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The main objective of this experiment was to study the metabolism of arginine in juvenile largemouth bass (Micropterus salmoides). A total of 300 healthy fish (average weight of 25 ± 0.5 g) were randomly assigned to ten groups. Experimental fish were orally administered or intraperitoneally injected with 0.9% sodium chloride, arginine, arginine-aspartate, citrulline, and glutamate solutions, respectively. They were euthanized at 10, 30, 60, 120, and 240 min after oral administration or intraperitoneal injection, and various tissue samples were subsequently collected for analysis. The results revealed that serum ornithine and citrulline concentrations of largemouth bass were significantly increased by oral administration of arginine or arginine-aspartate (P < 0.05). Intraperitoneal injection of arginine or arginine-aspartate solution significantly elevated the concentrations of ornithine and citrulline in the serum, liver, kidney, and muscles (P < 0.05). The concentrations of citrulline, ornithine, and arginine in serum and muscle increased significantly at 4 h after intraperitoneal injection of glutamate (P < 0.05). Intraperitoneal injection of citrulline significantly increased the concentrations of ornithine and arginine in the serum and muscles (P < 0.05). The research findings demonstrate that both free and small peptide forms of arginine were rapidly degraded to ornithine due to the high arginase activity in various tissues of largemouth bass. Additionally, the pathway of synthesizing citrulline from glutamate and then arginine from citrulline may exist in largemouth bass, but the exact location of this synthesis process may differ from that found in mammals. [ABSTRACT FROM AUTHOR]

Mutations in CHRNE encoding the epsilon subunit of acetylcholine receptor result in impaired neuromuscular transmission and congenital myasthenic syndrome (CMS) with variying severity of symptoms. Although the pathophysiology is well-known, blood biomarker signatures enabling a patient-stratification are lacking. This retrospective two-center-study includes 19 recessive CHRNE-patients (AChR deficiency; mean age 14.8 years) from 13 families which were clinically characterized according to disease severity. 15 patients were classified as mildly and 4 patients as moderate to severely affected. Seven known pathogenic and one unreported variant (c.1032 + 2_1032 + 3delinsGT) were identified. Biomarker discovery was carried out on blood samples: proteomics was performed on white blood cells (WBC; n = 12) and on extracellular vesicles (EV) purified from serum samples (n = 7) in addition to amino acid profiling (n = 9) and miRNA screening (n = 18). For miRNA studies, 7 patients with other CMS-subtypes were moreover included. WBC-proteomics unveiled a significant increase of 7 and a decrease of 36 proteins. In silico studies of these proteins indicated affection of secretory granules and the extracellular space. Comparison across patients unveiled increase of two vesicular transport proteins (SCAMP2 and SNX2) in severely affected patients and indeed EV-proteomics revealed increase of 7 and decrease of 13 proteins. Three of these proteins (TARSH, ATRN & PLEC) are known to be important for synaptogenesis and synaptic function. Metabolomics showed decrease of seven amino acids/ amino acid metabolites (aspartic and glutamic acids, phosphoserine, amino adipate, citrulline, ornithine, and 1-methyhistidine). miRNA-profiling showed increase miR − 483 − 3p, miR-365a-3p, miR − 365b − 3p and miR-99a, and decrease of miR-4433b-3p, miR-6873-3p, miR-182-5p and let-7b-5p in CHRNE-patients whereas a comparison with other CMS subtypes showed increase of miR − 205 − 5p, miR − 10b − 5p, miR-125a-5p, miR-499-5p, miR-3120-5p and miR − 483 − 5p and decrease of miR − 1290. Our combined data introduce a molecular fingerprint on protein, metabolic and miRNA level with some of those playing different roles along the neuromuscular axis. [ABSTRACT FROM AUTHOR]

The main purpose of this study was to optimize the L-citrulline production process using Plackett-Burman and Box-Behnken designs. L-citrulline-producing bacterium BH-01 was isolated from raw buffalo milk. The isolate was tested for probiotic activities such as tolerance to simulated gastric and intestinal juices, antagonistic activity against six antibiotic-resistant bacteria, and temperature tolerance. L-citrulline production and arginine deiminase (ADI) activity were optimized using statistical designs. The bacterial isolate was molecularly identified as Bacillus subtilis strain AUMC B-498 (accession number PP574248.1). The strain exhibited resistance at pH 2.0 and bile salt 0.5% for a two-hour exposure period. It could inhibit the growth of Escherichia coli, Klebsiella pneumonia, Serratia sp., Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and Streptococcus pneumoniae. From the results of statistical optimization, the Plackett-Burman design identified temperature, L-arginine, incubation period, and peptone as the most effective factors among the eight selected variables. Based on these, the Box-Behnken design was used to optimize the factors required to maximize citrulline production. The maximum L-citrulline was 632.5 µg/L, and ADI activity was 1.42 U/mL. Therefore, BH-01 isolated from Buffalo milk might be a promising candidate in food, biotechnological, and pharmaceutical applications due to its dual functionality for citrulline production and probiotic characteristics. [ABSTRACT FROM AUTHOR]

Purpose: To enhance the detection rate of Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) through newborn screening (NBS), we analyzed the metabolic profiles of missed patients and proposed a more reliable method for early diagnosis. Methods: In this retrospective study, NICCD patients were classified into "Newborn Screening" (64 individuals) and "Missed Screening" (52 individuals) groups. Metabolic profiles were analyzed using the non-derivatized MS/MS Kit, and genetic mutations were identified via next-generation sequencing and confirmed by Sanger sequencing. Receiver Operating Characteristic (ROC) analysis evaluated the predictive value of amino acids and acylcarnitines in dried blood spots (DBS) for identifying missed patients including 40 missed patients and 17,269 healthy individuals, with additional validation using 12 missed patients and 454 healthy controls. Results: The age of diagnosis was significantly higher in the "Missed Screening" group compared to the "Newborn Screening" group (74.50 vs. 18.00 days, P < 0.001). ROC analysis revealed that citrulline had excellent diagnostic accuracy for missed patients, with an AUC of 0.970 and a cut-off value of 17.57 µmol/L. Additionally, glycine, phenylalanine, ornithine, and C8 were significant markers, each with an AUC greater than 0.70. A combination of these markers achieved an AUC of 0.996 with a cut-off value of 0.00195. Validation demonstrated a true positive rate of 91.67% and a true negative rate of 96.48%. Common SLC25A13 mutations in both groups were c.852_855del, IVS16ins3kb, and c.615 + 5G > A. Conclusions: Combining multiple metabolic markers during NBS significantly improves sensitivity and specificity for detecting missed NICCD cases. However, the relationship between genetic mutations and missed cases remains unclear. [ABSTRACT FROM AUTHOR]

Background: Ornithine transcarbamylase deficiency exhibits a high degree of clinical heterogeneity, making its screening and classification challenging in some instances. In this study, we first established a simple and stable method for testing ornithine transcarbamylase activity using micro blood from newborns, rather than relying on venous blood. Methods: The activity of ornithine transcarbamylase was assessed by measuring the concentration of citrulline produced in the reaction with carbamoyl phosphate and ornithine, using serum, plasma or micro blood. Correlation analysis was evaluated using Sangerbox Tools. The Receiver Operating Characteristic curve was used in SPSS Statistics 17.0 to evaluate the diagnostic efficiency of Ornithine transcarbamylase deficiency. Results: A strong linear relationship was observed between ornithine transcarbamylase activity and both micro blood volume and reaction time (R2 = 0.9793, 0.9922 respectively). The intra-coefficient variation and inter-coefficient variation were 11% and 12.5% with a 1-h reaction time, and 6.77% and 9.58% with a 3-h reaction time, respectively. And the inter-coefficient variation was lower than the most widely used colorimetry method (5.1–21.1%). The Limit of Blank was 0.57 nmol/mL/h. The reference interval for normal newborn population is greater than or equal to 39.6 nmol/mL/h. Notably, the method exhibited a 100% sensitivity, surpassing the sensitivity of colorimetry method (94.3%), along with and a specificity of 96.9% for diagnosing ornithine transcarbamylase deficiency. Conclusions: We pioneered a method for testing OTC activity that normally carried on venous blood can be effectively performed on microblood heel samples. Meanwhile, our method presents a simpler, more stable and reproducible approach compared to colorimetry. [ABSTRACT FROM AUTHOR]

Background: Meat goat production is a worldwide industry with products such as meat, milk, soap, and fiber being produced. There are approximately 2.6 million meat goats in the United States. For breeding female ruminants, early pregnancy loss is estimated to be 30% within the first month of gestation. Extracellular L-citrulline (a precursor to L-arginine) is not degraded by ruminal microbes due to the lack of uptake. L-Arginine and thus L-citrulline, have beneficial impacts on placentation and, subsequently, fetal-placental development and survival. This study aimed to determine the impact of feeding L-citrulline to meat goats during gestation to improve reproductive success. Meat goats were fed either a control (CON) or L-citrulline (CIT) supplemented diet from d 12 to 82 of gestation. Blood samples were collected and sera were subjected to high-performance liquid chromatography analyses to quantify the abundance of amino acids. Pregnancy rates were determined on d 30, 61, and 90 of gestation, and litter weight, individual birth weights, and 90 d adjusted weaning weights were collected. Results: The concentrations of citrulline, ornithine, and arginine were greater in CIT does compared to CON does, but there was no difference in pregnancy rates between CON and CIT does. Birth weight was greater for male kids born as singles when compared to females, but this phenotype was not observed for kids born as twins or triplets. Further, males born to CON does had greater 90 d adjusted weaning weights than females, but this was not observed in the CIT group. Female kids born to CON and CIT Boer goats had heavier 90 d adjusted weaning weights than those born to Spanish or F1 Boer-Spanish does. Conclusion: This study provides proof of concept that feeding dietary L-citrulline increases concentrations of citrulline and arginine in blood of gestating meat goats. However, further studies are needed to understand the cellular mechanisms impacted by feeding this supplement. Regardless, this study demonstrated that feeding L-citrulline has the potential to increase reproductive performance in gestating ruminants. [ABSTRACT FROM AUTHOR]

Background/Objectives: Citrulline, an amino acid produced by small bowel enterocytes, has been proposed as a potential marker of intestinal absorptive capacity. The aim of this study is to evaluate whether measuring citrulline levels could be useful for celiac disease (CD) patients, both at the time of diagnosis and during follow-up. Methods: A multicenter prospective study was conducted. Citrulline levels were measured and compared in 93 pediatric patients classified into three groups. Group A: 28 patients with newly diagnosed CD. In this group, an additional measurement was performed after 3–6 months on a gluten-free diet (GFD). Group B: 32 patients with a prior CD diagnosis and on a GFD for at least 6 months. Group C: 33 healthy controls. Citrulline levels were correlated with clinical and laboratory variables, including serological markers. Statistical analysis: t-tests for paired groups and independent groups, Pearson and Spearman correlation tests. Results: Newly diagnosed CD patients had lower citrulline levels compared to those on a GFD for more than 6 months (27.13 vs. 32.42 µmol/L; p > 0.05). Citrulline levels were nearly identical between healthy controls and CD patients on a GFD for more than 6 months (32.48 vs. 32.42 µmol/L; p > 0.05). Starting a GFD led to a significant increase in citrulline levels in group A (from 27.13 to 37.43 µmol/L, p < 0.001). Conclusions: Plasma citrulline could serve as a valuable marker for mucosal recovery in the follow-up of diagnosed celiac patients adhering to a GFD. [ABSTRACT FROM AUTHOR]

Background/Objectives: The prevalence of cardiovascular-kidney-metabolic (CKM) syndrome is increasing rapidly, and cardiovascular complications pose significant risks in individuals with kidney disease and metabolic dysfunction. Understanding the mechanisms of CKM disorders is crucial, as is the discovery of novel preventive treatments. This study aimed to examine the therapeutic effects of a specially formulated nitric oxide-enhancing food additive in a mouse model of CKM syndrome induced by unilateral nephrectomy (UNX) in combination with chronic Western diet (WD) feeding. Methods: C57BL/6J mice underwent UNX and were fed a WD high in salt, sugar, and fat for 12 weeks, compared to sham-operated mice on standard chow. One group of UNX+WD mice received Flexovital (FLX), a food additive containing extracts of Rhodiola rosea and beetroot, and the amino acids L-arginine and L-citrulline. CKM parameters were assessed both in vivo and ex vivo alongside histological and biochemical analyses. Results: The UNX+WD mice showed an increase in body fat mass, the fat/lean mass ratio, and adipocyte area, of which most were significantly reduced by FLX. Elevated fasting glucose levels were also reduced by FLX, which tended towards improving glucose clearance. Elevated arterial blood pressure and endothelial dysfunction in UNX+WD mice were significantly reduced by FLX. FLX improved GFR and reduced glomerular and tubular injuries in UNX+WD mice. Additionally, FLX increased the P/O ratios of oxidative phosphorylation in the isolated renal mitochondria of UNX+WD mice. Conclusions: In this model of CKM syndrome, FLX effectively prevented the onset and progression of CKM dysfunctions induced by UNX+WD, as well as the associated organ injuries. These promising results highlight the need for validation in upcoming human trials. [ABSTRACT FROM AUTHOR]

Vine decline (VD) is a recalcitrant syndrome of watermelon, melon, and other cucurbits, often associated with soil-borne pathogens such as Monosporascus cannonballus and characterized by root necrosis, leaf chlorosis, and wilting at the later stage of fruit maturation. The present study examined VD's effects on watermelon fruits' metabolism. The VD-affected watermelon fruits had significantly lower lycopene and total solid contents. Still, polyphenols content and total antioxidant activities were comparable with the controls, suggesting that VD inhibited the ripening processes but maintained defensive processes in the fruits. The VD fruits showed a lower calcium level than the controls, while the contents of other major nutrition minerals were not significantly altered. The VD fruits had a lower content of total amino acids, and their composition was characterized by an increase in the percentage fractions for several amino acids, including citrulline, which may reflect the physiological response to the VD-related water deficit condition. The principal component analysis distinguished amino acid profiles between the VD and control fruits, demonstrating that VD significantly influenced their amino acid metabolisms. The present study revealed that VD imposed characteristic impacts on the biochemical behaviors in the watermelon fruits. [ABSTRACT FROM AUTHOR]

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age‐related diseases. This study examines age‐associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age‐dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging. Multi‐omics approaches identified chronological age‐related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and were influenced by genetic variation, sex, and body mass index. Integrating multi‐omics data and metabolite quantitative trait loci (mQTL) in humans and 525 diversity outbred mice functionally linked metabolism of arginine during RBC storage to increased vesiculation—a hallmark of RBC aging—and lower post‐transfusion hemoglobin increments. Thus, arginine metabolism is a biomarker of RBC and organismal aging, suggesting potential new targets for addressing sequelae of aging. [ABSTRACT FROM AUTHOR]

The primary objective of this study was to evaluate the effects of liquid (Fructose-added lactic acid bacteria, F-LAB) and commercial (Commercial LAB, C-LAB) probiotics sourced from Rye-Grass Lactic Acid Bacteria (LAB) on broiler chickens experiencing heat stress (HS). The research involved 240 broiler chicks, divided into six groups: control, F-LAB, C-LAB (raised at 24 °C), HS, F-LAB/HS, and C-LAB/HS (exposed to 5–7 h of 34–36 °C daily). The study followed a randomized complete block design, with each group consisting of 40 chicks. F-LAB and HS/F-LAB groups received a natural probiotic added to their drinking water at a rate of 0.5 ml/L, while C-LAB and HS/C-LAB groups were supplemented with a commercial probiotic at the same dosage. Control and HS groups received no probiotic supplementation. The duration of the study was 42 days, with data collected on growth performance, feed intake, feed conversion ratio, and health parameters. Statistical analyses were performed using ANOVA, and significant differences between groups were determined using post hoc tests. The results revealed that without probiotic supplementation, heat stress led to a decrease in body weight gain, T3 levels, citrulline, and growth hormone levels, along with an increase in the feed conversion ratio, serum corticosterone, HSP70, ALT, AST, and leptin levels (p < 0.05 for all). Heat stress also adversely affected cecal microbiota, reducing lactic acid bacteria count (LABC) while increasing Escherichia coli and coliform bacteria (CBC) counts. However, in the groups receiving probiotic supplementation under heat stress (F-LAB/HS and C-LAB/HS), these effects were alleviated (p < 0.05 for all). Particularly noteworthy was the observation that broiler chickens supplemented with natural lactic acid bacteria (F-LAB) exhibited greater resilience to heat stress compared to those receiving the commercial probiotic, as evidenced by improvements in growth, liver function, hormonal balance, intestinal health, and cecal microbiome ecology (p < 0.05). These findings suggest that the supplementation of naturally sourced probiotics (F-LAB) may positively impact the intestinal health of broiler chickens exposed to heat stress, potentially supporting growth and health parameters. [ABSTRACT FROM AUTHOR]

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Introduction: L-citrulline, a non-proteinogenic amino acid, is predominantly synthesized in the enterocytes of the small intestine, with smaller amounts produced in the kidneys, which plays a critical role in the detoxification of ammonia in the urea cycle, and serves as a precursor for nitric oxide (NO). Recent studies have highlighted citrulline's potential benefits in diverse physiological and pathological contexts, ranging from enhancing physical performance and muscle recovery to supporting cardiovascular health, mitigating endothelial dysfunction, and acting as a therapeutic agent in various health conditions. Aim of study: The study aims to provide a comprehensive summary of current knowledge on the biochemical characteristics, physiological functions, and therapeutic potential of citrulline. Materials and methods: A comprehensive scientific literature review was conducted using the PubMed database, focusing on studies published up to 2024, reporting experimental, clinical, or in vivo data related to citrulline's synthesis, biological functions, and therapeutic applications. Conclusion: Emerging evidence highlights citrulline's potential in treating various health conditions, such as erectile dysfunction, neurodegenerative diseases, and intestinal barrier dysfunction, as well as its protective effects in hepatic failure, wound healing, and oxidative stress-related damage. These findings suggest that citrulline may serve as a multifaceted therapeutic agent, meriting further research to optimize its clinical use.

Citrulline, a non-essential amino acid and precursor to L-arginine, plays a pivotal role in nitric oxide (NO) synthesis, with profound implications for vascular health and neuroprotection. By enhancing NO production, citrulline supports endothelial function, vasodilation, and cerebral circulation, thereby mitigating cognitive decline associated with aging and neurodegenerative diseases. Unlike direct arginine supplementation, citrulline offers superior bioavailability, bypassing first-pass metabolism and achieving sustained plasma levels of arginine. Furthermore, citrulline's antioxidant properties counteract oxidative stress by modulating reactive oxygen species (ROS), reducing lipid peroxidation, and protecting neuronal integrity. Emerging evidence suggests its potential in delaying endothelial senescence and preventing ferroptosis, establishing its role in vascular and neuroprotective strategies. Dietary sources, such as watermelon juice, further enhance citrulline’s accessibility, combining its bioactivity with additional antioxidants like lycopene. While existing studies underscore its promise, targeted research is needed to confirm its direct impact on cognitive function and explore its application in neurodegenerative populations. This review synthesizes current knowledge on citrulline's mechanisms, therapeutic potential, and broader implications for aging and vascular health.

Using a new red blood cell (RBC) metabolite extraction protocol, we performed a metabolomic analysis on RBCs in rheumatoid arthritis (RA) patients treated or not with methotrexate (MTX), with the two following objectives: to compare the RBC metabolic profiles of MTX-naïve RA patients and healthy controls (HC), and to investigate whether RBC profiles before and after MTX treatment in RA differed between responders and non-responders. Plasma analysis was performed in parallel. Metabolites were extracted and identified in RBCs and plasma by liquid chromatography-mass spectrometry. We compared the metabolomic fingerprints of 31 DMARD-naïve RA patients and 39 HCs. We also compared the RBC and plasma metabolomes of 25 RA patients who responded or not to MTX therapy before (M0) and after a 3-month treatment period (M3). Significance was determined by Storey's false discovery rate (FDR) q-values to correct for multiple testing. RA patients and HCs differed in the metabolomic signature of RBCs. The signature mainly contained amino acids (AA). Eleven metabolites, including 4 metabolites belonging to the carbohydrate subclass and 2 amino acids (creatine and valine) showed accumulation in RBCs from RA patients. Conversely, citrulline (fold change = 0.83; q = 0.025), histidine (fold change = 0.86; q = 0.014) and ergothioneine (EGT) (fold change = 0.66; q = 0.024), were lower in RBC of RA patients. Five plasma metabolites, including succinic acid and hydroxyproline, were higher in RA patients, and 7 metabolites, including DHEA sulfate, alanine, threonine and ornithine, were lower. Among RA patients undergoing MTX treatment pre-treatment (M0), EGT values were significantly lower in non-responders. In conclusion, low RBC levels of EGT, a food-derived AA barely detectable in plasma, characterize DMARD naïve RA patients and lack of response to MTX treatment. [ABSTRACT FROM AUTHOR]

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1–17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients' plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients' systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): −1.2 SDS (−1.9 to −0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from −0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = −0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The influence of molasses (M) and Lactobacillus rhamnosus (LR) on fermentation products, microbial communities, and metabolites in big-bale alfalfa silage was investigated. Alfalfa (Medicago sativa L.) was harvested at the third growth stage during the flowering stage in the experimental field of Linhui Grass Company from Tongliao City, Inner Mongolia. An alfalfa sample without additives was used as a control (C). M (20 g/kg) and LR (106 cfu/g) were added either alone or in combination. Alfalfa was fermented for 7, 14, and 56 d. Lactic acid content in the M, LR, and MLR groups increased, whereas the pH value and butyric acid, 2,3-butanediol, and ethanol contents decreased compared to those of C group after 7, 14, and 56 d of fermentation. A two-way analysis of variance (ANOVA) was performed to estimate the results. The LR group exhibited increased Lactobacillus abundance, whereas the M and MLR groups showed increased Weissella abundance compared to the C group. The relative contents of amino acids (tyrosine, isoleucine, threonine, arginine, valine, and citrulline) in the M and MLR groups were higher than those in the C group. During fermentation, the M, LR, and MLR groups showed decreased phenylalanine, isoleucine, and ferulic acid contents. Amino acids such as isoleucine and L-aspartic acid were positively correlated with Lactobacillus but negatively correlated with Weissella. In conclusion, combining high-throughput sequencing and liquid chromatography–mass spectrometry during anaerobic alfalfa fermentation can reveal new microbial community compositions and metabolite profiles, supporting the application of M, LR, and MLR as feed fermentation agents. [ABSTRACT FROM AUTHOR]

Endurance athletes often aim to improve their aerobic metabolism. The aim of this pilot study was to examine if malic acid and L-citrulline supplementation can improve aerobic metabolism and lactate elimination. Nine young (23.9 ± 1.9 years) recreational male athletes participated in this study. Following a standardised breakfast and a body composition analysis (InBody720), 6000 mg of citrulline and 3000 mg of malic acid or a placebo of 300 mL of water were consumed on three separate days in a cross-over design using a double-blind method. Sixty minutes after the supplementation, participants completed a ramp bicycle spiroergometer protocol (35 W/3 min) until reaching a respiratory exchange ratio (RER) of 1.1, followed by a 9 min active recovery. Cadence, heart rate (HR), rate of perceived exertion (RPE), respiratory parameters and lactate levels were registered. The RPExHR value was calculated to accurately characterise exhaustion. During the exercise protocol, citrulline supplementation induced significantly lower RER values at 70-105-140 W compared to malic acid and the placebo, respectively. There was no difference in lactate levels neither during rest nor at RER 1.1. RPExHR rate values were significantly lower after malic acid supplementation compared to placebo at 175 and 210 W. Power at RER 1.1 was higher after malic acid (+4 W) and citrulline (+5 W) supplementation. Although the supplementation failed to decrease lactate levels, lower RER and RPE values may indicate a performance-enhancing benefit. [ABSTRACT FROM AUTHOR]

Background: Arginine is a conditionally essential amino acid that is depleted in critically ill or surgical patients. In pediatric and adult patients, sepsis results in an arginine-deficient state, and the depletion of plasma arginine is associated with greater mortality. However, direct supplementation of arginine can result in the excessive production of nitric oxide (NO), which can contribute to the hypotension and macrovascular hypo-reactivity observed in septic shock. Pegylated arginine deiminase (ADI-PEG20, pegargiminase) reduces plasma arginine and generates citrulline that can be transported intracellularly to generate local arginine and NO, without resulting in hypotension, while maintaining microvascular patency. The objective of this study was to assess the efficacy of ADI-PEG20 with and without supplemental intravenous citrulline in mitigating hypovolemic shock, maintaining tissue levels of arginine, and reducing systemic inflammation in an endotoxemic pediatric pig model. Methods: Twenty 3-week-old crossbred piglets were implanted with jugular and carotid catheters as well as telemetry devices in the femoral artery to measure blood pressure, body temperature, heart rate, and respiration rate. The piglets were assigned to one of three treatments before undergoing a 5 h lipopolysaccharide (LPS) infusion protocol. Twenty-four hours before LPS infusion, control pigs (LPS; n=6) received saline, ADI-PEG20 pigs (n=7) received an injection of ADI-PEG20, and seven pigs (ADI-PEG20 + CIT pigs [n=7]) received ADI-PEG20 and 250 mg/kg citrulline intravenously. Pigs were monitored throughout LPS infusion and tissue was harvested at the end of the protocol. Results: Plasma arginine levels decreased and remained low in ADI-PEG20 + CIT and ADI-PEG20 pigs compared with LPS pigs but tissue arginine levels in the liver and kidney were similar across all treatments. Mean arterial pressure in all groups decreased from 90 mmHg to 60 mmHg within 1 h of LPS infusion but there were no significant differences between treatment groups. ADI-PEG20 and ADIPEG20 + CIT pigs had less CD45+ infiltrate in the liver and lung and lower levels of pro-inflammatory cytokines in the plasma. Conclusion: ADI-PEG20 and citrulline supplementation failed to ameliorate the hypotension associated with acute endotoxic sepsis in pigs but reduced systemic and local inflammation in the lung and liver. [ABSTRACT FROM AUTHOR]

Simple Summary: L-citrulline, as a non-essential amino acid, is recognized for its effectiveness in enhancing arginine bioavailability and nitric oxide (NO) synthesis, drawing significant attention from the scientific community for its potential to improve athletic performance. This study investigated the effects of L-citrulline supplementation on the racing performance of Yili horses as well as on the blood acid–base balance, physiological and biochemical blood indices, and antioxidant markers before and after an exercise. Additionally, changes in the plasma amino acid metabolism and polyamine levels were examined. The results indicate that the supplementation of 50 g of L-citrulline to the horses' diet significantly increased the plasma concentrations of citrulline and arginine and provided a certain improvement in the athletic performance of the Yili horses. Additionally, compared to a control group, the total protein and lactate dehydrogenase levels were significantly elevated 2 h before and 2 h after the race, while the lactate concentration immediately post-race was significantly reduced. The objective of this study was to evaluate the effects of pre-exercise L-citrulline supplementation on the athletic performance of Yili speed-racing horses during a high-intensity exercise. On the 20th day of the experiment, blood samples were collected at 3 h and 6 h post-supplementation to measure the amino acid and polyamine concentrations. On the 38th day of the experiment, the horses participated in a 2000 m speed race, and three distinct blood samples were gathered for assessing blood gases, hematological parameters, the plasma biochemistry, antioxidant parameters, and NO concentrations. The results indicate that the L-citrulline group showed a significant increase in the plasma citrulline and arginine concentrations. Conversely, the concentrations of alanine, serine, and threonine were significantly decreased. The glycine concentration decreased significantly, while there was a trend towards an increase in the glutamine concentration. Additionally, the levels of putrescine and spermidine in the plasma of the L-citrulline group were significantly increased. In terms of exercise performance, L-citrulline can improve the exercise performance of sport horses, significantly reduce the immediate post-race lactate levels in Yili horses, and accelerate the recovery of blood gas levels after an exercise. Furthermore, in the L-citrulline group of Yili horses, The levels of the total protein of plasma, superoxide dismutase, catalase, and lactate dehydrogenase were significantly increased both 2 h before and 2 h after the race. The total antioxidant capacity showed a highly significant increase, while the malondialdehyde content significantly decreased. In the immediate post-race period, the creatinine content in the L-citrulline group significantly increased. In conclusion, this study demonstrates that L-citrulline supplementation can influence the circulating concentrations of L-citrulline and arginine in Yili horses, enhance the antioxidant capacity, reduce lactate levels, and improve physiological and biochemical blood parameters, thereby having a beneficial effect on the exercise performance of athletic horses. [ABSTRACT FROM AUTHOR]

Pseudomonas fragi (P. fragi) is usually detected in low-temperature meat products, and seriously threatens food safety and human health. Therefore, the study investigated the antibacterial mechanism of linalool against P. fragi from membrane damage and metabolic disruption. Results from field-emission transmission electron microscopy (FETEM) and atomic force microscopy (AFM) showed that linalool damage membrane integrity increases surface shrinkage and roughness. According to Fourier transform infrared (FTIR) spectra results, the components in the membrane underwent significant changes, including nucleic acid leakage, carbohydrate production, protein denaturation and modification, and fatty acid content reduction. The data obtained from amino acid metabolomics indicated that linalool caused excessive synthesis and metabolism of specific amino acids, particularly tryptophan metabolism and arginine biosynthesis. The reduced activities of glucose 6-phosphate dehydrogenase (G6PDH), malate dehydrogenase (MDH), and phosphofructokinase (PFK) suggested that linalool impair the respiratory chain and energy metabolism. Meanwhile, genes encoding the above enzymes were differentially expressed, with pfkB overexpression and zwf and mqo downregulation. Furthermore, molecular docking revealed that linalool can interact with the amino acid residues of G6DPH, MDH and PFK through hydrogen bonds. Therefore, it is hypothesized that the mechanism of linalool against P. fragi may involve cell membrane damage (structure and morphology), disturbance of energy metabolism (TCA cycle, EMP and HMP pathway) and amino acid metabolism (cysteine, glutamic acid and citrulline). These findings contribute to the development of linalool as a promising antibacterial agent in response to the food security challenge. [ABSTRACT FROM AUTHOR]

This study investigated the correlation between oxidative stress and blood amino acids associated with nitric oxide metabolism in adult patients with coronavirus disease (COVID-19) pneumonia. Clinical data and serum samples were prospectively collected from 100 adult patients hospitalized for COVID-19 between July 2020 and August 2021. Patients with COVID-19 were categorized into three groups for analysis based on lung infiltrates, oxygen inhalation upon admission, and the initiation of oxygen therapy after admission. Blood data, oxidative stress-related biomarkers, and serum amino acid levels upon admission were compared in these groups. Patients with lung infiltrations requiring oxygen therapy upon admission or starting oxygen post-admission exhibited higher serum levels of hydroperoxides and lower levels of citrulline compared to the control group. No remarkable differences were observed in nitrite/nitrate, asymmetric dimethylarginine, and arginine levels. Serum citrulline levels correlated significantly with serum lactate dehydrogenase and C-reactive protein levels. A significant negative correlation was found between serum levels of citrulline and hydroperoxides. Levels of hydroperoxides decreased, and citrulline levels increased during the recovery period compared to admission. Patients with COVID-19 with extensive pneumonia or poor oxygenation showed increased oxidative stress and reduced citrulline levels in the blood compared to those with fewer pulmonary complications. These findings suggest that combined oxidative stress and abnormal citrulline metabolism may play a role in the pathogenesis of COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

Background: Testicular torsion is a critical urological emergency that can lead to testicular ischemia and significant tissue damage. Citrulline, a supplement known for enhancing cellular metabolism and mitigating oxidative stress and inflammation, has been explored for its protective effects against testicular injury resulting from torsion and detorsion in rat models. Methods: This study involved 42 Wistar rats, divided into six groups: Sham, torsion/detorsion (T/D), and four groups receiving varying doses of Citrulline (300, 600, 900 mg/kg) and vitamin E (20 mg/kg). A surgical procedure was performed to induce torsion by rotating the left testicle for 4 hr, followed by reperfusion. Daily oral administration of the supplements continued for one week post-surgery. Assessments included oxidative stress markers, apoptosis, inflammation, pathology, and sperm parameters. Statistical analysis was conducted using GraphPad Prism. Results: Citrulline administration at doses of 600 and 900 mg/kg significantly reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels. Additionally, it increased glutathione (GSH) levels and decreased protein carbonyl levels at the 900 mg/kg dose. The expression of interleukin-6 (IL-6) decreased at 900 mg/ kg, tumor necrosis factor-alpha (TNF-α) levels dropped at 600 and 900 mg/kg, and the pro-apoptotic factor Bax was reduced at all doses. Sperm analysis showed improved sperm count and motility at the 900 mg/kg dose. Histological examination revealed significant positive effects of Citrulline on testicular tissue. Conclusion: Citrulline effectively lowers oxidative stress, inflammation, while enhancing sperm quality and pathological outcomes. These results indicate that Citrulline has potential as a therapeutic agent for testicular torsion. [ABSTRACT FROM AUTHOR]

Canine parvovirus (CPV) poses a significant threat to dogs globally, leading to both illness and death. Examining biomarkers may enhance early detection of the disease, gauge hospital stay duration, increase disease severity, and estimate patient prognosis. The purpose of this study was to examine the influence of diagnostic (hematological and biochemical) and prognostic biomarkers (Citrulline, serum amyloid A (SAA), thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), and interferon (IFN)) in CPV infection. Blood samples were collected from CPV-positive dogs (Experimental Group, n=20) and healthy dogs (Control Group, n=20) included in the study. Consequently of laboratory analyses, it was observed that citrulline, TNF-α, and SOD levels were significantly increased in CPV-positive animals compared to healthy animals, while IL-6 and SAA levels decreased. Also, leukocyte (WBC), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), thrombocyte (THR), pH, chloride (Cl), lactate (Lac), glucose, sO2, and HCO3 levels were lower in CPV-positive dogs compared to the healthy ones (P<0.05). As a result, it was interpreted that the inflammatory and oxidative response changes can be measured with the investigated parameters and thus the animals can be in the recovery period despite the clinical symptoms. It was concluded that the measured biomarkers can provide important information in terms of the prognosis of CPV infection when measuring in different periods of the disease or in experimental infection model studies. [ABSTRACT FROM AUTHOR]

Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and compare them with results from 51 healthy subjects. A sample analysis was conducted using liquid chromatography–tandem mass spectrometry. We obtained levels of 28 substances, including amino acids, biogenic amines, carnitine, and acetylcarnitine. Kynurenine (p = 0.000001), tyrosine (p = 0.0002), asparagine (p = 0.001), proline (p = 0.012), and the kynurenine/tryptophan ratio (p < 0.000001) were identified as features that differed between the studied groups, being significantly lower in patients with PKU. Glycine (p = 0.000012), putrescine (p = 0.0055), asymmetric dimethylarginine (p = 0.01), creatinine (p = 0.035) levels, as well as the total level of glucogenic amino acids (p = 0.0018), and the ratios of putrescine/ornithine (p = 0.003) and citrulline/ornithine (p = 0.0043) were significantly higher in the PKU group. In conclusion, the amino acid profiles in patients with PKU differ significantly from those in healthy peers, with potential clinical implications. These findings confirm the importance of metabolic testing in clinical practice and highlight the necessity for adequate dietary monitoring and adjustment. [ABSTRACT FROM AUTHOR]

This article provides information on superficial necrolytic dermatitis (SND), a dermatologic condition that affects humans, dogs, and rarely cats. SND is often associated with metabolic disturbances and can be caused by glucagon-secreting tumors or hepatopathy. It is characterized by cutaneous lesions and is most commonly found in older, smaller-breed dogs. Diagnostic findings include increased alkaline phosphatase and alanine aminotransferase levels, as well as hypoaminoacidemia. The article discusses the cause, diagnosis, and treatment options for SND, emphasizing the importance of early recognition and treatment to improve survival times. The optimal treatment involves a combination of intravenous amino acid infusions, enteral supplements, and high-protein home-cooked diets. [Extracted from the article]

Introduction: Proliferative diabetic retinopathy (PDR) is a common diabetes complication, significantly impacting vision and quality of life. Previous studies have suggested a potential link between arginine pathway metabolites and diabetic retinopathy (DR). Connective tissue growth factor (CTGF) plays a role in the occurrence and development of fibrovascular proliferation (FVP) in PDR patients. However, the relationship between arginine pathway metabolites and FVP in PDR remains undefined. This study aimed to explore the correlation between four arginine pathway metabolites (arginine, asymmetric dimethylarginine[ADMA], ornithine, and citrulline) and the severity of FVP in PDR patients. Methods: In this study, plasma and aqueous humor samples were respectively collected from 30 patients with age-related cataracts without diabetes mellitus (DM) and from 85 PDR patients. The PDR patients were categorized as mild-tomoderate or severe based on the severity of fundal FVP. The study used KruskalWallis test to compare arginine, ADMA, ornithine, and citrulline levels across three groups. Binary logistic regression identified risk factors for severe PDR. Spearman correlation analysis assessed associations between plasma and aqueous humor metabolite levels, and between ADMA and CTGF levels in aqueous humor among PDR patients. Results: ADMA levels in the aqueous humor were significantly greater in patients with severe PDR than in those with mild-to-moderate PDR(P=0.0004). However, the plasma and aqueous humor levels of arginine, ornithine, and citrulline did not significantly differ between mild-to-moderate PDR patients and severe PDR patients (P>0.05). Binary logistic regression analysis indicated that the plasma (P=0.01) and aqueous humor (P=0.006) ADMA levels in PDR patients were risk factors for severe PDR. Furthermore, significant correlations were found between plasma and aqueous humor ADMA levels (r=0.263, P=0.015) and between aqueous humor ADMA and CTGF levels (r=0.837, P<0.001). Conclusion: Elevated ADMA levels in plasma and aqueous humor positively correlate with the severity of FVP in PDR, indicating ADMA as a risk factor for severe PDR. [ABSTRACT FROM AUTHOR]

Objective: The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients. Methods: We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model. Results: For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1mmol/L, Cit higher than 26 mmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR. Conclusion: Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors. [ABSTRACT FROM AUTHOR]

Simple Summary: L-Glutamate (Glu) and L-glutamine (Gln) are abundant amino acids in feedstuffs and ruminants. Dietary Gln is extensively utilized by ruminal microbes, but dietary Glu undergoes little catabolism by these microbes because they do not take up extracellular Glu due to the lack of the necessary transporters. Microbial proteins and dietary Glu exit the rumen into the abomasum and then the small intestine, where proteins undergo hydrolysis to release amino acids (including Glu and Gln) and small peptides for transport into enterocytes. Most dietary Gln escapes the underdeveloped rumen of preruminants, instead entering the abomasum and the small intestine. Within the enterocytes, Glu and Gln are extensively oxidized to provide ATP and are actively used to synthesize glutathione and other amino acids (alanine, ornithine, citrulline, arginine, proline, and aspartate), whereas Gln and aspartate are essential for purine and pyrimidine syntheses. Under normal feeding conditions, all diet- and rumen-derived Glu and Gln are extracted by the small intestine and, therefore, do not enter the portal circulation. De novo synthesis plays a crucial role in maintaining the homeostasis of Glu and Gln in the whole body but may be insufficient for maximal growth performance, production (e.g., lactation and pregnancy), and optimal health in ruminants. Dietary supplementation with Glu or Gln can safely improve the digestive, endocrine, and reproduction functions of ruminants and thus augment health and production parameters. Although both L-glutamate (Glu) and L-glutamine (Gln) have long been considered nutritionally nonessential in ruminants, these two amino acids have enormous nutritional and physiological importance. Results of recent studies revealed that extracellular Gln is extensively degraded by ruminal microbes, but extracellular Glu undergoes little catabolism by these cells due to the near absence of its uptake. Ruminal bacteria hydrolyze Gln to Glu plus ammonia and, intracellularly, use both amino acids for protein synthesis. Microbial proteins and dietary Glu enter the small intestine in ruminants. Both Glu and Gln are the major metabolic fuels and building blocks of proteins, as well as substrates for the syntheses of glutathione and amino acids (alanine, ornithine, citrulline, arginine, proline, and aspartate) in the intestinal mucosa. In addition, Gln and aspartate are essential for purine and pyrimidine syntheses, whereas arginine and proline are necessary for the production of nitric oxide (a major vasodilator) and collagen (the most abundant protein in the body), respectively. Under normal feeding conditions, all diet- and rumen-derived Glu and Gln are extensively utilized by the small intestine and do not enter the portal circulation. Thus, de novo synthesis (e.g., from branched-chain amino acids and α-ketoglutarate) plays a crucial role in the homeostasis of Glu and Gln in the whole body but may be insufficient for maximal growth performance, production (e.g., lactation and pregnancy), and optimal health (particularly intestinal health) in ruminants. This applies to all types of feeding systems used around the world (e.g., rearing on a milk replacer before weaning, pasture-based production, and total mixed rations). Dietary supplementation with the appropriate doses of Glu or Gln [e.g., 0.5 or 1 g/kg body weight (BW)/day, respectively] can safely improve the digestive, endocrine, and reproduction functions of ruminants to enhance their productivity. Both Glu and Gln are truly functional amino acids in the nutrition of ruminants and hold great promise for improving their health and productivity. [ABSTRACT FROM AUTHOR]

Objective: Amino acid (AA) metabolism plays a vital role in liver regeneration. However, its measuring utility for post-hepatectomy liver regeneration under different conditions remains unclear. We aimed to combine machine learning (ML) models with AA metabolomics to assess liver regeneration in health and non-alcoholic steatohepatitis (NASH). Methods: The liver index (liver weight/body weight) was calculated following 70% hepatectomy in healthy and NASH mice. The serum levels of 39 amino acids were measured using ultra-high performance liquid chromatography-tandem mass spectrometry analysis. We used orthogonal partial least squares discriminant analysis to determine differential AAs and disturbed metabolic pathways during liver regeneration. The SHapley Additive exPlanations algorithm was performed to identify potential AA signatures, and five ML models including least absolute shrinkage and selection operator, random forest, K-nearest neighbor (KNN), support vector regression, and extreme gradient boosting were utilized to assess the liver index. Results: Eleven and twenty-two differential AAs were identified in the healthy and NASH groups, respectively. Among these metabolites, arginine and proline metabolism were commonly disturbed metabolic pathways related to liver regeneration in both groups. Five AA signatures were identified, including hydroxylysine, L-serine, 3-methylhistidine, L-tyrosine, and homocitrulline in healthy group, and L-arginine, 2-aminobutyric acid, sarcosine, beta-alanine, and L-cysteine in NASH group. The KNN model demonstrated the best evaluation performance with mean absolute error, root mean square error, and coefficient of determination values of 0.0037, 0.0047, 0.79 and 0.0028, 0.0034, 0.71 for the healthy and NASH groups, respectively. Conclusion: The KNN model based on five AA signatures performed best, which suggests that it may be a valuable tool for assessing post-hepatectomy liver regeneration in health and NASH. [ABSTRACT FROM AUTHOR]

Citrulline malate (CM) has been touted as a nutritional ergogenic aid for sports performance, with purported mechanisms of increased muscle blood flow, ammonia clearance, and adenosine triphosphate resynthesis. Combined, these physiological benefits may be best applied to whole-body endurance exercises, such as swimming, though this postulate has not yet been explored. In a double-blind, randomised, and crossover design, 11 national-level swimmers (age: 17 ± 3 years, height: 1.71 ± 0.05 m, body mass: 60.6 ± 8.3 kg) from a high-performance swimming club ingested either 15 g CM or a placebo (PLA) 60 min before six × 300 m freestyle bouts (at 4.5 min intervals). Blood lactate, blood pressure, and ratings of perceived exertion were measured at baseline, 60 min post-ingestion, and immediately post-exercise. Neither mean 300 m swimming time (CM: 212.0 ± 9.6 vs. PLA: 212.8 ± 7.7 s, p = 0.683, g = 0.09) nor any individual swimming bouts (p = 0.679, Pŋ2 = 0.02) were improved with CM ingestion. Moreover, no differences in any physiological or subjective measures were identified between conditions (all p > 0.05). Whether the proposed CM mechanisms were active was unclear as more direct physiological measures (i.e., plasma NO, ammonia) may have been required. Resultantly, these observations do not support an ergogenic effect of acute CM ingestion in highly trained swimmers. [ABSTRACT FROM AUTHOR]

Citrulline (C6H13N3O3) is an amino acid found in the body as a zwitterion. This means its carboxylic and amine groups can act as Lewis donors to chelate metal cations. In addition, citrulline possesses a terminal ureido group on its aliphatic chain, which also appears to coordinate. Here, two new mixed complexes of citrulline were made with 1,10-phenanthroline and 2,2′-bipyridine. These compounds, once dissolved in water, gave aquo-complexes that were subject to DFT studies and in vitro toxicity studies on cancer cell lines (HeLa, MDA-MB-231, HCT 15, and MCF7) showed promising results. Docking studies with DNA were also conducted, indicating potential anticancer properties. [ABSTRACT FROM AUTHOR]

Simple Summary: The first and second limiting amino acids in ruminants 66 are methionine and lysine, respectively, and an appropriate lysine-to-methionine ratio is necessary for amino acid balance in a low-protein diet. A Lys/Met ratio of 1:1 increased the antioxidant capacity and the activities of digestive enzymes and reduced the production of ammonia nitrogen in Tibetan sheep. In addition, 16S rDNA sequencing revealed that a Lys/Met ratio of 1:1 significantly increased the Ace and Chao1 indices, and non-target metabolomics analysis revealed that cis-jasmone and Val-Asp-Arg could be involved in mediating the antioxidant capacity and increasing the activity of digestive enzyme activities in Tibetan sheep rumen. Phosphoric acid, one of the metabolic products, increased cellulase activity by regulating the abundance of Succiniclasticum through the oxidative phosphorylation pathway. In ruminants, supplementing appropriate amounts of amino acids improves growth, feed utilization efficiency, and productivity. This study aimed to assess the effects of different Lys/Met ratios on the ruminal microbial community and the metabolic profiling in Tibetan sheep using 16S rDNA sequencing and non-target metabolomics. Ninety-two-month-old Tibetan rams (initial weight = 15.37 ± 0.92 kg) were divided into three groups and fed lysine/methionine (Lys/Met) of 1:1 (LP-L), 2:1 (LP-M), and 3:1 (LP-H) in low-protein diet, respectively. Results: The T-AOC, GSH-Px, and SOD were significantly higher in the LP-L group than in LP-H and LP-M groups (p < 0.05). Cellulase activity was significantly higher in the LP-L group than in the LP-H group (p < 0.05). In the fermentation parameters, acetic acid concentration was significantly higher in the LP-L group than in the LP-H group (p < 0.05). Microbial sequencing analysis showed that Ace and Chao1 indicators were significantly higher in LP-L than in LP-H and LP-M (p < 0.05). At the genus level, the abundance of Rikenellaceae RC9 gut group flora and Succiniclasticum were significantly higher in LP-L than in LP-M group (p < 0.05). Non-target metabolomics analyses revealed that the levels of phosphoric acid, pyrocatechol, hydrocinnamic acid, banzamide, l-gulono-1,4-lactone, cis-jasmone, Val-Asp-Arg, and tropinone content were higher in LP-L. However, l-citrulline and purine levels were lower in the LP-L group than in the LP-M and LP-H groups. Banzamide, cis-jasmone, and Val-Asp-Arg contents were positively correlated with the phenotypic contents, including T-AOC, SOD, and cellulase. Phosphoric acid content was positively correlated with cellulase and lipase activities. In conclusion, the Met/Lys ratio of 1:1 in low-protein diets showed superior antioxidant status and cellulase activity in the rumen by modulating the microbiota and metabolism of Tibetan sheep. [ABSTRACT FROM AUTHOR]

Pyruvate carboxylase, a mitochondrial enzyme, catalyses the conversion of glycolytic end-product pyruvate to tricarboxylic acid cycle intermediate, oxaloacetate. Rare pyruvate carboxylase deficiency manifests in three clinical and biochemical phenotypes: neonatal onset type A, infantile onset type B and a benign C type. The objective of this case series is to expand the knowledge of overlapping clinical and biochemical phenotypes of pyruvate carboxylase deficiency. We report three Sri Lankan neonates including two siblings, of two unrelated families with pyruvate carboxylase deficiency. All three developed respiratory distress within the first few hours of birth. Two siblings displayed typical biochemical findings reported in type B. The other proband with normal citrulline, lysine, moderate lactate, paraventricular cystic lesions, bony deformities, and a novel missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC gene, biochemically favoured type A. Our findings indicate the necessity of prompt laboratory investigations in a tachypneic neonate with coexisting metabolic acidosis, as early recognition is essential for patient management and family counselling. Further case studies are required to identify overlapping symptoms and biochemical findings in different types of pyruvate carboxylase deficiency phenotypes. [ABSTRACT FROM AUTHOR]

Simple Summary: Given the escalating production of livestock and poultry, coupled with the surging cost of soybean meal, the search for alternative raw materials that can replace soybean meal is becoming more important. Agricultural by-products like rapeseed meal, cottonseed meal, and sunflower seed meal present a promising plant-based protein alternative to soybean meal in pig production. This study revealed that corn–soybean–miscellaneous meals and corn–miscellaneous meals significantly enhanced the average daily growth of pigs weighing 25–50 kg compared to a corn–soybean meal diet. These findings suggest that miscellaneous meals can effectively serve as an alternative feed ingredient to soybean meal in pig diets. This research can be helpful to further develop miscellaneous meals (rapeseed meal, cottonseed meal, and sunflower meal) as a functional alternative feed ingredient to soybean meal. The present study aims to determine the effect of miscellaneous meals (rapeseed meal, cottonseed meal, and sunflower meal) replacing soybean meal in feed on growth performance, apparent digestibility of nutrients, serum biochemical parameters, serum free amino acid content, microbiota composition and SCFAs content in growing pigs (25–50 kg). A total of 72 (Duroc × Landrace × Yorkshire) growing pigs with initial weights of 25.79 ± 0.23 kg were randomly divided into three treatments. The pigs were fed corn–soybean meal (CON), corn–soybean–miscellaneous meals (CSM), and corn–miscellaneous meals (CMM). Each treatment included six replicates with four pigs per pen (n = 24, 12 barrows and 12 gilts). Soybean meal accounted for 22.10% of the basal diet in the CON group. In the CSM group, miscellaneous meals partially replaced soybean meal with a mixture of 4.50% rapeseed meal, 3.98% cottonseed meal, and 4.50% sunflower meal. In the CMM group, miscellaneous meals entirely replaced soybean meal with a mixture of 8.50% rapeseed meal, 8.62% cottonseed meal, and 8.5% sunflower. The results showed that compared with the CON, the CSM and CMM groups significantly improved the average daily gain (ADG) of growing pigs during the 25–50 kg stage (p < 0.05) but had no effects on average daily feed intake (ADFI) and average daily feed intake/average daily gain (F/G) (p > 0.05). Moreover, the CMM group significantly reduced nutrient apparent digestibility of gross energy compared with the CON group. The serum biochemical parameters results showed that the CSM group significantly improved the contents of total protein (TP) compared with the CON group (p < 0.05). The CMM group significantly improved the contents of total protein (TP), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) compared with the CON group in serum (p < 0.05). In comparison with the CON group, the CMM group also significantly improved lysine (Lys), threonine (Thr), valine (Val), isoleucine (Ile), leucine (Leu), phenylalanine (Phe), arginine (Arg), and citrulline (Cit) levels in serum (p < 0.05). However, the CMM group significantly decreased non-essential amino acid content glycine (Gly) in serum compared with CON (p < 0.05), while compared with the CON group, the CSM and CMM groups had no significant effects on the relative abundance, the alpha-diversity, or the beta-diversity of fecal microbiota. Moreover, compared with the CON group, the CSM group significantly increased butyric acid and valeric acid contents of short-chain fatty acids (SCFAs) in feces (p < 0.05). In contrast to the CON group, the CMM group significantly reduced the contents of SCFAs in feces, including acetic acid, propionic acid, and isobutyric acid (p < 0.05). Collectively, the results of the present study indicate that miscellaneous meals (rapeseed meal, cottonseed meal, and sunflower meal) can partially replace the soybean meal and significantly improve the growth performance of growing pigs during the 25–50 kg stage. Thus, miscellaneous meals are a suitable protein source as basal diets to replace soybean meals for 25–50 kg growing pigs. These results can be helpful to further develop miscellaneous meals as a functional alternative feed ingredient to soybean meal. [ABSTRACT FROM AUTHOR]

Depression will be the disease with the highest incidence worldwide by 2030. Data indicate that postmenopausal women have a higher incidence of mood disorders, and this high vulnerability seems to be related to hormonal changes and weight gain. Although research evaluating the profile of metabolites in mood disorders is advancing, further research, maintaining consistent methodology, is necessary to reach a consensus. Therefore, the objective of the present study was to carry out an exploratory analysis of the plasma polar metabolites of pre- and postmenopausal women to explore whether the profile is affected by depression. The plasma analysis of 50 polar metabolites was carried out in a total of 67 postmenopausal women, aged between 50 and 65 years, either without depression (n = 25) or with depression symptoms (n = 42), which had spontaneous onset of menopause and were not in use of hormone replacement therapy, insulin, or antidepressants; and in 42 healthy premenopausal women (21 without depression and 21 with depression symptoms), aged between 40 and 50 years and who were not in use of contraceptives, insulin, or antidepressants. Ten metabolites were significantly affected by depression symptoms postmenopause, including adenosine (FDR = 3.778 × 10−14), guanosine (FDR = 3.001 × 10−14), proline (FDR = 1.430 × 10−6), citrulline (FDR = 0.0001), lysine (FDR = 0.0004), and carnitine (FDR = 0.0331), which were down-regulated, and dimethylglycine (FDR = 0.0022), glutathione (FDR = 0.0048), creatine (FDR = 0.0286), and methionine (FDR = 0.0484) that were up-regulated. In premenopausal women with depression, oxidized glutathione (FDR = 0.0137) was down-regulated, and dimethylglycine (FDR = 0.0406) and 4-hydroxyproline (FDR = 0.0433) were up-regulated. The present study provided new data concerning the consequences of depression on plasma polar metabolites before and after the establishment of menopause. The results demonstrated that the postmenopausal condition presented more alterations than the premenopausal period and may indicate future measures to treat the disturbances involved in both menopause and depression. [ABSTRACT FROM AUTHOR]

Watermelons are one of the most important crop species, and they are enjoyed across the globe; however, the cultivation of watermelon commercial varieties in arid regions is challenging, as they are highly susceptible to water deficit. Conversely, their wild relatives and traditional landraces have shown a higher tolerance to water deficit, which makes them important study material. Therefore, this study was undertaken to evaluate the potential roles of two compatible osmolytes (citrulline and arginine) in the tolerance of local watermelon accessions to drought stress. Four commonly cultivated watermelon accessions were used in this study to evaluate their response when exposed to water deficit stress. The accessions were planted in stress boxes in the greenhouse and allowed to grow until the fourth leaf was fully open and then the water deficit stress was initiated by withholding water for a period of nine days, before rewatering for three days. Data and leaf samples were collected at three-day intervals. The common drought indicators that were assessed, like chlorophyll fluorescence, showed that Clm-08 (wild watermelon) had significantly different results when compared to the other accessions; the Fv/Fm values for days 3, 6, and 9 were significantly higher than those of the other accessions, while phiNPQ was higher in the Clm-08 with average values of 0.41 and 0.41 on days 6 and 9 of the drought stress, respectively. This suggests that the wild watermelon responded differently to drought stress when compared with the other accessions. Arginine and citrulline are important osmolytes that play an important role in stress tolerance, and the results of the current study correlate with the common physiological indicators. The expression pattern for both the biochemical and molecular analyses of the two compatible osmolytes was higher in Clm-08 in comparison with that of the other accessions. The gene expressions of the enzymes in the citrulline and arginine pathways were higher in Clm-08; Cla022915 (CPS) recorded a 6-fold increase on day 6 and Cla002611 (ASS) recorded an 11-fold increase. This suggests that citrulline and arginine play an important role in watermelon tolerance to drought stress. [ABSTRACT FROM AUTHOR]

All forms of life are presumed to synthesize arginine from citrulline via a two-step pathway consisting of argininosuccinate synthetase and argininosuccinate lyase using citrulline, adenosine 5'-triphosphate (ATP), and aspartate as substrates. Conversion of arginine to citrulline predominantly proceeds via hydrolysis. Here, from the hyperthermophilic archaeon Thermococcus kodakarensis, we identified an enzyme which we designate "arginine synthetase". In arginine synthesis, the enzyme converts citrulline, ATP, and free ammonia to arginine, adenosine 5'-diphosphate (ADP), and phosphate. In the reverse direction, arginine synthetase conserves the energy of arginine deimination and generates ATP from ADP and phosphate while releasing ammonia. The equilibrium constant of this reaction at pH 7.0 is [Cit][ATP][NH3]/[Arg][ADP][Pi] = 10.1 ± 0.7 at 80 °C, corresponding to a ΔG°' of -6.8 ± 0.2 kJ mol-1. Growth of the gene disruption strain was compared to the host strain in medium composed of amino acids. The results suggested that arginine synthetase is necessary in providing ornithine, the precursor for proline biosynthesis, as well as in generating ATP. Growth in medium supplemented with citrulline indicated that arginine synthetase can function in the direction of arginine synthesis. The enzyme is widespread in nature, including bacteria and eukaryotes, and catalyzes a long-overlooked energy-conserving reaction in microbial amino acid metabolism. Along with ornithine transcarbamoylase and carbamate kinase, the pathway identified here is designated the arginine synthetase pathway. [ABSTRACT FROM AUTHOR]

Background: L-Arginine (Arg) is an essential amino acid and a precursor for the synthesis of vascular nitric oxide, while L-Citrulline is a non-essential amino acid substrate for increasing L-arginine. Both L-arginine and L-Citrulline in translational studies may acutely lower the blood pressure. Current meta-analysis for L-arginine or L-Citrulline interventions in blood pressure have identified significant heterogeneity. Clinical trial evidence for L-arginine or L-Citrulline in chronic blood pressure reduction in the general population requires an examination of trial designs, as not all translational studies may have influenced vascular reactivity. Our aims are to explore whether L-arginine and L-citrulline intervention trials in chronic blood pressure consider standardized end points relevant to the general adult populations. Methods: A step-wise search on clinicaltrials.gov, the U.S. Library of Medicine registry for clinical trials, was performed including the following keyword search parameters: "completed" "L-Citrulline" "L-arginine" trial", and "adults", involving "blood pressure" reduction as a primary end point in adult humans. Results: Of the forty-four completed trials, only five were included for analysis. Following the careful evaluation of trial design, we observed heterogeneity across participant inclusion criteria (population sample size, age range, sex), interventional design (dosages, duration), and primary outcomes, measured with respect to changes in diastolic or systolic blood pressure. Conclusion: In conclusion, there is a lack of robust trial design evidence to suggest that L-arginine or L-Citrulline, based on current RCTs in the general population, have an overall positive effect on vascular endothelial reactivity and a beneficial chronic blood pressure-lowering effect. Indeed, conclusions drawn from human meta-analysis studies have been heterogenous between studies, which may be attributed to study design heterogeneity, including differences in sample population, age, and blood pressure at the time of entry. Inconsistencies in the study design poses a challenge for systematic reviews and meta-analysis to accurately assess the effect size and impact of L-arginine or L-citrulline on both systolic and diastolic blood pressure. [ABSTRACT FROM AUTHOR]

Background: Altered concentrations of cerebrospinal fluid (CSF) and blood amino acids may be related to epilepsy or the severity of the seizure. In the present study, we assessed the concentrations of amino acids in CSF and plasma in neonates with refractory seizures. Methods: In this prospective cohort study, 27 neonates aged 1 to 56 days with refractory seizures were included. Blood and CSF samples were collected from each neonate within 24 hours after receiving 2nd antiseizure medications. All plasma and CSF samples were sent to the laboratory to measure amino acid concentrations. The associations between CSF and plasma amino acid levels with different variables were evaluated. Results: Except for leucine (P=0.15) and isoleucine (P=0.07), the levels of all amino acids were significantly higher in plasma than CSF. Significant associations were observed between types of seizure and plasma citrulline (P=0.008) and leucine concentrations (P=0.04). The mean of CSF glutamic acid was also statistically different among neonates with different EEG results (P=0.02). Conclusion: Our findings indicate that several plasma and CSF amino acids could be candidate biomarkers for neonatal refractory seizures. Further studies with larger sample size are to confirm our findings. [ABSTRACT FROM AUTHOR]

BackgroundArginine is a conditionally essential amino acid that is depleted in critically ill or surgical patients. In pediatric and adult patients, sepsis results in an arginine-deficient state, and the depletion of plasma arginine is associated with greater mortality. However, direct supplementation of arginine can result in the excessive production of nitric oxide (NO), which can contribute to the hypotension and macrovascular hypo-reactivity observed in septic shock. Pegylated arginine deiminase (ADI-PEG20, pegargiminase) reduces plasma arginine and generates citrulline that can be transported intracellularly to generate local arginine and NO, without resulting in hypotension, while maintaining microvascular patency. The objective of this study was to assess the efficacy of ADI-PEG20 with and without supplemental intravenous citrulline in mitigating hypovolemic shock, maintaining tissue levels of arginine, and reducing systemic inflammation in an endotoxemic pediatric pig model.MethodsTwenty 3-week-old crossbred piglets were implanted with jugular and carotid catheters as well as telemetry devices in the femoral artery to measure blood pressure, body temperature, heart rate, and respiration rate. The piglets were assigned to one of three treatments before undergoing a 5 h lipopolysaccharide (LPS) infusion protocol. Twenty-four hours before LPS infusion, control pigs (LPS; n=6) received saline, ADI-PEG20 pigs (n=7) received an injection of ADI-PEG20, and seven pigs (ADI-PEG20 + CIT pigs [n=7]) received ADI-PEG20 and 250 mg/kg citrulline intravenously. Pigs were monitored throughout LPS infusion and tissue was harvested at the end of the protocol.ResultsPlasma arginine levels decreased and remained low in ADI-PEG20 + CIT and ADI-PEG20 pigs compared with LPS pigs but tissue arginine levels in the liver and kidney were similar across all treatments. Mean arterial pressure in all groups decreased from 90 mmHg to 60 mmHg within 1 h of LPS infusion but there were no significant differences between treatment groups. ADI-PEG20 and ADI-PEG20 + CIT pigs had less CD45+ infiltrate in the liver and lung and lower levels of pro-inflammatory cytokines in the plasma.ConclusionADI-PEG20 and citrulline supplementation failed to ameliorate the hypotension associated with acute endotoxic sepsis in pigs but reduced systemic and local inflammation in the lung and liver.

The role of arginine in the development of primary arterial hypertension continues to be clarified up to the present moment. During natural metabolic processes in cells, methylated forms of arginine are produced – symmetric (SDMA) and asymmetric (ADMA) dimethylarginine. ADMA is a nitric oxide synthase inhibitor and is now considered a well-established marker for endothelial dysfunction. SDMA is not a nitric oxide synthase inhibitor, but may indirectly reduce nitric oxide production through competitive interaction with cellular L-arginine.Currently, arginine preparations are practically not used for the treatment of primary arterial hypertension. This was the rationale for the given scientific review. The article summarizes the information available in the literature (2018–2022) on the pathogenetic mechanisms of the relationship between arginine and the development of impaired vascular tone. We used PubMed and RSCI databases for our review. Using keywords, 1784 publications were found over the past 5 years. The final selection criteria were time frame and matching keywords. The review provides data on the increased ADMA concentrations in experimental hypertensive animals and individuals with essential hypertension. The role of arginine metabolites in the genesis of endothelial dysfunction and arterial hypertension and the prospects for the therapeutic use of this compound are discussed.

BackgroundIonizing radiation can cause damage to animal's intestinal tissue. Citrulline is produced in the intestinal epithelial cell and has been proven to possess a protective effect on the gastrointestinal tract.PurposeThis study aims to investigate the protective effects and the underlying mechanisms of citrulline in the context of radiation-induced intestinal injuries.MethodsFirstly, a mouse model of an acute radiation-induced intestinal injury was established, incorporating a normal control, a simple irradiation, and an irradiation plus citrulline group. Then, these groups were employed to scrutinize the protective effects and mechanisms associated with citrulline. Subsequently, hematoxylin-eosin staining was used to examine the morphology of the mice's intestinal tissue, and the Elisa kit was employed to quantify endotoxin levels in plasma, as well as nitric oxide and inducible nitric oxide synthase in the intestinal tissue. Finally, focal adhesion kinase and Occludin levels in the intestinal tissue were assessed using western blotting.ResultsThe experimental results demonstrate that intraperitoneal injection of 1 g∙kg-1∙d-1 citrulline for one week following irradiation significantly extend the median survival time of irradiated mice and increase their body weight. Moreover, it markedly reduces plasma endotoxin levels, elevate the expression levels of focal adhesion kinase (FAK) and intestinal tight junction protein (Occludin), and decreases the expression levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in the intestinal tissue.ConclusionsCitrulline enhances the integrity of the intestinal barrier in irradiated mice, improves barrier function, mitigates nitrosative stress, and demonstrates a protective impact on radiation-induced intestinal damage in mice.

Background/Objectives: Citrulline, an amino acid produced by small bowel enterocytes, has been proposed as a potential marker of intestinal absorptive capacity. The aim of this study is to evaluate whether measuring citrulline levels could be useful for celiac disease (CD) patients, both at the time of diagnosis and during follow-up. Methods: A multicenter prospective study was conducted. Citrulline levels were measured and compared in 93 pediatric patients classified into three groups. Group A: 28 patients with newly diagnosed CD. In this group, an additional measurement was performed after 3–6 months on a gluten-free diet (GFD). Group B: 32 patients with a prior CD diagnosis and on a GFD for at least 6 months. Group C: 33 healthy controls. Citrulline levels were correlated with clinical and laboratory variables, including serological markers. Statistical analysis: t-tests for paired groups and independent groups, Pearson and Spearman correlation tests. Results: Newly diagnosed CD patients had lower citrulline levels compared to those on a GFD for more than 6 months (27.13 vs. 32.42 µmol/L; p > 0.05). Citrulline levels were nearly identical between healthy controls and CD patients on a GFD for more than 6 months (32.48 vs. 32.42 µmol/L; p > 0.05). Starting a GFD led to a significant increase in citrulline levels in group A (from 27.13 to 37.43 µmol/L, p < 0.001). Conclusions: Plasma citrulline could serve as a valuable marker for mucosal recovery in the follow-up of diagnosed celiac patients adhering to a GFD.

Metabolic syndrome (MetS) is a group of several metabolic conditions predisposing to chronic diseases. Individuals diagnosed with MetS are physiologically heterogeneous, with significant sex-specific differences. Therefore, we aimed to investigate the potential sex-specific serum modifications of amino acids and acylcarnitines (ACs) and their relationship with MetS in the Mexican population. This study included 602 participants from the Health Workers Cohort Study. Forty serum metabolites were analyzed using a targeted metabolomics approach. Multivariate regression models were used to test associations of clinical and biochemical parameters with metabolomic profiles. Our findings showed a serum amino acid signature (citrulline and glycine) and medium-chain ACs (AC14:1, AC10, and AC18:10H) associated with MetS. Glycine and AC10 were specific metabolites representative of discrimination according to sex-dependent MetS. In addition, we found that glycine and short-chain ACs (AC2, AC3, and AC8:1) are associated with age-dependent MetS. We also reported a significant correlation between body fat and metabolites associated with sex-age-dependent MetS. In conclusion, the metabolic profile varies by MetS status, and these differences are sex-age-dependent in the Mexican population.