The enzyme arginase metabolizes L-arginine to L-ornithine and urea. Besides its fundamental role in the hepatic urea cycle, arginase is also expressed the immune system of mice and man. While significant interspecies differences exist regarding expression, subcellular localization and regulation of immune cell arginase, associated pathways of immunopathology are comparable between species. Arginase is induced in murine myeloid cells mainly by Th2 cytokines and inflammatory agents and participates in a variety of inflammatory diseases by down-regulation of nitric oxide synthesis, induction of fibrosis and tissue regeneration. In humans, arginase I is constitutively expressed in polymorphonuclear neutrophils and is liberated during inflammation. Myeloid cell arginase-mediated L-arginine depletion profoundly suppresses T cell immune responses and this has emerged as a fundamental mechanism of inflammation-associated immunosuppression. Pharmacological interference with L-arginine metabolism is a novel promising strategy in the treatment of cancer, autoimmunity or unwanted immune deviation.

/pdf/arginase-an-emerging-key-player-in-the-mammalian-immune-4ou3adq3l7.pdf

Arginase: an emerging key player in the mammalian immune system

https://archive-ouverte.unige.ch/unige:112949/ATTACHMENT01

EASL Clinical Practice Guidelines on nutrition in chronic liver disease

Arginine has multiple metabolic fates and thus is one of the most versatile amino acids. Not only is it metabolically interconvertible with the amino acids proline and glutamate, but it also serves as a precursor for synthesis of protein, nitric oxide, creatine, polyamines, agmatine, and urea. These processes do not all occur within each cell but are differentially expressed according to cell type, age and developmental stage, diet, and state of health or disease. Arginine metabolism also is modulated by activities of various transporters that move arginine and its metabolites across the plasma and mitochondrial membranes. Moreover, several key enzymes in arginine metabolism are expressed as multiple isozymes whose expression can change rapidly and dramatically in response to a variety of different stimuli in health and disease. As illustrated by the questions raised in this article, we currently have an imperfect and incomplete picture of arginine metabolism for any mammalian species. It has become clear that a more complete understanding of arginine metabolism will require integration of information obtained from multiple approaches, including genomics, proteomics, and metabolomics.

Arginine Metabolism: Boundaries of Our Knowledge

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• L-Arginine is a semiessential amino acid that is converted to nitric oxide (NO) by NO synthase (NOS).

• NO improves endothelial function by elevating cyclic guanosine monophosphate.

• However, oral L-arginine treatment in humans is hampered by extensive metabolism.

WHAT THIS STUDY ADDS

• Oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.

• L-Citrulline may thus be an alternative to L-arginine in patients with impaired NOS activity.

AIMS
Oral L-arginine supplementation has been used in several studies to improve endothelium-dependent, nitric oxide (NO)-mediated vasodilation. L-Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L-citrulline is readily absorbed and at least in part converted to L-arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects.

METHODS
In a double-blind, randomized, placebo-controlled cross-over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (Cmax, Tmax, Cmin, AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L-arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow-mediated vasodilation (FMD) was measured to assess pharmacodynamic effects.

RESULTS
L-Citrulline dose-dependently increased AUC and Cmax of plasma L-arginine concentration more effectively than L-arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the Cmin of plasma L-arginine and improved the L-arginine/ADMA ratio from 186 ± 8 (baseline) to 278 ± 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 ± 10 to 125 ± 15 µmol mmol−1 creatinine (P = 0.01, 95% CI 8, 58) and from 38 ± 3.3 to 50 ± 6.7 nmol mmol−1 creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD.

CONCLUSION
Our data show for the first time that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.2007.02990.x

Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.

Sports nutrition is a constantly evolving field with hundreds of research papers published annually. In the year 2017 alone, 2082 articles were published under the key words ‘sport nutrition’. Consequently, staying current with the relevant literature is often difficult. This paper is an ongoing update of the sports nutrition review article originally published as the lead paper to launch the Journal of the International Society of Sports Nutrition in 2004 and updated in 2010. It presents a well-referenced overview of the current state of the science related to optimization of training and performance enhancement through exercise training and nutrition. Notably, due to the accelerated pace and size at which the literature base in this research area grows, the topics discussed will focus on muscle hypertrophy and performance enhancement. As such, this paper provides an overview of: 1.) How ergogenic aids and dietary supplements are defined in terms of governmental regulation and oversight; 2.) How dietary supplements are legally regulated in the United States; 3.) How to evaluate the scientific merit of nutritional supplements; 4.) General nutritional strategies to optimize performance and enhance recovery; and, 5.) An overview of our current understanding of nutritional approaches to augment skeletal muscle hypertrophy and the potential ergogenic value of various dietary and supplemental approaches. This updated review is to provide ISSN members and individuals interested in sports nutrition with information that can be implemented in educational, research or practical settings and serve as a foundational basis for determining the efficacy and safety of many common sport nutrition products and their ingredients.

https://researchbank.swinburne.edu.au/file/15e35c6c-4774-4c52-9925-46c78269bed4/1/2018-kerksick-issn_exercise_sports.pdf

ISSN exercise & sports nutrition review update: research & recommendations

Citrulline (Cit, C6H13N3O3), which is a ubiquitous amino acid in mammals, is strongly related to arginine. Citrulline metabolism in mammals is divided into two fields: free citrulline and citrullinated proteins. Free citrulline metabolism involves three key enzymes: NO synthase (NOS) and ornithine carbamoyltransferase (OCT) which produce citrulline, and argininosuccinate synthetase (ASS) that converts it into argininosuccinate. The tissue distribution of these enzymes distinguishes three “orthogonal” metabolic pathways for citrulline. Firstly, in the liver, citrulline is locally synthesized by OCT and metabolized by ASS for urea production. Secondly, in most of the tissues producing NO, citrulline is recycled into arginine via ASS to increase arginine availability for NO production. Thirdly, citrulline is synthesized in the gut from glutamine (with OCT), released into the blood and converted back into arginine in the kidneys (by ASS); in this pathway, circulating citrulline is in fact a masked form of arginine to avoid liver captation. Each of these pathways has related pathologies and, even more interestingly, citrulline could potentially be used to monitor or treat some of these pathologies. Citrulline has long been administered in the treatment of inherited urea cycle disorders, and recent studies suggest that citrulline may be used to control the production of NO. Recently, citrulline was demonstrated as a potentially useful marker of short bowel function in a wide range of pathologies. One of the most promising research directions deals with the administration of citrulline as a more efficient alternative to arginine, especially against underlying splanchnic sequestration of amino acids. Protein citrullination results from post-translational modification of arginine; that occurs mainly in keratinization-related proteins and myelins, and insufficiencies in this citrullination occur in some auto-immune diseases such as rheumatoid arthritis, psoriasis or multiple sclerosis.

Almost all about citrulline in mammals.

Proteins and amino acids are widely considered to be subcomponents in nutritional support. However, proteins and amino acids are fundamental to recovery and survival, not only for their ability to preserve active tissue (protein) mass but also for a variety of other functions. Understanding the optimal amount of protein intake during nutritional support is therefore fundamental to appropriate clinical care. Although the body adapts in some ways to starvation, metabolic stress in patients causes increased protein turnover and loss of lean body mass. In this review, we present the growing scientific evidence showing the importance of protein and amino acid provision in nutritional support and their impact on preservation of muscle mass and patient outcomes. Studies identifying optimal dosing for proteins and amino acids are not currently available. We discuss the challenges physicians face in administering the optimal amount of protein and amino acids. We present protein-related nutrition concepts, including adaptation to starvation and stress, anabolic resistance, and potential adverse effects of amino acid provision. We describe the methods for assessment of protein status, and outcomes related to protein nutritional support for critically ill patients. The identification of a protein target for individual critically ill patients is crucial for outcomes, particularly for specific subpopulations, such as obese and older patients. Additional research is urgently needed to address these issues.

/pdf/proteins-and-amino-acids-are-fundamental-to-optimal-25vxb2l5gb.pdf

Proteins and amino acids are fundamental to optimal nutrition support in critically ill patients.

Purpose of review To analyze the recent literature (2011-2013) on glutamine supplementation of parenteral and enteral nutrition in critically ill patients. Potential confounding factors that may explain conflicting results are suggested. Recent findings Some recent, prospective, multicenter trials and two small trials yielded conflicting results that weigh heavily in the conclusions of a recent meta-analysis. Heterogeneity of the patients enrolled (especially in terms of injury severity, age, and basal nutritional status) and difficulties in identifying patients truly in need of glutamine supplementation may explain the discrepancies. Summary Glutamine supplementation has been recognized as beneficial in acutely injured patients. However, recent conflicting results in either 'real-life conditions' or very severe situations suggest that its indications need to be more precisely determined.

Glutamine in the intensive care unit.

Objective: This work compared the nutritional efficiency of a recently available enteral formula enriched with arginine, -3 fatty acids, and antioxidants and supplied nitrogen as peptides (Crucial, Nestle Clinical Nutrition) with that of a standard polymeric formula (Sondalis HP, Nestle Clinical Nutrition) in endotoxemic rats Methods: Male Wistar rats (209 2 g) underwent catheter gastrostomy and received Sondalis HP until they recovered their preoperative weight At that time (day 0), an endotoxemic shock was induced by an intraperitoneal injection of lipopolysaccharide (Escherichia coli, 8 mg/kg) and rats then received 290 kcal · kg 1 ·d 1 and 329 g of nitrogen · kg 1 ·d 1 in the form of Crucial (IED group, n 7) or Sondalis HP (S group, n 6) for 3 d Another group underwent no treatment and was fed ad libitum (AL group) Rats were killed on day 3 Results are presented as mean standard error of the mean (analysis of variance and Newman-Keuls test) Results: The endotoxemic shock induced a weight loss in group S on days 1 and 2 and a weight gain in group IED (35 13 g in group S versus 60 22 g in group IED, P 005) In the same way, atrophy of extensor digitorum longus muscle was observed in group S, whereas wasting was limited in group IED (102 4 mg in group IED versus 90 3 mg in group S versus 119 3 mg in group AL, P 005) Muscular atrophy was associated with muscular glutamine depletion and correlated with hyperphenylalaninemia (R 060), with the latter being blunted in group IED (57 1 M/L in group AL versus 77 4 M/L in group S versus 66 2 M/L in group IED, P 005) No difference was observed between the experimental groups of endotoxemic rats with respect to nitrogen balance, urinary excretion of 3-methyl histidine, or total tissue protein content Conclusion: Crucial counteracts injury-mediated weight loss, extensor digitorum longus muscle atrophy, and hyperphenylalaninemia in endotoxemic rats © 2005 Elsevier Inc All rights reserved

L. Cynober

Papers

Almost all about citrulline in mammals.

Proteins and amino acids are fundamental to optimal nutrition support in critically ill patients.

Glutamine in the intensive care unit.

Basic nutritional investigation Effects of an immune-enhancing diet in endotoxemic rats

Amino Acid Metabolism in Health and Nutritional Disease