated the potential synergistic effects of aspergillusidone G (Asp G) when combined with Pol. Remarkably, co-treatment with low doses of Asp G enhanced the NO inhibition by Pol from approximately 30% to 80% in LPS-induced BV2 microglia, indicating a synergistic anti-inflammatory effect. A bioinformatics analysis suggested that the synergistic mechanism of Asp G and Pol might be attributed to several targets, including NFκB1, NRF2, ABL1, TLR4, and PPARα. These findings highlight the anti-neuroinflammatory properties of Pol and its enhanced efficacy when combined with Asp G, proposing a novel therapeutic strategy for managing neuroinflammation in NDs.
... The main role of acetylcarnitine is to transport fatty acids into the mitochondrial matrix where fatty acid metabolism occurs [29]. In addition, carnosine has many physiological roles, including pH buffering, antioxidant capacity, and the capacity to protect against the formation of advanced glycation and lipoxidation end-products [30]. Pantothenic acid is involved in the metabolism of carbohydrates, lipids, and proteins. ...
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The Lueyang black-bone chicken is a specific native chicken strain in China. This study aimed to investigate the effects of different rearing systems on the meat quality of Lueyang black-bone chickens. Six hundred Lueyang black-bone hens were randomly divided into two groups at 7 weeks of age and raised in cage and cage-free systems for 20 weeks. The carcass yield, meat quality, and total metabolites were measured in both the leg and breast muscles. By comparison, the carcass yield of hens in the cage-free (CF) group (1.26 ± 0.09 kg) was significantly lower than that in the caged rearing (CR) group (1.52 ± 0.15 kg). However, the shear force of leg muscles in the CF group (27.98 ± 2.43 N) was significantly greater than that in the CR group (24.15 ± 1.93 N). In addition, six samples from each group were randomly selected and their metabolites were detected by the non-targeted metabolomics technique. Among these metabolites, 408 and 354 significantly differentially abundant metabolites were identified in breast and leg muscles, which were mainly involved in glycerophospholipid metabolism, unsaturated fatty acid biosynthesis, arginine and proline metabolism, and nucleotide metabolism. We found that the levels of 19 phospholipids, mainly phosphatidylcholines and lysophosphatidylcholines, were significantly greater in the CF group than in the CR group. Additionally, the contents of eight unsaturated fatty acids, linoleic acid, and linolenic acid were dramatically greater in the CF group than in the caged group. The accumulation of 4-hydroxy-proline, glutamate, and adenosine 3′-monophosphate (AMP) was enhanced in the CF group. Moreover, many more volatile organic compounds were identified in the muscles of the cage-free group, enhancing the flavor of the chicken meat. In conclusion, the cage-free rearing mode facilitates the accumulation of nutrients and flavor substances in the chicken meat and is a better rearing system for Lueyang black-bone chickens.
... Previous research in murine models has demonstrated that elevations in brain carnosine were associated with a reduction in anxiety and an improvement in memory in animals exposed to predator scent stress (Hoffman et al., 2015) and low-pressure blast waves . It has been suggested that the increased resiliency to these stressors is related to carnosine's role as an antioxidant (Boldyrev et al., 2013). ...
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Full-scan mass spectrometry (MS) data from both liquid chromatography (LC) and MS imaging capture multiple ion forms, including their in-source fragments. Here we leverage such fragments to structurally annotate full-scan data from LC-MS or MS imaging by matching against peak intensity scaled tandem MS spectral libraries using precursor-tolerant reverse match scoring. Applied to inflammatory bowel disease and imaging datasets, we show the approach facilitates re-analyses of data in public repositories.
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Importance Associations of body mass index (BMI) with survival in pancreatic ductal adenocarcinoma (PDA) have substantial variability in literature, potentially due to heterogeneous patient populations and retrospective analyses. Additionally, BMI may inadequately describe body composition (ie, morphomics; including subcutaneous and visceral fats, muscle, and fascia), which might have independent biological roles and associations with survival. Objective To study the associations of BMI and morphomics with survival and metabolomics in metastatic PDA. Design, Setting, and Participants This cohort study prospectively collected patient data, imaging, and serum on the phase 3 trial (Avenger500), which investigated the efficacy and safety of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) versus modified FOLFIRINOX plus devimistat. The randomized trial accrued 528 patients with chemotherapy-naive, metastatic PDA from Europe, Israel, Korea, and the US between 2018 and 2020. In the present study, per-protocol patients with L1 to L4, T10 to T12 vertebral levels were evaluated. Data analysis occurred from January 2023 to April 2024. Exposure Patient data were collected by clinical staff. Morphomics were analyzed from baseline imaging. Metabolites were extracted from baseline serum. Main Outcome and Measures A multifaceted statistical approach evaluated associations of BMI and morphomics with progression-free survival (PFS) and overall survival (OS). Associations of morphomics with metabolites were also studied. Results Of the 528 initial patients, 476 (median [IQR] age, 63 [56-68] years; 280 male [58.8%]; median [IQR] BMI, 25.0 [22.1-25.9]) were evaluable for the present study. BMI (obese [≥30] compared with normal [18.5-24.9]) was not associated with OS (hazard ratio [HR], 0.90; 95% CI, 0.67-1.22; P for trend = .33). More subcutaneous fat was associated with longer OS (HR, 0.62; 95% CI, 0.41-0.94; P for trend = .02). Higher visceral fat density was associated with shorter PFS (HR, 1.74; 95% CI, 1.23-2.48; P for trend = .002) and OS (HR, 1.50; 95% CI, 1.12-2.00; P for trend = .008). A higher muscle-to-fascia ratio was associated with longer PFS (HR, 0.58; 95% CI, 0.40-0.84; P for trend = .005) and OS (HR, 0.56; 95% CI, 0.41-0.75; P for trend = 1.7 × 10 ⁻⁴ ). Subcutaneous fat was positively associated with long-chain fatty acid metabolism including pristanic acid, decanoylcarnitine, decenoylcarnitine, and octanoylcarnitine. Muscle-to-fascia was positively associated with metabolites including acetylcarnosine (β = 0.34; 95% CI, 0.21-0.47; P = 1.27 × 10 ⁻⁶ ). Conclusions and Relevance In cohort study of patients with metastatic PDA, BMI was not associated with survival. Higher visceral fat density, subcutaneous fat area, and muscle-to-fascia ratio were associated with survival independent of BMI. The latter 2 were associated with higher levels of animal product metabolism. These findings could represent novel focuses for prognostication and intervention to improve survival of patients with PDA.
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In this work, the cryoprotective properties of dipeptide L-carnosine (β-alanyl-L-histidine) were studied on slices of the olfactory cortex of the brain of rats. Changes in the activity of N-methyl-D-aspartate receptors were analyzed as the most vulnerable to the effect of cryopreservation (CP), for this purpose, extracellular NMDA potentials were recorded. Slices were incubated with L-carnosine (20 mM) in the medium and frozen at a slow rate (0.1°C/min) down to –10°C and after CS (30 days) they were heated at the same rate (0.1°C/min) to +37°C. The effectiveness of cryoprotection of L-carnosine was determined by changes in the amplitudes of NMDA potentials after CP compared to before CP. The dipeptide restored the pH of the freezing medium 6.9 (without L-carnosine) to the optimum pH 7.3—7.4, promoted dehydration of free water from slices after CP, inhibited the development of glutamate excitotoxicity in slices. The data obtained prove that L-carnosine exhibits the properties of a non-toxic effective cryoprotector in the nervous tissue of warm-blooded non-hibernating animals.
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Histidine dipeptides (HDs) are synthesized in brain oligodendrocytes by carnosine synthase (carns1), but their role is unknown. Using metabolomics and in vivo experiments with both constitutive and oligodendrocyte‐selective carns1‐KO mouse models, we found that HDs are critical for oligodendrocyte survival and protect against oxidative stress. Carns1‐KO mouse models had lower numbers of mature oligodendrocytes, increased lipid peroxidation, and behavioral changes. Cuprizone administration, which increases reactive oxygen species in vivo, resulted in higher oligodendrocyte death, demyelination, axonal alterations, and oxidative damage in the corpus callosum of carns1‐KO mice. Gliosis and oxidative damage by cuprizone were prevented by pretreatment with the antioxidant N‐acetylcysteine. NADPH levels were increased threefold in the brains of carns1‐KO mice as an antioxidant response to oxidative stress through acceleration of the pentose phosphate pathway (PPP). This was due to overexpression of glucose‐6‐phosphate dehydrogenase, the rate‐limiting enzyme of the PPP. Likewise, expression of NAD kinase, the biosynthetic enzyme for NADP+, and NAMPT, which replenishes the NAD+ pool, was higher in carns1‐KO mice brains than in controls. Our observations suggest that HDs cell‐autonomously protect oligodendrocytes from oxidative stress, with implications for demyelinating diseases.
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Objective Environmental factors are important in the generation or aggravation of sensitive skin syndrome (SSS). Creams can be useful for patients with SSS, particularly when triggering factors cannot be avoided. Several clinical studies have investigated the safety and efficacy of specific creams in patients with SSS, but the majority were assessed with a single type of triggering factor and were non‐comparative. Therefore, this study's aim was to investigate, the benefit of a specific dermo‐cosmetic product in response to physical and chemical factors in subjects with SSS. Methods Three clinical studies were performed on subjects presenting SSS. The physical impact was assessed in a stripping test, and in a randomized intra‐individual study with a newly developed heat–cold stress model. To assess chemical factors, a capsaicin test on the nasolabial fold was performed. Results The product significantly reduced the increase in skin microcirculation caused by stripping after 30 min versus. The untreated condition (45.8% vs. 62.0%; p < 0.01). Immediately and at D28, the product induced a significant increase in skin hydration even after a heat–cold stress, while the overall score of unpleasant symptoms significantly decreased compared with the control (8.1 vs. 10.7 and 3.7 vs. 8.0, respectively; p < 0.01). Regarding chemical factors, a significant difference in the sensation intensity (p < 0.001) was observed after capsaicin stress, also in terms of the sensation duration due to the product application versus the control (192 s vs. 403 s; p < 0.001). Conclusion These studies show that topical application of a dermo‐cosmetic product can prevent unpleasant symptoms and improve the skin state in SSS exposed to physical and chemical triggering factors.
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BACKGROUND Carnosine, a natural bioactive dipeptide derived from meat muscle, possesses strong antioxidant properties. Dexamethasone, widely employed for treating various inflammatory diseases, raises concerns regarding its detrimental effects on bone health. This study aimed to investigate the protective effects of carnosine against dexamethasone‐induced oxidative stress and bone impairment, along with its underlying mechanisms, utilizing chick embryos and a zebrafish model in vivo, as well as MC3T3‐E1 cells in vitro. RESULTS Our findings revealed that carnosine effectively mitigated bone injury in dexamethasone‐exposed chick embryos, accompanied by reduced oxidative stress. Further investigation demonstrated that carnosine alleviated impaired osteoblastic differentiation in MC3T3‐E1 cells and zebrafish by suppressing the excessive production of reactive oxygen species (ROS) and enhancing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, mechanistic studies elucidated that carnosine promoted the expression and nuclear translocation of nuclear factor erythroid 2‐related factor 2 (NRF2), thereby facilitating the transcription of its downstream antioxidant response elements, including heme oxyense‐1 (HO‐1), glutamate cysteine ligase modifier (GCLM), and glutamate cysteine ligase catalytic (GCLC) to counteract dexamethasone‐induced oxidative stress. CONCLUSION Overall, this study underscores the potential therapeutic efficacy of carnosine in mitigating oxidative stress and bone damage induced by dexamethasone exposure, shedding light on its underlying mechanism of action by activating the NRF2 signaling pathway. © 2024 Society of Chemical Industry.
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Background Keratosis pilaris (KP) is a prevalent benign dermatological condition characterized by small bumps at the hair follicles alongside surrounding redness, significantly impacting both aesthetics and mental well‐being. Objective This study investigated the potential benefits of a non‐cross‐linked hyaluronic acid (HA) compound for treating KP. Methods A split‐body, investigator‐blinded, randomized, intraindividual comparative clinical trial was conducted. The non‐cross‐linked HA compound was injected into KP‐affected regions on both upper arms. The treatment was delivered across four sessions scheduled at 4‐week intervals. Blinded physicians and patients assessed differences in erythema, skin roughness, and overall scores between treated and control areas at the final follow‐up visit. At the 12th and 24th weeks post‐treatment, a four‐point scale was utilized to assess subjects' perceived treatment efficacy. Additionally, dermoscopic images, histological alterations, and adverse events were monitored. Results Physician assessments revealed a significant reduction in roughness and overall scores for treated areas compared to controls. Patient self‐assessments also reflected improvements in roughness, redness, and overall scores for treated sides at the final visit, with 35.71% of patients demonstrating sustained improvement in redness and 71.43% reporting persistent improvements in roughness at 24th weeks post‐treatment. The dermatoscopic examinations revealed a notable enhancement in both the quantity of follicular plugs and the extent of erythema among the subjects in the treatment group. Histopathological outcomes also demonstrated improvement. Conclusion This study suggests that the non‐cross‐linked HA compound effectively improves skin roughness and promotes hair shaft growth in KP treatment, demonstrating a favorable safety profile. These findings position it as a potentially viable alternative therapy in clinical practice.
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Despite the overwhelming number of sports supplements on the market, only seven are currently recognized as effective. Biological functions are largely regulated through redox reactions, yet no comprehensive analysis of the redox properties of these supplements has been compiled. Here, we analyze the redox characteristics of these seven supplements: bicarbonates, beta- alanine, caffeine, creatine, nitrates, carbohydrates, and proteins. Our findings suggest that all sports supplements exhibit some degree of redox activity. However, the precise physiological implications of these redox properties remain unclear. Future research, employing unconventional perspectives and methodologies, will reveal new redox pixels of the exercise physiology and sports nutrition picture.
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Introduction The prevention and mitigation of intestinal immune challenge is crucial for poultry production. This study investigated the effects of dietary Macleaya cordata extract (MCE) supplementation on the prevention of intestinal injury in broiler chickens challenged with lipopolysaccharide (LPS). Methods A total of 256 one-day-old male Arbor Acres broilers were randomly divided into 4 treatment groups using a 2×2 factorial design with 2 MCE supplemental levels (0 and 400 mg/kg) and 2 LPS challenge levels (0 and 1 mg/kg body weight). The experiment lasted for 21 d. Results and discussion The results showed that MCE supplementation increased the average daily feed intake during days 0-14. MCE supplementation and LPS challenge have an interaction on the average daily gain during days 15-21. MCE supplementation significantly alleviated the decreased average daily gain of broiler chickens induced by LPS. MCE supplementation increased the total antioxidant capacity and the activity of catalase and reduced the level of malondialdehyde in jejunal mucosa. MCE addition elevated the villus height and the ratio of villus height to crypt depth of the ileum. MCE supplementation decreased the mRNA expression of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 in the jejunum. MCE addition mitigated LPS-induced mRNA up-expression of pro-inflammatory factors IL-1β and IL-17 in the jejunum. MCE supplementation increased the abundance of probiotic bacteria (such as Lactobacillus and Blautia) and reduced the abundance of pathogenic bacteria (such as Actinobacteriota, Peptostretococcaceae, and Rhodococcus), leading to alterations in gut microbiota composition. MCE addition altered several metabolic pathways such as Amino acid metabolism, Nucleotide metabolism, Energy metabolism, Carbohydrate metabolism, and Lipid metabolism in broilers. In these pathways, MCE supplementation increased the levels of L-aspartic acid, L-Glutamate, L-serine, etc., and reduced the levels of phosphatidylcholine, phosphatidylethanolamine, thromboxane B2, 13-(S)-HODPE, etc. In conclusion, dietary supplementation of 400 mg/kg MCE effectively improved the growth performance and intestinal function in LPS-challenged broiler chickens, probably due to the modulation of gut microbiota and plasma metabolites.
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Context Successful freezing of ram semen has not yet reached the desired levels. The main reason for this situation could be due to the fact that the spermatozoa of this species have a lipid composition different from that of other species. Aims The objective of the study was to evaluate the effect of different concentrations of L-carnosine added to the extender on ram semen after being frozen and thawed. Methods Semen was collected from six Akkaraman rams twice a week for a period of 3 weeks. Pooling was performed at each time. The semen were reconstituted with a pre-prepared tris + egg yolk solution and different amounts of L-carnosine to form experimental groups (Group 1: 1 mM, Group 2: 5 mM, Group 3: 10 mM, Group 4: 20 mM, Group 5: control) and were drawn into 0.25 mL mini straws. Subsequently, the samples were subjected to freezing by using an automated freezing device. Following the freezing process, the straws were placed in containers containing liquid nitrogen and thawed after 24 h. Key results After thawing, it was found that the samples containing 5 mM L-carnosine had superior results in all analyses. This concentration exhibited significantly higher percentages of progressive, total, and rapid sperm motility, live spermatozoa, high mitochondrial membrane potential rate, and higher GSH-Px concentrations. In addition, it was determined that 5 mM L-carnosine group protected the membrane integrity and significantly decreased the rate of abnormal spermatozoa, acrosomal damage rate, low mitochondrial membrane potential and apoptotic cell rate. Conclusions As a result, It was determined that adding 5 mM of L-carnosine to the semen extender during the freezing of ram samples would be beneficial for successful freezing. Implications The addition of 5 mM L-carnosine to ram-semen extenders ensures the freezability of the semen of this species; thus, this protocol could be used to perform artificial insemination with frozen ram semen.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction and death of motor neurons through multifactorial mechanisms that remain unclear. ALS has been recognized as a multisystemic disease, and the potential role of skeletal muscle in disease progression has been investigated. Reactive aldehydes formed as secondary lipid peroxidation products in the redox processes react with biomolecules, such as DNA, proteins, and amino acids, resulting in cytotoxic effects. 4-Hydroxy-2-nonenal (HNE) levels are elevated in the spinal cord motor neurons of ALS patients, and HNE-modified proteins have been identified in the spinal cord tissue of an ALS transgenic mice model, suggesting that reactive aldehydes can contribute to motor neuron degeneration in ALS. One biological pathway of aldehyde detoxification involves conjugation with glutathione (GSH) or carnosine (Car). Here, the detection and quantification of Car, GSH, GSSG (glutathione disulfide), and the corresponding adducts with HNE, Car-HNE, and GS-HNE, were performed in muscle and liver tissues of a hSOD1G93A ALS rat model by reverse-phase high-performance liquid chromatography coupled to electrospray ion trap tandem mass spectrometry in the selected reaction monitoring mode. A significant increase in the levels of GS-HNE and Car-HNE was observed in the muscle tissue of the end-stage ALS animals. Therefore, analyzing variations in the levels of these adducts in ALS animal tissue is crucial from a toxicological perspective and can contribute to the development of new therapeutic strategies.
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Background Nitrite salts are frequently utilized as meat additives to improve the quality and safety of processed meat products. However, these salts are associated with the formation of carcinogenic nitrosamines. Given its potential regulating effect on the formation of intermediate molecules, such as nitric oxide, it is hypothesized that carnosine, a meat constituent possessing antioxidant activity and other multiple health benefits, could dampen the formation of nitrosamines. The current study therefore assessed the effect of carnosine on nitrosamine formation in both a monophasic aqueous system and a biphasic water–lipid system simulating a gastric environment. Results In the monophasic system, relatively high levels of carnosine were required to significantly reduce the formation of different species of nitrosamine compared with the control (no carnosine). While higher levels of some nitrosamines were generated in both phases of the biphasic system, low carnosine concentrations significantly suppressed nitrosamine formation in the aqueous phase, while in the lipid phase, intermediate levels of carnosine were required. At higher carnosine levels, further reduction in nitrosamines was observed in the lipid phase. Conclusions This study demonstrates the capacity of carnosine to reduce nitrosamine formation in aqueous and lipid environments and suggests the potential of dietary carnosine to lower the risks associated with the consumption of processed meat products. © 2024 His Majesty the King in Right of Canada and The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. Reproduced with the permission of the Minister of Agriculture and Agri‐Food Canada.
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The stability of carnosine, pyrrolylcarnosine (PC) and salicylcarnosine (SC) to the action of leucine aminopeptidase, carboxypeptidases B and Y was evaluated. It was found that proteolysis of carnosine, PC and SC under the action of leucine aminopeptidase does not occur. Carboxypeptidases B and Y, as well as the enzyme system of blood plasma and plasma membranes of rat brain cells, degraded peptides containing β-alanyl, N-pyrrolyl, N-salicylic fragments to varying degrees. In all cases, histidine is formed. The formation of pyrrole or salicylic acid does not occur. It was found that carnosine, PC and SC showed high stability to the action of amino- and carboxypeptidases in in vitro experiments.
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Here we report the cloning and functional characterization of a rat novel peptide/histidine transporter (PHT1), which was expressed in the brain and the retina. The cDNA encodes the predicted protein of 572 amino acid residues with 12 putative membrane-spanning domains. The amino acid sequence has moderate homology with a nonspecific peptide transporter found in the plant. When expressed in Xenopus laevis oocytes, PHT1 cRNA induced high affinity proton-dependent histidine transport activity. This transport process was inhibited by dipeptides and tripeptides but not by free amino acids such as glutamate, glycine, leucine, methionine, and aspartate. Dipeptide carnosine transport activity was also confirmed by direct uptake measurement. By in situ hybridization analysis, PHT1 mRNA was widely distributed throughout whole brain. Especially, intense hybridization signals were found in the hippocampus, choroid plexus, cerebellum, and pontine nucleus. Signals were located in both the neuronal and small nonneuronal cells in these areas. PHT1 protein could contribute to uptake of oligopeptides, which function as neuromodulators, and clearance of degraded neuropeptides and be a new member in the growing superfamily of proton-coupled peptide and nitrate transporters, although its structure, localization, and pharmacological characteristics are unique among these members.
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Muscle carnosine synthesis is limited by the availability of β-alanine. Thirteen male subjects were supplemented with β-alanine (CarnoSyn™) for 4 wks, 8 of these for 10 wks. A biopsy of the vastus lateralis was obtained from 6 of the 8 at 0, 4 and 10 wks. Subjects undertook a cycle capacity test to determine total work done (TWD) at 110% (CCT110%) of their maximum power (Wmax). Twelve matched subjects received a placebo. Eleven of these completed the CCT110% at 0 and 4 wks, and 8, 10 wks. Muscle biopsies were obtained from 5 of the 8 and one additional subject. Muscle carnosine was significantly increased by +58.8% and +80.1% after 4 and 10 wks β-alanine supplementation. Carnosine, initially 1.71 times higher in type IIa fibres, increased equally in both type I and IIa fibres. No increase was seen in control subjects. Taurine was unchanged by 10 wks of supplementation. 4 wks β-alanine supplementation resulted in a significant increase in TWD (+13.0%); with a further +3.2% increase at 10 wks. TWD was unchanged at 4 and 10 wks in the control subjects. The increase in TWD with supplementation followed the increase in muscle carnosine.
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It has been suggested that histidine-containing dipeptide carnosine ( -alanyl-L-histidine), which is believed to act as a cytosolic buffering agent, is present predominantly in skeletal muscle. The purpose of this study was to investigate the effects of sprint training (30-s maximal cycle ergometer sprinting) on muscle carnosine concentration. Six untrained males trained 2 days per week for 8 weeks on an electronic-braked cycle ergometer. Muscle biopsy samples were taken from the vastus lateralis before and two days after the last training session and were analyzed for carnosine concentration by the use of an amino acid autoanalyzer. The carnosine concentration was signifi cantly increased after sprint training ( P concentration was signifi cantly increased after sprint training ( P concentration was signifi cantly increased after sprint training ( < 0.05). The mean power P < 0.05). The mean power P during 30-s maximal cycle ergometer sprinting was signifi cantly increased following training. When dividing the 30-s sprinting into 6 phases (0-5, 6-10, 11-15, 16-20, 21-25, 26-30 s), the magnitude of increase in mean power was signifi cantly larger for the last 2 phases than the fi rst phase ( P fi rst phase ( P fi rst phase ( < 0.05). These results suggest that the increases in skeletal muscle carnosine P < 0.05). These results suggest that the increases in skeletal muscle carnosine P concentration following sprint training may be associated with the increase in sustainability of high power during 30-s maximal cycle ergometer sprinting.
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Significance The concentration of Ca ²⁺ ions is kept low in cells by specialized ion-pumping proteins at the membrane. We show that in cardiac cells, cytoplasm also has an intrinsic ability to pump Ca ²⁺ . Histidyl dipeptides and ATP are diffusible cytoplasmic buffer molecules. By exchanging Ca ²⁺ for H ⁺ , they act like local “pumps,” producing uphill Ca ²⁺ movement within cytoplasm in response to H ⁺ ion gradients. Intracellular H ⁺ ions are generated locally by metabolism and competitively inhibit many Ca ²⁺ -activated biochemical processes. Recruiting Ca ²⁺ to acidic zones facilitates these processes. Cytoplasmic histidyl dipeptides and ATP thus act like a biological pump without a membrane.
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Anserine (beta-alanyl-N(Pi)-methyl-L-histidine), a naturally occurring derivative of carnosine (beta-alanyl-L-histidine), is an abundant constituent of skeletal muscles and brain of many vertebrates. Although it has long been proposed to serve as a proton buffer, radicals scavenger and transglycating agent, its physiological function remains obscure. The formation of anserine is catalyzed by carnosine N-methyltransferase which exhibits unknown molecular identity. In the present investigation, we have purified carnosine N-methyltransferase from chicken pectoral muscle about 640-fold until three major polypeptides of about 23, 26 and 37 kDa coeluting with the enzyme were identified in the preparation. Mass spectrometry analysis of these polypeptides resulted in an identification of histamine N-methyltransferase-like (HNMT-like) protein as the only meaningful candidate. Analysis of GenBank database records indicated that the hnmt-like gene might be a paralogue of histamine N-methyltransferase gene, while comparison of their protein sequences suggested that HNMT-like protein might have acquired a new activity. Chicken HNMT-like protein was expressed in COS-7 cells, purified to homogeneity, and shown to catalyze the formation of anserine as confirmed by both chromatographic and mass spectrometry analysis. Both specificity and kinetic studies carried out on the native and recombinant enzyme were in agreement with published data. Particularly, several compounds structurally related to carnosine, including histamine and L-histidine, were tested as potential substrates for the enzyme, and carnosine was the only methyl group acceptor. The identification of the gene encoding carnosine N-methyltransferase might be beneficial for estimation of the biological functions of anserine.
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Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22-23, and polymorphisms within the carnosine dipeptidase 1 gene (CNDP1), located on 18q22.3, have been shown to be associated with diabetic nephropathy in European subjects with type 2 diabetes. However, the association of this locus with diabetic nephropathy has not been evaluated in the Japanese population. In this study, we examined the association of polymorphisms within the CNDP1/CNDP 2 locus with diabetic nephropathy in Japanese subjects with type 2 diabetes. We genotyped a leucine repeat polymorphism (D18S880) that is within CNDP1 along with 29 single nucleotide polymorphisms (SNPs) in the CNDP1/CNDP2 locus for 2,740 Japanese subjects with type 2 diabetes (1,205 nephropathy cases with overt nephropathy or with end-stage renal disease [ESRD], and 1,535 controls with normoalbuminuria). The association of each polymorphism with diabetic nephropathy was analysed by performing logistic regression analysis. We did not observe any association between D18S880 and diabetic nephropathy in Japanese subjects with type 2 diabetes. None of the 29 SNPs within the CNDP1/CNDP2 locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in CNDP1 was nominally associated with diabetic nephropathy in women (rs12604675-A; p = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19-2.61). Rs12604675 was associated with overt proteinuria (p = 0.002, OR = 2.18, 95% CI, 1.32-3.60), but not with ESRD in Japanese women with type 2 diabetes. Rs12604675-A in CNDP1 may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes.
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The enzyme myeloperoxidase generates significant amounts of hypochlorous acid (HOCl) at sites of inflammation to inflict oxidative damage upon invading pathogens. However, excessive production of this potent oxidant is associated with numerous inflammatory diseases. Recent kinetic measurements suggest that the endogenous antioxidant carnosine is an effective HOCl scavenger. On the basis of computational modeling, we suggest a possible mechanism for this antioxidant activity. We find that a unique structural relationship between three adjacent functional groups (imidazole, carboxylic acid, and terminal amine) enables an intramolecular chlorine transfer to occur. In particular, two sequential proton shifts are coupled with a Cl(+) shift converting the kinetically favored product (chlorinated at the imidazole nitrogen) into the thermodynamically favored product (chlorinated at the terminal amine) effectively trapping the chlorine. We proceed to design systems that share similar structural features to those of carnosine but with even greater HOCl-scavenging capabilities.
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Autism spectrum disorders (ASD) are a group of biological disorders with associated metabolic derangement. This study aimed to identify a pattern of metabolic perturbance in ASD using metabolomics in urinary specimens from 48 children with ASD and 53 age matched controls. Using a combination of liquid- and gas-chromatography-based mass spectrometry, we detected the levels of 82 metabolites (53 of which were increased) that were significantly altered between the ASD and the control groups using osmolality normalized data. Pattern analysis showed that the levels of several amino acids such as glycine, serine, threonine, alanine, histidine, glutamyl amino acids and the organic acid, taurine were significantly (p≤0.05) lower in ASD children. The levels of antioxidants such as carnosine were also reduced in ASD (p=0.054). Furthermore, several gut bacterial metabolites were significantly altered in ASD children who had gastrointestinal dysfunction. Overall, this study detected abnormal amino acid metabolism, increased oxidative stress, and altered gut microbiomes in ASD. The relationship of altered gut microbial co-metabolism and the disrupted metabolisms requires further investigation.
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Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Carnosine is a naturally occurring dipeptide and has a scavenging property. The aim of present study was to assess the lipid peroxidation and antioxidant enzymes in association with oxidative stress in cisplatin -treated and 10 subsequent doses of carnosine-pretreated rats. 24 male Albino Wistar rats, were randomly divided into four groups (n=6). Group I remains untreated; Group II received Cisplatin (3 mg / kg) for 5 alternate days; Group III received Carnosine (10 mg / kg) for consecutive 10 days; Group IV received Carnosine (10 mg / kg) before administration of Cisplatin (3 mg / kg). The effects of carnosine on cisplatin-induced nephrotoxicity were evaluated by plasma creatinine, urea, malondialdehyde, nitrate; kidney tissue malondialdehyde, 4-HNE, superoxide dismutase and catalase activities. Cisplatin-induced oxidative stress was indicated by increased level of tissue MDA, 4-HNE and decreased level of tissue GSH, SOD and Catalase. Marked elevation of kidney weight and reduced body weight and pathological changes in kidney tissues were also observed in Cisplatin-treated rats. Carnosine reduced these pathological changes and counteracted the deleterious effects of cisplatin. The results divulge the beneficial effect of Carnosine pretreatment with cisplatin in experimental rat model.
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Our goal in this study was to determine whether or not feeding young (4 months old) Alzheimer's disease model transgenic mice with a high fat diet (HFD), consisting of 32% fat, is capable of causing cognitive decline and whether treatment with β-alanyl-L-histidine (carnosine) is capable of reducing these effects. Carnosine is an endogenous antioxidant and antiglycating agent that is abundantly present in the brain and muscle tissues of vertebrates. After 8 weeks of feeding with HFD, we observed a significant decline in the contextual memory in transgenic mice fed with HFD as compared to transgenic mice fed with a normal diet as well as to normal diet-wild type mice. Treatment with carnosine at a dose of 5 mg/day for 6 weeks was effective in preventing cognitive decline, as the transgenic group fed with HFD and treated with carnosine displayed a level of cognition comparable to controls. No differences in senile plaque load were observed between all groups. However, we observed an increase in the expression of RAGE in blood vessels as well as increased microglial activation in the hippocampus of animals fed with HFD, effects that were reversed when treated with carnosine. Given these results, there is a possibility that inflammation and cerebrovascular abnormalities might be the cause of cognitive decline in this model.
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β-alanine, a popular supplement for muscle building, induces itch and tingling after consumption, but the underlying molecular and neural mechanisms are obscure. Here we show that, in mice, β-alanine elicited itch-associated behavior that requires MrgprD, a G-protein-coupled receptor expressed by a subpopulation of primary sensory neurons. These neurons exclusively innervate the skin, respond to β-alanine, heat, and mechanical noxious stimuli but do not respond to histamine. In humans, intradermally injected β-alanine induced itch but neither wheal nor flare, suggesting that the itch was not mediated by histamine. Thus, the primary sensory neurons responsive to β-alanine are likely part of a histamine-independent itch neural circuit and a target for treating clinical itch that is unrelieved by anti-histamines.
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This manuscript concerns the tissue specific transcription of mouse and cattle glutamate decarboxylase-like 1 (GADL1) and the biochemical activities of human GADL1 recombinant protein. Bioinformatic analysis suggested that GADL1 appears late in evolution, only being found in reptiles, birds, and mammals. RT-PCR determined that GADL1 mRNA is transcribed at high levels in mouse and cattle skeletal muscles and also in mouse kidneys. Substrate screening determined that GADL1, unlike its name implies, has no detectable GAD activity, but it is able to efficiently catalyze decarboxylation of aspartate, cysteine sulfinic acid, and cysteic acid to β-alanine, hypotaurine, and taurine, respectively. Western blot analysis verified the presence of GADL1 in mouse muscles, kidneys, C2C12 myoblasts, and C2C12 myotubes. Incubation of the supernatant of fresh muscle or kidney extracts with cysteine sulfinic acid resulted in the detection of hypotaurine or taurine in the reaction mixtures, suggesting the possible involvement of GADL1 in taurine biosynthesis. However, when the tissue samples were incubated with aspartate, no β-alanine production was observed. We proposed several possibilities that might explain the inactivation of ADC activity of GADL1 in tissue protein extracts. Although β-alanine-producing activity was not detected in the supernatant of tissue protein extracts, its potential role in β-alanine synthesis cannot be excluded. There are several inhibitors of the ADC activity of GADL1 identified. The discovery of GADL1 biochemical activities, in conjunction with its expression and activities in muscles and kidneys, provide some tangible insight towards establishing its physiological function(s).
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Spektrophotometrische, pH-metri - sche und teilweise 13C-NMR-spektroskopische Untersuchungen der Komplexe von Co(II), Ni(Il) und Zn(II) mit Gly-L-His, L-His-Gly und L-Camosin zeigen die unterschiedliche Art der Koordination und die dadurch bedingte Bildung verschiedener Gemischt-ligand-Komplexe mit Gly, Gly-Gly, His und 2,2′-Bipyridyl als zweitem Liganden.
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Carnosine (β-alanyl-L-histidine) exhibits anti-oxidant and anti-glycation properties, which are attributed to carnosine's ability to scavenge radicals and sugar aldehydes. Carnosine protects against glycation-induced loss of enzyme activity and prevents glycation-induced changes in protein structure. Carnosine's anti-glycation properties coincide with adduct formation between carnosine and sugar aldehydes. This study examined the glycation product formed during incubation of carnosine with glyceraldehyde 3-phosphate (Glyc3P) using mixtures containing unreactive reactants. The initially clear solution became bright yellow upon incubation. The fluorescence and absorbance properties were studied. The increase in fluorescence (365 nm ex; 460 nm em) was time-, concentration- and temperature-dependent. The absorbance spectra exhibited a 288 nm peak. The carnosine-Glyc3P adduct had a decreased amino group content suggesting a role for the β-alanyl's amino group in the formation of a Maillard reaction product (The Maillard Reaction, R. Ikan, ed., John Wiley & Sons, 1996). Aspartate aminotransferase activity, which was used as a measure of glycation-induced inactivation, was only moderated affected by the carnosine-Glyc3P glycation product in comparison to Glyc3P, supporting carnosine's role as a protective agent.
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Background: Substantial differences exist between traditionally cooked and chemically designed ready-to-serve products and raise questions about the general principles and requirements of current food law. Methods: Differences in amino acid patterns were analyzed in four examples of chicken preparations (boiled chicken meat, traditionally prepared broth from whole chicken, and two commercial chicken broths), and four examples of vegetable broth (traditionally prepared, two commercial products one of which was claimed a BIO-product, and the classic German bouillon cube). Results: Chicken meat contained 284 mg of free amino acids in 100 ml of the boiled meat homogenate, with physiological peaks of glutamate (14.5 mg/100 ml), glutamine (8.5 mg/100 ml), anserine (88 mg/100 ml) and carnosine (55 mg/100 ml). The patterns significantly differ in industrially designed chicken soups with elevated peaks of glutamate, and missing anserine or carnosine. Similar results were obtained in vegetable broths. In the classic German bouillon cube, glutamate accounts for 96% of all free amino acids. Conclusions: The amino acid composition of modern ready-to-serve chicken soups and vegetable broths are far from being similar to any natural composition. We need to question current legal definitions of food, and consider its impact on eating habits, appetite regulation and obesity.
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The effect of carnosine on the life span and several brain biochemical characteristics in senescence-accelerated mice-prone 1 (SAMP1) was investigated. A 50% survival rate of animals treated with carnosine increased by 20% as compared to controls. Moreover, the number of animals that lived to an old age significantly increased. The effect of carnosine on life span was accompanied by a decrease in the level of 2'-tiobarbituric acid reactive substances (TBARS), monoamine oxidase b (MAO b), and Na/K-ATPase activity. There was also an increase in glutamate binding to N-methyl-D-aspartate receptors. These observations are consistent with the conclusion that carnosine increases life span and quality of life by diminishing production of lipid peroxides and reducing the influence of reactive oxygen species (ROS) on membrane proteins.
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Objective dietary intake markers for meat would be useful to assess meat intake in observational studies and as compliance markers in dietary intervention studies. A number of compounds are specific to meat compared with most other dietary items but there is some overlap between protein rich foods. A number of single compounds have been analysed in urine, plasma, serum or hair samples in studies of their relationship to meat or total protein intake. Among potential markers of dietary meat intake are urea, creatine, creatinine, carnitine, carnosine, anserine, ophidine, 1- and 3-methylhistidine, and sulphate or sulphite. Anserine and 1-methylhistidine come close to being meat-specific markers but true quantitative biomarker may not exist. Modern profiling techniques are increasingly used to look for useful biomarkers or for constructing them from latent information in complex profiles. Metabolomics by NMR spectroscopy of urine has also been applied to search for meat intake markers. Studies on single com
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Objective dietary intake markers for meat would be useful to assess meat intake in observational studies and as compliance markers in dietary intervention studies. A number of compounds are specific to meat compared with most other dietary items but there is some overlap between protein rich foods. A number of single compounds have been analysed in urine, plasma, serum or hair samples in studies of their relationship to meat or total protein intake. Among potential markers of dietary meat intake are urea, creatine, creatinine, carnitine, carnosine, anserine, ophidine, 1- and 3-methylhistidine, and sulphate or sulphite. Anserine and 1-methylhistidine come close to being meat-specific markers but true quantitative biomarker may not exist. Modern profiling techniques are increasingly used to look for useful biomarkers or for constructing them from latent information in complex profiles. Metabolomics by NMR spectroscopy of urine has also been applied to search for meat intake markers. Studies on single compounds or metabolomics markers are shortly reviewed here
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Carnosine in the chemoreceptor neurons of the olfactory epithelium can be labeled in vivo by intranasal irrigation with either(14)C-β-alanine or(14)C-L-histidine. This newly synthesized carnosine (but not the precursor amino acids) is translocated to the olfactory bulb, where the olfactory chemoreceptor axons synapse with the dendrites of mitral cells and other second-order neurons. Labeled carnosine arrives in the bulb several hours after intranasal administration of precursor. Similar arrival time is seen for macromolecules after intranasal administration of [(3)H]L-fucose, [(14)C]L-proline, or [(14)C]L-histidine. Macromolecules labeled with [(3)H]uridine take much longer to reach the bulb. Carnosine is also labeled after [(3)H]uridine administration. No labeling of macromolecules is observed after administration of 1-[(14)C]-β-alanine. Oral administration of the same dose of [(14)C]-β-alanine gives almost no labeled carnosine in bulb or epithelium. This method has permitted us to estimate that the half-life of labeled carnosine in both the bulb and epithelium is about 20 h. This method provides a means of selectively prelabeling the olfactory chemoreceptor neurons in the olfactory epithelium and their synapses in the olfactory bulb prior to cellular and subcellular separation procedures, and may also enable us to monitor the influences of olfactory stimulation on synthesis and transport of carnosine.
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The aim of this work was to test the hypothesis that in vivo carnosine biosynthesis is dependent upon endogenous ß-alanine availability, by studying the effect of sustained dietary ß-alanine supplementation in the horse on the carnosine concentration in types I, IIA and IIB skeletal muscle fibres. The diets of 6 Thoroughbred horses were supplemented 3 times/day with ß-alanine (100 mg/kg bwt) and L-histidine (12.5 mg/kg bwt) for a period of 30 days. Percutaneous biopsies of the m. gluteus medius from a depth of 6 cm were taken on the days immediately before and after the supplementation period. Heparinised blood samples were collected at hourly intervals on the first and last days of supplementation, and on every sixth day during the supplementation period, 2 h after each ration. Individual muscle fibres were dissected from freeze-dried biopsies, weighed and characterised histochemically. ß-alanine, histidine and carnosine concentrations were measured in plasma. The areas under the plasma concentration-time curves (AUC) for ß-alanine and histidine were calculated as indicators of the doses absorbed. Carnosine concentrations were measured in types I, IIA and IIB muscle fibres.
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Carnosine (α-alanyl-l-histidine), a dipeptide, the exact functions of which are unknown, is found at millimolar concentrations in muscle cells. In skinned skeletal muscle fibers, carnosine released calcium from the sarcoplasmic reticulum and generated tension, and carnosine (ED50 = 6.6 mM) was less potent than caffeine (ED50 = 1.5 mM). The effect of carnosine on the ryanodine receptor calcium release channel (Ry1) was investigated in single Ryl molecules incorporated into an artificial lipid bilayer for recording channel activity. Carnosine (0.1-10 mM) increased open-state probability (Po) of Ry1 with a fourfold maximal increase occurring at 2.5 mM. Carnosine (5 mM) caused a twofold increase in the open-state dwell time. Carnosine also altered the Ry1 channel’s response to changes in calcium concentration, shifting the Po-versus-pCa relationship to the left. The presence of carnosine at a millimolar concentration in muscle cells and its effects on the major calcium release channel in skeletal muscle suggest an important function for this unique dipeptide in regulation of contractility. One possible function of carnosine is the sensitization of key proteins to activation and/or inactivation by Ca2+.Copyright © 1997 S. Karger AG, Basel
Article
1.1. From the muscle of 20 species of fresh-water fishes, l-histidine, carnosine, anserine, and balenine were analysed by high-performance liquid chromatography.2.2. All cyprinoidei fishes contained significant amount of l-histidine and trace of dipeptides.3.3. High concentration of anserine was found in salmonoidei fishes, irrespective of salmonidae and osmeridae.4.4. Two species of anguilloidei contained large amount of carnosine, small of l-histidine, and determinable of anserine and balenine.5.5. Only trace amounts of these compounds were found in percoidei fishes.6.6. The levels of these compounds represented no large difference among species belonging to sub-order group as well as family.
Article
The glycyl-L-histidine (GlyHis), L-histidylglycine (HisGly), and L-carnosine (ligands HA) parent complexes of cobalt(II), nickel(II), and zinc(II) were studied by pH-metry, spectrophotometry, and in part 13C n.m.r. spectroscopy. All three metal ions were found to promote deprotonation of the peptide amide group of GlyHis. HisGly co-ordinates ‘histidine-like’ to the metal ions, i.e. without deprotonation of the peptide amide group. With carnosine, only nickel(II) induces deprotonation of this group. Studies were also made of mixed-ligand systems involving Gly, GlyGly, His, and occasionally 2,2′-bipyridyl as second ligand B, including those containing copper(II). Gly and GlyGly do not hinder the co-ordination of GlyHis via three nitrogens, and mixed-ligand complexes are therefore not present in detectable concentration. With His as ligand B, although mixed-ligand complexes are formed at comparable GlyHis and His concentrations, in the presence of an excess of His the parent complex [M(HisO)2] predominates. A mixed-ligand complex is obtained in significant amount with 2,2′-bipyridyl as ligand B. Appreciable formation of mixed-ligand complexes also occurs in the nickel(II)–carnosine–ligand B systems. For cobalt(II), however, practically only the parent complexes of ligands B are formed. The cobalt(II) complexes of all three dipeptides examined are able to take up molecular oxygen reversibly, the oxygen being released partially or almost completely. For GlyHis it is highly likely that the active complex is [Co(AH–1)], while for HisGly and carnosine the presence of the bis complexes is presumed necessary for oxygen uptake.
Article
The stability of the copper(II)–carnosine dimer in aqueous solutions at pH 7.2 has been investigated with Fourier transform–i.r. and e.s.r. spectroscopies. At subsaturated concentrations, the dimer dissociates into two identical monomers. However, the dimer does not dissociate in saturated solutions even at temperatures as high as 80 °C according to Fourier-transform i.r. spectra. Motional averaging of the dipolar coupling tensors occurs at temperatures at least as low as 15 °C. Thus at temperatures above the freezing point of the solvent the copper(II) dimer in saturated solution exhibits a spectrum with only four hyperfine lines. These are broader than the hyperfine lines of monomeric copper(II) complexes because of dipole–dipole interaction. This is the first spectroscopic confirmation to our knowledge that a copper(II) dimer need not dissociate in aqueous solution at temperatures above the freezing point of water.
Article
A feeding experiment involving histidine supplementation to broiler feed resulted in increased concentration of the histidine containing dipeptides anserine and carnosine in broiler breast muscle. Supplementation with 1 g histidine per kg feed gave a 64% increase in carnosine, and about 10% increase in anserine in the muscle. The standard broiler feed concentrate now in use in Norway seems to contain less histidine than what may be needed for optimal synthesis of carnosine and anserine. These dipeptides have important roles as antioxidants, pH buffering agents and anti-glycation agents. They may have important roles in meat for increasing its stability, shelf life and antioxidant capacity, and it might be speculated that broiler meat rich in anserine and carnosine in the future will be considered a type of functional food, having possible health-beneficial effects. Histidine supplementation of standard Norwegian broiler feed concentrate should be considered.
Article
— Singlet molecular oxygen was generated by illumination of phenosafranin in phosphate buffer at pH 7.5. Relative efficiencies of various imidazole compounds to form endoperoxides were assayed by following at 25°C the rate of light- and imidazole-dependent bleaching of N,N-dimethyl-4-nitrosoaniline. Of over 30 imidazole compounds tested, imidazole-4-acetic acid, a major catabolite of histamine in mammals, exhibited the highest activity. l-Carnosine (β-alanyl-l-histidine), a natural dipeptide prevalent in striated muscle of mammals, possessed several properties important for a physiologically significant scavenger of singlet oxygen. On a molar basis, this readily water-soluble C-terminal histidine dipeptide reacted with singlet oxygen two-to four-fold faster than free L-histidine and approximately two-fold faster than the N-terminal l-histidine dipeptides tested. Furthermore scavenging ability of L-carnosine did not appreciably increase or decrease with time of reaction, in contrast to behaviors exhibited by a number of other imidazole compounds that included some other C-terminal L-histidine dipeptides. The fungal metabolite, ergothioneine, blocked singlet oxygen generation by illuminated phenosafranin.
Article
We have previously suggested that carnosine may serve as a reservoir for histidine to be used as a source of histamine in the trauma response of rats. In this study we report the effect of stimulation of histamine-forming capacity by compound on muscle carnosinase (C'ASE) and histidine decarboxylase (HDC) activities as well as on muscle carnosine and histamine concentrations. Male rats (180 g) were injected i.p. with 5 mg/kg bw of compound and C'ASE