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Protein Solvent Interaction: Transition of Protein-solvent Interaction Concept from Basic Research into Solvent Manipulation of Chromatography.
Arakawa, T, Kita, Y
Current protein & peptide science. 2019;(1):34-39
Abstract
Previously, we have reviewed in this journal (Arakawa, T., Kita, Y., Curr. Protein Pept. Sci., 15, 608-620, 2014) the interaction of arginine with proteins and various applications of this solvent additive in the area of protein formulations and downstream processes. In this special issue, we expand the concept of protein-solvent interaction into the analysis of the effects of solvent additives on various column chromatography, including mixed-mode chromatography. Earlier in our research, we have studied the interactions of such a variety of solvent additives as sugars, salts, amino acids, polymers and organic solvents with a variety of proteins, which resulted in mechanistic understanding on their protein stabilization and precipitation effects, the latter known as Hofmeister series. While such a study was then a pure academic research, rapid development of genetic engineering technologies and resultant biotechnologies made it a valuable knowledge in fully utilizing solvent additives in manipulation of protein solution, including column chromatography.
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Effect of l-arginine supplementation on C-reactive protein and other inflammatory biomarkers: A systematic review and meta-analysis of randomized controlled trials.
Nazarian, B, Fazeli Moghadam, E, Asbaghi, O, Zeinali Khosroshahi, M, Choghakhori, R, Abbasnezhad, A
Complementary therapies in medicine. 2019;:102226
Abstract
OBJECTIVES We carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of L-arginine on inflammatory biomarkers including C-reactive protein (CRP), interleukin-6 (IL-6) and TNFα. METHODS A systematic search was carried out in PubMed, Embase, Scopus, Cochrane library databases and ISI web of sciences to retrieve the RCTs which examined the effect of L-arginine supplementation on inflammatory biomarkers up to October 2019, with no language and time restriction. Meta-analysis was performed using a random effects model, and I2 index was used to evaluate the heterogeneity. RESULTS Search yielded 2452 publications. Eleven RCTs were eligible. Results indicated that L-arginine supplementation had no significant effect on inflammatory biomarkers including CRP, IL-6 and TNFα. However, when subgroup analysis was performed, we found that L-arginine supplementation increased CRP levels in subjects with ages >60 years old, participants with baseline circulating CRP levels >3 mg/dl, patients with cancer and when used in enteral formula. CONCLUSION Results of the present meta-analysis indicated that L-arginine supplementation increased the circulating concentrations of CRP in subjects with ages >60 years old, subjects with higher levels of CRP, patients with cancer and when used in enteral formula. Therefore, L-arginine should be used with caution in these subjects. However, further well designed, large-scale studies are needed.
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Arginine-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a prospective diagnostic study.
Winzeler, B, Cesana-Nigro, N, Refardt, J, Vogt, DR, Imber, C, Morin, B, Popovic, M, Steinmetz, M, Sailer, CO, Szinnai, G, et al
Lancet (London, England). 2019;(10198):587-595
Abstract
BACKGROUND Differential diagnosis of diabetes insipidus is challenging. The most reliable approach is hypertonic saline-stimulated copeptin measurements. However, this test is based on the induction of hypernatraemia and requires close monitoring of plasma sodium concentrations. Arginine-stimulated copeptin measurements might provide an alternative, simple, and safe test. METHODS In this prospective diagnostic study, we recruited a development cohort from University Hospital Basel, Basel, Switzerland, and a validation cohort from five centres in Basel, Aarau, Luzern, Bern, and St Gallen, Switzerland, and the University Hospital Würzburg, Würzburg, Germany. For both cohorts, patients were eligible for inclusion if they were aged 18 years or older, were newly referred with polyuria (>50 mL/kg bodyweight per day) or had a known diagnosis of central diabetes insipidus or primary polydipsia. We also recruited a comparator cohort of healthy controls in parallel to each cohort, comprising adults (aged 18 years and older, with normal drinking habits, and no history of polyuria) and children who underwent arginine stimulation to diagnose growth hormone deficiency (children were only included in the comparator cohort to the development cohort as proof of concept). Patients and healthy controls underwent arginine stimulation with measurement of plasma copeptin at baseline and 30, 45, 60, 90, and 120 min. The primary objective in the development cohort was to determine the diagnostic accuracy of plasma copeptin concentrations to discriminate between diabetes insipidus and primary polydipsia, and in the validation cohort was to confirm those results. Adverse effects of the test were monitored in all participants, with tolerability of the test rated using a visual analogue scale (VAS) that ranged from no (0) to maximum (10) discomfort. This trial is registered with ClinicalTrials.gov, number NCT00757276. FINDINGS Between May 24, 2013, and Jan 11, 2017, 52 patients were enrolled in the development cohort (12 [23%] with complete diabetes insipidus, nine [17%] with partial diabetes insipidus, and 31 [60%] with primary polydipsia) alongside 20 healthy adults and 42 child controls. Between Oct 24, 2017, and June 27, 2018, 46 patients were enrolled in the validation cohort (12 [26%] with complete diabetes insipidus, seven [15%] with partial diabetes insipidus, and 27 [59%] with primary polydipsia) alongside 30 healthy adult controls (two patients in this cohort were excluded from the main analysis because of early vomiting during the test). In the pooled patient and control datasets, median arginine-stimulated copeptin concentrations increased in healthy adult controls (from 5·2 pM [IQR 3·3-10·9] to a maximum of 9·8 pM [6·4-19·6]) and in participants with primary polydipsia (from 3·6 pM [IQR 2·4-5·7] to a maximum of 7·9 pM [5·1-11·8]), but only minimally in those with diabetes insipidus (2·1 pM [IQR 1·9-2·7] to a maximum of 2·5 pM [1·9-3·1]). In the development cohort, a cutoff of 3·5 pM at 60 min provided the highest diagnostic accuracy of 94% (95% CI 84-98). The accuracy of this cutoff in the validation cohort was 86% (95% CI 73-94). By pooling the data from both cohorts, an optimal accuracy of 93% (95% CI 86-97) was reached at a cutoff of 3·8 pM copeptin at 60 min (sensitivity 93%, 95% CI 86-98; specificity 92%, 95% CI 84-100). The test was safe and well tolerated, with median VAS scores of 3·5 (IQR 2-4) in patients with diabetes insipidus, 3 (2-4) in those with primary polydipsia, 1 (1-3) in healthy adults, and 1 (0-5) in healthy children in the pooled participant dataset. INTERPRETATION Arginine-stimulated copeptin measurements are an innovative test for diabetes insipidus with high diagnostic accuracy, and could be a simplified, novel, and safe diagnostic approach to diabetes insipidus in clinical practice. FUNDING Swiss National Science Foundation and University Hospital Basel.
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Acute porphyrias: a German monocentric study of the biochemical, molecular genetic, and clinical data of 62 families.
Bronisch, O, Stauch, T, Haverkamp, T, Beykirch, MK, Petrides, PE
Annals of hematology. 2019;(12):2683-2691
Abstract
In Germany, analyses of clinical and laboratory features of patients with acute porphyrias are only available for hereditary coproporphyria (HCP) but not with other acute porphyrias, acute intermittent porphyria (AIP) and variegate porphyria (VP). The aim of the study was to analyze a large cohort of patients with particular focus upon quality of life aspects. Sixty-two individuals from separate families with acute porphyrias (57 AIP, 5 VP) were included into an observational study collecting biochemical, genetic, and clinical data. A questionnaire was designed to complete anamnestic information and to assess the influence on quality of life. Most frequent signs and symptoms or laboratory abnormalities were abdominal colicky pain, red coloration of urine, and hyponatremia. Depression or anxiety was reported by 61% or 52% individuals, respectively. Fatigue was mentioned as the most quality of life-limiting symptom. In 59/61 patients, mutations could be identified. 44% (20/45) had to be admitted to an intensive care unit. Heme arginate was used in 64% (29/45) of patients for treatment of acute attacks at least once and in 33% for long-term treatment with high frequency of administration. Serum creatinine values increased in 47% (7/17) of the patients with recurrent attacks. Our analysis confirms a substantial influence of the diseases on the quality of life on patients. Percentages of urine discoloration and intensive care unit admissions were much higher than in other reports. Long-term treatment with heme arginate requires careful monitoring of iron status and renal values.
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Exceptionally versatile - arginine in bacterial post-translational protein modifications.
Lassak, J, Koller, F, Krafczyk, R, Volkwein, W
Biological chemistry. 2019;(11):1397-1427
Abstract
Post-translational modifications (PTM) are the evolutionary solution to challenge and extend the boundaries of genetically predetermined proteomic diversity. As PTMs are highly dynamic, they also hold an enormous regulatory potential. It is therefore not surprising that out of the 20 proteinogenic amino acids, 15 can be post-translationally modified. Even the relatively inert guanidino group of arginine is subject to a multitude of mostly enzyme mediated chemical changes. The resulting alterations can have a major influence on protein function. In this review, we will discuss how bacteria control their cellular processes and develop pathogenicity based on post-translational protein-arginine modifications.
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Metabolic Profile of Supragingival Plaque Exposed to Arginine and Fluoride.
Nascimento, MM, Alvarez, AJ, Huang, X, Browngardt, C, Jenkins, R, Sinhoreti, MC, Ribeiro, APD, Dilbone, DA, Richards, VP, Garrett, TJ, et al
Journal of dental research. 2019;(11):1245-1252
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Abstract
Caries lesions develop when acid production from bacterial metabolism of dietary carbohydrates outweighs the various mechanisms that promote pH homeostasis, including bacterial alkali production. Therapies that provide arginine as a substrate for alkali production in supragingival oral biofilms have strong anticaries potential. The objective of this study was to investigate the metabolic profile of site-specific supragingival plaque in response to the use of arginine (Arg: 1.5% arginine, fluoride-free) or fluoride (F: 1,100 ppm F/NaF) toothpastes. Eighty-three adults of different caries status were recruited and assigned to treatment with Arg or F for 12 wk. Caries lesions were diagnosed using International Caries Detection and Assessment System II, and plaque samples were collected from caries-free and carious tooth surfaces. Taxonomic profiles were obtained by HOMINGS (Human Oral Microbe Identification using Next Generation Sequencing), and plaque metabolism was assessed by the levels of arginine catabolism via the arginine deiminase pathway (ADS), acidogenicity, and global metabolomics. Principal component analysis (PCA), partial least squares-discriminant analysis, analysis of variance, and random forest tests were used to distinguish metabolic profiles. Of the 509 active lesions diagnosed at baseline, 70 (14%) were inactive after 12 wk. Generalized linear model showed that enamel lesions were significantly more likely to become inactive compared to dentin lesions (P < 0.0001), but no difference was found when treatment with Arg was compared to F (P = 0.46). Arg significantly increased plaque ADS activity (P = 0.031) and plaque pH values after incubation with glucose (P = 0.001). F reduced plaque lactate production from endogenous sources (P = 0.02). PCA revealed differences between the metabolic profiles of plaque treated with Arg or F. Arg significantly affected the concentrations of 16 metabolites, including phenethylamine, agmatine, and glucosamine-6-phosphate (P < 0.05), while F affected the concentrations of 9 metabolites, including phenethylamine, N-methyl-glutamate, and agmatine (P < 0.05). The anticaries mechanisms of action of arginine and fluoride are distinct. Arginine metabolism promotes biofilm pH homeostasis, whereas fluoride is thought to enhance resistance of tooth minerals to low pH and reduce acid production by supragingival oral biofilms.
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Evaluation of kinetic data: What the numbers tell us about PRMTs.
Frankel, A, Brown, JI
Biochimica et biophysica acta. Proteins and proteomics. 2019;(3):306-316
Abstract
Protein arginine N-methyltransferase (PRMT) kinetic parameters have been catalogued over the past fifteen years for eight of the nine mammalian enzyme family members. Like the majority of methyltransferases, these enzymes employ the highly ubiquitous cofactor S-adenosyl-l-methionine as a co-substrate to methylate arginine residues in peptidic substrates with an approximately 4-μM median KM. The median values for PRMT turnover number (kcat) and catalytic efficiency (kcat/KM) are 0.0051 s-1 and 708 M-1 s-1, respectively. When comparing PRMT metrics to entries found in the BRENDA database, we find that while PRMTs exhibit high substrate affinity relative to other enzyme-substrate pairs, PRMTs display largely lower kcat and kcat/KM values. We observe that kinetic parameters for PRMTs and arginine demethylase activity from dual-functioning lysine demethylases are statistically similar, paralleling what the broader enzyme families in which they belong reveal, and adding to the evidence in support of arginine methylation reversibility.
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Application of multivariate longitudinal models in SIRT6, FBS, and BMI analysis of the elderly.
Gilani, N, Haghshenas, R, Esmaeili, M
The aging male : the official journal of the International Society for the Study of the Aging Male. 2019;(4):260-265
Abstract
Objective: SIRT6 is a main regulator of metabolism and lifespan and its importance has been implicated in the prevention against aging-related diseases. The objective of this study was to examine the application of multivariate longitudinal models in SIRT6, FBS, and BMI analysis in the elderly men after eight weeks concurrent training with supplementation of l-arginine (l-Arg). Methods: Thirty two elderly men with mean age of 63.09 ± 3.71 years were randomly divided into four equal-sized groups (each n = 8); Exercise + supplement (ES) group; exercise + placebo (EP) group; supplement (S) group and control (C) group. The ES and EP groups performed the eight weeks of concurrent training, three sessions per week. Group ES and group S consumed 1000 mg of l-Arg per day at 8:00 pm. Measurements of biochemical variables were done by ELISA Reader method. For analytical purposes, we used the paired sample t-test and multivariate longitudinal modeling with generalized estimating equation (GEE) methodology. All analyses have been implemented in R-3.4.1. p Values less than .05 were considered statistically significant. Results: With respect to significant association between sirt6, FBS, and BMI, this study showed that synergy effect of training and supplementation was greater than the sum of their individual effects on SIRT6 (β = 0.79, p < .001), FBS (β = -5.56, p = .022), and BMI (β = -3.89; p = .041). Also exercise alone had a significantly larger effect than supplementation alone on responses. Conclusions: It can be concluded that the joint usage of concurrent training and supplement of l-Arg for elderly men could improve the metabolism and body composition.
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Oral Supplementation with Beta-Hydroxy-Beta-Methylbutyrate, Arginine, and Glutamine Improves Lean Body Mass in Healthy Older Adults.
Ellis, AC, Hunter, GR, Goss, AM, Gower, BA
Journal of dietary supplements. 2019;(3):281-293
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Abstract
Oral intake of beta-hydroxy-beta-methylbutyrate (HMB), arginine, and glutamine may ameliorate muscle loss by stimulating protein synthesis and decreasing protein degradation while simultaneously decreasing inflammation. Previous studies provide evidence for improvement in body composition with dietary supplementation of these ingredients among patients with muscle-wasting diseases. The objectives of this study were to examine the effects of this amino acid mixture on lean body mass, muscle volume, and physical function among healthy older adults. Thirty-one community-dwelling men and women, aged 65-89 years, were randomized to either two oral doses of the amino acid supplement (totaling 3 g HMB, 14 g arginine, 14 g glutamine) or placebo daily for six months. At baseline and month six, lean body mass was measured by air displacement plethysmography, dual-energy X-ray absorptiometry (DXA), and four-compartment model. Muscle volume of quadriceps was quantified by magnetic resonance imaging (MRI), and participants performed a battery of tests to assess physical function. As compared to the placebo group, the treatment group exhibited improvement in a timed stair climb (p =.016) as well as significant increases in lean body mass by all methods of assessment (p <.05). Regional analysis by DXA revealed increased arm lean mass in the supplement group only (p =.035). However, no change was observed in MRI-derived quadriceps volume. Dietary supplementation with HMB, arginine, and glutamine improved total body lean mass among a small sample of healthy older adults. Further research is indicated to elucidate mechanisms of action and to determine whether supplementation may benefit frail elders. Registered under ClinicalTrials.gov identifier no. NCT01057082.
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Arginine Biosynthesis Modulates Pyoverdine Production and Release in Pseudomonas putida as Part of the Mechanism of Adaptation to Oxidative Stress.
Barrientos-Moreno, L, Molina-Henares, MA, Pastor-García, M, Ramos-González, MI, Espinosa-Urgel, M
Journal of bacteriology. 2019;(22)
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Abstract
Iron is essential for most life forms. Under iron-limiting conditions, many bacteria produce and release siderophores-molecules with high affinity for iron-which are then transported into the cell in their iron-bound form, allowing incorporation of the metal into a wide range of cellular processes. However, free iron can also be a source of reactive oxygen species that cause DNA, protein, and lipid damage. Not surprisingly, iron capture is finely regulated and linked to oxidative-stress responses. Here, we provide evidence indicating that in the plant-beneficial bacterium Pseudomonas putida KT2440, the amino acid l-arginine is a metabolic connector between iron capture and oxidative stress. Mutants defective in arginine biosynthesis show reduced production and release of the siderophore pyoverdine and altered expression of certain pyoverdine-related genes, resulting in higher sensitivity to iron limitation. Although the amino acid is not part of the siderophore side chain, addition of exogenous l-arginine restores pyoverdine release in the mutants, and increased pyoverdine production is observed in the presence of polyamines (agmatine and spermidine), of which arginine is a precursor. Spermidine also has a protective role against hydrogen peroxide in P. putida, whereas defects in arginine and pyoverdine synthesis result in increased production of reactive oxygen species.IMPORTANCE The results of this study show a previously unidentified connection between arginine metabolism, siderophore turnover, and oxidative stress in Pseudomonas putida Although the precise molecular mechanisms involved have yet to be characterized in full detail, our data are consistent with a model in which arginine biosynthesis and the derived pathway leading to polyamine production function as a homeostasis mechanism that helps maintain the balance between iron uptake and oxidative-stress response systems.