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Oral L-Arginine (5 g/day) for 14 Days Improves Microcirculatory Function in Healthy Young Women and Healthy and Type 2 Diabetes Mellitus Elderly Women.
Costa, G, Shushanof, M, Bouskela, E, Bottino, D
Journal of vascular research. 2022;(1):24-33
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Abstract
OBJECTIVE The aim of this study was to investigate the effect of oral supplementation with L-arginine on serum biochemical profile, blood pressure, microcirculation, and vasoreactivity/endothelial function in young controls, and elderly women with and without type 2 diabetes mellitus (T2DM). METHODS Healthy young (n = 25), healthy elderly (n = 25), and elderly women with type 2 diabetes mellitus (T2DME, n = 23, glycated Hb ≥6.4% and mean of 7.7 years for duration of the disease), aged 18-30 and older than 65 years, respectively, were included in the study. All patients underwent biochemical analysis (fasting glycemia and lipidogram), arterial blood pressure, nailfold videocapillaroscopy (capillary diameters, functional capillary density [FCD], peak red blood cell velocity [RBCVmax] after 1 min ischemia, time to reach peak RBCV [TRBCVmax]), and venous occlusion plethysmography (vasoreactivity), before and after 14 days of oral supplementation with L-arginine (5 g/day). RESULTS L-Arginine did not change fasting glycemia and lipidogram, but it decreased systolic, diastolic, and mean arterial pressure in elderly women, increased RBCVmax in all groups, and did not decrease TRBCVmax in T2DME. Capillary diameters and FCD remained unchanged in all groups. L-Arginine improved vasoreactivity during reactive hyperemia and after sublingual nitroglycerin (0.4 mg) in all groups. CONCLUSION L-Arginine supplementation (5g/day during 14 days) was able to improve vascular/microvascular health in the elderly women with or without T2DM.
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Postoperative arginine-enriched immune modulating nutrition: Long-term survival results from a randomised clinical trial in patients with oesophagogastric and pancreaticobiliary cancer.
Adiamah, A, Rollins, KE, Kapeleris, A, Welch, NT, Iftikhar, SY, Allison, SP, Lobo, DN
Clinical nutrition (Edinburgh, Scotland). 2021;(11):5482-5485
Abstract
BACKGROUND & AIMS Immune modulating nutrition (IMN) has been shown to reduce postoperative infectious complications and length of stay in patients with gastrointestinal cancer. Two studies of IMN in patients undergoing surgery for head and neck cancer also suggested that this treatment might improve long-term survival and progression-free survival. In the present study, we analysed follow-up data from our previous randomised controlled trial of IMN, in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer, in order to evaluate the long-term impact on survival of postoperative IMN versus an isocaloric, isonitrogenous control feed. METHODS This study included patients undergoing surgery for cancers of the pancreas, oesophagus and stomach, who had been randomised in a double-blind manner to receive postoperative jejunostomy feeding with IMN (Stresson, Nutricia Ltd.) or an isonitrogenous, isocaloric feed (Nutrison High Protein, Nutricia) for 10-15 days. The primary outcome was long-term overall survival. RESULTS There was complete follow-up for all 108 patients, with 54 patients randomised to each group. There were no statistically significant differences between groups by demographics [(age, p = 0.63), sex (p = 0.49) or site of cancer (p = 0.25)]. 30-day mortality was 11.1% in both groups. Mortality in the intervention group was 13%, 31.5%, 70.4%, 85.2%, 88.9%, and 96.3% at 90 days, and 1, 5, 10, 15 and 20 years respectively. Corresponding mortality in the control group was 14.8%, 35.2%, 68.6%, 79.6%, 85.2% and 98.1% (p > 0.05 for all comparisons). CONCLUSION Early postoperative feeding with arginine-enriched IMN had no impact on long-term survival in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer.
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Acute Inositol-Stabilized Arginine Silicate Improves Cognitive Outcomes in Healthy Adults.
Gills, JL, Campitelli, A, Jones, M, Paulson, S, Myers, JR, Madero, EN, Glenn, JM, Komorowski, J, Gray, M
Nutrients. 2021;(12)
Abstract
Inositol-stabilized arginine silicate (ASI) is an ergogenic aid that upregulates nitric oxide. Acute ASI supplementation improves working memory and processing speed in young adults but there is a lack of data examining other cognitive tasks. Therefore, the purpose of this study was to examine acute ASI effects on young healthy adults by assessing multiple cognitive domains. Nineteen young adults (20.9 ± 3.2 years) completed this randomized, double-blind, crossover study consuming ASI (1.5 g ASI + 12 g dextrose) and placebo (12 g dextrose). The participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and two digital cognitive assessments before consuming the supplement and then completed the same battery of tests 60 min post-supplementation. Repeated measures ANOVA demonstrated that ASI consumption significantly improved total RBANS and immediate memory scores compared to the placebo (p < 0.05). However, no significant differences were displayed between trials for other cognitive domains (p > 0.05). Acute ASI ingestion increased overall RBANS scores and immediate memory scores in young adults. More research is needed to examine the acute effects of ASI on other domains of cognition, in older populations, and its long-term effects on cognition.
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L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation.
Castejón-Vega, B, Rubio, A, Pérez-Pulido, AJ, Quiles, JL, Lane, JD, Fernández-Domínguez, B, Cachón-González, MB, Martín-Ruiz, C, Sanz, A, Cox, TM, et al
Cells. 2021;(11)
Abstract
AIMS: Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by β-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay-Sachs and Sandhoff diseases. RESULTS Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities. INNOVATION Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases. CONCLUSIONS We contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy.
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Arginine methylation: the promise of a 'silver bullet' for brain tumours?
Samuel, SF, Barry, A, Greenman, J, Beltran-Alvarez, P
Amino acids. 2021;(4):489-506
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Despite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 years and have now entered oncology clinical trials, including for brain tumours. This review collates recent advances in the understanding of the role of PRMTs and arginine methylation in brain tumours. We provide an up-to-date literature review on the mechanisms for PRMT regulation. These include endogenous modulators such as alternative splicing, miRNA, post-translational modifications and PRMT-protein interactions, and synthetic inhibitors. We discuss the relevance of PRMTs in brain tumours with a particular focus on PRMT1, -2, -5 and -8. Finally, we include a future perspective where we discuss possible routes for further research on arginine methylation and on the use of PRMT inhibitors in the context of brain tumours.
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Effects of Inositol-Enhanced Bonded Arginine Silicate Ingestion on Cognitive and Executive Function in Gamers.
Sowinski, R, Gonzalez, D, Xing, D, Yoo, C, Jenkins, V, Nottingham, K, Dickerson, B, Humphries, M, Leonard, M, Ko, J, et al
Nutrients. 2021;(11)
Abstract
Inositol stabilized arginine silicate (ASI) ingestion has been reported to increase nitric oxide levels while inositol (I) has been reported to enhance neurotransmission. The current study examined whether acute ASI + I (Inositol-enhanced bonded arginine silicate) ingestion affects cognitive function in e-sport gamers. In a double blind, randomized, placebo controlled, and crossover trial, 26 healthy male (n = 18) and female (n = 8) experienced gamers (23 ± 5 years, 171 ± 11 cm, 71.1 ± 14 kg, 20.7 ± 3.5 kg/m2) were randomly assigned to consume 1600 mg of ASI + I (nooLVL®, Nutrition 21) or 1600 mg of a maltodextrin placebo (PLA). Prior to testing, participants recorded their diet, refrained from consuming atypical amounts of stimulants and foods high in arginine and nitrates, and fasted for 8 h. During testing sessions, participants completed stimulant sensitivity questionnaires and performed cognitive function tests (i.e., Berg-Wisconsin Card Sorting task test, Go/No-Go test, Sternberg Task Test, Psychomotor Vigilance Task Test, Cambridge Brain Sciences Reasoning and Concentration test) and a light reaction test. Participants then ingested treatments in a randomized manner. Fifteen minutes following ingestion, participants repeated tests (Pre-Game). Participants then played their favorite video game for 1-h and repeated the battery of tests (Post-Game). Participants observed a 7-14-day washout period and then replicated the study with the alternative treatment. Data were analyzed by General Linear Model (GLM) univariate analyses with repeated measures using weight as a covariate, paired t-tests (not adjusted to weight), and mean changes from baseline with 95% Confidence Intervals (CI). Pairwise comparison revealed that there was a significant improvement in Sternberg Mean Present Reaction Time (ASI + I vs. PLA; p < 0.05). In Post-Game assessments, 4-letter Absent Reaction Time (p < 0.05), 6-letter Present Reaction Time (p < 0.01), 6-letter Absent Reaction Time (p < 0.01), Mean Present Reaction Time (p < 0.02), and Mean Absent Reaction Time (p < 0.03) were improved with ASI + I vs. PLA. There was a non-significant trend in Pre-Game Sternberg 4-letter Present Reaction time in ASI + I vs. PLA (p < 0.07). ASI + I ingestion better maintained changes in Go/No-Go Mean Accuracy and Reaction Time, Psychomotor Vigilance Task Reaction Time, and Cambridge Post-Game Visio-spatial Processing and Planning. Results provide evidence that ASI + I ingestion prior to playing video games may enhance some measures of short-term and working memory, reaction time, reasoning, and concentration in experienced gamers.
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Effects of tree nut and groundnut consumption compared with those of l-arginine supplementation on fasting and postprandial flow-mediated vasodilation: Meta-analysis of human randomized controlled trials.
Smeets, ETHC, Mensink, RP, Joris, PJ
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1699-1710
Abstract
INTRODUCTION l-arginine supplementation may improve vascular endothelial function. As tree nuts and groundnuts are a source of the amino acid l-arginine, we performed a meta-analysis of human randomized controlled trials (RCTs) to compare effects of tree nut and groundnut consumption with those of l-arginine supplementation on fasting and postprandial endothelial function as assessed by flow-mediated vasodilation of the brachial artery (FMD). METHODS Summary estimates of weighted mean differences (WMDs) in FMD and 95% confidence intervals (CIs) were calculated using random-effect meta-analyses. RESULTS A total of thirteen RCTs focusing on tree nut and groundnut consumption and nineteen RCTs investigating effects of l-arginine supplementation were included. Longer-term consumption of tree nuts and groundnuts increased fasting FMD by 1.09 %-point (PP) (95% CI: 0.49, 1.69, P < 0.001; I2: 76.7%, P < 0.001), while l-arginine supplementation (daily range: 3-21 g) increased fasting FMD by 0.53 PP (95% CI: 0.12, 0.93; P = 0.012; I2: 91.6%, P < 0.001). Effects between treatments were not statistically different (P = 0.31). Tree nut and groundnut consumption did not affect postprandial FMD responses (1.25 PP, 95% CI: -0.31, 2.81, P = 0.12; I2: 91.4%, P < 0.001), whereas l-arginine supplementation (range: 3-15 g) improved FMD during the postprandial phase by 2.02 PP (95% CI: 0.92, 3.13, P < 0.001; I2: 99.1%, P < 0.001). However, treatment effects did not differ significantly (P = 0.60). Overall, these results derive from high-quality evidence. CONCLUSION Longer-term consumption of tree nuts and groundnuts, as well as l-arginine supplementation did improve fasting endothelial function, as assessed by FMD. However, the positive effects of tree nuts and groundnuts could not be fully explained by the amount of l-arginine in these nuts. Only l-arginine supplementation did improve postprandial FMD, but effects were not different from those of tree nuts and groundnuts. Future studies should focus on the identifications of the bioactive nutrients in tree nuts and groundnuts and mechanistic pathways behind differences in postprandial and longer-term fasting changes in FMD.
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Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease.
Harrison, SA, Baum, SJ, Gunn, NT, Younes, ZH, Kohli, A, Patil, R, Koziel, MJ, Chera, H, Zhao, J, Chakravarthy, MV
The American journal of gastroenterology. 2021;(12):2399-2409
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INTRODUCTION AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF -22.9% vs -5.7%, HOMA-IR -4.4 vs +0.7, ALT -21.9% vs -7.2%, K-18 M65 -13.6% vs +20.1%, cT1 -69.6 vs +18.3 ms (P < 0.05), and Pro-C3 -13.6% vs -3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF -8.1%, HOMA-IR +8.4, ALT -20.7%, K-18 M65 6.6%, cT1 -34.7 ms, and Pro-C3 -15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.
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The Role of Immunonutrition in Patients Undergoing Pancreaticoduodenectomy.
Jabłońska, B, Mrowiec, S
Nutrients. 2020;(9)
Abstract
Pancreaticoduodenectomy (PD) is one of the most difficult and complex surgical procedures in abdominal surgery. Malnutrition and immune dysfunction in patients with pancreatic cancer (PC) may lead to a higher risk of postoperative infectious complications. Although immunonutrition (IN) is recommended for enhanced recovery after surgery (ERAS) in patients undergoing PD for 5-7 days perioperatively, its role in patients undergoing pancreatectomy is still unclear and controversial. It is known that the proper surgical technique is very important in order to reduce a risk of postoperative complications, such as a pancreatic fistula, and to improve disease-free survival in patients following PD. However, it has been proven that IN decreases the risk of infectious complications, and shortens hospital stays in patients undergoing PD. This is a result of the impact on altered inflammatory responses in patients with cancer. Both enteral and parenteral, as well as preoperative and postoperative IN, using various nutrients, such as glutamine, arginine, omega-3 fatty acids and nucleotides, is administered. The most frequently used preoperative oral supplementation is recommended. The aim of this paper is to present the indications and benefits of IN in patients undergoing PD.
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Contrast-enhanced ultrasound for determining muscular perfusion after oral intake of L-citrulline, L-arginine, and galloylated epicatechines: A study protocol.
Doll, J, Bürkle, F, Neide, A, Tsitlakidis, S, Bruckner, T, Schmidmaier, G, Fischer, C
Medicine. 2020;(41):e22318
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INTRODUCTION The market for dietary supplements in the sports sector has been growing rapidly for several years, though there is still lacking evidence regarding their claimed benefits. One group is that of nitric oxide increasing supplements, so-called "NO-boosters," which are claimed to improve the supply of oxygen and nutrients to the muscle by enhancing vasodilation.The aim of this study was to investigate 3 of these supplements in healthy male athletes for their muscle perfusion-enhancing potential using contrast-enhanced ultrasound (CEUS). METHODS This placebo-controlled, double-blind, randomized cross-over trial will be carried out at the Center for Orthopedics, Trauma Surgery and Spinal Cord Injury of the University Hospital Heidelberg. Three commercial NO enhancing products including 300 mg of the specific green tea extract VASO6 and a combination of 8 g L-citrulline malate and 3 g L-arginine hydrochloride will be examined for their potential to increase muscular perfusion in 30-male athletes between 18 and 40 years and will be compared with a placebo. On each of the 3 appointments CEUS of the dominant biceps muscle will be performed at rest and after a standardized resistance training. Every athlete receives each of the 3 supplements once after a wash-out period of at least 1 week. Perfusion will be quantified via VueBox quantification software. The results of CEUS perfusion measurements will be compared intra- and interindividually and correlated with clinical parameters. DISCUSSION The results of this study may help to establish CEUS as a suitable imaging modality for the evaluation of potentially vasodilatory drugs in the field of sports. Other supplements could also be evaluated in this way to verify the content of their advertising claims. TRIAL REGISTRATION German Clinical Trials Register (DRKS), ID: DRKS00016972, registered on 25.03.2019.