| Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the amino and guanidino groups are protonated, resulting in a cation. Only the l-arginine (symbol Arg or R) enantiomer is found naturally. Arg residues are common components of proteins. It is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG. The guanidine group in arginine is the precursor for the biosynthesis of nitric oxide. Like all amino acids, it is a white, water-soluble solid.
The one-letter symbol R was assigned to arginine for its phonetic similarity. |
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| InChI=1S/C6H14N4O2/c7-4(5(11)12)2-1-3-10-6(8)9/h4H,1-3,7H2,(H,11,12)(H4,8,9,10)/t4-/m0/s1 |
| ODKSFYDXXFIFQN-BYPYZUCNSA-N |
| N[C@@H](CCCNC(N)=N)C(O)=O |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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Escherichia coli
(NCBI:txid562)
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PubMed
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
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Escherichia coli metabolite
Any bacterial metabolite produced during a metabolic reaction in Escherichia coli.
micronutrient
Any nutrient required in small quantities by organisms throughout their life in order to orchestrate a range of physiological functions.
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
fundamental metabolite
Any metabolite produced by all living cells.
(via arginine )
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nutraceutical
A product in capsule, tablet or liquid form that provide essential nutrients, such as a vitamin, an essential mineral, a protein, an herb, or similar nutritional substance.
biomarker
A substance used as an indicator of a biological state.
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View more via ChEBI Ontology
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(2S)-2-amino-5-(carbamimidamido)pentanoic acid
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IUPAC
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(2S)-2-amino-5-guanidinopentanoic acid
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JCBN
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(S)-2-amino-5-guanidinopentanoic acid
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ChEBI
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(S)-2-Amino-5-guanidinovaleric acid
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KEGG COMPOUND
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Arg
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DrugBank
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L-(+)-arginine
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NIST Chemistry WebBook
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L-Arg
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DrugBank
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L-Arginin
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ChEBI
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L-Arginine
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KEGG COMPOUND
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R
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MetaCyc
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1549
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DrugCentral
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ARG
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MetaCyc
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ARG
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PDBeChem
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C00001340
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KNApSAcK
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C00062
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KEGG COMPOUND
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D02982
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KEGG DRUG
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DB00125
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DrugBank
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ECMDB00517
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ECMDB
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GND
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PDBeChem
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HMDB0000517
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HMDB
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L-arginine
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Wikipedia
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YMDB00592
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YMDB
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1725413
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Reaxys Registry Number
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Reaxys
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74-79-3
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CAS Registry Number
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KEGG COMPOUND
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74-79-3
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CAS Registry Number
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NIST Chemistry WebBook
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74-79-3
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CAS Registry Number
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ChemIDplus
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83283
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Gmelin Registry Number
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Gmelin
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Khazaei M, Mobarakeh JI, Rahimi AA, Razavi MR (2012)
Effect of chronic L-Arginine supplementation on aortic fatty streak formation and serum nitric oxide concentration in normal and high-cholesterol fed rabbits.
Acta physiologica Hungarica 99, 87-93 [PubMed:22425811]
[show Abstract]
Several reports indicated the beneficial effects of short-term L-Arginine (L-Arg) administration on atherosclerosis processes. The aim of this study was to evaluate the effect of chronic L-Arg supplementation on serum lipid profile, aortic Fatty Streak (FS) formation, and serum Nitric oxide (NO) concentration in Normal Diet (ND) and High-Cholesterol Diet (HCD) fed rabbits. 24 male rabbits were randomly divided into four groups (n=6 in each group) (i): ND for seven months; (ii): ND for 1 month plus ND + L-Arg for six months; (iii): HCD (1%) for 1 month plus HCD (0.5%) for six months; (iv): HCD (1%) for 1 month plus HCD (0.5%) + L-Arg for six months. At the end of the study, histological evaluation of aortic FS formation was performed. Blood samples were taken for serum lipid profile and NO concentrations. L-Arg did not change serum total cholesterol, triglyceride, LDL and LDL/HDL ratio in normal and hypercholesterolemic rabbits (p>0.05). Histological examination of thoracic aortae revealed that the HCD group had higher FS formation compared to the ND group (2.1 ± 0.16 vs. 0 ± 0; respectively; p<0.05) and L-Arg supplementation did not attenuate FS formation in the HCD group (1.93 ± 0.17 compare to 2.1 ± 0.16; p>0.05). Serum NO level in the HCD group was higher than ND groups (p<0.05). Chronic L-Arg supplementation did not alter serum NO concentration either in the hypercholesterolemic or in the ND group (p>0.05). It seems that chronic L-Arg supplementation does not have beneficial effects on aortic fatty streak formation, serum lipids and NO concentrations in this model of experimental hypercholesterolemia. | Chen GF, Moningka NC, Sasser JM, Zharikov S, Cunningham M, Tain YL, Schwartz IF, Baylis C (2012)
Arginine and asymmetric dimethylarginine in puromycin aminonucleoside-induced chronic kidney disease in the rat.
American journal of nephrology 35, 40-48 [PubMed:22179117]
[show Abstract]
Background/aimsReduced renal L-arginine (L-Arg) synthesis/transport, induction of arginases and increased endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) will inhibit NO production. This study investigated pathways of L-Arg synthesis/uptake/utilization, ADMA degradation and oxidant/antioxidants in puromycin aminonucleoside (PAN) chronic kidney disease (CKD).MethodsRats were given low- (LD) or high-dose (HD) PAN and followed for 11 weeks for proteinuria. BP was measured and blood and tissues were harvested and analyzed for abundance of argininosuccinate synthase (ASS) and lyase (ASL), arginase, cationic amino acid transporter (CAT1) and dimethylargininedimethylaminohydrolase (DDAH) in kidney, cortex, aorta and liver. Arginase and DDAH activity, plasma L-Arg and ADMA, renal pathology and creatinine clearances were also measured.ResultsPAN caused dose-dependent kidney damage and hypertension and creatinine clearance fell in HD-PAN. Renal ASS fell in HD-PAN, renal cortex and aortic ASL and membrane CAT1 fell in both PAN groups. There was no activation of renal arginase, but aortic arginase increased in LD-PAN. Renal DDAH activity fell moderately in LD-PAN and markedly in HD-PAN where hepatic DDAH activity also fell. Plasma L-Arg was unchanged while ADMA rose moderately and dose-dependently with PAN. There were several indices of oxidative stress which was most prominent in HD-PAN.ConclusionReduction in renal ASS/ASL and loss of renal cortex CAT1 compromises renal L-Arg synthesis and release. Loss of aortic CAT1 impairs L-Arg uptake. Increased plasma ADMA was associated with progressive loss of renal DDAH activity. However, loss of renal clearance and falls in hepatic DDAH activity in HD-PAN did not have additive effects on plasma ADMA. | Singh K, Coburn LA, Barry DP, Boucher JL, Chaturvedi R, Wilson KT (2012)
L-arginine uptake by cationic amino acid transporter 2 is essential for colonic epithelial cell restitution.
American journal of physiology. Gastrointestinal and liver physiology 302, G1061-73 [PubMed:22361732]
[show Abstract]
Restoration of the colonic epithelial barrier is an important response during colitis. L-arginine (L-Arg) is a semiessential amino acid that reduces murine colitis induced by Citrobacter rodentium. Cationic amino acid transporter (CAT) proteins increase L-Arg uptake into cells. L-Arg is utilized to produce nitric oxide (NO), by inducible NO synthase (iNOS), or L-ornithine (L-Orn) by arginase (Arg) enzymes. The latter is followed by generation of polyamines by ornithine decarboxylase (ODC) and L-proline (L-Pro) by ornithine aminotransferase (OAT). We show that L-Arg enhanced epithelial restitution in conditionally immortalized young adult mouse colon (YAMC) cells in a wound repair model, and in isolated mouse colonic epithelial cells (CECs), using a cell migration assay. Restitution was impaired by C. rodentium. Wounding induced CAT2, and inhibition of L-Arg uptake by the competitive inhibitor L-lysine (L-Lys) or by CAT2 shRNA, but not CAT1 shRNA, decreased restitution. Migration was impaired in CECs treated with L-Lys or from CAT2(-/-) mice. Wounding increased Arg1 expression, and inhibition of arginase with S-(2-boronoethyl)-L-cysteine (BEC) or Arg1 shRNA inhibited restitution in YAMC cells; cell migration in CECs was also impaired by BEC. Inhibition of ODC or iNOS did not alter restitution. L-Orn or L-Pro restored restitution in cells treated with BEC or Arg1 shRNA, whereas the polyamine putrescine had no benefit. Wounding increased OAT levels, OAT shRNA inhibited restitution, and L-Pro restored restitution in cells with OAT knockdown. Uptake of L-Arg, and its metabolism by Arg1 to L-Orn and conversion to L-Pro by OAT is essential for colonic epithelial wound repair. | Giordano E, Hillary RA, Vary TC, Pegg AE, Sumner AD, Caldarera CM, Zhang XQ, Song J, Wang J, Cheung JY, Shantz LM (2012)
Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy.
Amino acids 42, 507-518 [PubMed:21814794]
[show Abstract]
Ornithine decarboxylase (ODC), the first enzyme of polyamine metabolism, is rapidly upregulated in response to agents that induce a pathological cardiac hypertrophy. Transgenic mice overexpressing ODC in the heart (MHC-ODC mice) experience a much more dramatic left ventricular hypertrophy in response to β-adrenergic stimulation with isoproterenol (ISO) compared to wild-type (WT) controls. ISO also induced arginase activity in transgenic hearts but not in controls. The current work studies the cooperation between the cardiac polyamines and L-arginine (L-Arg) availability in MHC-ODC mice. Although ISO-induced hypertrophy is well-compensated, MHC-ODC mice administered L-Arg along with ISO showed a rapid onset of systolic dysfunction and died within 48 h. Myocytes isolated from MHC-ODC mice administered L-Arg/ISO exhibited reduced contractility and altered calcium transients, suggesting an alteration in [Ca(2+)] homeostasis, and abbreviated action potential duration, which may contribute to arrhythmogenesis. The already elevated levels of spermidine and spermine were not further altered in MHC-ODC hearts by L-Arg/ISO treatment, suggesting alternative L-Arg utilization pathways lead to dysregulation of intracellular calcium. MHC-ODC mice administered an arginase inhibitor (Nor-NOHA) along with ISO died almost as rapidly as L-Arg/ISO-treated mice, while the iNOS inhibitor S-methyl-isothiourea (SMT) was strongly protective against L-Arg/ISO. These results point to the induction of arginase as a protective response to β-adrenergic stimulation in the setting of high polyamines. Further, NO generated by exogenously supplied L-Arg may contribute to the lethal consequences of L-Arg/ISO treatment. Since considerable variations in human cardiac polyamine and L-Arg content are likely, it is possible that alterations in these factors may influence myocyte contractility. | Alvares TS, Conte CA, Paschoalin VM, Silva JT, Meirelles Cde M, Bhambhani YN, Gomes PS (2012)
Acute l-arginine supplementation increases muscle blood volume but not strength performance.
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 37, 115-126 [PubMed:22251130]
[show Abstract]
l-Arginine (L-arg) is an amino acid precursor to nitric oxide (NO). Dietary supplements containing L-arg have been marketed with the purpose of increasing vasodilation, thereby elevating blood flow to the exercising muscle and enhancing the metabolic response to exercise. Our goal was to identify the acute effect of L-arg supplementation on biceps strength performance, indicators of NO production (nitrite and nitrate - NOx), and muscle blood volume (Mbv) and oxygenation (Mox) during recovery from 3 sets of resistance exercise. Fifteen males participated in a randomized, double-blind, placebo-controlled study. After withdrawing resting blood samples, the subjects were supplemented with 6 g of L-arg (ARG) or placebo (PLA). Monitoring of Mbv and Mox with near-infrared spectroscopy began 30 min after supplementation and lasted for 60 min. The exercise protocol (3 sets of 10 maximal voluntary contractions of isokinetic concentric elbow extension at 60°·s(-1), 2-min rest between sets) was initiated 80 min after supplementation. Blood samples were drawn at 30, 60, 90, and 120 min after supplementation. Repeated measures ANOVA showed that Mbv significantly (p ≤ 0.05) increased in ARG compared with the PLA during the recovery period of each set of resistance exercise. NOx, Mox, peak torque, total work, and set total work were not significantly different between groups. We found that acute L-arg supplementation increases Mbv during recovery from sets of resistance exercise with no increase in strength performance. It is still premature to recommend nutritional supplements containing L-arg as an ergogenic aid to increase muscle strength during resistance training in healthy subjects. | Yoneda M, Ikawa M, Arakawa K, Kudo T, Kimura H, Fujibayashi Y, Okazawa H (2012)
In vivo functional brain imaging and a therapeutic trial of L-arginine in MELAS patients.
Biochimica et biophysica acta 1820, 615-618 [PubMed:21600268]
[show Abstract]
BackgroundMitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common type of mitochondrial disease and is characterized by stroke-like episodes (SEs), myopathy, lactic acidosis, diabetes mellitus, hearing-loss and cardiomyopathy. The causal hypotheses for SEs in MELAS presented to date are angiopathy, cytopathy and neuronal hyperexcitability. L-arginine (Arg) has been applied for the therapy in MELAS patients.Scope of reviewWe will introduce novel in vivo functional brain imaging techniques such as MRI and PET, and discuss the pathogenesis of SEs in MELAS patients. We will further describe here our clinical experience with L-arg therapy and discuss the dual pharmaceutical effects of this drug on MELAS.Major conclusionsAdministration of L-arg to MELAS patients has been successful in reducing neurological symptoms due to acute strokes and preventing recurrences of SEs in the chronic phase. L-Arg has dual pharmaceutical effects on both angiopathy and cytopathy in MELAS.General significanceIn vivo functional brain imaging promotes a better understanding of the pathogenesis and potential therapies for MELAS patients. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010. | Stasyuk N, Smutok O, Gayda G, Vus B, Koval'chuk Y, Gonchar M (2012)
Bi-enzyme L-arginine-selective amperometric biosensor based on ammonium-sensing polyaniline-modified electrode.
Biosensors & bioelectronics 37, 46-52 [PubMed:22626826]
[show Abstract]
A novel L-arginine-selective amperometric bi-enzyme biosensor based on recombinant human arginase I isolated from the gene-engineered strain of methylotrophic yeast Hansenula polymorpha and commercial urease is described. The biosensing layer was placed onto a polyaniline-Nafion composite platinum electrode and covered with a calcium alginate gel. The developed sensor revealed a good selectivity to L-arginine. The sensitivity of the biosensor was 110 ± 1.3 nA/(mM mm(2)) with the apparent Michaelis-Menten constant (K(M)(app)) derived from an L-arginine (L-Arg) calibration curve of 1.27 ± 0.29 mM. A linear concentration range was observed from 0.07 to 0.6mM, a limit of detection being 0.038 mM and a response time - 10s. The developed biosensor demonstrated good storage stability. A laboratory prototype of the proposed amperometric biosensor was applied to the samples of three commercial pharmaceuticals ("Tivortin", "Cytrarginine", "Aminoplazmal 10% E") for L-Arg testing. The obtained L-Arg-content values correlated well with those declared by producers. | Monti LD, Setola E, Lucotti PC, Marrocco-Trischitta MM, Comola M, Galluccio E, Poggi A, Mammì S, Catapano AL, Comi G, Chiesa R, Bosi E, Piatti PM (2012)
Effect of a long-term oral l-arginine supplementation on glucose metabolism: a randomized, double-blind, placebo-controlled trial.
Diabetes, obesity & metabolism 14, 893-900 [PubMed:22553931]
[show Abstract]
AimThis study assessed the efficacy of long-term l-arginine (l-arg) therapy in preventing or delaying type 2 diabetes mellitus.MethodsA mono-centre, randomized, double-blind, parallel-group, placebo-controlled, phase III trial (l-arg trial) was conducted on 144 individuals affected by impaired glucose tolerance (IGT) and metabolic syndrome (MS). l-Arg/placebo was administered (6.4 g/day) on a background structured lifestyle intervention for 18 months plus a 12-month extended follow-up period after study drug termination. Fasting glucose levels and glucose tolerance after oral glucose tolerance test were evaluated throughout the study.ResultsAfter 18 months, l-arg as compared with placebo did not reduce the cumulative incidence of diabetes [21.4 and 20.8%, respectively, hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.58-1.86] while the cumulative probability to become normal glucose tolerant (NGT) increased (42.4 and 22.1%, respectively, HR, 2.60; 95% CI, 1.51-4.46, p < 0.001). The higher cumulative probability to become of NGT was maintained during the extended period in subjects previously treated with l-arg (HR, 3.21; 95% CI, 1.87-5.51; p < 0.001). At the end of the extended period, the cumulative incidence of diabetes in subjects previously treated with l-arg was reduced as compared with placebo (27.2 and 47.1%, respectively, HR, 0.42; 95% CI, 0.24-0.75, p < 0.05). During both periods, l-arg significantly improved insulin sensitivity and β-cell function.ConclusionAmong persons with IGT and MS, the supplementation of l-arg for 18 months does not significantly reduce the incidence of diabetes but does significantly increase regression to NGT. | Correa-Costa M, Landgraf MA, Landgraf MA, Cavanal MF, Semedo P, Vieira DA, De Marco DT, Hirata AE, Câmara NO, Gil FZ (2012)
Inflammatory milieu as an early marker of kidney injury in offspring rats from diabetic mothers.
European journal of pharmacology 689, 233-240 [PubMed:22652429]
[show Abstract]
The present study investigated the early presence of inflammatory response in renal tissue of young offspring from diabetic mothers. The effect of L-arginine (L-arg) supplementation was also investigated. The offspring was divided into four groups: group CO (controls); group DO (diabetic offspring); group CA (CO receiving 2% L-arg solution) and group DA (DO receiving the 2% L-arg solution). Glycemia, arterial pressure and renal function were evaluated; gene and protein expression of pro-inflammatory cytokines were also measured. Blood pressure levels were significantly increased in 2 and 6 month-old DO rats, whereas L-arg administration caused a significant decrease in the DA group, at both ages. DO rats showed a significantly blunted glycemic response to exogenous insulin. In 2 month-old DO animals, renal protein expression of pro-inflammatory molecules was significantly increased. At six months of age, we also observed an increase in gene expression of pro-inflammatory molecules, whereas L-arg supplementation prevented this increase at both ages. Our data suggest that activation of inflammatory pathways is present early in the kidney of DO rats, and that L-arg can attenuate the expression of these markers of tissue inflammation. Our results also reinforce the concept that intrauterine environmental factors are a fundamental determinant in the development of metabolic and vascular diseases later in life. | Brenner T, Fleming TH, Rosenhagen C, Krauser U, Mieth M, Bruckner T, Martin E, Nawroth PP, Weigand MA, Bierhaus A, Hofer S (2012)
L-arginine and asymmetric dimethylarginine are early predictors for survival in septic patients with acute liver failure.
Mediators of inflammation 2012, 210454 [PubMed:22619480]
[show Abstract]
Dysfunctions of the L-arginine (L-arg)/nitric-oxide (NO) pathway are suspected to be important for the pathogenesis of multiple organ dysfunction syndrome (MODS) in septic shock. Therefore plasma concentrations of L-arg and asymmetric dimethylarginine (ADMA) were measured in 60 patients with septic shock, 30 surgical patients and 30 healthy volunteers using enzyme linked immunosorbent assay (ELISA) kits. Plasma samples from patients with septic shock were collected at sepsis onset, and 24 h, 4 d, 7 d, 14 d and 28 d later. Samples from surgical patients were collected prior to surgery, immediately after the end of the surgical procedure as well as 24 h later and from healthy volunteers once. In comparison to healthy volunteers and surgical patients, individuals with septic shock showed significantly increased levels of ADMA, as well as a decrease in the ratio of L-arg and ADMA at all timepoints. In septic patients with an acute liver failure (ALF), plasma levels of ADMA and L-arg were significantly increased in comparison to septic patients with an intact hepatic function. In summary it can be stated, that bioavailability of NO is reduced in septic shock. Moreover, measurements of ADMA and L-arg appear to be early predictors for survival in patients with sepsis-associated ALF. | Zhu X, Pan Y, Li Y, Cui L, Cao Y (2012)
Supplement of L-Arg improves protective immunity during early-stage Plasmodium yoelii 17XL infection.
Parasite immunology 34, 412-420 [PubMed:22709481]
[show Abstract]
L-arginine (L-Arg), the precursor of nitric oxide (NO), plays multiple important roles in nutrient metabolism and immune regulation. L-Arg supplement serves as a potential adjunctive therapy for severe malaria, because it improves NO bioavailability and reverses endothelial dysfunction in severe malaria patients. In this study, we investigated the effect of dietary L-Arg supplement on host immune responses during subsequent malaria infection using the Plasmodium yoelii 17XL - BALB/c mouse model. We have shown that pretreatment of mice with L-Arg significantly decreased parasitemia and prolonged the survival time of mice after infection. L-Arg supplement led to significant increases in activated CD4(+)T-bet(+)IFN-γ(+) T cells and F4/80(+)CD36(+) macrophages during early-stage infection, which were accompanied by enhanced synthesis of IFN-γ, TNF-α and NO by spleen cells. Moreover, L-Arg-pretreated mice developed more splenic myeloid and plasmacytoid dendritic cells with up-regulated expression of MHC II, CD86 and TLR9. In comparison, L-Arg treatment did not change the number of regulatory T cells and the level of anti-inflammatory cytokine IL-10. Taken together, our results showed that L-Arg pretreatment could improve the protective immune response in experimental malaria infection in mice, which underlines potential importance of L-Arg supplement in malaria-endemic human populations. | Coburn LA, Gong X, Singh K, Asim M, Scull BP, Allaman MM, Williams CS, Rosen MJ, Washington MK, Barry DP, Piazuelo MB, Casero RA, Chaturvedi R, Zhao Z, Wilson KT (2012)
L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis.
PloS one 7, e33546 [PubMed:22428068]
[show Abstract]
Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis (UC), results in substantial morbidity and is difficult to treat. New strategies for adjunct therapies are needed. One candidate is the semi-essential amino acid, L-arginine (L-Arg), a complementary medicine purported to be an enhancer of immunity and vitality in the lay media. Using dextran sulfate sodium (DSS) as a murine colonic injury and repair model with similarities to human UC, we assessed the effect of L-Arg, as DSS induced increases in colonic expression of the y(+) cationic amino acid transporter 2 (CAT2) and L-Arg uptake. L-Arg supplementation improved the clinical parameters of survival, body weight loss, and colon weight, and reduced colonic permeability and the number of myeloperoxidase-positive neutrophils in DSS colitis. Luminex-based multi-analyte profiling demonstrated that there was a marked reduction in proinflammatory cytokine and chemokine expression with L-Arg treatment. Genomic analysis by microarray demonstrated that DSS-treated mice supplemented with L-Arg clustered more closely with mice not exposed to DSS than to those receiving DSS alone, and revealed that multiple genes that were upregulated or downregulated with DSS alone exhibited normalization of expression with L-Arg supplementation. Additionally, L-Arg treatment of mice with DSS colitis resulted in increased ex vivo migration of colonic epithelial cells, suggestive of increased capacity for wound repair. Because CAT2 induction was sustained during L-Arg treatment and inducible nitric oxide (NO) synthase (iNOS) requires uptake of L-Arg for generation of NO, we tested the effect of L-Arg in iNOS(-/-) mice and found that its benefits in DSS colitis were eliminated. These preclinical studies indicate that L-Arg supplementation could be a potential therapy for IBD, and that one mechanism of action may be functional enhancement of iNOS activity. | Astashkin AV, Elmore BO, Chen L, Fan W, Guillemette JG, Feng C (2012)
Pulsed ENDOR determination of the arginine location in the ferrous-NO form of neuronal NOS.
The journal of physical chemistry. A 116, 6731-6739 [PubMed:22667467]
[show Abstract]
Mammalian nitric oxide synthases (NOSs) are enzymes responsible for oxidation of L-arginine (L-Arg) to nitric oxide (NO). Mechanisms of reactions at the catalytic heme site are not well understood, and it is of current interest to study structures of the heme species that activates O(2) and transforms the substrate. The NOS ferrous-NO complex is a close mimic of the obligatory ferric (hydro)peroxo intermediate in NOS catalysis. In this work, pulsed electron-nuclear double resonance (ENDOR) was used to probe the position of the l-Arg substrate at the NO(•)-coordinated ferrous heme center(s) in the oxygenase domain of rat neuronal NOS (nNOS). The analysis of (2)H and (15)N ENDOR spectra of samples containing d(7)- or guanidino-(15)N(2) labeled L-Arg has resulted in distance estimates for the nearby guanidino nitrogen and the nearby proton (deuteron) at C(δ). The L-Arg position was found to be noticeably different from that in the X-ray crystal structure of nNOS ferrous-NO complex [Li et al. J. Biol. Inorg. Chem.2006, 11, 753-768], with the nearby guanidino nitrogen being ~0.5 Å closer to, and the nearby H(δ) about 1 Å further from, the NO ligand than in the X-ray structure. The difference might be related to the structural constraints imposed on the protein by the crystal. Importantly, in spite of its closer position, the guanidino nitrogen does not form a hydrogen bond with the NO ligand, as evidenced by the absence of significant isotropic hfi constant for N(g1). This is consistent with the previous reports that it is not the L-Arg substrate itself that would most likely serve as a direct proton donor to the diatomic ligands (NO and O(2)) bound to the heme. | Arora TK, Malhotra AK, Ivatury R, Mangino MJ (2012)
L-arginine infusion during resuscitation for hemorrhagic shock: impact and mechanism.
The journal of trauma and acute care surgery 72, 397-402 [PubMed:22439203]
[show Abstract]
BackgroundOur previous work showed a survival advantage with L-arginine (L-Arg) pretreatment in a swine model of severe hemorrhagic shock. This study was designed to evaluating whether the benefit is sustained when L-Arg is given during resuscitation and whether the mechanism is mediated by enzymatic activation of nitric oxide (NO) synthesis.MethodsAdult rats (n = 30) underwent 40% blood volume loss and were resuscitated with saline (3 shed blood volume). Animals were divided into five treatment groups of six animals each: (1) Sham, (2) Control (resuscitation alone), (3) L-Arg (300 mg/kg)with resuscitation, (4) L-Arg + L-nitroarginine methyl ester pretreatment, and (5) D-arginine (300 mg/kg) with resuscitation.Animals were observed for 240 minutes postresuscitation or until death. Hemodynamic, metabolic, histologic, and survival outcomes were measured.ResultsAdministration of L-Arg after hemorrhage and before resuscitation significantly improved outcomes, relative to the control group.The L-Arg infusion improved terminal arterial pressures, lowered lactate, improved small bowel histologic signs of reperfusion injury, and increased survival (p < 0.05). Endpoints of the L-Arg group were similar to the Sham group. The benefits of L-Arg infusion were abolished or attenuated when animals were pretreated with L-nitro arginine methyl ester and potentiated with D-arginine, suggesting a NO-specific mechanism of L-Arg. Finally, severe shock and resuscitation injury significantly elevated circulating asymmetric dimethylarginine levels, which are potent competitive inhibitors of NO synthetase.ConclusionL-Arg infusion during resuscitation offers a significant functional, metabolic, and survival benefit after severe hemorrhagic shock.The mechanism seems to be by activation of NO synthesis with its attendant benefits to local perfusion and inflammation after global reperfusion. | Hsu CN, Huang LT, Lau YT, Lin CY, Tain YL (2012)
The combined ratios of L-arginine and asymmetric and symmetric dimethylarginine as biomarkers in spontaneously hypertensive rats.
Translational research : the journal of laboratory and clinical medicine 159, 90-98 [PubMed:22243793]
[show Abstract]
Hypertension and hypertensive end-organ damage have been associated with decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) both can inhibit NO availability by competition with L-arginine (L-Arg). However, whether a combined analysis of these 3 parameters can serve as an ideal biomarker of hypertension remains unclear. We measured the plasma and renal levels of L-Arg, ADMA, and SDMA in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) control rats at 3 stages: 4 weeks old (prehypertensive), 12 weeks old (hypertensive), and 24 weeks old (end-organ damage). The plasma and renal L-Arg/ADMA ratio (AAR) and the ADMA/SDMA ratio (ASR) were computed for all 3 age stages. Our results revealed an ADMA level increase, and an AAR decrease in plasma and kidneys may develop early on, even before the onset of hypertension in 4-week-old SHRs. The renal ADMA level and AAR were restored in SHRs at 24 weeks of age, which might protect SHRs against kidney injury. We found that the plasma AAR is superior to the levels of L-Arg and ADMA in plasma, and it predicted blood pressure and urinary NOx levels. Renal AAR is a strong independent marker of renal dimethylarginine dimethylaminohydrolase (DDAH) activity. The plasma ASR was correlated strongly to blood pressure. However, renal DDAH activity was related to the renal ASR but not the plasma ASR. In conclusion, the AAR and ASR may serve as better markers for disease activity and progression than each individual parameter. Clinical use of these ratios to elucidate the role of ADMA in hypertension awaits further validation. | Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J, Carey Satterfield M, Smith SB, Spencer TE, Yin Y (2009)
Arginine metabolism and nutrition in growth, health and disease.
Amino acids 37, 153-168 [PubMed:19030957]
[show Abstract]
L-Arginine (Arg) is synthesised from glutamine, glutamate, and proline via the intestinal-renal axis in humans and most other mammals (including pigs, sheep and rats). Arg degradation occurs via multiple pathways that are initiated by arginase, nitric-oxide synthase, Arg:glycine amidinotransferase, and Arg decarboxylase. These pathways produce nitric oxide, polyamines, proline, glutamate, creatine, and agmatine with each having enormous biological importance. Arg is also required for the detoxification of ammonia, which is an extremely toxic substance for the central nervous system. There is compelling evidence that Arg regulates interorgan metabolism of energy substrates and the function of multiple organs. The results of both experimental and clinical studies indicate that Arg is a nutritionally essential amino acid (AA) for spermatogenesis, embryonic survival, fetal and neonatal growth, as well as maintenance of vascular tone and hemodynamics. Moreover, a growing body of evidence clearly indicates that dietary supplementation or intravenous administration of Arg is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions, as well as facilitating wound healing, enhancing insulin sensitivity, and maintaining tissue integrity. Additionally, Arg or L-citrulline may provide novel and effective therapies for obesity, diabetes, and the metabolic syndrome. The effect of Arg in treating many developmental and health problems is unique among AAs, and offers great promise for improved health and wellbeing of humans and animals. | Castrillo JI, Zeef LA, Hoyle DC, Zhang N, Hayes A, Gardner DC, Cornell MJ, Petty J, Hakes L, Wardleworth L, Rash B, Brown M, Dunn WB, Broadhurst D, O'Donoghue K, Hester SS, Dunkley TP, Hart SR, Swainston N, Li P, Gaskell SJ, Paton NW, Lilley KS, Kell DB, Oliver SG (2007)
Growth control of the eukaryote cell: a systems biology study in yeast.
Journal of biology 6, 4 [PubMed:17439666]
[show Abstract]
BackgroundCell growth underlies many key cellular and developmental processes, yet a limited number of studies have been carried out on cell-growth regulation. Comprehensive studies at the transcriptional, proteomic and metabolic levels under defined controlled conditions are currently lacking.ResultsMetabolic control analysis is being exploited in a systems biology study of the eukaryotic cell. Using chemostat culture, we have measured the impact of changes in flux (growth rate) on the transcriptome, proteome, endometabolome and exometabolome of the yeast Saccharomyces cerevisiae. Each functional genomic level shows clear growth-rate-associated trends and discriminates between carbon-sufficient and carbon-limited conditions. Genes consistently and significantly upregulated with increasing growth rate are frequently essential and encode evolutionarily conserved proteins of known function that participate in many protein-protein interactions. In contrast, more unknown, and fewer essential, genes are downregulated with increasing growth rate; their protein products rarely interact with one another. A large proportion of yeast genes under positive growth-rate control share orthologs with other eukaryotes, including humans. Significantly, transcription of genes encoding components of the TOR complex (a major controller of eukaryotic cell growth) is not subject to growth-rate regulation. Moreover, integrative studies reveal the extent and importance of post-transcriptional control, patterns of control of metabolic fluxes at the level of enzyme synthesis, and the relevance of specific enzymatic reactions in the control of metabolic fluxes during cell growth.ConclusionThis work constitutes a first comprehensive systems biology study on growth-rate control in the eukaryotic cell. The results have direct implications for advanced studies on cell growth, in vivo regulation of metabolic fluxes for comprehensive metabolic engineering, and for the design of genome-scale systems biology models of the eukaryotic cell. | Masic LP (2006)
Arginine mimetic structures in biologically active antagonists and inhibitors.
Current medicinal chemistry 13, 3627-3648 [PubMed:17168727]
[show Abstract]
Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability. | Bronte V, Zanovello P (2005)
Regulation of immune responses by L-arginine metabolism.
Nature reviews. Immunology 5, 641-654 [PubMed:16056256]
[show Abstract]
L-Arginine is an essential amino acid for birds and young mammals, and it is a conditionally essential amino acid for adult mammals, as it is important in situations in which requirements exceed production, such as pregnancy. Recent findings indicate that increased metabolism of L-arginine by myeloid cells can result in the impairment of lymphocyte responses to antigen during immune responses and tumour growth. Two enzymes that compete for L-arginine as a substrate - arginase and nitric-oxide synthase - are crucial components of this lymphocyte-suppression pathway, and the metabolic products of these enzymes are important moderators of T-cell function. This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions. | Roth E, Wessner B (2005)
[L-arginine: an amino acid with multiple effects].
Wiener klinische Wochenschrift 117, 666-672 [PubMed:16416365] | Rhoads JM, Chen W, Gookin J, Wu GY, Fu Q, Blikslager AT, Rippe RA, Argenzio RA, Cance WG, Weaver EM, Romer LH (2004)
Arginine stimulates intestinal cell migration through a focal adhesion kinase dependent mechanism.
Gut 53, 514-522 [PubMed:15016745]
[show Abstract]
BackgroundL-Arginine is a nutritional supplement that may be useful for promoting intestinal repair. Arginine is metabolised by the oxidative deiminase pathway to form nitric oxide (NO) and by the arginase pathway to yield ornithine and polyamines.AimsTo determine if arginine stimulates restitution via activation of NO synthesis and/or polyamine synthesis.MethodsWe determined the effects of arginine on cultured intestinal cell migration, NO production, polyamine levels, and activation of focal adhesion kinase, a key mediator of cell migration.ResultsArginine increased the rate of cell migration in a dose dependent biphasic manner, and was additive with bovine serum concentrate (BSC). Arginine and an NO donor activated focal adhesion kinase (a tyrosine kinase which localises to cell matrix contacts and mediates beta1 integrin signalling) after wounding. Arginine stimulated cell migration was dependent on focal adhesion kinase (FAK) signalling, as demonstrated using adenovirus mediated transfection with a kinase negative mutant of FAK. Arginine stimulated migration was dependent on NO production and was blocked by NO synthase inhibitors. Arginine dependent migration required synthesis of polyamines but elevating extracellular arginine concentration above 0.4 mM did not enhance cellular polyamine levels.ConclusionsThese results showed that L-arginine stimulates cell migration through NO and FAK dependent pathways and that combination therapy with arginine and BSC may enhance intestinal restitution via separate and convergent pathways. | Gornik HL, Creager MA (2004)
Arginine and endothelial and vascular health.
The Journal of nutrition 134, 2880S-2887S; discussion 2895S [PubMed:15465805]
[show Abstract]
The vascular endothelium is a crucial regulator of vascular function and homeostasis. Nitric oxide (NO) is an important paracrine substance released by the endothelium to regulate vasomotor tone. Risk factors for atherosclerosis, as well as atherosclerosis per se, are associated with endothelial dysfunction and decreased bioavailablilty of NO. Indeed, endothelial dysfunction is integral to the pathogenesis of atherosclerosis and other cardiovascular diseases. Moreover, endothelial dysfunction relates to an increased risk of adverse cardiovascular outcomes. L-Arginine is an essential amino acid required by the constitutive enzyme, endothelial NO oxide synthase (eNOS), to produce NO. Administration of L-arginine improves endothelial function in animal models and in humans with hypercholesterolemia and with atherosclerosis. Clinical trials to date support potential clinical applications of L-arginine in the treatment of coronary artery disease and peripheral arterial disease, as well as in the prevention of in-stent restenosis. The mechanism of benefit of L-arginine on endothelial function is unclear, because intracellular concentrations of L-arginine far exceed that required by eNOS. One potential explanation of this "arginine paradox" is that L-arginine restores endothelial function in atherosclerotic patients, in whom there are elevated levels of asymmetric dimethylarginine, an endogenous inhibitor of eNOS. Given the promising findings of early studies of L-arginine as a potential therapy for cardiovascular disorders, large-scale clinical trials are warranted. | Takeya M, Hasuo H, Akasu T (2003)
Contribution of nitric oxide to the depression of neuronal activity induced by temperature increase in the rat hippocampal CA1 area.
Neuroscience letters 344, 153-156 [PubMed:12812828]
[show Abstract]
Using optical recording techniques, we examined whether nitric oxide (NO) is implicated in the impairment of the activity of hippocampal CA1 neurons induced by mild heat stress. A temperature increase from 32 to 38 degrees C reversibly depressed the neuronal activity in hippocampal slices. L-Arginine (1 mM), an NO donor, enhanced the heat-induced depression of the activity of hippocampal CA1 neurons. N(omega)-Nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, attenuated the inhibition of the neuronal activity induced by a temperature increase. Methylcobalamin (10 microM), a vitamin B(12) analogue that reduces NO production, reduced the heat-induced depression of the neuronal activity. These results suggest that NO contributes, at least in part, to the heat-induced depression of the neuronal activity in the hippocampal CA1 region. | Durante W (2001)
Regulation of L-arginine transport and metabolism in vascular smooth muscle cells.
Cell biochemistry and biophysics 35, 19-34 [PubMed:11898853]
[show Abstract]
L-Arginine is a semi-essential amino acid that is metabolized to important regulatory molecules. L-Arginine is transported into vascular smooth muscle cells (SMC) by the cationic amino acid transporter (CAT) family of proteins where it is metabolized to nitric oxide (NO), polyamines, or L-proline. Inflammatory mediators, growth factors, and hemodynamic forces stimulate the transport of L-arginine in vascular SMC by inducing CAT gene expression. However, they exert highly specific and divergent regulatory effects on L-arginine metabolism. Inflammatory cytokines induce the expression of inducible NO synthase (iNOS) and direct the metabolism of L-arginine to the antiproliferative gas, NO. In contrast, growth factors stimulate the expression of arginase I and ornithine decarboxylase (ODC) and channel the metabolism of L-arginine to growth stimulatory polyamines. Alternatively, cyclic mechanical strain blocks both iNOS and ODC activity and stimulates arginase I gene expression, directing the metabolism of L-arginine to the formation of L-proline and collagen. Thus, specific biochemical and biophysical stimuli that are found in the circulation regulate the transport and metabolism of L-arginine in vascular SMC. The ability of these physiologically relevant stimuli to upregulate L-arginine transport and generate specific L-arginine metabolites modulates SMC function and may influence the development of vascular disease. | Taheri F, Ochoa JB, Faghiri Z, Culotta K, Park HJ, Lan MS, Zea AH, Ochoa AC (2001)
L-Arginine regulates the expression of the T-cell receptor zeta chain (CD3zeta) in Jurkat cells.
Clinical cancer research : an official journal of the American Association for Cancer Research 7, 958s-965s [PubMed:11300497]
[show Abstract]
L-Arginine is a versatile amino acid that plays a central role in the normal function of several organ systems including the immune system. Its availability is tightly controlled and varies significantly in different organs and tissues in the body. L-Arginine plays an important role in supporting T-cell proliferation. Its depletion in certain disease states results in a diminished T-cell response. The main purpose of this study was to determine the effect of the depletion of L-arginine on the expression of the T-cell receptor (TCR) proteins. When the helper T-cell line Jurkat was cultured in arginine-free medium, there was a preferential decrease in the expression of the TCR zeta chain (CD3zeta). The reduced expression of CD3zeta was observed within 24 h of culture in L-arginine-free medium and was completely reversed with the replenishment of L-arginine. Furthermore, the absence of L-arginine blocked the normal re-expression of the TCR that had been internalized after antigen stimulation. There also was a significant decrease in proliferation of Jurkat cells in the absence of L-arginine; however, L-arginine depletion did not prevent the up-regulation of the interleukin 2 receptor chains upon stimulation, nor did it significantly diminish the production of interleukin 2. The changes in the expression of CD3zeta chain were not induced by apoptosis. Thus, the availability of L-arginine in the microenvironment may play a significant role in regulating the expression of the TCR. | Pham NH, Weiner JM, Reisner GS, Baldo BA (2000)
Anaphylaxis to chlorhexidine. Case report. Implication of immunoglobulin E antibodies and identification of an allergenic determinant.
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 30, 1001-1007 [PubMed:10848923]
[show Abstract]
BackgroundThere are many reports of allergic reactions, including anaphylaxis, following exposure to chlorhexidine. Reactions may occur via contact with the skin and mucous membranes or from catheters treated with the antibacterial agent. Apart from implicating chlorguanide in immunoglobulin (Ig) E antibody-binding studies on serum from an anaphylactic patient, little work has been done on the molecular basis of recognition of the agent in sensitive subjects.ObjectivesThe molecular basis of IgE-binding to chlorhexidine was closely examined with the view of defining its fine structural recognition features by antibodies from a subject who experienced anaphylaxis following contact with the antiseptic.MethodsTryptase determinations, different drug-solid phases, immunoassays and quantitative hapten inhibition studies with chlorhexidine and selected structural analogues were employed together with serum from the anaphylactic patient. Results were analysed to define the complete drug allergenic determinant and to identify the important structural features complementary to the IgE antibody combining sites.ResultsThe subject's serum tryptase levels sampled after the reaction were elevated and employment of a chlorhexidine-EA Sepharose solid phase showed the presence of serum IgE antibodies to the drug. Lack of inhibition by 4-chlorophenol and other selected substituted phenyl compounds showed that the terminal groups at each end of the chlorhexidine molecule, alone, did not account for antibody recognition of the antibacterial agent. Although chlorguanide and alexidine, the structures of which each comprise part of the chlorhexidine molecule, showed significant inhibition of the binding of IgE antibodies to chlorhexidine, neither compound was as potent an inhibitor as chlorhexidine itself. Two molecules of chlorguanide make up the symmetrical molecule of chlorhexidine while the interior structure of alexidine (that is excluding the terminal 2-ethylhexyl groups) is identical to part of the chlorhexidine molecule.ConclusionsTaken together, for this patient, these results lead to the conclusion that the whole chlorhexidine molecule is complementary to the IgE antibody combining sites and that the 4-chlorophenol, biguanide and hexamethylene structures together comprise the allergenic determinant. Hence, like one of the trimethoprim determinants identified, but unlike most drug allergenic determinants identified so far, the chlorhexidine allergenic determinant identified here encompasses the entire molecule. | Lerman A, Suwaidi JA, Velianou JL (1999)
L-Arginine: a novel therapy for coronary artery disease?
Expert opinion on investigational drugs 8, 1785-1793 [PubMed:11139824]
[show Abstract]
Coronary artery disease (CAD) is a significant cause of morbidity and mortality today. The treatment of CAD is improving, but its prevalence is increasing: both primary and secondary prevention measures are of vital importance. Atherosclerosis starts at an early age; it is initiated at the vascular endothelium level, a single layer entity that modulates vascular function. Modulation of vascular function is carried out through the L-arginine/nitric oxide (NO) pathway. Normal endothelial function requires an intact L-arginine/NO pathway and endothelium. Endothelial dysfunction may be a precursor to overt CAD. CAD risk factors have been shown to influence endothelial function, and the treatment of these risk factors can restore endothelial function. L-Arginine is a safe, novel, semiessential amino acid that increases NO production, thereby improving endothelial function. L-Arginine/NO has numerous beneficial neurohormonal modulating properties. Numerous animal model and human studies have been carried out to assess L-arginine in CAD and other related disorders such as congestive heart failure (CHF), peripheral vascular disease (PVD) and acute myocardial infarction (AMI). Prospective clinical trials are required to assess the promising role of L-arginine in CAD and related disorders | Taneda S, Monnier VM (1994)
ELISA of pentosidine, an advanced glycation end product, in biological specimens.
Clinical chemistry 40, 1766-1773 [PubMed:8070089]
[show Abstract]
Pentosidine is a fluorescent protein cross-link and glycoxidation marker for the advanced glycation reaction in diabetes, aging, and uremia. We raised polyclonal antibodies in New Zealand White rabbits against this hapten coupled to keyhole limpet hemocyanin. The antibodies detected by ELISA reacted strongly with free pentosidine but not with pentosidine-like compounds. The working range of the competitive ELISA for standard pentosidine was 0.1-100 pmol. Pentosidine was detectable in bovine serum albumin incubated with ribose as a function of incubation time. Immunoblotting studies showed that pentosidine specifically stained in oligomers of lysozyme incubated with ribose. Digestion with protease (Pronase E, 20 g/kg) as well as acid hydrolysis enhanced the immunoreactivity of samples, the pentosidine values in digested human plasma correlating with those measured by HPLC (r = 0.98). Pentosidine in diabetic and uremic plasma digested with Pronase E was significantly higher than normal (P < 0.01; mean +/- SD): 1620 +/- 1940 and 2630 +/- 1320 [corrected] nmol/L, respectively, vs 151 +/- 55 nmol/L (normal). Amounts of pentosidine in hydrolyzed skin collagen increased with age and were increased in diabetes and uremia. This ELISA provides a new tool for assessing the role of the advanced Maillard reaction in aging and age-related diseases. |
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