Citrulline

Previous experimental studies have highlighted that citrulline (CIT) could be a promising pharmaconutrient. However, its pharmacokinetic characteristics and tolerance to loading have not been studied to date. The objective was to characterise the plasma kinetics of CIT in a multiple-dosing study design and to assess the effect of CIT intake on the concentrations of other plasma amino acids (AA). The effects of CIT loading on anabolic hormones were also determined. Eight fasting healthy males underwent four separate oral loading tests (2, 5, 10 or 15 g CIT) in random order. Blood was drawn ten times over an 8 h period for measurement of plasma AA, insulin and growth hormone (Gh). Urine samples were collected before CIT administration and over the next 24 h. None of the subjects experienced side effects whatever the CIT dose. Concerning AA, only CIT, ornithine (ORN) and arginine (ARG) plasma concentrations were affected (maximum concentration 146 (sem 8) to 303 (sem 11) μmol/l (ARG) a...

With the aim of developing a new enzyme-linked immunosorbent assay test to detect autoantibodies in the sera of rheumatoid arthritis patients with a high sensitivity and specificity using synthetic citrullinated peptides of fibrin (which is abundant in rheumatoid synovium) as antigenic substract, peptides belonging to α- and β-fibrin chains were selected by computer-aided prediction of antigenicity and epitope mapping and synthesized in solid phase. We analysed by enzyme-linked immunosorbent assay 133 sera from patients with well-characterized rheumatic diseases, including 67 patients with rheumatoid arthritis. The results of the immunoassays reported highlight the usefulness of fibrin-related peptides in rheumatoid arthritis diagnosis and, especially, the ability and specificity of the [Cit621,627,630]α-fibrin(617–631) (αfib617) peptide sequence to recognize the autoantibodies that are present in rheumatoid arthritis patients.

Objective-To design a new class of selective neuronal nitric oxide synthase (nNOS) inhibitors and demonstrate that administration in a rabbit model for cerebral palsy (CP) prevents hypoxiaischemia induced deaths and reduces the number of newborn kits exhibiting signs of CP.

Citrulline, a nonprotein amino acid, is an important source of endogenous arginine. The gut is the main source of citrulline in humans. Hence, citrulline is a potential biomarker of short bowel function. Conversely, citrulline uptake by the gut is important for an oral supply of this amino acid as an alternative to arginine. This review discusses these two aspects of citrulline, as well as the recent developments in the understanding of its metabolism.

The aim of this study is to report 5-year outcomes in patients who have received serial transverse enteroplasty (STEP) using clinical and biochemical assessments of intestinal function. Methods: Thirty-one STEP procedures have been performed at our institution. Twelve patients who received STEP before January 2005 were analyzed. Clinical and biochemical outcomes were performed pre-STEP and post-STEP on an annual basis. Paired t tests were used to compare post-STEP outcomes to pre-STEP values (P b .05 was significant). Main Results: There were 12 patients (3 females; median age, 5.5 months). Serial transverse enteroplasty resulted in mean increase in length of dilated bowel segment of 89% ± 26% and increase in total small bowel length of 46% ± 40%. Two patients received liver-intestinal transplants post-STEP (at 4 and 5 months), and 2 patients died of liver failure at 3 and 8 months. The remaining 8 of 12 patients all show stable intestinal absorptive capacity (data not shown). Of 8 patients, 7 were weaned off parenteral nutrition by 4 years. No patient has required repeat STEP or bowel tapering. Two patients developed staple line leak, and 1 patient developed gastrointestinal bleed from staple line ulcers. Conclusion: This report represents the largest series of STEP patients followed up beyond 5 years. Longterm clinical, biochemical, and radiologic outcomes appear to be robust.

No blood marker assessing the functional absorptive bowel length has been identified. Plasma citrulline, a nonprotein amino acid produced by intestinal mucosa, is one candidate. We tested this hypothesis in adult patients with the shortbowel syndrome, whose condition can lead to intestinal failure. Methods: In 57 patients, after a minimal follow-up of 2 years subsequent to final digestive circuit modification, postabsorptive citrulline concentration was measured and parenteral nutrition dependence was used to define permanent (n ‫؍‬ 37) and transient (n ‫؍‬ 20) intestinal failure. Absorptive function, studied over a 3-day period, was evaluated by net digestive absorption for protein and fat (n ‫؍‬ 51). Relations between quantitative values were assessed by linear regression analysis and cutoff citrulline threshold, for a diagnosis of intestinal failure by linear discriminant analysis. Cox model was used to compare citrulline threshold and anatomic variables of the short bowel as indicators of transient as opposed to permanent intestinal failure. Results: In patients with short-bowel syndrome, citrulline levels were lower than in controls (n ‫؍‬ 51): 20 ؎ 13 vs. 40 ؎ 10 mol/L (mean ؎ SD), respectively (P < 0.001). After multivariate analysis, citrullinemia was correlated to small bowel length (P < 0.0001, r ‫؍‬ 0.86) and to net digestive absorption of fat, but to neither body mass index nor creatinine clearance. A 20-mol/L threshold citrullinemia, (1) classified short bowel patients with permanent intestinal failure with high sensitivity (92%), specificity (90%), positive predictive value (95%), and negative value (86%); and (2) was a more reliable indicator (odds ratio, 20.0; 95% confidence interval, 1.9 -206.1) than anatomic variables (odds ratio, 2.9; 95% confidence interval, 0.5-15.8) to separate transient as opposed to permanent intestinal failure. Conclusions: In patients with short-bowel syndrome, postabsorptive plasma citrulline concentration is a marker of functional absorptive bowel length and, past the 2-year adaptive period, a powerful independent indicator allowing distinction of transient from permanent intestinal failure.

Histone proteins are modified in response to various external signals; however, their mechanisms are still not fully understood. Citrullination is a post-transcriptional modification that converts arginine in proteins into citrulline. Here we show in vivo and in vitro citrullination of the arginine 3 residue of histone H4 (cit-H4R3) in response to DnA damage through the p53-PADI4 pathway. We also show DnA damage-induced citrullination of Lamin C. Cit-H4R3 and citrullinated Lamin C localize around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 leads to chromatin decondensation and promotes DnA cleavage, whereas Padi4 − / − mice exhibit resistance to radiation-induced apoptosis in the thymus. Furthermore, the level of cit-H4R3 is negatively correlated with p53 protein expression and with tumour size in non-small cell lung cancer tissues. our findings reveal that cit-H4R3 may be an 'apoptotic histone code' to detect damaged cells and induce nuclear fragmentation, which has a crucial role in carcinogenesis.

Objectives The aims of this study were to assess the association between area-level socio-economic deprivation and the phenotype of rheumatoid arthritis (RA), defi ned by rheumatoid factor (RF) and anticitrullinated peptide antibody (AC PA) status, and to determine whether any observed association can be explained by smoking. Methods The authors performed logistic regression analysis of 6298 patients with RA, defi ned by American College of Rheumatology classifi cation criteria modifi ed for genetic studies. Analysis was stratifi ed by cohort/ recruitment centre. Socio-economic deprivation was measured using the Townsend Index. Results Deprivation predicted RF but not ACPA positivity, independent of smoking. The ORs for trend across tertiles, adjusted for smoking, gender, period of birth and cohort/ recruitment centre, were 1.14 (95% CI 1.01 to 1.29) for RF and 1.01 (95% CI 0.87 to 1.16) for ACPA. Even after adjusting for deprivation, smoking was strongly associated with ACPA positivity (OR 1.38, 95% CI 1.22 to 1.55). There was no evidence of any effect modifi cation by the RA risk alleles (HLA-DRB1 shared epitope and PTPN22 rs2476601) that have previously been shown to modify the effect of smoking on ACPA and RF positivity. Conclusions Among patients with RA, deprivation predicted RF positivity but not ACPA positivity. The effect of deprivation did not appear to be explained by smoking. Deprivation may be a marker for previously unrecognised, potentially modifi able environmental infl uences on the immunological phenotype of RA. Furthermore, given the known associations of RF positivity with prognosis and response to treatment in RA, these fi ndings have potential implications for resource allocation and healthcare delivery.

Hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome is caused by mutations in the SLC25A15 (ORNT1) gene encoding the mitochondrial ornithine transporter, but the mechanism of pathogenesis of the encephalopathy, spastic paraparesis and hepatopathy remains undetermined. HHH syndrome was diagnosed in a 2-year-old Palestinian boy with developmental delay and seizures, and subsequently in his 13-year-old brother with developmental delay. Direct sequencing of the PCR products of SLC25A15 exon amplifications revealed that both brothers were homozygous for a novel 446G deletion in exon 3 as well as for a 760A>T (I254L) polymorphism in exon 5, which is downstream of a premature termination codon produced by the frameshift resulting from the 446G deletion. The index patient had elevated liver enzymes as well as hyperalaninemia, lactic acidemia with an elevated lactate to pyruvate ratio, and increased urinary excretion of lactate, glutarate and Krebs cycle intermediates. These findings are indicative of mitochondrial dysfunction and are in accordance with ultrastructural studies showing increased numbers of large and bizarre mitochondria in liver, muscle, leukocytes and fibroblasts of some HHH patients. Neurologic and hepatic manifestations are characteristic of some primary mitochondrial disorders. Secondary mitochondrial dysfunction may contribute to the pathogenesis of these same features in HHH syndrome. D

The new-AEDs, whose developments were motivated following the discovery of the valproate and its marketing in the U.S in 1978, have presented more therapeutic options. There are approximately twenty four FDAapproved antiepileptic drugs for use in patients with epilepsy, five of which were identified and have come on to the market between 2009 and 2012. The new-AEDs are of interest, not due to their efficacy, but rather owing to better tolerance, favorable pharmacokinetic profile, fewer interactions, and in some instances, lesser protein binding. No standard AED or those in developing have all properties of an ideal antiepileptic drug, thus to achieve desirable outcome, physicians should be aware of pharmacokinetics (PKs) and pharmacodynamics (PDs) of drugs. This review describes briefly the major features of the new AEDs. The pharmacological aspects of the new AEDs Ir J neurol 2013; 12(4) 159 http://ijnl.tums.ac.ir 6 October

Objective: Watermelon is a rich source of citrulline, an amino acid that can be metabolized to arginine, a conditionally essential amino acid for humans. Arginine is the nitrogenous substrate used in the synthesis of nitric oxide and plays an essential role in cardiovascular and immune functions. No detailed studies have been conducted to evaluate plasma arginine response in humans after long-term feeding of citrulline from natural plant sources. This study investigated if watermelon juice consumption increases fasting concentrations of plasma arginine, ornithine, and citrulline in healthy adult humans. Methods: Subjects (n ϭ 12-23/treatment) consumed a controlled diet and 0 (control), 780, or 1560 g of watermelon juice per day for 3 wk in a crossover design. The treatments provided 1 and 2 g of citrulline per day. Treatment periods were preceded by washout periods of 2 to 4 wk. Results: Compared with the baseline, fasting plasma arginine concentrations increased 12% after 3 wk of the lower-dose watermelon treatment; arginine and ornithine concentrations increased 22% and 18%, respectively, after 3 wk of the higher-dose watermelon treatment. Fasting citrulline concentrations did not increase relative to the control but remained stable throughout the study. Conclusion: The increased fasting plasma concentrations of arginine and ornithine and stable concentrations of plasma citrulline in response to watermelon juice consumption indicated that the citrulline from this plant origin was effectively converted into arginine. These results demonstrate that plasma concentration of arginine can be increased through intake of citrulline from watermelon.

Watermelon (Citrullus vulgaris Schrad.) is a natural and rich source of the non-essential amino acid citrulline. Citrulline is used in the nitric oxide system in humans and has potential antioxidant and vasodilatation roles. A method using gas chromatography-mass spectrometry (GC-MS) was developed to separate citrulline from glutamic acid, which co-elute when analyzed by high performance liquid chromatography. Watermelons were analyzed by GC-MS to determine the citrulline content among varieties, types, flesh colors, and tissues. Citrulline content ranged from 3.9 to 28.5 mg/g dry weight (dwt) and was similar between seeded and seedless types (16.6 and 20.3 mg/g dwt, respectively). Red flesh watermelons had slightly less citrulline than the yellow or orange flesh watermelons (7.4, 28.5 and 14.2 mg/g dwt, respectively). Rind contained more citrulline than flesh on a dry weight basis (24.7 and 16.7 mg/g dwt, respectively) but a little less on a fresh weight (fwt) basis (1.3 and 1.9 mg/g fwt, respectively). These results indicate that watermelon rind, an underutilized agricultural waste, offers a source of natural citrulline. Published by Elsevier B.V.

L-citrulline is an excellent candidate to reduce muscle soreness, and 16 watermelon is a fruit rich in this amino acid. This study investigated the potential of 17 watermelon juice as a functional drink for athletes. An in vitro study of intestinal 18 absorption of L-citrulline in Caco-2 cells was performed using unpasteurized (NW), 19 pasteurized (80 ºC for 40 s) watermelon juice (PW) and, as control a standard of L-20 citrulline. L-citrulline bioavailability was greater when it was contained in a matrix of 21 watermelon and when no heat treatment was applied. In the in vivo experiment 22 (maximum effort test in a cycloergometer), seven athletes were supplied with 500 mL of 23 natural watermelon juice (1.17 g of L-citrulline), enriched watermelon juice (4.83 g of 24 L-citrulline plus 1.17 g from watermelon) and placebo. Both watermelon juices helped 25 to reduce the recovery heart rate and the muscle soreness after 24 h.

This is an extract  about urea cycle relation with syndrome intestine irritable and some diseases like arthritis reumathoid, created by JoanCarles Testagorda Garcia of the work Anatomia Magna vol.I created by JoanCarles Testagorda Garcia. The total content of this extract (9pages) and the total content, the total original ideas, equations, reasonings of the work Anatomia Magna vol.I more than 150pages are created by JoanCarles Testagorda Garcia

Background: 'Relaxers' are used by more than two thirds of African females to straighten hair, with easy grooming and increased length often cited as reasons. A recent study reported relaxed hair lengths much shorter than expected, suggesting increased fragility; the potential for scalp inflammation and scarring alopecia remains unclear.

Objective: To compare the frequency of different autoantibodies in a group of patients with Jaccoud's arthropathy (JA) secondary to systemic lupus erythematosus (SLE) with those without JA. Methods: A group of SLE patients with JA was compared with another group of SLE patients without this complication, matched by age and gender, regarding the presence of autoantibodies. Antibodies to cyclical citrullinated peptides (anti-CCP) and to mutated citrullinated vimentin (anti-MCV) as well as anti-SSA/Ro, anti-SSB/La, anti-Sm and anti-RNP and anticardiolipin (aCL) antibodies were searched by ELISA, using commercial kits. Rheumatoid factor was determined by nephelometry and antinuclear and anti-dsDNA antibodies by IIF. Results: Forty-eight individuals were included in the study, being 24 patients with JA and 24 without JA, matched by gender and age. The frequency of anti-CCP antibodies in the whole population was 12.5% (6 cases), with no difference between the 2 groups. Anti-MCV antibodies were detected in 10.4% (5 cases), being found only in those with JA ( p ¼ 0.05). There was no association between the presence of JA and aCL, anti-Sm, anti-RNP and anti-SSB/La antibodies. On the other hand, a statistically significant association between the presence of anti-dsDNA antibodies and JA was observed ( p ¼ 0.04) as well as a marginal association with a decrease in serum levels of C3 ( p ¼ 0.06). Conclusion: In the present study, there was an association between the presence of JA and anti-dsDNA antibodies, and anti-MCV antibodies were found only in those SLE patients with JA. Whether these antibodies have an etiopathogenic role in JA is entirely unknown.

Background: Impaired microcirculation during endotoxemia correlates with a disturbed arginine-nitric oxide (NO) metabolism and is associated with deteriorating organ function. Improving the organ perfusion in endotoxemia, as often seen in patients with severe infection or systemic inflammatory response syndrome (SIRS) is, therefore, an important therapeutic target. We hypothesized that supplementation of the arginine precursor citrulline rather than arginine would specifically increase eNOS-induced intracellular NO production and thereby improve the microcirculation during endotoxemia.

The synthesis of citrulline from arginine in the small intestine depends on the provision of ornithine. To test the hypothesis that arginase II plays a central role in the supply of ornithine for citrulline synthesis, the contribution of dietary arginine, glutamine, and proline was determined by utilizing multitracer stable isotope protocols in arginase II knockout (AII−/−) and wild-type (WT) mice. The lack of arginase II resulted in a lower citrulline rate of appearance (121 vs. 137 μmol·kg−1·h−1) due to a reduced availability of ornithine; ornithine supplementation was able to restore the rate of citrulline production in AII−/− to levels comparable with WT mice. There were significant differences in the utilization of dietary citrulline precursors. The contribution of dietary arginine to the synthesis of citrulline was reduced from 45 to 10 μmol·kg−1·h−1 due to the lack of arginase II. No enteral utilization of arginine was observed in AII−/− mice (WT = 25 μmol·kg−1·h−1), and the ...

The new-AEDs, whose developments were motivated following the discovery of the valproate and its marketing in the U.S in 1978, have presented more therapeutic options. There are approximately twenty four FDAapproved antiepileptic drugs for use in patients with epilepsy, five of which were identified and have come on to the market between 2009 and 2012. The new-AEDs are of interest, not due to their efficacy, but rather owing to better tolerance, favorable pharmacokinetic profile, fewer interactions, and in some instances, lesser protein binding. No standard AED or those in developing have all properties of an ideal antiepileptic drug, thus to achieve desirable outcome, physicians should be aware of pharmacokinetics (PKs) and pharmacodynamics (PDs) of drugs. This review describes briefly the major features of the new AEDs. The pharmacological aspects of the new AEDs Ir J neurol 2013; 12(4) 159 http://ijnl.tums.ac.ir 6 October

OBJECTIVES: To test the efficacy and safety of oral L-citrulline supplementation in improving erection hardness in patients with mild erectile dysfunction (ED). L-arginine supplementation improves nitric oxidemediated vasodilation and endothelial function; however, oral administration has been hampered by extensive presystemic metabolism. In contrast, L-citrulline escapes presystemic metabolism and is converted to L-arginine, thus setting the rationale for oral L-citrulline supplementation as a donor for the L-arginine/nitric oxide pathway of penile erection.

Biomarkers are decision-making tools at the basis of clinical diagnostics and essential for guiding therapeutic treatments. In this context, autoimmune diseases represent a class of disorders that need early diagnosis and steady monitoring. These diseases are usually associated with humoral or cell-mediated immune reactions against one or more of the body's own constituents. Autoantibodies fluctuating in biological fluids can be used as disease biomarkers and they can be, thus, detected by diagnostic immunoassays using native autoantigens. However, it is now accepted that post-translational modifications may affect the immunogenicity of self-protein antigens, triggering an autoimmune response and creating neo-antigens. In this case, post-translationally modified peptides represent a more valuable tool with respect to isolated or recombinant proteins. In fact, synthetic peptides can be specifically modified to mimic neo-antigens and to selectively detect autoantibodies as disease biomarkers. A ‘chemical reverse approach’ to select synthetic peptides, bearing specific post-translational modifications, able to fishing out autoantibodies from patients' biological fluids, can be successfully applied for the development of specific in vitro diagnostic/prognostic assays of autoimmune diseases. Herein, we report the successful application of this approach to the identification of biomarkers in different autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.

In lysinuric protein intolerance (LPI), defective transport of cationic amino acids at the basolateral membrane of the polar epithelial cells in the intestine and renal tubules leads to decreased intestinal absorption and excessive renal loss of lysine, arginine, and ornithine. Citrulline supplementation partially restores the function of the urea cycle that is impaired by deficiency of arginine and ornithine, but does not correct the chronic lysine deficiency. Previous attempts to supplement lysine orally have been hindered by profuse diarrhea, probably caused by excess lysine remaining unabsorbed in the gut. However, individually adjusted minute doses of l-lysine hydrochloride at mealtimes are tolerated well, but the long-term benefits of this therapy remain unknown. The aim of the study was to investigate the long-term benefits and possible adverse effects of oral lysine supplementation in patients with LPI. Supplementation of meals with low doses of oral lysine improved fasting plasma lysine concentrations in 27 Finnish patients with LPI without causing hyperammonemia or other recognizable side effects during 12 months of follow-up. In conclusion, low-dose oral lysine supplementation is potentially beneficial to patients with LPI and can be started safely at an early age. D

Purpose: Splanchnic hypoperfusion is a physiological phenomenon during strenuous exercise. It has been associated with gastrointestinal symptoms and intestinal injury and may hamper athletic performance. We hypothesized that L-citrulline supplementation improves splanchnic perfusion and decreases intestinal injury by enhancing arginine availability. The aim of this study was to determine the effect of L-citrulline intake on splanchnic perfusion, intestinal injury, and barrier function during exercise. Methods: In this randomized, double-blind crossover study, 10 men cycled for 60 min at 70% of their maximum workload after L-citrulline (10 g) or placebo (L-alanine) intake. Splanchnic perfusion was assessed using gastric air tonometry. Sublingual microcirculation was evaluated by sidestream dark field imaging. Plasma amino acid levels and intestinal fatty acid binding protein concentrations, reflecting enterocyte damage, were assessed every 10 min. Urinary excretion of sugar probes was measured to evaluate intestinal permeability changes. Results: Oral L-citrulline supplementation enhanced plasma citrulline (1840.3 T 142.3 HM) and arginine levels (238.5 T 9.1 HM) compared with that in placebo (45.7 T 4.8 HM and 101.5 T 6.1 HM, respectively, P G 0.0001), resulting in increased arginine availability. Splanchnic hypoperfusion was prevented during exercise after L-citrulline ingestion (reflected by unaltered gap g-a pCO 2 levels), whereas gap g-a pCO 2 increased with placebo treatment (P G 0.01). Accordingly, L-citrulline intake resulted in an increased number of perfused small sublingual vessels compared with that in placebo (7.8 T 6.0 vs j2.0 T 2.4, P = 0.06). Furthermore, plasma intestinal fatty acid binding protein levels were attenuated during exercise after L-citrulline supplementation compared with that in placebo (AUC 0-60 min , j185% T 506% vs 1318% T 553%, P G 0.01). No significant differences were observed for intestinal permeability. Conclusions: Pre-exercise L-citrulline intake preserves splanchnic perfusion and attenuates intestinal injury during exercise in athletes compared with placebo, probably by enhancing arginine availability. These results suggest that oral L-citrulline supplementation is a promising intervention to combat splanchnic hypoperfusion-induced intestinal compromise.

Objectives:  Fetal hemoglobin (HbF) induction involves NO-cGMP signaling pathways. l-arginine, an NO precursor, and the phosphodiesterase (PDE) 5 inhibitor sildenafil, which potentiates cGMP, were studied in adults with sickle cell disease (SCD) who were stably on HU.Methods:  Twenty four courses of l-arginine (0.1–0.2 g/kg divided TID) or sildenafil (25–100 mg TID), assigned based on gender due to concerns about sildenafil-related priapism, were successfully completed. Biochemical assays, pulmonary pressures, and cardiopulmonary exercise capacity are reported from patients in whom serial values are available. Hematologic responses are reported in 14 subjects with HbSS who had stable baseline HbF levels.Results: l-arginine increased plasma arginine and ornithine, but not citrulline, suggesting diversion by plasma arginase from NO, and citrulline, generation. Glutathione increased only in patients on l-arginine. Sildenafil increased plasma cGMP and citrulline, but not other amino acids. Pulmonary pressures and 6-min walk distances improved only in patients on sildenafil. In subjects with stable baseline HbF levels, HbF levels changed little from a normalized baseline on l-arginine, decreasing by 2.9 ± 16.1%, n = 6; P = n.s., but increased on sildenafil, by 7.5 ± 11.7%, n = 8, P < 0.05. Absolute reticulocyte counts initially decreased in patients on sildenafil.Conclusions: l-arginine, at doses that increase plasma arginine levels, altered redox potential in red cells. The lack of clinically detectable efficacy of l-arginine may be due to increased arginine metabolism in SCD patients. In vivo augmentation of the cyclic nucleotide pathway by PDE inhibition may induce HbF slightly, but strikingly improves hemodynamic and functional status in SCD.

A metabolic relation exists between glutamine and arginine, 2 amino acids with properties that enhance the recovery of seriously ill patients. It is possible that glutamine exerts part of its beneficial effects by enhancing the availability of arginine. We aimed to quantify under postabsorptive conditions the metabolic pathway of plasma glutamine into arginine via the intermediate citrulline and to establish the contribution of the kidneys to the synthesis of arginine. The study was conducted in patients during surgery. The metabolism of glutamine, citrulline, and arginine was studied by using intravenous administration of stable isotope tracers of the amino acids. Results were interpreted by using established equations. Parametric tests were used to test and correlate results. P &lt; 0.05 was regarded as significant. Mean (+/-SE) whole-body plasma turnover rates of glutamine, citrulline, and arginine were 240 +/- 14, 6.2 +/- 0.6, and 42 +/- 2.9 micromol x kg(-1) x h(-1), respective...

Watermelon is a tropical fruit whose flesh is consumed throughout Colombia because of its nutritional benefits, but the non-edible portion composed of rind and skin is used occasionally to feed pigs and in culinary recipes; the rest is discarded generating sources of environmental pollution. For this reason, it was proposed to identify its nutritional composition and determine the citrulline content of the watermelon rind consumed in Valledupar. The citrulline was extracted with solvent using a factorial design 23 with three replicates in the central point being the factors: Solvent (99.5% ethanol solution with HCl 6M) (30% and 80%); Preheating time (20 and 40 min) and temperature (50 and 70 °C). It was found that in Valledupar 2610 t / year of fresh watermelon from Meta, Guajira and Bolívar crops were consumed, producing 827.37 tons of bark per year with 13.15 ± 0.76% of fiber, 10.12 ± 0, 92% protein and 14.7 mg g-1 of dried rind citrulline extracted. The best treatment was obtained after 20 minutes at 50 °C and 30% solvent. The obtained citrulline can be used in the elaboration of functional products such as drinks or syrups to improve the cardiovascular system and to diminish the muscular fatigue after a physical effort or the elaboration of flour for bakery with reduced energetic value and greater content in dietary fiber that can help the gastrointestinal system.

Oral l-arginine, the nitric oxide precursor, can reduce resting blood pressure (BP) via improved nitric oxide production in patients with cardiovascular risk factors. In healthy individuals, oral l-arginine has been associated with decrease 4 or no change 5 in resting brachial BP. It has been suggested that an increased arginase activity makes chronic oral l-arginine supplementation somewhat ineffective. 6 Conversely, oral l-citrulline provides greater plasma l-arginine levels due to an efficient conversion of l-citrulline to l-arginine. 7 Recent data have shown that oral l-citrulline treatment reduced peripheral BP by improving aortic relaxation in rats. Although elevated brachial pulse pressure (PP) is associated with increased cardiovascular mortality, 10 aortic systolic BP (SBP) and PP may be better predictors of cardiovascular risk than brachial BP. 11,12 As vasoactive drugs may affect aortic BP more than brachial BP, 13,14 aortic BP measurements have been proposed as the treatment target. Sympathetic-mediated vasoconstriction induced by the cold pressor test (CPT) leads to acute increases in peripheral (brachial and digital) BP, aortic BP, and wave reflection in healthy subjects without increasing the heart rate. The CPT has been used to evaluate the efficacy of lifestyle 3,18 and pharmacological interventions 19 on BP and vascular reactivity. In addition, oral l-arginine supplementation was found effective in reducing the brachial BP response to CPT in men with hypercholesterolemia. 3 Thus, the CPT may be a suitable tool to evaluate the effect of oral l-citrulline on BP and aortic hemodynamics. Therefore, the purpose of the study was to test the hypothesis that oral l-citrulline supplementation would reduce brachial BP, aortic BP, and wave reflection responses to CPT.

The effect of L-arginine and L-citrulline on blood pressure and right ventricular function in heart failure patients with preserved ejection fraction (HFpEF) is unknown. We have therefore evaluated, in a randomized clinical trial, the effect of these aminoacids in chronic outstanding and stable patients with HFpEF. All patients underwent an echocardiogram and radioisotopic ventriculography rest/exercise, and were randomized in a consecutive manner to the L-arginine group (n = 15; 8 g/day); and the citrulline malate group (n = 15; 3 g/day). The duration of follow-up was two months. The principal echocardiographic finding was a statistically significant decrease in pulmonary artery pressure in the L-arginine (56.3 ± 10 vs 44 ± 16.5 mm Hg, p &lt; 0.05) and the citrulline (56.67 ± 7.96 vs 47.67 ± 8.59 mm Hg, p &lt; 0.05) groups. Duration on treadmill and right ventricular ejection fraction post exercise increased, while diastolic and systolic artery pressure decreased significantly in b...

Here we used solid-phase methods to prepare oligonucleotides carrying fibrin/ filaggrin citrullinated peptides. Post-synthetic conjugation protocols were successfully applied for the synthesis of oligonucleotides carrying small peptides. A stepwise protocol using acid treatment for the final deprotection allowed the preparation of polypyrimidine oligonucleotides carrying longer and arginine-rich peptides. An ELISA-based test using the oligonucleotide-citrullinated peptide conjugates was developed for the detection of anti-citrullinated protein/peptide antibodies in human serum from rheumatoid arthritis patients.

Alterations in neuronal nitric oxide (NO) production may play a role in the pathophysiology of Parkinson's disease (PD) Alzheimer's disease (AD), and multiple system atrophy (MSA). The biosynthesis of NO is dependent on the availability of L-arginine, the substrate for NO-synthase (NOS), and on L-glutamate, which stimulates NO synthesis via the NMDA receptor. In this process L-citrulline is formed. We measured the levels of these amino acids in cerebrospinal fluid (CSF) of 108 PD patients, 12 AD patients, 15 MSA patients and 21 healthy subjects. A slight but statistically significant elevation of CSF L-citrulline was found in MSA patients, while CSF L-glutamate was found to be significantly decreased in AD patients. We found no significant changes in L-arginine levels. Although the relation between the CSF levels of these amino acids and neuronal NO production is still unclear, our findings suggest that AD is associated with a decrease in NO synthesis.

Objective: Pulmonary hypertension may complicate surgical correction of congenital heart defects, resulting in increased morbidity and mortality. We have previously shown that plasma levels of the nitric oxide precursors citrulline and arginine drop precipitously after congenital cardiac surgery and that oral citrulline supplementation may be protective against the development of pulmonary hypertension. In this study, we assessed the safety and pharmacokinetic profile of intravenous citrulline as a potential therapy for postoperative pulmonary hypertension.

Background Rheumatoid arthritis (RA) is characterised by autoimmunity to citrullinated proteins, and there is increasing epidemiologic evidence linking Porphyromonas gingivalis to RA. P gingivalis is apparently unique among periodontal pathogens in possessing a citrullinating enzyme, peptidylarginine deiminase (PPAD) with the potential to generate antigens driving the autoimmune response. Objectives To examine the immune response to PPAD in patients with RA, individuals with periodontitis (PD) and controls (without arthritis), confirm PPAD autocitrullination and identify the modified arginine residues. Methods PPAD and an inactivated mutant (C351A) were cloned and expressed and autocitrullination of both examined by immunoblotting and mass spectrometry. ELISAs using PPAD, C351A and another P gingivalis protein arginine gingipain (RgpB) were developed and antibody reactivities examined in patients with RA (n=80), individuals with PD (n=44) and controls (n=82). Results Recombinant PPAD was a potent citrullinating enzyme. Antibodies to PPAD, but not to Rgp, were elevated in the RA sera (median 122 U/ml) compared with controls (median 70 U/ml; p<0.05) and PD (median 60 U/ml; p<0.01). Specificity of the anti-peptidyl citrullinated PPAD response was confirmed by the reaction of RA sera with multiple epitopes tested with synthetic citrullinated peptides spanning the PPAD molecule. The elevated antibody response to PPAD was abolished in RA sera if the C351A mutant was used on ELISA. Conclusions The peptidyl citrulline-specific immune response to PPAD supports the hypothesis that, as a bacterial protein, it might break tolerance in RA, and could be a target for therapy.

The distribution of the arginine succinyltransferase pathway was examined in representative strains of Pseudomonas and related bacteria able to use arginine as the sole carbon and nitrogen source for growth. The arginine succinyltransferase pathway was induced in arginine-grown cells. The accumulation of succinylornithine following in vivo inhibition of succinylornithine transaminase activity by aminooxyacetic acid showed that this pathway is responsible for the dissimilation of the carbon skeleton of arginine. Catabolism of citrulline as a carbon source was restricted to relatively few of the organisms tested. In P. putida, P . cepacia and P . indigofera, ornithine was the main product of citrulline degradation. In most strains which possessed the arginine succinyltransferase pathway, the first step of ornithine utilization as a carbon source was the conversion of ornithine into succinylornithine through an ornithine succinyltransferase. However P . cepacia and P. putida used ornithine by a pathway which proceeded via proline as an intermediate and involved an ornithine cyclase activity.

Huntington&#39;s disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD. The resultant ammonia toxicity might exacerbate the neurological deficits of HD. Suppression of C/EBPalpha, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in HD. We found that in the presence of mutant Htt, C/EBPalpha loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBPalpha into aggregates, as well as suppressed expression of the C/EBPalpha gene. Consumption of protein-restricted diets not only led to the restoration of C/EBPalpha&#39;s activity, and repair of the urea cycle deficiency and hyperammonem...

Background: A metabolic relation exists between glutamine and arginine, 2 amino acids with properties that enhance the recovery of seriously ill patients. It is possible that glutamine exerts part of its beneficial effects by enhancing the availability of arginine. Objectives: We aimed to quantify under postabsorptive conditions the metabolic pathway of plasma glutamine into arginine via the intermediate citrulline and to establish the contribution of the kidneys to the synthesis of arginine. Design: The study was conducted in patients during surgery. The metabolism of glutamine, citrulline, and arginine was studied by using intravenous administration of stable isotope tracers of the amino acids. Results were interpreted by using established equations. Parametric tests were used to test and correlate results. P 0.05 was regarded as significant. Results: Mean (ȀSE) whole-body plasma turnover rates of glutamine, citrulline, and arginine were 240 Ȁ 14, 6.2 Ȁ 0.6, and 42 Ȁ 2.9 mol ⅐ kg Ҁ1 ⅐ h Ҁ1 , respectively (P 0.01). Plasma turnover of citrulline derived from glutamine was shown to be 5.1 Ȁ 0.7 mol ⅐ kg Ҁ1 ⅐ h Ҁ1 , and arginine derived from citrulline was shown to be 4.9 Ȁ 0.9 mol ⅐ kg Ҁ1 ⅐ h Ҁ1 (P 0.01). The contribution of plasma glutamine to plasma arginine derived from plasma citrulline was calculated to be 64%. The kidneys were observed to take up 50% of circulating plasma citrulline and to release equimolar amounts of arginine into plasma. Conclusions: This study shows that glutamine is an important precursor for the synthesis of arginine in humans. It also provides a firm basis for future studies exploring the effect of a treatment dose and the route of administration (enteral or parenteral) of glutamine.

1. Treatment with haemodialysis and continuous ambulatory peritoneal dialysis (CAPD) presents different pathophysiological profiles and it has been suggested that clinical outcome in chronic renal failure may depend on the mode of dialysis. The transport of L-arginine, a precursor of nitric oxide, into blood cells is increased in uraemic patients on haemodialysis. The present study was designed to investigate L-arginine transport into red blood cells (RBC) in uraemic patients not yet on dialysis and on CAPD therapy. 2. Eleven uraemic patients not yet on dialysis and 17 on CAPD were included in the study. L-Arginine transport into RBC and plasma and RBC amino acid profiles were analysed in these sets of patients. 3. L-Arginine transport via system y(+), but not y(+)L, into RBC, was significantly increased in undialysed uraemic patients (459 +/- 40 micromol/L per cell per h) and CAPD patients (539 +/- 61 micromol/L per cell per h) compared with controls (251 +/- 39 micromol/L per cell per h). High-pressure liquid chromatography measurements demonstrated low levels of plasma L-arginine in uraemic patients both on CAPD (54 +/- 3 micromol/L) and not yet on dialysis (80 +/- 6 micromol/L) compared with control subjects (146 +/- 14 micromol/L). 4. Our findings provide the first evidence that uraemic patients not yet on dialysis and on CAPD present with an activation of L-arginine transport via system y(+) into RBC associated with reduced plasma levels of L-arginine.