L-Citrulline

OBJECTIVE: This study aims to systematically evaluate the synergistic effects of long-term supplementation of L-citrulline combined with exercise on body composition in adults through a meta-analysis. METHODS: This study primarily summarized and analyzed outcome indicators including body weight (BW), body mass index (BMI), body fat (BF) (including fat mass [FM] and body fat percentage [BFP]), android fat mass (AFM), gynoid fat mass (GFM), and total lean mass (TLM). Statistical analyses were performed using RevMan (Version 5.4) software provided by the Cochrane Collaboration. For continuous variables, the pooled effect sizes were expressed as standardized mean differences (SMD) with their 95% confidence intervals (CI). RESULTS: A total of 9 randomized controlled trials (RCTs) were included that investigated the effects of long-term supplementation of L-citrulline combined with exercise on body composition in adults. The results indicated that, compared to exercise alone, L-citrulline supplementation combined with exercise significantly improved BF (SMD = -0.21, 95% CI: -0.40 to -0.01, P = 0.03) and AFM (SMD = -0.32, 95% CI: -0.57 to -0.07, P = 0.01). However, no significant effects were observed on BW (SMD = -0.01, 95% CI: -0.27-0.25, P = 0.95), BMI (SMD = 0.01, 95% CI: -0.31-0.33, P = 0.93), GFM (SMD = -0.17, 95% CI: -0.42-0.08, P = 0.18), and TLM (SMD = -0.02, 95% CI: -0.23-0.19, P = 0.83). CONCLUSION: This study is the first to demonstrate through a meta-analysis that long-term supplementation of L-citrulline combined with exercise can synergistically improve BF and AFM in adults.

BACKGROUND/OBJECTIVES: L-Citrulline (CIT) is a non-essential amino acid abundant in watermelon and commonly used as a dietary supplement to enhance exercise performance. Although its benefits for endurance and resistance training are well documented, its effects on body composition remain uncertain. This systematic review and dose-response meta-analysis aimed to assess the impact of CIT supplementation on anthropometric parameters. METHODS: A comprehensive search of major databases identified relevant randomized controlled trials (RCTs) published until March 2025. A random-effects model was used to synthesize the data. RESULTS: Twenty-one RCTs were included. Overall, CIT supplementation had no substantial effects on body mass index (BMI), body weight, fat mass (FM), waist circumference (WC), body fat percentage (BFP), and fat-free mass (FFM). Subgroup analyses revealed reductions in FM among participants over 40 years of age and in those administered more than 6 g/day of CIT. Interventions lasting 3 to 8 weeks were associated with a significant increase in FFM. Dose-response analyses suggested a non-linear association between CIT supplementation duration and changes in FM and FFM. CONCLUSIONS: CIT supplementation appears to have no overall effect on body composition. However, exploratory findings indicated potential benefits at higher doses or shorter durations. Rigorous trials controlling for dietary intake and training variables are needed to clarify its long-term effects.

OBJECTIVE: This study aims to investigate the effects of l-citrulline supplementation and watermelon intake on blood pressure (BP) in middle-aged and elderly individuals. METHODS: Data analysis was conducted using RevMan 5.4.1 software, employing a random effects model to statistically analyze the pooled effect sizes of the obtained systolic blood pressure (SBP) and diastolic blood pressure (DBP) data. Results are reported as weighted mean differences (WMD) with 95 % confidence intervals (95 % CI). RESULTS: A total of 15 randomized controlled trials (RCTs) investigating the effects of l-citrulline supplementation and watermelon intake on BP in middle-aged and elderly individuals were included, comprising 24 datasets involving 415 participants. The results indicate that l-citrulline supplementation and watermelon intake significantly reduced SBP (-4.02 mmHg [95 % CI: -6.54 to -1.50], P = 0.002) and DBP (-2.54 mmHg [95 % CI: -4.27 to -0.81], P = 0.004) in the elderly. Subgroup analysis showed that the combined supplementation of l-citrulline and l-arginine significantly decreased SBP (-10.44 mmHg [95 % CI: -13.57 to -7.31], P < 0.00001) and DBP (-4.86 mmHg [95 % CI: -7.93 to -1.79], P = 0.002) in this population. CONCLUSION: l-citrulline supplementation and watermelon intake overall lowered BP in middle-aged and elderly individuals. Subgroup analysis indicates that the combined supplementation of l-citrulline and l-arginine is superior to l-citrulline or watermelon supplementation alone. These findings provide new dietary recommendations for BP management in the elderly, suggesting that dietary interventions can effectively improve cardiovascular health and reduce the risk of cardiovascular disease (CVD).

BACKGROUND: Evidence suggests L-arginine may be effective at reducing pre-eclampsia and related outcomes. However, whether L-arginine can prevent or only treat pre-eclampsia, and thus the target population and timing of initiation, remains unknown. OBJECTIVES: To evaluate the effects of L-arginine and L-citrulline (precursor of L-arginine) on the prevention and treatment of pre-eclampsia. SEARCH STRATEGY: MEDLINE, Embase, CINAHL, Global Index Medicus and the Cochrane Library were searched through 7 February 2024. SELECTION CRITERIA: Trials administering L-arginine or L-citrulline to pregnant women, with the comparison group receiving placebo or standard care, were included. DATA COLLECTION AND ANALYSIS: Meta-analyses were conducted separately for prevention or treatment trials, using random-effects models. MAIN RESULTS: Twenty randomised controlled trials (RCTs) (2028 women) and three non-randomised trials (189 women) were included. The risk of bias was 'high' in eight RCTs and showed 'some concerns' in 12. In prevention trials, L-arginine was associated with a reduced risk of pre-eclampsia (relative risk [RR] 0.52; 95% confidence interval [CI], 0.35, 0.78; low-certainty evidence, four trials) and severe pre-eclampsia (RR 0.23; 95% CI, 0.09, 0.55; low-certainty evidence, three trials). In treatment trials, L-arginine may reduce mean systolic blood pressure (MD -5.64 mmHg; 95% CI, -10.66, -0.62; very low-certainty evidence, three trials) and fetal growth restriction (RR 0.46; 95% CI, 0.26, 0.81; low-certainty evidence, two trials). Only one study (36 women) examined L-citrulline and reported no effect on pre-eclampsia or blood pressure. CONCLUSIONS: L-arginine may be promising for pre-eclampsia prevention and treatment, but findings should be interpreted cautiously. More trials are needed to determine the optimal dose and time to commence supplementation and support clinical decision-making. © 2025 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.

The repercussions on oxidative and inflammatory stress markers under the effects of arginine and citrulline in response to exercise are not fully reached. We completed a systematic review to investigate the effects of L-Citrulline or L-Arginine on oxidative stress and inflammatory biomarkers following exercise. EMBASE, MEDLINE (PubMed), Cochrane Library, CINAHL, LILACS, and Web of Science databases were used to record the trials. This study includes randomized controlled trials (RCTs) and non-RCTs with subjects over 18 years old. Those under the intervention protocol consumed L-Citrulline or L-Arginine, and the controls ingested placebo. We recognized 1080 studies, but only 7 were included (7 studies in meta-analysis). We observed no difference between pre- vs. post-exercise for oxidative stress (subtotal = -0.21 [CI: -0.56, 0.14], p = 0.24, and heterogeneity = 0%. In the sub-group "L-Arginine" we found a subtotal = -0.29 [-0.71, 0.12], p = 0.16, and heterogeneity = 0%. For the "L-Citrulline" subgroup we observed a subtotal = 0.00 [-0.67, 0.67], p = 1.00, and heterogeneity was not applicable. No differences were observed between groups (p = 0.47), and I² = 0%) or in antioxidant activity (subtotal = -0.28 [-1.65, 1.08], p = 0.68, and heterogeneity = 0%). In the "L-Arginine" sub-group, we found a subtotal = -3.90 [-14.18, 6.38], p = 0.46, and heterogeneity was not applicable. For the "L-Citrulline" subgroup, we reported a subtotal = -0.22 [-1.60, 1.16], p = 0.75, and heterogeneity was not applicable. No differences were observed between groups (p = 0.49), and I² = 0%), inflammatory markers (subtotal = 8.38 [-0.02, 16.78], p = 0.05, and heterogeneity = 93%. Tests for subgroup differences were not applicable, and anti-inflammatory markers (subtotal = -0.38 [-1.15, 0.39], p = 0.34 and heterogeneity = 15%; testing for subgroup differences was not applicable). In conclusion, our systematic review and meta-analysis found that L-Citrulline and L-Arginine did not influence inflammatory biomarkers and oxidative stress after exercise.

BACKGROUND: Increasing nitric oxide bioavailability may induce physiological effects that enhance endurance exercise performance. This review sought to evaluate the performance effects of consuming foods containing compounds that may promote nitric oxide bioavailability. METHODS: Scopus, Web of Science, Ovid Medline, EMBASE and SportDiscus were searched, with included studies assessing endurance performance following consumption of foods containing nitrate, L-arginine, L-citrulline or polyphenols. Random effects meta-analysis was conducted, with subgroup analyses performed based on food sources, sex, fitness, performance test type and supplementation protocol (e.g. duration). RESULTS: One hundred and eighteen studies were included in the meta-analysis, which encompassed 59 polyphenol studies, 56 nitrate studies and three L-citrulline studies. No effect on exercise performance following consumption of foods rich in L-citrulline was identified (SMD=-0.03, p=0.24). Trivial but significant benefits were demonstrated for consumption of nitrate and polyphenol-rich foods (SMD=0.15 and 0.17, respectively, p<0.001), including performance in time-trial, time-to-exhaustion and intermittent-type tests, and following both acute and multiple-day supplementation, but no effect of nitrate or polyphenol consumption was found in females. Among nitrate-rich foods, beneficial effects were seen for beetroot, but not red spinach or Swiss chard and rhubarb. For polyphenol-rich foods, benefits were found for grape, (nitrate-depleted) beetroot, French maritime pine, Montmorency cherry and pomegranate, while no significant effects were evident for New Zealand blackcurrant, cocoa, ginseng, green tea or raisins. Considerable heterogeneity between polyphenol studies may reflect food-specific effects or differences in study designs and subject characteristics. Well-trained males (V̇O2max ≥65 ml.kg.min-1) exhibited small, significant benefits following polyphenol, but not nitrate consumption. CONCLUSION: Foods rich in polyphenols and nitrate provide trivial benefits for endurance exercise performance, although these effects may be food dependent. Highly trained endurance athletes do not appea

Citrulline malate (CitMal) is a dietary supplement that is suggested to enhance strength training performance. However, there is conflicting evidence on this matter. Thus, the purpose of this meta-analysis was to determine whether supplementing with CitMal prior to strength training could increase the total number of repetitions performed before reaching voluntary muscular failure. A systematic search was conducted wherein the inclusion criteria were double-blind, placebo-controlled studies in healthy participants that examined the effect of CitMal on repetitions to failure during upper body and lower body resistance exercises. The Hedges's g standardized mean differences (SMD) between the placebo and CitMal trials were calculated and used in a random effect model. Two separate subanalyses were performed for upper body and lower body exercises. Eight studies, including 137 participants who consisted of strength-trained men (n = 101) and women (n = 26) in addition to untrained men (n = 9), fulfilled the inclusion criteria. Across the studies, 14 single-joint and multijoint exercises were performed with an average of 51 ± 23 total repetitions during 5 ± 3 sets per exercise at ∼70% of one-repetition maximum. Supplementing with 6-8 g of CitMal 40-60 min before exercise increased repetitions by 3 ± 5 (6.4 ± 7.9%) compared with placebo (p = .022) with a small SMD (0.196). The subanalysis for the lower body resulted in a tendency for an effect of the supplement (8.1 ± 8.4%, SMD: 0.27, p = .051) with no significant effect for the upper body (5.7 ± 8.4%, SMD: 0.16, p = .131). The current analysis observed a small ergogenic effect of CitMal compared with placebo. Acute CitMal supplementation may, therefore, delay fatigue and enhance muscle endurance during high-intensity strength training.

BACKGROUND: Citrulline is one of the non-essential amino acids that is thought to improve exercise performance and reduce post-exercise muscle soreness. We conducted a systematic review and meta-analysis to determine the effect of citrulline supplements on the post-exercise rating of perceived exertion (RPE), muscle soreness, and blood lactate levels. METHODS: A random effects model was used to calculate the effect sizes due to the high variability in the study design and study populations of the articles included. A systematic search of PubMed, Web of Science, and ClinicalTrials.gov was performed. Eligibility for study inclusion was limited to studies that were randomized controlled trials involving healthy individuals and that investigated the acute effect of citrulline supplements on RPE, muscle soreness, and blood lactate levels. The supplementation time frame was limited to 2 h before exercise. The types and number of participants, types of exercise tests performed, supplementation protocols for L-citrulline or citrulline malate, and primary (RPE and muscle soreness) and secondary (blood lactate level) study outcomes were extracted from the identified studies. RESULTS: The analysis included 13 eligible articles including a total of 206 participants. The most frequent dosage used in the studies was 8 g of citrulline malate. Citrulline supplementation significantly reduced RPE (n = 7, p = 0.03) and muscle soreness 24-h and 48-h after post-exercise (n = 7, p = 0.04; n = 6, p = 0.25, respectively). However, citrulline supplementation did not significantly reduce muscle soreness 72-h post-exercise (n = 4, p = 0.62) or lower blood lactate levels (n = 8, p = 0.17). CONCLUSION: Citrulline supplements significantly reduced post-exercise RPE and muscle soreness without affecting blood lactate levels.

PURPOSE OF REVIEW: Several interventional studies assessed the impact of dietary supplements on blood pressure. The aim of the present systematic review and meta-analysis was to determine the efficacy of L-citrulline supplementation on blood pressure. RECENT FINDING: Pubmed, Scopus, Google Scholar, and ISI Web of Science were comprehensively searched until May 2018 to assess whether L-citrulline reduces blood pressure. Human clinical trials which reported the effect of L-citrulline supplementation on aortic and brachial blood pressure were included. Characteristics of studies and potential sources of heterogeneity were tabulated. A subgroup analysis was performed to attenuate observed inter-study heterogeneity. A total of five interventions were found for meta-analysis. The impact of L-citrulline on brachial systolic (change 0.28 mmHg; 95% CI - 2.87, 2.31 mmHg) and diastolic (change - 1.56 mmHg; 95% CI - 4.32, 1.20 mmHg) blood pressure was not significant. Also, there was no changes in aortic systolic (change 0.22 mmHg; 95% CI - 4.81, 4.38 mmHg) and diastolic (change 0.26 mmHg; 95% CI - 2.27, 2.80 mmHg) blood pressure after L-citrulline supplementation. Participants' body weight status was a source of observed heterogeneity. The present systematic review and meta-analysis suggests that L-citrulline supplementation had no beneficial effect on blood pressure.

BACKGROUND: High-intensity interval training (HIIT) with or without L-citrulline (CIT) oral supplementation improves body composition, functional capacities and muscle health in obese older adults, potentially through microRNA-driven regulation. We aimed to (1) investigate the impact of a 12-week HIIT on the expression level of microRNAs in vastus lateralis muscle biopsies and serum of obese older adults and (2) assess whether the differential expression level of microRNAs was associated with clinico-biological adaptations to HIIT and provide potential biomarkers of HIIT response. METHODS: In this secondary exploratory analysis of a double-blind randomized trial, 36 women and 32 men (67.2 ± 5.2 years) following 12 weeks HIIT randomized in two groups were supplemented daily with CIT (HIIT-CIT, n = 37) or with placebo (HIIT-PLA, n = 31). Phenotypic variables, serum parameters, muscle biopsies and subcutaneous abdominal adipose tissue outcomes were collected pre-intervention and postintervention. To assess the microRNA profile, the miRNome of muscle biopsy and serum was analysed using next generation sequencing in participants' subsets (n = 13). The microRNAs' differential expression level was analysed pre-intervention and postintervention by TaqMan-real-time qPCR in 68 participants. RESULTS: The expression of myo-microRNAs (miR-133a, b, -1, -206) and muscle-related-microRNAs (miR-499, -208) was not altered following HIIT with or without CIT. In HIIT-PLA, HIIT-CIT and subgroups (based on sex, age, body mass index, dynapenic status), the change in muscle (miR-504-5p, -744-5p, -151a-3p, -106b-5p, -127-5p) and circulating (miR-4433b-5p, 151a-3p, -744-5p, 483-3p, -106b-5p, -484) microRNA levels was associated with changes of clinico-biological parameters. Supplementing HIIT with CIT decreased the muscle miR-504-5p level (p = 0.022), correlating with lower body fat, improved functional capacities, muscle power and increased IGF-1 level (r = -0.6, p < 0.05). MiR-744-5p expression increased in dynapenic participants (p = 0.04), associated with lean mass gain (r = 0.50, p < 0.05), while miR-151a-3p downregulation in men's muscle (p = 0.01) was associated with better insuli

Background: Acute and chronic hyperglycemia in patients with type 2 diabetes mellitus (T2DM) causes endothelial dysfunction and arterial stiffness, contributing to early mortality from cardiovascular disease (CVD). Although L-citrulline (CIT) supplementation improves endothelial function in older women and decreases fasting glucose in those with T2DM, whether it improves vascular function and blood glucose during acute hyperglycemic states in T2DM is unknown. Methods: We randomized 16 patients with T2DM (age 62 ± 6 years) to consume either CIT (6 g/day) or placebo for 4 weeks. Brachial artery flow-mediated dilation (FMD), brachial and aortic blood pressure, aortic and leg arterial stiffness (pulse wave velocity, PWV), and blood glucose concentration were assessed in the fasted state and 60 min following glucose ingestion (during acute hyperglycemia). Results: Four weeks of L-citrulline supplementation improved FMD, femoral-ankle PWV, aortic systolic blood pressure, and blood glucose concentration in the fasted state compared to placebo (all p < 0.05). During acute hyperglycemia, CIT supplementation increased FMD and reduced femoral-ankle PWV, aortic systolic BP, and glucose levels compared to placebo (all p < 0.05). Conclusions: CIT supplementation is beneficial to improve vascular function and glucose levels during chronic and acute hyperglycemia in middle-aged and older adults with T2DM.

Background/Objectives: Watermelon (Citrullus lanatus) is a natural dietary source of L-citrulline and L-arginine, the two amino acids involved in nitric oxide (NO) production and vasodilation. Pre-clinical and clinical studies using isolated amino acids or watermelon extracts suggest blood pressure (BP)-lowering potential; however, limited research has been conducted on the impact of watermelon flesh (WM) on BP in adults at risk for hypertension. Therefore, the primary objective of this study was to assess the effect of daily WM intake for four weeks on 24 h ambulatory BP in adults with elevated blood pressure. The secondary outcomes of this study include changes in glucose and insulin markers, lipid profile, NO, L-citrulline, L-arginine, asymmetric dimethylarginine (ADMA) concentrations, and the L-arginine/ADMA ratio. Methods: In this randomized, placebo controlled parallel study design, 39 adults (age: 41 ± 14 years, BMI: 31 ± 6 kg/m2, mean ± SD) with elevated BP were randomly assigned to one of three groups for a 4-week intervention: control (0 g WM), WM-1 cup (152 g/day), or WM-2 cups (304 g/day). Ambulatory BP was measured over 24 h at baseline and the end of the intervention period. Fasting plasma samples were analyzed for metabolic biomarkers on a clinical analyzer and NO using a colorimetric assay. L-citrulline, L-arginine, and ADMA were analyzed using an ultra-high-performance liquid chromatography triple quadrupole mass spectrometer (UHPLC-QQQ-MS/MS). Statistical analyses were conducted using SPSS software (IBM SPSS Statistics, Version 29.0.0). Results: After 4 weeks, mean 24 h ambulatory BP was 130.2 ± 3.9 mm Hg (control), 130 ± 3.2 mm Hg (WM-1 cup), and 124.9 ± 3.9 mm Hg (WM-2 cups), with no statistically significant differences between study interventions (p > 0.05). Similarly, no significant changes were observed in fasting plasma glucose, insulin, lipid profile, or NO concentrations. However, plasma L-arginine concentrations and L-arginine/ADMA ratios significantly increased in the WM groups compared to the control (p = 0.009) after adjusting for age, BMI, race, and gender in the statistical model. Conclusion: Overall, BP was not significantly dif

Oral lyophilized fecal microbiota transplantation (FMT) can induce remission in patients with active ulcerative colitis (UC); however, our understanding of how this form of FMT alters the patient microbiome remains limited. Here, we analyzed data from a recent randomized, double-blind, placebo-controlled clinical trial of FMT in UC to assess donor species colonization and factors responsible for efficacy using this form of therapy. The gut microbiome of donors and patients was profiled longitudinally using deep shotgun metagenomic sequencing, and microbiome diversity, species-genome bin presence, functional profiles, and the resistome were studied. The gut microbiome of patients treated with oral lyophilized FMT significantly increased in species-genome bin richness and shifted in composition toward the donor profiles; this was not observed in patients receiving placebo. While species-genome bin richness was not associated with clinical response in this trial, we identified donor- and patient-specific features associated with the induction of remission and maintenance of response. However, the presence of a Clostridium species-genome bin, as well as L-citrulline biosynthesis contributed by Alistipes spp., was seen in responders treated by either donor. Several of the above outcomes were found to be consistent when data were analyzed at the level of metagenome-assembled genomes. FMT was also found to deplete the resistome within patients treated with antibiotics to levels lower than the UC baseline. Single donor oral lyophilized FMT substantially modifies taxonomic diversity and composition as well as microbiome function and the resistome in patients with UC, with several features identified as strongly linked to response regardless of the donor used. IMPORTANCE: There is a limited amount of work examining the effects of oral lyophilized fecal microbiota transplantation (FMT) on the microbiome of patients with ulcerative colitis (UC), and less so studies examining species-level dynamics and functional changes using this form of FMT. We performed deep shotgun metagenomic sequencing to provide an in-depth species-genome bin-level analysis of the microbiome of patie

PURPOSE: This study aimed to investigate and compare the effects of chronic supplementation with L-Citrulline (LC) vs. L-Citrulline DL-malate (CM) on resistance training (RT) performance. METHODS: Thirty-three resistance-trained men were randomly assigned to ingest LC (8 g), CM (12 g), or Placebo (PL) daily, along with participation in a 6-week RT protocol. Muscular strength (1-repetition maximum [1RM] for hack squat [HS] and bench press [BP]), muscular endurance (repetitions to failure [RTF] for HS, leg extension [LE], BP, and incline press [IP]), rating of perceived exertion (RPE), and blood biomarkers (lactate, urea, and nitric oxide metabolites [NOX]) were assessed before and after the intervention. This study was registered on irct.ir (IRCTID: IRCT20221128056642N1). RESULTS: Comparing mean ∆ scores revealed a significant difference between LC and PL (p < 0.001) and between CM and PL (p = 0.026) for total upper body (the sum of BP and IP) RTF, but only a trend for difference between LC and PL (p = 0.070) for total lower body (the sum of HS and LE) RTF. A significant time effect for NOX was detected only for LC (p = 0.014) and CM (p = 0.003). In addition, a significant difference between CM and PL (p = 0.009) and a marginally significant difference between LC and PL (p = 0.057) was detected regarding post-exercise NOX values at post-intervention. There were no other between-group differences for any outcome measure. CONCLUSION: Chronic citrulline supplementation seems to enhance upper body muscular endurance and post-exercise NOX response to RT, but there is no apparent difference between LC and CM in these aspects.

This study examined the effects of L-citrulline (L-CIT) and sodium bicarbonate (Sb) supplementation during short sprint interval training (SSIT), both individually and combined, over a 28-day period, to assess the impact on the physical performance and hormonal adaptations of basketball players. Forty young (age = 21.5 ± 1.7 years) male basketball players were randomly assigned into five groups of eight subjects including either L-CIT (6 g daily), Sb (0.3 g·kg-1 of Sb daily), L-CIT+Sb, placebo (PL), and or an active control group (CON). The training groups engaged in SSIT sessions, consisting of three sets of ten repetitions of five-second all-out sprints, three times per week over four weeks. A series of physical performance tests including countermovement vertical jump, a 20-m linear sprint, Illinois change of direction speed, Wingate anaerobic power, and an incremental exercise test were conducted before and after the training period. In addition, blood samples were obtained to analyze resting testosterone and cortisol levels before and after the training period. Significant improvements in physical performance were observed across all training groups after the 4-week intervention (p < 0.05). Notably, the groups receiving supplements exhibited more pronounced improvements in the physical performance tests (p < 0.01) in comparison to the PL group, indicating superior adaptations. In addition, no significant (p > 0.05) changes were seen in testosterone, but the supplement groups showed lower cortisol levels than other groups following the 4-week intervention. There were no significant differences in physical performance adaptations among the supplement groups. The study reveals that short-term supplementation of L-citrulline and sodium bicarbonate in the capsule form effectively enhance physical performance of basketball players in comparison to a placebo. © Journal of Sports Science and Medicine.

BACKGROUND: The consumption of sports drinks before, during, and after endurance exercise is a common practice among athletes. These drinks typically contain a variety of components, each of which has been shown to offer individual benefits. However, the combined effects of these components, as formulated in many sports drinks, have not been thoroughly investigated. This study aims to evaluate the impact of typical sports drink components on endurance performance, perceived exertion, and carbohydrate and fat metabolism, using a sequential additive design. METHODS: Twelve healthy, trained endurance athletes aged 20 to 35 years participated in a randomized, double-blind, placebo-controlled study. The study involved a baseline assessment and four exercise protocols, each separated by a 7-day washout period. During each exercise protocol, participants cycled for 40 minutes at 80% of their previously determined peak oxygen uptake , followed by an incremental protocol performed to voluntary exhaustion. Participants were randomly assigned to ingest one of four 300 ml solutions 60 and 30 minutes before each exercise protocol: solution A (placebo mineral water), solution B (dextrose and sodium), solution C (solution B + beetroot extract), or solution D (solution C + arginine and L-citrulline). Ventilation and heart rate were continuously monitored before and throughout the exercise. Lactate and glucose levels were measured at specific time points before and during the exercise, while ratings of perceived exertion were recorded every 10 minutes. Power output was continuously tracked throughout the exercise protocol. Body weight was assessed both before and after each exercise session. RESULTS: There were no significant differences between the four solutions in terms of time to exhaustion (p = .703), power output (p = .822), peak oxygen uptake (p = 990), maximum lactate concentration (p = .720), and maximum heart rate (p = .884). During the exercise, no significant differences were observed in lactate and glucose concentrations, heart rate, or ventilatory parameters (ps > .050). However, significant differences (p < .001) in blood glucose concentrations were noted at rest

Background: The dietary supplement citrulline might increase nitric oxide levels, leading to vasodilation and improved blood flow, potentially benefiting athletes' aerobic exercise performance. However, rapid oxidative impairment of the L-arginine/nitric oxide (NO) pathway limits these effects. This is countered by Bergamot Polyphenolic Fraction Gold® (BPFG), a strong natural antioxidant. To investigate L-citrulline + BPFG supplementation's effects, we performed a randomized, double-blind, placebo-controlled pilot trial on athletic performance and blood flow in trained athletes (cyclists). Methods: Random assignment of 90 male athletes resulted in nine different groups: placebo for Group 1, BPFG at 500 and 1000 mg daily for Groups 2 and 3, L-citrulline at 1000 and 2000 mg/daily for Groups 4 and 5, and the combination product of BPFG plus citrulline (N.O. Max) for Groups 6-9. Baseline and 3-month pre- and post-exercise biochemical, reactive vasodilation (RHI), and maximal oxygen consumption measurements were taken for all subjects. Results: Three months of the combination of BPFG and L-citrulline (N.O. Max) produced a significant synergistic effect, markedly increasing NO (p < 0.001 vs. placebo) release and RHI (p < 0.001 vs. placebo). Cardiorespiratory fitness improved significantly with the BPFG and L-citrulline combination, resulting in substantially higher VO2 max, VT1, VT2, and peak power and a significantly lower heart rate (p < 0.01 vs. placebo). No harmful adverse effects were observed. Conclusions: N.O. Max supplementation, providing beneficial effects on the antioxidant state and preserving the vascular endothelium might be a supplementation strategy to improve athletic performance and potentiate results. Given the small sample size, this study serves as a pilot, and further research is needed to validate these findings on a larger scale.

PURPOSE: Athletes often use sport supplements to improve their physical and physiological performance. This randomized, double-blind, placebo (PL) -controlled study aimed to investigate the effects of combined versus single supplementation of creatine (Cr), beta-alanine (BA), and L-citrulline (L-Cit) during short sprint interval training (SSIT) on basketball players' physical and physiological performance over a period of 28 days. METHODS: Forty-eight basketball players were equally assigned to 6 groups of Cr (0.1 g/kg of Cr monohydrate daily), BA (4.8 g daily), L-Cit (6 g daily), combined supplementation, PL, and an active control group, and each group consisted of 8 participants. The training groups participated in SSIT (3 sets of 10 repetitions of 5-s all-out runs) sessions 3 times a week for 4 weeks. Physical (vertical jump, 20-m sprint, Illinois change of direction) and physiological (Wingate anaerobic power and cardiorespiratory fitness test) performance were evaluated before and after the training period. RESULTS: All training groups (Cr, BA, L-Cit, combined, and PL) showed significant improvements in physical and physiological performance over the 4-week intervention (P < .05). Interestingly, the supplement groups displayed significantly (P = .001) greater changes than the PL group, indicating better outcomes in performance adaptations. However, significant differences in performance variables were observed among the supplement groups. CONCLUSION: Our findings indicate that short-term supplementation with Cr, BA, and L-Cit, as well as a combination of them during SSIT, can significantly improve the physical and physiological performance of basketball players compared to a PL.

BACKGROUND: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and obesity contribute to vascular dysfunction through oxidative stress, heightening cardiovascular risk. Oral supplementation with L-citrulline (L-cit), a precursor of L-arginine (L-arg) and nitric oxide, and high-intensity interval training (HIIT) may improve vascular function and cardiometabolic health. OBJECTIVES: This study aimed to evaluate the combined effects of L-cit supplementation and HIIT on arterial stiffness, body composition, glucose metabolism, lipid profile, and blood pressure (BP) in adolescents with MASLD and obesity. METHODS: In this double-blind, placebo-controlled, randomized clinical trial (ClinicalTrials.gov (NCT05778266), 44 adolescents (15-19 years) with MASLD and obesity were assigned to HIIT + L-cit (n = 14), HIIT + placebo (n = 14), or L-cit (n = 15) for 12 weeks. HIIT sessions (85% and 60% peak heart rate during intense and recovery periods) occurred thrice weekly. Training volume progressively increased, and participants performed 20 min of HITT per session in the last 8 weeks. RESULTS: Outcomes included pulse wave velocity (PWV), augmentation index (Aix75), VO2peak, body composition, BP, glucose and lipid profiles, and hepatic steatosis. Compared to L-cit, HIIT + L-cit improved non-high-density lipoprotein cholesterol (p = 0.04), very-low-density lipoprotein cholesterol (p = 0.01), triglycerides (p = 0.02), and VO2peak (p = 0.001). No significant between-group changes were found in PWV, AIx75, hepatic steatosis, and body composition. HIIT + placebo improved VO2peak (p = 0.002), and L-cit decreased the degree of steatosis (p = 0.038). CONCLUSIONS: HIIT + L-cit supplementation enhanced lipid profile and cardiorespiratory fitness, while HIIT + placebo improved cardiorespiratory capacity, and L-cit alone decreased hepatic steatosis. Thus, L-cit could be an adjuvant strategy to manage obesity-related MASLD in adolescents.

We investigated the effects of combining 1 g of l-citrulline and 1 g of l-arginine as oral supplementation on plasma l-arginine levels in healthy males. Oral l-citrulline plus l-arginine supplementation more efficiently increased plasma l-arginine levels than 2 g of l-citrulline or l-arginine, suggesting that oral l-citrulline and l-arginine increase plasma l-arginine levels more effectively in humans when combined.

BACKGROUND: Chronic supplementation with L-citrulline plus L-arginine has been shown to exhibit anti-atherosclerotic effects. However, the short-term action of this combination on the nitric oxide (NO)-cGMP pathway remains to be elucidated. The objective of the present study was to investigate the acute effects of a combination of oral L-citrulline and L-arginine on plasma L-arginine and NO levels, as well as on blood circulation. METHODS: Rats or New Zealand white rabbits were treated orally with L-citrulline, or L-arginine, or a combination of each at half dosage. Following supplementation, plasma levels of L-arginine, NOx, cGMP and changes in blood circulation were determined sequentially. RESULTS: L-Citrulline plus L-arginine supplementation caused a more rapid increase in plasma L-arginine levels and marked enhancement of NO bioavailability, including plasma cGMP concentrations, than with dosage with the single amino acids. Blood flow in the central ear artery in rabbits was also significantly increased by L-citrulline plus L-arginine administration as compared with the control. CONCLUSION: Our data show for the first time that a combination of oral L-citrulline and L-arginine effectively and rapidly augments NO-dependent responses at the acute stage. This approach may have clinical utility for the regulation of cardiovascular function in humans.

PURPOSE: The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, L-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats. EXPERIMENTAL DESIGN: The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and L-arginine. BTB permeability, defined by the unidirectional transport constant, Ki, for [14C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, L-citrulline, and cGMP in the tumor and normal brain tissue were measured. RESULTS: Oral administration of l-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (KCa) channel that is a cGMP pathway effector. The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, L-citrulline, a byproduct of NO formation from L-arginine, and cGMP were enhanced in the tumor tissue by oral administration of L-arginine and/or hydroxyurea. CONCLUSIONS: Oral administration of L-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.

The purpose of the present study was to examine the possibility of using molecularly imprinted polymers (MIPs) to screen for bitterness-suppressing agents. Quinine was selected as the bitter substance standard. L-arginine (L-Arg), L-ornithine (L-Orn), L-lysine (L-Lys), and L-citrulline (L-Ctr) were tested as bitterness suppressant candidates. In a high-performance liquid chromatography study using a uniformly sized MIP for cinchonidine, which has a very similar structure to quinine, the retention factor (k) of quinine was significantly shortened by the addition of L-Arg or L-Orn to the mobile phase, whereas slight or no decrease was observed when L-Ctr and L-Lys were added. The abilities of these amino acids to decrease the k of quinine were ranked in the following order: L-Arg = (L-Orn >(L-Ctr >>(L-Lys. A linear relationship between the reciprocal of k and the concentration of the amino acids indicated a single competitive model at a single site. The magnitude of the association constants obtained seemed to be directly related to the inhibitory effect of the test substances on the affinity of quinine for the receptor site. Nuclear magnetic resonance and molecular modeling studies suggested a one-to-two hydrogen-bonding-based complex formation of one quinine molecule with two methacrylic acid molecules (Q-2MAA) in chloroform. In the molecular modeling studies, the N--N distance of the quinine molecule in the assumed Q-2MAA complex was calculated to be 5.12 angstroms, similar to the N - N distances of the two amino acid complexes (L-Arg-2MAA, L-Orn-2MAA), which were 4.84 and 5.30 angstroms, respectively. This suggests that L-Arg and L-Orn may compete with the quinine molecule in the cinchonidine-imprinted space. Finally, the results of human gustatory sensation tests correlated well with the MIP data. The proposed method using MIPs seems to have a potential for screening bitterness-suppressing agents for quinine. Copyright 2004 Wiley-Liss, Inc.

INTRODUCTION: Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve endothelial function in Type 1 diabetes. However, the potential of ACE inhibitors (ACE-I) to enhance the haemodynamic effects of L-arginine (L-arg), the precursor of nitric oxide (NO), has not been evaluated. Furthermore, angiotensin receptor blockers (ARBs), another group of inhibitors of the renin-angiotensin system (RAS), have not been studied in this context. METHODS: Using a randomised, crossover design, the acute effects of L-arg (200 mg/kg) on blood pressure (BP) and renal haemodynamics were determined in uncomplicated Type 1 diabetic patients before and after three weeks of treatment with the ACE-I ramipril (5 mg/day) or the ARB losartan (50 mg/day). RESULTS: L-arg alone did not influence BP or renal haemodynamics. BP responses to L-arg were not modulated by ACE-I or ARB. In contrast to the systemic responses, L-arg induced significant renal vasodilation after treatment with ramipril (p<0.05). Unlike ramipril, losartan did not modulate renal haemodynamic responses to L-arg. L-arg administration was paralleled by increments in plasma L-citrulline levels, determined as a measure of L-arg-induced systemic NO production. These responses were not influenced by RAS inhibitors. No changes in other indicators of the systemic and renal NO production, such as plasma and urinary nitrates/nitrites, were detected in response to L-arg alone or after treatment with RAS inhibitors. CONCLUSIONS: ACE-Is have greater potential than ARBs to enhance L-arg effects in the kidney in uncomplicated Type 1 diabetes. Neither RAS inhibitor influenced the systemic effects of L-arg. The lack of changes in renal NO indicators parallelling the haemodynamic responses, suggests that the effects of ACE-I on L-arg-induced renal haemodynamic changes could be also attributable to NO-independent mechanisms.

The aim of this study was to examine the effects of procyanidins derived from cocoa on vascular smooth muscle. Two hypotheses were tested: 1) extracts of cocoa, which are rich in procyanidins, cause endothelium-dependent relaxation (EDR), and 2) extracts of cocoa activate endothelial nitric oxide synthase (NOS). The experiments were carried out on aortic rings obtained from New Zealand White rabbits. The polymeric procyanidins (tetramer through decamer of catechin) caused an EDR. In addition, the Ca(2+)-dependent NOS activity, measured by the L-arginine to L-citrulline conversion assay, was significantly increased in aortic endothelial cells exposed to polymeric procyanidins, whereas monomeric compounds had no such effect. These findings demonstrate that polymeric procyanidins cause an EDR that is mediated by activation of NOS.

Expression of the inducible isoform of nitric oxide synthase (iNOS) is stimulated by cytokines in human epithelial cells. This work indicates that incubation of human umbilical cord endothelial cells with combinations of interleukin-1beta, tumor necrosis factor alpha, and interferon-gamma stimulated the synthesis of iNOS mRNA, as detected by reverse transcriptase-polymerase chain reaction. It is important to note that 50, 100, and 200 microM hydrogen peroxide was able to stimulate iNOS directly. Furthermore, 100 microM H2O2 enhanced synthesis of the oxidation products, nitrite (NO2-) and nitrate (NO3-) at 12 and 36 h. iNOS protein, detected by Western blot analysis, as well as L-citrulline levels, were also increased. When endothelial cell monolayers were incubated for 1 h with 100 microM H2O2 and subsequently with cytokines, iNOS mRNA was further augmented. Under the same conditions, we regularly observed an inhibition (25%) of intercellular adhesion molecule-1 (ICAM-1/CD54) expression. The latter was reversed when the NOS inhibitor N(G)-monomethyl-L-arginine was added, as shown by flow cytometry. These data suggest a specific effect of endogenous hydroperoxides on the biosynthesis and processing of the human endothelial iNOS isoform. We propose that H2O2 induces a temporary NO-dependent modulation of adhesion molecule expression to limit the tissue destruction that accompanies the vascular recruitment of leukocytes. Role of nitric oxide in the anti-tumoral effect of retinoic acid and 1,25-dihydroxyvitamin D3 on human promonocytic leukemic cells. Dugas N(1), Mossalayi MD, Calenda A, Léotard A, Bécherel P, Mentz F, Ouaaz F, Arock M, Debré P, Dornand J, Dugas B. Author information: (1)Laboratorie Virus Neurone et Immunité IFR du Kremlin Bicètre, Kremlin Bicètre, Montpellier, France. All trans retinoic acid and vitamin D3 derivatives are well known for their antileukemic activity, while the precise mechanism of this effect remains to be clarified. Using human leukemic U937 and THP-1 promonocytic cell lines, we analyzed the effect of all-trans retinoic acid (RA) and/or 1,25-dihydroxyvitamin D3 (VD) on the generation of nitric oxide (NO), a potent antitumoral me

31. Blood. 1996 Nov 1;88(9):3528-34. Role of nitric oxide in the anti-tumoral effect of retinoic acid and 1,25-dihydroxyvitamin D3 on human promonocytic leukemic cells. Dugas N(1), Mossalayi MD, Calenda A, Léotard A, Bécherel P, Mentz F, Ouaaz F, Arock M, Debré P, Dornand J, Dugas B. Author inf

Vasorelaxant activity induced by nitric oxide has been associated with a regulator activity on the blood pressure. In the present study we evaluated the nitric oxide contribution of the regulation of angiotensin II-induced vasoconstriction in normotensive rats and aortic coarctation-induced hypertensive rats. Renal vascular reactivity to angiotensin II was evaluated in the presence and absence of nitric oxide synthesis inhibitor; NG-nitro-L-arginine methyl ester. Nitrite concentration in perfusate was measured as an index of nitric oxide released and nitric oxide synthase activity was determined by production of 3H-L-citrulline. Renal NG-nitro-L-arginine methyl ester perfusion potentiated angiotensin II-induced vasoconstriction in normotensive rats but did not affect angiotensin II effect on hypertensive rats. The release of nitrites was lower in the kidneys from hypertensive rats than normotensive rats. Renal nitric oxide synthase activity was decreased in the hypertensive rats compared to the normotensive rats. We suggest that in normotensive rats, nitric oxide counteracts angiotensin II vasoconstrictor action, whereas, in hypertensive rats this mechanism is impaired, therefore, potentiating angiotensin II increase in vascular resistance thereby contributing to the developing of high blood pressure.

BACKGROUND: Many human studies report that nitric oxide (NO) improves sport performance. This is because NO is a potential modulator of blood flow, muscle energy metabolism, and mitochondrial respiration during exercise. L-Citrulline is an amino acid present in the body and is a potent endogenous precursor of L-arginine, which is a substrate for NO synthase. Here, we investigated the effect of oral L-citrulline supplementation on cycling time trial performance in humans. METHODS: A double-blind randomized placebo-controlled 2-way crossover study was employed. Twenty-two trained males consumed 2.4 g/day of L-citrulline or placebo orally for 7 days. On Day 8 they took 2.4 g of L-citrulline or placebo 1 h before a 4-km cycling time trial. Time taken to complete the 4 km cycle, along with power output/VO2 ratio (PO/VO2), plasma nitrite and nitrate (NOx) and amino acid levels, and visual analog scale (VAS) scores, was evaluated. RESULTS: L-Citrulline supplementation significantly increased plasma L-arginine levels and reduced completion time by 1.5 % (p < 0.05) compared with placebo. Moreover, L-citrulline significantly improved subjective feelings of muscle fatigue and concentration immediately after exercise. CONCLUSIONS: Oral L-citrulline supplementation reduced the time take to complete a cycle ergometer exercise trial. TRIAL REGISTRATION: Current Controlled Trials UMIN000014278.

BACKGROUND AND PURPOSE: Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke-like episodes (MELAS) is a rare multisystem mitochondrial disorder with clinical heterogeneity. Diagnostic criteria and management strategies for MELAS and mitochondrial stroke-like episodes (SLE) remain inconsistent. This work provides international consensus recommendations on the definition, diagnosis, and management of MELAS and SLE in pediatric and adult populations. METHODS: An international Delphi consensus process was conducted within the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD), in collaboration with the US Mitochondrial Medicine Society, the ERN for Hereditary Metabolic Disorders (MetabERN), and patient representatives. Following a systematic literature review, 54 statements addressing diagnostic definitions and management of MELAS were evaluated. Statements not reaching consensus were revised and re-evaluated during a face-to-face meeting. RESULTS: Consensus supported defining MELAS as a clinical syndrome characterized by one or more SLE in the context of mitochondrial dysfunction caused by a pathogenic mitochondrial DNA variant, particularly m.3243A>G in MT-TL1. The use of terms such as "MELAS-like" or "MELAS spectrum" was discouraged. The panel agreed that the efficacy of L-arginine, L-taurine, L-citrulline, coenzyme Q10, vitamins, and other supplements remains unproven and requires validation in clinical trials. Antiseizure medications should be initiated promptly when seizures are suspected during SLE, and intravenous corticosteroids may be beneficial acutely. Multidisciplinary management of neurological, neuropsychiatric, and systemic complications was endorsed. CONCLUSIONS: This international consensus provides updated definitions and practical guidance for the diagnosis and management of MELAS and SLE, aiming to harmonize clinical practice and inform future evidence-based research. © 2026 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.