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The Journal of Nutrition Dec 2016Mammalian arginine metabolism is complex due to the expression of multiple enzymes that utilize arginine as substrate and to interactions or competition between specific... (Review)
Review
Mammalian arginine metabolism is complex due to the expression of multiple enzymes that utilize arginine as substrate and to interactions or competition between specific enzymes involved in arginine metabolism. Moreover, cells may contain multiple intracellular arginine pools that are not equally accessible to all arginine metabolic enzymes, thus presenting additional challenges to more fully understanding arginine metabolism. At the whole-body level, arginine metabolism ultimately results in the production of a biochemically diverse range of products, including nitric oxide, urea, creatine, polyamines, proline, glutamate, agmatine, and homoarginine. Included in this group of compounds are the methylated arginines (e.g., asymmetric dimethylarginine), which are released upon degradation of proteins containing methylated arginine residues. Changes in arginine concentration also can regulate cellular metabolism and function via a variety of arginine sensors. Although much is known about arginine metabolism, elucidation of the physiologic or pathophysiologic roles for all of the pathways and their metabolites remains an active area of investigation, as exemplified by current findings highlighted in this review.
Topics: Animals; Arginine; Mammals
PubMed: 27934648
DOI: 10.3945/jn.115.226621 -
Cell Metabolism Aug 2022Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently...
Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine. Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporter SLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotes HCC cell-cycle arrest and quiescence, dependent on the general control nonderepressible 2 (GCN2) kinase. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescent phenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinical models confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapy promote HCC cell apoptosis and tumor regression. These data suggest novel strategies to treat human liver cancers through targeting SLC7A1 and/or a combination of arginine restriction, inhibition of GCN2, and senolytic agents.
Topics: Arginine; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Protein Serine-Threonine Kinases; Senotherapeutics
PubMed: 35839757
DOI: 10.1016/j.cmet.2022.06.010 -
Paediatric Drugs Jun 2020Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with... (Review)
Review
Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, L-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.
Topics: Adolescent; Adult; Arginine; Child; Citrulline; Female; Humans; Male; Pharmacology, Clinical; Young Adult
PubMed: 32140997
DOI: 10.1007/s40272-020-00384-5 -
Nursing Open Nov 2022Pressure injuries (PIs) are one of the most common complications related to immobility, especially in hospitalized patients, which lead to increased morbidity, infection... (Meta-Analysis)
Meta-Analysis Review
AIM
Pressure injuries (PIs) are one of the most common complications related to immobility, especially in hospitalized patients, which lead to increased morbidity, infection and overall decreased quality of life. Arginine supplementation may prevent the development of PIs. This study has summarized the findings of studies on the effect of arginine supplementation on PI healing.
DESIGN
Systematic review and meta-analysis.
METHODS
This study was conducted on online electronic databases including PubMed, Scopus, Web of Science, Google Scholar and Embase to identify relevant clinical trial studies up to September 2020. The pooled effect size of arginine supplement effects on PI was evaluated with standard mean difference (SMD) with 95% confidence interval (CI).
RESULTS
Eight studies met the inclusion criteria for this meta-analysis with 196 patients. PIs were significantly improved with Arginine supplementation (SMD: -0.6; CI 95%: -0.9 to -0.3, I : 72.5%, p = .001). Subgroup analysis showed that administering Arginine supplement more than 15 g/day had more beneficial effects on the healing of PIs (SMD: -2.8; CI 95%: -4.08 to -1.52, I : 54.7%, p = .138).
CONCLUSIONS
Our findings suggest that the administration of Arginine supplement in patients with PIs can accelerate the healing of this type of ulcer. Arginine is a supplement, and primary treatment is still needed to optimize PI healing. Therefore, arginine supplementation in addition to primary treatment seems to be an appropriate approach for the healing of PIs. Further well-designed studies are necessary to prevent the development of PIs compared to their primary treatment.
Topics: Humans; Arginine; Dietary Supplements; Enteral Nutrition; Quality of Life; Wound Healing; Pressure Ulcer
PubMed: 34170617
DOI: 10.1002/nop2.974 -
The Journal of Nutrition Jun 2007For many years, dietary arginine supplementation, often combined with other substances, has been used as a mechanism to boost the immune system. Considerable... (Review)
Review
For many years, dietary arginine supplementation, often combined with other substances, has been used as a mechanism to boost the immune system. Considerable controversy, however, exists as to the benefits and indications of dietary arginine due in part to a poor understanding of the role played by this amino acid in maintaining immune function. Emerging knowledge promises to clear this controversy and allow for arginine's safe use. In myeloid cells, arginine is mainly metabolized either by inducible nitric oxide (NO) synthases (iNOS) or by arginase 1, enzymes that are stimulated by T helper 1 or 2 cytokines, respectively. Thus, activation of iNOS or arginase (or both) reflects the type of inflammatory response in a specific disease process. Myeloid suppressor cells (MSC) expressing arginase have been described in trauma (in both mice and humans), intra-abdominal sepsis, certain infections, and prominently, cancer. Myeloid cells expressing arginase have been shown to accumulate in patients with cancer. Arginase 1 expression is also detected in mononuclear cells after trauma or surgery. MSC efficiently deplete arginine and generate ornithine. Through arginine depletion, MSC may control NO production and regulate other arginine-dependent biological processes. Low circulating arginine has been documented in trauma and cancer, suggesting that MSC may exert a systemic effect and cause a state of arginine deficiency. Simultaneously, T lymphocytes depend on arginine for proliferation, zeta-chain peptide and T-cell receptor complex expression, and the development of memory. T-cells cocultured with MSC exhibit the molecular and functional effects associated with arginine deficiency. Not surprisingly, T-cell abnormalities, including decreased proliferation and loss of the zeta-chain, are observed in cancer and after trauma.
Topics: Animals; Arginine; Humans; Immune System; Myeloid Cells; T-Lymphocytes
PubMed: 17513447
DOI: 10.1093/jn/137.6.1681S -
Journal of Surgical Oncology Mar 2017Arginine is an important player in numerous biologic processes and studies have demonstrated its importance for cellular growth that becomes limiting in states of rapid... (Review)
Review
Arginine is an important player in numerous biologic processes and studies have demonstrated its importance for cellular growth that becomes limiting in states of rapid turnover (e.g., malignancy). Thus, arginine deprivation therapy is being examined as an adjuvant cancer therapy, however, arginine is also necessary for immune destruction of malignant cells. Herein we review the data supporting arginine deprivation or supplementation in cancer treatment and the currently registered trials aimed at understanding these divergent strategies. J. Surg. Oncol. 2017;115:273-280. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Arginine; Dietary Supplements; Humans; Neoplasms
PubMed: 27861915
DOI: 10.1002/jso.24490 -
The Journal of Nutrition Dec 2016l-Arginine (Arg) appears to have a beneficial effect on the regulation of nutrient metabolism to enhance lean tissue deposition and on insulin resistance in humans. The... (Review)
Review
l-Arginine (Arg) appears to have a beneficial effect on the regulation of nutrient metabolism to enhance lean tissue deposition and on insulin resistance in humans. The observed safe level for oral administration of Arg is ∼20 g/d, but higher levels have been tested in short-term studies without serious adverse effects; however, more data are needed in both animal models and humans to fully evaluate safety as well as efficacy. The primary objective of this review is to summarize the current knowledge of the safety, pharmacokinetics, and effectiveness of oral Arg in adults. Arg supplementation has been used safely in vulnerable populations, such as pregnant women, preterm infants, and individuals with cystic fibrosis. Several recent studies have shown beneficial effects of Arg in individuals with obesity, insulin resistance, and diabetes. Collectively, the data suggest that Arg supplementation is a safe and generally well-tolerated nutriceutical that may improve metabolic profiles in humans.
Topics: Administration, Oral; Adult; Arginine; Humans
PubMed: 27934649
DOI: 10.3945/jn.116.234740 -
Biochemical Society Transactions Apr 2023Arginine methylation is a ubiquitous and relatively stable post-translational modification (PTM) that occurs in three types: monomethylarginine (MMA), asymmetric...
Arginine methylation is a ubiquitous and relatively stable post-translational modification (PTM) that occurs in three types: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Methylarginine marks are catalyzed by members of the protein arginine methyltransferases (PRMTs) family of enzymes. Substrates for arginine methylation are found in most cellular compartments, with RNA-binding proteins forming the majority of PRMT targets. Arginine methylation often occurs in intrinsically disordered regions of proteins, which impacts biological processes like protein-protein interactions and phase separation, to modulate gene transcription, mRNA splicing and signal transduction. With regards to protein-protein interactions, the major 'readers' of methylarginine marks are Tudor domain-containing proteins, although additional domain types and unique protein folds have also recently been identified as methylarginine readers. Here, we will assess the current 'state-of-the-art' in the arginine methylation reader field. We will focus on the biological functions of the Tudor domain-containing methylarginine readers and address other domains and complexes that sense methylarginine marks.
Topics: Arginine; Methylation; Protein Processing, Post-Translational; Protein-Arginine N-Methyltransferases; RNA-Binding Proteins
PubMed: 37013969
DOI: 10.1042/BST20221147 -
The Journal of Nutrition Oct 2004The kidney plays a major role in arginine metabolism in 3 principal ways: arginine synthesis, creatine synthesis, and arginine reabsorption. Appreciable quantities of... (Review)
Review
The kidney plays a major role in arginine metabolism in 3 principal ways: arginine synthesis, creatine synthesis, and arginine reabsorption. Appreciable quantities of arginine are synthesized in the kidney from citrulline produced by the intestine. The renal enzymes of arginine synthesis, argininosuccinate synthetase and argininosuccinate lyase, occur in the cells of the proximal tubule. The rate of arginine synthesis depends on citrulline delivery and does not appear to be regulated by dietary arginine availability. Renal arginine synthesis in humans produces approximately 2 g arginine/d, which may be compared to an intake, from a Western diet, of approximately 4 to 5 g/d. Spontaneous, nonenzymatic breakdown of creatine and creatine phosphate to creatinine causes the excretion of 1 to 2 g creatinine/d and requires the replacement of an equivalent amount of creatine from the diet and by endogenous synthesis. The first enzyme of creatine biosynthesis, L-arginine:glycine amidinotransferase, occurs in the kidney and produces guanidinoacetate, which is released into the renal vein. The renal output of guanidinoacetate, however, is rather low, and we propose that the entire pathway of creatine synthesis may also occur in the liver. Renal arginine reabsorption salvages approximately 3 g arginine/d. At the apical membrane of proximal tubular cells, arginine shares a transporter with lysine, ornithine, and cystine. Defects in this heteromeric transporter cause cystinuria, which is also characterized by urinary loss of arginine, lysine, and ornithine. Arginine is transported out of the proximal tubular cells at the basolateral membrane by another heteromeric transporter, which also transports lysine and ornithine. Defects in this transporter cause lysinuric protein intolerance.
Topics: Absorption; Animals; Arginine; Citrulline; Creatine; Humans; Kidney
PubMed: 15465786
DOI: 10.1093/jn/134.10.2791S -
International Journal of Molecular... Nov 2022Amino acids are crucial nutrients involved in several cellular and physiological processes, including fertilization and early embryo development. In particular, Leucine...
Amino acids are crucial nutrients involved in several cellular and physiological processes, including fertilization and early embryo development. In particular, Leucine and Arginine have been shown to stimulate implantation, as lack of both in a blastocyst culture system is able to induce a dormant state in embryos. The aim of this work was to evaluate the effects of Leucine and Arginine withdrawal on pluripotent mouse embryonic stem cell status, notably, their growth, self-renewal, as well as glycolytic and oxidative metabolism. Our results show that the absence of both Leucine and Arginine does not affect mouse embryonic stem cell pluripotency, while reducing cell proliferation through cell-cycle arrest. Importantly, these effects are not related to Leukemia Inhibitory Factor (LIF) and are reversible when both amino acids are reconstituted in the culture media. Moreover, a lack of these amino acids is related to a reduction in glycolytic and oxidative metabolism and decreased protein translation in mouse embryonic stem cells (mESCs), while maintaining their pluripotent status.
Topics: Animals; Mice; Mouse Embryonic Stem Cells; Leucine; Embryonic Stem Cells; Arginine; Cell Differentiation; Cell Proliferation
PubMed: 36430764
DOI: 10.3390/ijms232214286