Nutritional interventions for the prevention and treatment of cancer therapy-induced oral mucositis: an umbrella review of systematic reviews and meta-analysis.

CONTEXT: To date, the efficacy of nutritional interventions on oral mucositis (OM) in patients with cancer, and the quality of this evidence have not been explored. OBJECTIVE: The goal of this umbrella review was to provide a comprehensive evaluation of nutritional interventions for patients with cancer with OM, as well as to assess the quality of this evidence. DATA SOURCES: Meta-analyses were searched for using PubMed, Scopus, and ISI Web of Science databases until December 2021, with no time restrictions. DATA EXTRACTION: Meta-analyses of randomized control trials that evaluated the effects of nutritional interventions on the incidence of OM in patients with cancer had inclusion criteria for this umbrella review. Data extraction, quality assessment of meta-analyses, and primary studies were done independently by 2 authors. The Grading of Recommendations Assessment, Development, and Evaluation technique was used to grade the certainty of evidence. DATA ANALYSIS: A total of 26 meta-analyses were included in this umbrella review. The results showed that honey, glutamine, and propolis can reduce the incidence of severe OM, based on moderate evidence quality. In addition, zinc supplementation significantly reduced the incidence of OM, regardless of symptom severity; however, low certainty of the evidence was observed. The effects of vitamin E, curcumin, and probiotics on OM were not statistically significant. CONCLUSION: This umbrella review shows that honey, glutamine, and propolis can significantly reduce the incidence of severe OM. These findings need to be confirmed with well-designed, longitudinal randomized controlled trials. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022301010.

A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries.

BACKGROUND: Glutamine is thought to have beneficial effects on the metabolic and stress response to severe injury. Clinical trials involving patients with burns and other critically ill patients have shown conflicting results regarding the benefits and risks of glutamine supplementation. METHODS: In a double-blind, randomized, placebo-controlled trial, we assigned patients with deep second- or third-degree burns (affecting ≥10% to ≥20% of total body-surface area, depending on age) within 72 hours after hospital admission to receive 0.5 g per kilogram of body weight per day of enterally delivered glutamine or placebo. Trial agents were given every 4 hours through a feeding tube or three or four times a day by mouth until 7 days after the last skin grafting procedure, discharge from the acute care unit, or 3 months after admission, whichever came first. The primary outcome was the time to discharge alive from the hospital, with data censored at 90 days. We calculated subdistribution hazard ratios for discharge alive, which took into account death as a competing risk. RESULTS: A total of 1209 patients with severe burns (mean burn size, 33% of total body-surface area) underwent randomization, and 1200 were included in the analysis (596 patients in the glutamine group and 604 in the placebo group). The median time to discharge alive from the hospital was 40 days (interquartile range, 24 to 87) in the glutamine group and 38 days (interquartile range, 22 to 75) in the placebo group (subdistribution hazard ratio for discharge alive, 0.91; 95% confidence interval [CI], 0.80 to 1.04; P = 0.17). Mortality at 6 months was 17.2% in the glutamine group and 16.2% in the placebo group (hazard ratio for death, 1.06; 95% CI, 0.80 to 1.41). No substantial between-group differences in serious adverse events were observed. CONCLUSIONS: In patients with severe burns, supplemental glutamine did not reduce the time to discharge alive from the hospital. (Funded by the U.S. Department of Defense and the Canadian Institutes of Health Research; RE-ENERGIZE ClinicalTrials.gov number, NCT00985205.).

Coadministration of L-alanine and L-glutamine ameliorate blood glucose levels, biochemical indices and histological features in alloxan-induced diabetic rats.

We evaluated the effects of supplementation of L-alanine and L-glutamine on blood glucose levels and biochemical parameters in alloxan-induced diabetic rat. Forty-nine animals were distributed into seven equal groups. Except for the non-diabetic control, diabetes was induced in all groups by intravenous alloxan injection followed by daily supplementation with amino acids for 14 days. Weight and blood glucose were monitored during supplementation, while biochemical parameters such as liver and renal functions, lipid profile, and antioxidant markers were evaluated post-intervention. A significant increase (p < .05) in weight and decrease in blood glucose were observed in the amino acid(s) treated groups. The supplementation with both amino acids restored important tissue antioxidants, liver and kidney functions and rescued islets cells degeneration. Histopathological examinations of important tissues showed the restoration of alloxan-induced physiopathological changes by the amino acids. Thus, these amino acids might serve as nutraceuticals for the management and treatment of diabetes. PRACTICAL APPLICATIONS: The discovery and production of antidiabetic bioactive compounds are often challenging, and the existing antidiabetic drugs are expensive. Amino acids are key regulators of glucose metabolism, insulin secretion, and insulin sensitivity; thus, they can play a crucial role in alleviating diabetes. Here, we present findings that strongly suggest the potential of pure amino acids (L-alanine and L-glutamine) for the management and treatment of diabetes. We show that these amino acids, when supplemented singly or coadministered can lower blood glucose levels and restore several other biochemical parameters implicated in diabetes. Hence, these cheap amino acids may be consumed as nutraceuticals or food supplements by diabetics for the treatment/management of diabetes. Foods rich in these amino acids may also be consumed as part of the diet of diabetic patients.

Evaluation of the recovery after heart surgery following preoperative supplementation with a combination of beta-hydroxy-beta-methylbutyrate, L-arginine, and L-glutamine: a double-blind randomized placebo-controlled clinical trial.

BACKGROUND: The preoperative period is a good time to improve nutrition status, compensate for nutrient deficiencies, and optimize immune function in patients' underlying surgery. In some medical conditions, supplementation with a combination of L-glutamine (Gln), ß-hydroxy-ß-methylbutyrate (HMB), and L-arginine (Arg) had promising effects on improving recovery. The present study aimed to evaluate the effect of supplementation with Gln/Arg/HMB in patients undergoing heart surgery. METHODS: This randomized clinical trial was conducted on 70 patients undergoing cardiac surgery. Participants were requested to consume 2 sachets of a combination of 7 g L-arginine, 7 g L-glutamine, and 1.5 g daily HMB or placebo 30 days before operation. At the baseline and end of the study, left ventricular ejection fraction and the serum levels of troponin, creatine phosphokinase (CPK), CPK-MB, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin were measured. Also, the Sequential Organ Failure Assessment (SOFA) score, time of stay in hospital and intensive care unit (ICU), and postoperative complications were recorded after surgery. RESULTS: In total, 60 preoperative patients (30 in each group) with a mean age of 53.13 ± 14.35 years completed the study (attrition rate = 85.7%). Subjects in the Gln/Arg/HMB group had lower serum levels of CPK-MB (median [IQR] = 49 [39.75] vs. 83 [64.55]; P = 0.011), troponin (median [IQR] = 2.13 [1.89] vs. 4.34 [1.99]; P < 0.001), bilirubin (median [IQR] = 0.50 [0.20] vs. 0.40 [0.22]; P < 0.001), and SOFA score (median [IQR] = 2 [2] vs. 5 [2]; P < 0.001) at end of the study compared to the placebo. Also, the time of stay in the hospital (median [IQR] = 5 [1] vs. 6 [3]; P < 0.001) and ICU (median [IQR] = 2.50 [1.00] vs. 3.50 [1.50]; P = 0.002) was lower in the Gln/Arg/HMB group. CONCLUSION: The present study showed that perioperative supplementation with a combination of Gln, Arg, and HMB enhances the recovery, reduces myocardial injury, and decreases the time of hospital and ICU stay in cardiac surgery patients. These results need to be confirmed in a larger trial. TRIAL REGISTRATION: IRCT.ir IRCT20120913010826N31. Registered on 13 October 2020.

The Effect of Amino Acids on Wound Healing: A Systematic Review and Meta-Analysis on Arginine and Glutamine.

Under stress conditions, the metabolic demand for nutrients increases, which, if not met, may slow down or indeed stop the wound from healing, thus, becoming chronic wounds. This study aims to perform a systematic review and meta-analysis of the effect of arginine and glutamine supplementation on wound healing. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for the systematic review and ten electronic databases were used. Five and 39 human studies met the inclusion criteria for arginine and glutamine, respectively. The overall meta-analysis demonstrated a significant effect of arginine supplementation on hydroxyproline content (MD: 4.49, 95% CI: 3.54, 4.45, p < 0.00001). Regarding glutamine supplementation, there was significant effect on nitrogen balance levels (MD: 0.39, 95% CI: 0.21, 0.58, p < 0.0001), IL-6 levels (MD: -5.78, 95% CI: -8.71, -2.86, p = 0.0001), TNFα levels (MD: -8.15, 95% CI: -9.34, -6.96, p < 0.00001), lactulose/mannitol (L/M) ratio (MD: -0.01, 95% CI: -0.02, -0.01, p < 0.00001), patient mortality (OR: 0.48, 95% CI: 0.32, 0.72, p = 0.0004), C-reactive protein (CRP) levels (MD: -1.10, 95% CI: -1.26, -0.93, p < 0.00001) and length of hospital stay (LOS) (MD: -2.65, 95% CI: -3.10, -2.21, p < 0.00001). Regarding T-cell lymphocytes, a slight decrease was observed, although it failed to reach significance (MD: -0.16, 95% CI: -0.33, 0.01, p = 0.07). Conclusion: The wound healing might be enhanced in one or at various stages by nutritional supplementation in the right dose.

Effect of glutamine supplementation on cardiometabolic risk factors and inflammatory markers: a systematic review and meta-analysis.

BACKGROUND: Evidence exists that glutamine plays multiple roles in glucose metabolism, insulin sensitivity, and anti-inflammatory effects. This systematic review and meta-analysis of controlled trials aimed to assess the effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers. METHODS: The processes of systematic reviews and meta-analyses were performed according to the PRISMA checklist. PubMed, Web of Sciences, Cochrane library, and Scopus databases were search for relevant studies without time or language restrictions up to December 30, 2020. All randomized clinical trials which assessed the effect of glutamine supplementation on "glycemic indices", "level of triglyceride, "and "inflammatory markers" were included in the study. The effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers was assessed using a standardized mean difference (SMD) and 95% confidence interval (CI). Heterogeneity between among studies was assessed using Cochran Q-statistic and I-square. Random/fixed-effects meta-analysis method was used to estimate the pooled SMD. The risk of bias for the included trials was evaluated using the Cochrane quality assessment tool. RESULTS: In total, 12 studies that assessed the effect of glutamine supplementation on cardio-metabolic risk factors were included in the study. Meta-analysis showed that glutamine supplementation significantly decreased significantly serum levels of FPG [SMD: - 0.73, 95% CI - 1.35, - 0.11, I2: 84.1%] and CRP [SMD: - 0.58, 95% CI - 0.1, - 0.17, I2: 0%]. The effect of glutamine supplementation on other cardiometabolic risk factors was not statistically significant (P > 0.05). CONCLUSION: Our findings showed that glutamine supplementation might have a positive effect on FPG and CRP; both of which are crucial as cardio-metabolic risk factors. However, supplementation had no significant effect on other cardio-metabolic risk factors.

To assess the effective and safety of compound glutamine entersoluble capsules in irritable bowel syndrome: A protocol for systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is one the common medical condition of functional GI disorder (FGD) characterized by bowel-related symptoms without other organic gastrointestinal (GI) disease. Compound Glutamine Entersoluble Capsules(CGEC),a compound preparation in which each capsule contains 120 mg L-glutamine, 50 mg ginseng, 50 mg licorice, 50 mg Atractylodes macrocephala and 50 mg Poria cocos, have been reported the efficacy of CGEC for patients with IBS in improving the clinical symptoms and quality of patients' life. However, there is no a systematic review related to CGEC for IBS to this day. In this study, we will systematically evaluate the effectiveness and safety of CGEC in the treatment of IBS-D with a meta-analysis method, so as to provide a solid evidence for clinical practice. METHODS: In this study, a literature search was performed by using the Chinese and English databases, which include PubMed, Embase, MEDLINE, Cochrane Library Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI) database, Wanfang Data Knowledge Service Platform, the VIP information resource integration service platform (cqvip), China Biology Medicine Disc (Sino Med),and the Chinese Clinical Trial Registry (ChiCTR), to find the related literature of CGEC in the treatment of IBS published from the inception date of each predefined database upto January 2021. The evaluation of the risk of bias for eligible studies will be performed by two investigators. Data synthesis will be performed by RevMan 5.4 software. Heterogeneity between studies can be assessed by a heterogeneity X2 test. The degree of heterogeneity among multiple included studies can be measured by I2. The stability of systematic review or meta-analysis outcomes will be evaluated by Sensitivity analysis. Reporting bias will be evaluated by funnel plot. Finally, The Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to assess the quality of evidence obtained. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: Whether it is the effectiveness and safety of CGEC in the treatment of IBS will be judged in the result of this systematic review.

Effects of glutamine for prevention of radiation-induced esophagitis: a double-blind placebo-controlled trial.

Purpose Acute radiation-induced esophagitis (ARIE) leads to treatment delays, decreased quality of life (QOL), and secondary adverse events such as weight loss. Grade 3 ARIE occurs in 15%-30% of patients undergoing radiotherapy to the esophagus, leading to disruption or discontinuation of treatment. The purpose of this study was to assess the effects of glutamine, a common nutritional supplement, on ARIE in patients with thoracic malignancies. Patients and methods This double-blind, placebo-controlled trial enrolled patients with advanced thoracic malignancies receiving concurrent chemotherapy/radiotherapy or radiotherapy alone, with radiation doses to the esophagus ≥45 Gy. Patients were randomized (1:1) to receive 4 g of glutamine or glycine placebo twice daily. The primary objective was to determine whether glutamine decreases the severity of ARIE in these patients. Secondary objectives included assessment of the effects of glutamine on other measures of ARIE, weight, symptom burden measure assessed by the MD Anderson Symptom Inventory (MDASI-HN) questionnaire and the toxicity profile of glutamine. Results At the time of interim analysis, 53 patients were enrolled: 27 in the glutamine arm and 26 in the placebo arm. There was no difference in the incidence of esophagitis in the first 6 weeks of radiotherapy between the glutamine and placebo arms (74% versus 68%; P = 1.00). There were no significant differences between the two arms for time to onset of esophagitis. The duration of ARIE was shorter (6.3 versus 7.1 weeks; P = 0.54) and median weight loss was lower (0.9 kg versus 2.8 kg; p = 0.83) in the glutamine arm versus the placebo arm. The groups differ significantly in core symptom severity (2.1 vs 1.5, p < .03) but not in head and neck specific symptom severity (1.2 vs 1.1, p < .60) nor in symptom interference (2.1 vs 1.7, p < .22). There was no grade 3 or higher adverse event at least possibly related to glutamine. The study was terminated for futility following interim analysis. Conclusion Oral glutamine was not associated with significant improvement in severity of ARIE, weight loss, head and neck specific symptoms or symptom interference compared with placebo in patients with advanced thoracic malignancies receiving radiotherapy to the esophagus.Clinical trial information. NCT01952847, and date of registration is September 30, 2013.

Glutamine-stimulated in vitro hypertrophy is preserved in muscle cells from older women.

Age-related loss of muscle mass may result from reduced protein synthesis stimulation in response to anabolic stimuli, such as amino acid (AA) supplementation. The exact etiology of anabolic resistance to AA remains unclear. Therefore, the aim of this study was to investigate the anabolic response [cell size, protein synthesis and mechanistic target of rapamycin (mTOR) pathway] to the AA glutamine (a strong anabolic AA highly present in skeletal muscle) in myotubes obtained from 8 young (YW; 21-35 yrs) and 8 older (OW; 65-70 yrs) healthy women. This in vitro model of human primary myogenic cells explores the intrinsic behavior of muscle cells, while excluding potential influences of external factors. We showed that despite lower muscle mass, strength and cardiorespiratory fitness in OW compared to YW, myotube size (myotube diameter and area) and protein synthesis were not altered in OW, and glutamine-induced myotube hypertrophy and protein synthesis were preserved in OW. Apart from a lower glutamine-induced increase in P70S6 kinase phosphorylation in OW, no significant differences in other components of the mTOR pathway were observed between groups. Altogether, our data support the idea that the intrinsic capacity of muscle cells to respond to glutamine stimulation is preserved in healthy older women.

Efficacy and safety of Guhong injection for treating coronary microvascular disease: study protocol for a randomized controlled trial.

BACKGROUND: Coronary microvascular disease (CMVD) can be described as one of the cardiovascular diseases with normal coronary angiography but evidence of myocardial ischemia or microcirculatory lesions, often presenting as angina pectoris attacks. Coronary artery microtubular dysfunction is one of the pathogenic features of coronary heart disease, but its occurrence and development and the current CMVD-intervention therapy needs further research. Chinese traditional medicine (TCM) has advantages for the treatment of cardiovascular diseases. Hence, this article describes an ongoing randomized controlled clinical trial based on the theory of TCM for the purpose of evaluating the efficacy and safety of Guhong injection versus placebo in patients with CMVD. METHODS/DESIGN: This is a multicenter, randomized, parallel-arm, open-label, double-blind, placebo-controlled clinical trial. A total of 260 eligible patients will be allocated and randomly assigned, in a ratio of 1:1, to either the experimental group or the control group. The treatment course is 10 consecutive days, and with an 8-week follow-up. The primary outcome is therapeutic efficacy. Secondary outcomes include the quantitative score of TCM syndromes (a series of TCM symptoms and signs of coronary heart disease), the average frequency of anginal attacks, electrocardiogram (ECG) changes, inflammatory response, endothelial function indicators and myocardial metabolites. DISCUSSION: This trial is strictly designed in accordance with principles and regulations issued by the China Food and Drug Administration (CFDA). The results should provide high-quality evidence on the efficacy and safety of Guhong injection in the treatment of CMVD. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ID: ChiCTR1900022902. Registered on 27 April 2019.

The glutamine debate in surgery and critical care.

PURPOSE OF REVIEW: Glutamine (GLN) is a versatile amino acid, long believed to have important implications in ICU and surgical patients. An extensive body of data examining GLN supplementation of TPN demonstrated a consistent signal of improved outcomes. However, recently signals of risk have come from two large-scale multicenter trials evaluating GLN (and other nutrients) at high dose and as primary pharmaconutrients, not as supplementation to complete nutrition. These trials indicate a risk of increased mortality when GLN is given to patients in shock, renal failure, and early in acute phase of critical care. RECENT FINDINGS: Recent literature continues to confirm that low and high admission GLN levels are associated with increased ICU mortality and adverse outcomes. Further, a recent meta-analysis examined trials utilizing GLN-supplemented TPN in stabile ICU patients consistent with current clinical guidelines. This analysis showed GLN supplementation of TPN led to reduced infections, LOS and hospital mortality. SUMMARY: Three recent meta-analyses have confirmed traditional GLN-supplemented (or 'GLN-Complemented' - providing GLN for completeness of amino acid content) TPN is safe, reduces mortality and improves outcome in surgical and ICU patients. Patients in need of TPN, burns, trauma or malignancies should continue to benefit from supplemental GLN, administered either intravenously at less than 0.35 g/kg/day or enterally at less than 0.5 g/kg/day. Further, a large trial of EN GLN supplementation in burns is ongoing. Thus, when used per guideline recommendations, the GLN story is likely still relevant to ICU outcomes and research.

The effect of glutamine supplementation on athletic performance, body composition, and immune function: A systematic review and a meta-analysis of clinical trials.

BACKGROUND & AIM: This systematic review and meta-analysis of available evidence was conducted to obtain a conclusive result on the effects of glutamine supplementation on athletes. METHODS: Systematic review and meta-analysis. Data related to body mass, lean body mass, body fat percentage, Vo2 max, lymphocytes, leukocytes and neutrophil counts were extracted to determine the effects of GLN on performance outcomes. DATA SOURCES: The literature search was conducted across the databases Pubmed, Scopus, ISI Web of Science, SID (Scientific Information Database) and Cochrane Central Register of Controlled Trials, covering a period up to January 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Clinical trials evaluating glutamine supplementation outcomes on athletes aged over 18 were included. RESULTS: A total of 47 studies were included in the systematic review, and 25 trials matched the inclusion criteria for the meta-analysis. According to the meta-analysis, glutamine has a significant effect on weight reduction (WMD = -1.36 [95% CI: -2.55 to -0.16], p = 0.02). Moreover, neutrophil numbers were reduced following glutamine intake at doses greater than 200 mg/kg body weight (WMD = -605.77 [95% CI: -1200.0 to 52.1]; P = 0.03). Also, supplementation by glutamine dipeptide resulted in higher blood glucose after exercise (WMD = 0.51 [95% CI: 0.18, 0.83] mmol/l; P = 0.002). There was no association between glutamine ingestion and other outcomes investigated. CONCLUSION: According to this meta-analysis, generally, glutamine supplementation has no effect on athletics immune system, aerobic performance, and body composition. However, the current study showed that glutamine resulted in greater weight reduction. In addition, the present study suggests that the efficacy of glutamine supplementation on neutrophil numbers could be affected by supplement type and dose.

The Renal Safety of L-Carnitine, L-Arginine, and Glutamine in Athletes and Bodybuilders.

One of the major concerns about taking amino acid supplements is their potential adverse effects on the kidney as a major organ involved in the metabolism and excretion of exogenous substances. The aim of this study is to review available data about renal safety of the most prominent amino acid supplements including L-arginine, glutamine and also L-carnitine as well as creatine (as amino acid derivatives) in athletes and bodybuilders. The literature was searched by keywords such as "L-carnitine", "L-arginine", "glutamine", and "kidney injury" in databases such as Scopus, Medline, Embase, and ISI Web of Knowledge. Articles published from 1950 to December 2017 were included. Among 3171, 5740, and 1608 records after primary search in the relevant databases, 8, 7, and 5 studies have been finally included, respectively, for L-carnitine, L-arginine, and glutamine in this review. Arginine appears to have both beneficial and detrimental effects on kidney function. However, adverse effects are unlikely to occur with the routine doses (from 3 to >100 g/day). The risks and benefits of L-carnitine on the athletes' and bodybuilders' kidney have not been evaluated yet. However, L-carnitine up to 6000 mg/day is generally considered to be a safe supplement at least in healthy adults. Both short-term (20-30 g within a few hours) and long-term (0.1 g/kg four times daily for 2 weeks) glutamine supplementation in healthy athletes were associated with no significant adverse effects, but it can cause glomerulosclerosis and serum creatinine level elevation in the setting of diabetic nephropathy. Creatine supplementation (ranged from 5 to 30 g/day) also appears to have no detrimental effects on kidney function of individuals without underlying renal diseases. More clinical data are warranted to determine the optimal daily dose and intake duration of common supplemental amino acids associated with the lowest renal adverse effects in sportsmen and sports women.

Anaplerotic therapy in propionic acidemia.

BACKGROUND: Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates. PURPOSE: The objective of this study was to determine whether supplements with glutamine (400mg/kg per day), citrate (7.5mEq/kg per day), or ornithine α-ketoglutarate (400mg/kg per day) (anaplerotic agents that could fill up the citric acid cycle) would affect plasma levels of glutamine and ammonia, the urinary excretion of Krebs cycle intermediates, and the clinical outcome in 3 patients with propionic acidemia. METHODS: Each supplement was administered daily for four weeks with a two week washout period between supplements. The supplement that produced the most favorable changes was supplemented for 30 weeks following the initial study period and then for a 2 year extension. RESULTS: The urinary excretion of the Krebs cycle intermediates, α-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation, but not with the other two supplements. For this reason, citrate supplements were continued in the second part of the study. The urinary excretion of methylcitric acid and 3-hydroxypropionic acid did not change with any intervention. No significant changes in ammonia or glutamine levels were observed with any supplement. However, supplementation with any anaplerotic agents normalized the physiological buffering of ammonia by glutamate, with plasma glutamate and alanine levels significantly increasing, rather than decreasing with increasing ammonia levels. No significant side effects were observed with any therapy and safety labs (blood counts, chemistry and thyroid profile) remained unchanged. Motor and cognitive development was severely delayed before the trial and did not change significantly with therapy. Hospitalizations per year did not change during the trial period, but decreased significantly (p<0.05) in the 2years following the study (when citrate was continued) compared to the 2years before and during the study. CONCLUSIONS: These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: α-ketoglutarate, succinate and fumarate. Citrate supplements were safe and might have contributed to reduce hospitalizations in patients with propionic acidemia.

Effects of two different glutamine-containing enteral supplements on stool frequency and density in elderly patients recovering from acute critical illness.

AIM: Glutamine has various beneficial functions in the gastrointestinal tract. The present study was designed to investigate the effect of two different glutamine supplements on bowel movement at the start of enteral feeding in elderly inpatients. METHODS: This was a double-blind, prospective, randomized comparison study. A total of 25 patients aged >75 years recovering from a critical illness in a non-intensive care unit and scheduled for tube feeding were recruited. Of them, 22 consenting patients were randomly assigned to two groups: glutamine-fiber-oligosaccharide treatment group (n = 11) and glutamine F treatment group (n = 11). They were given glutamine three times daily at a dosage of 9 g/day. Enteral nutrition was given at the same dosage to both groups for the duration of the study. The end-points were stool frequency, Bristol Scale Form Score, bowel function index (Bristol Scale Form Score × stool frequency), the percentage of patients with stool frequency over three per day and those with a BSFS of 6 or 7 in each group. RESULTS: There were no significant differences between the two groups in terms of patient characteristics before the study. All the end-points in the glutamine F group were significantly lower than those in the glutamine-fiber-oligosaccharide group. CONCLUSIONS: Compared with glutamine-fiber-oligosaccharide, glutamine F administration resulted in stool hardening and reduced stool frequency in elderly inpatients recovering from acute critical illness in non-intensive care units. The effects might be caused by the different additive components of glutamine supplements. Geriatr Gerontol Int 2017; 17: 2514-2519.

Glutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: A systematic evaluation of randomised controlled trials.

BACKGROUND & AIMS: Early randomised controlled trials (RCTs) testing whether parenteral nutrition regimens that include glutamine dipeptides improves the outcomes of critically ill patients demonstrated convincingly that this regimen associates with reduced mortality, infections, and hospital stays. However, several new RCTs on the same question challenged this. To resolve this controversy, the present meta-analysis was performed. Stringent eligibility criteria were used to select only those RCTs that tested the outcomes of critically ill adult patients without hepatic and/or renal failure who were haemodynamically and metabolically stabilised and who were administered glutamine dipeptide strictly according to current clinical guidelines (via the parenteral route at 0.3-0.5 g/kg/day; max. 30% of the prescribed nitrogen supply) in combination with adequate nutrition. METHODS: The literature research (PubMed, Embase, Cochrane Central Register of Controlled Trials) searched for English and German articles that had been published in peer-review journals (last entry March 31, 2015) and reported the results of RCTs in critically ill adult patients (major surgery, trauma, infection, or organ failure) who received parenteral glutamine dipeptide as part of an isoenergetic and isonitrogenous nutrition therapy. The following data were extracted: infectious complications, lengths of stay (LOS) in the hospital and intensive care unit (ICU), duration of mechanical ventilation, days on inotropic support, and ICU and hospital mortality rates. The selection of and data extraction from studies were performed by two independent reviewers. RESULTS: Fifteen RCTs (16 publications) fulfilled all selection criteria. They involved 842 critically ill patients. None had renal and/or hepatic failure. The average study quality (Jadad score: 3.8 points) was well above the predefined cut-off of 3.0. Common effect estimates indicated that parenteral glutamine dipeptide supplementation significantly reduced infectious complications (relative risk [RR] = 0.70, 95% CI 0.60, 0.83, p < 0.0001), ICU LOS (common mean difference [MD] -1.61 days, 95% CI -3.17, -0.05, p = 0.04), hospital LOS (MD -2.30 days, 95% CI -4.14, -0.45, p = 0.01), and mechanical ventilation duration (MD -1.56 days, 95% CI -2.88, -0.24, p = 0.02). It also lowered the hospital mortality rate by 45% (RR = 0.55, 95% CI 0.32, 0.94, p = 0.03) but had no effect on ICU mortality. Visual inspection of funnel plots did not reveal any potential selective reporting of studies. CONCLUSIONS: This meta-analysis clearly confirms that when critically ill patients are supplemented with parenteral glutamine dipeptide according to clinical guidelines as part of a balanced nutrition regimen, it significantly reduces hospital mortality, infectious complication rates, and hospital LOS. The latter two effects indicate that glutamine dipeptide supplementation also confers economic benefits in this setting. The present analysis indicates the importance of delivering glutamine dipeptides together with adequate parenteral energy and nitrogen so that the administered glutamine serves as precursor in various biosynthetic pathways rather than simply as a fuel.

The effects of oral glutamine on clinical and survival outcomes of non-small cell lung cancer patients treated with chemoradiotherapy.

PURPOSE: To assess the efficacy of oral glutamine (Gln) supplementation on clinical and survival outcomes of patients with locally advanced non-small cell lung cancer (LA-NSCLC). MATERIALS/METHODS: Between 2010 and 2014, 122 stage III NSCLC patients were retrospectively analyzed. All patients received curative intent chemoradiotherapy (CRT). Prophylactic oral Gln powder was applied at a dose of 10 g tid. Effect of oral Gln supplementation in the prevention of severe (≥grade 2-3) acute radiation-induced esophagitis (ARE) and weight loss, and their relation with overall survival (OS) and disease-free survival (DFS) was measured. RESULTS: Median follow-up was 13.14 months (range; 1.97-55.36). Fifty-six (46%) patients had received oral Gln. Severe ARE was significantly lower in Gln-supplemented group (30% vs 70%; p = 0.002). Gln-free patients demonstrated a higher weight loss (p = 0.0001). In multivariate analysis hemoglobin (hb) level (<12 g/dL; p = 0.01) and nodal stage (N3; p = 0.01) were poor prognostic factors that affect OS; Weight loss (p = 0.06) and Gln-free (p = 0.05) reached nearly significant levels that poorly affect OS. Similarly, nodal stage (N3, p = 0.014) and Gln-free (p = 0.035) were poor prognostic factors that affect DFS. Weight loss (≥2%, p = 0.06) and hb level (<12 g/dL, p = 0.07) reached borderline significance that poorly affect DFS. Nodal stage (N3) was the only poor prognostic factor that affect OS and DFS in univariate analysis (p = 0.01, p = 0.009; respectively). CONCLUSION: Oral Gln supplementation significantly reduces grade 2-3 esophagitis and weight loss and also no negative impact on tumor control and survival outcomes in patients with LA-NSCLC.

Efeito da suplementação com L-glutamina e L-alanina, livres ou como dipeptídeo, sobre a lesão, inflamação e citoproteção em modelos de estresse in vivo e in vitro / Effects of supplementation with L-glutamine and L-alanine, in their free form or as dipeptide, on muscle damage, inflammation and cytoprotection of in vivo and in vitro stress models

Subprojeto 1: Determinação do efeito anti-inflamatório e citoprotetor da suplementação com L-glutamina e L-alanina, ou com L-alanil-L-glutamina (DIP) em ratos submetidos a treinamento resistido. Exercícios intensos reduzem a disponibilidade de glutamina, comprometendo a função imune e a recuperação de atletas. O objetivo do estudo foi avaliar os efeitos da suplementação oral crônica com L-glutamina e L-alanina, nas formas livres ou como dipeptídeo (DIP), sobre parâmetros de lesão, inflamação e citoproteção em ratos Wistar adultos submetidos a treinamento resistido (TR). Neste estudo, o TR reduziu a concentração de glutamina no plasma e no músculo EDL. No entanto, este efeito foi atenuado pelos suplementos contendo L-glutamina, os quais aumentaram os conteúdos da proteína de resposta ao estresse (HSP70) em células do sistema imune (PBMC) e no EDL, concomitantemente à redução da ativação do NF-kB e a da concentração de citocinas no EDL. O efeito protetor das suplementações também foi evidenciado pela atenuação de marcadores de lesão (CK e LDH) e inflamação (TNF-α e IL-1ß), bem como pelo aumento nas concentrações de marcadores anti-inflamatórios (IL-6, IL-10 e MCP-1) no plasma. Nossos resultados sugerem que a suplementação oral crônica com L-glutamina (administrada com L-alanina livre ou como DIP) promoveu efeitos citoprotetores mediados pela HSP70 em resposta à lesão e inflamação induzidas pelo TR. Subprojeto 2: Efeitos da L-alanil-L-glutamina sobre as vias de sinalização da insulina e da mTOR/S6K, e citoproteção em células musculoesqueléticas C2C12. O dipeptídeo L-alanil-L-glutamina é conhecido por modular o metabolismo e a viabilidade celular. Contudo, os efeitos sobre os componentes clássicos das vias de sinalização da insulina e da mTOR/S6K, bem como o efeito citoprotetor em células musculares, são pouco esclarecidos. O objetivo deste estudo foi investigar o efeito do DIP sobre as vias de sinalização da insulina e da mTOR/S6K em miotubos C2C12, em condições normais ou resistentes à insulina. A exposição crônica à insulina (24h) promoveu resistência à insulina, reduzindo os conteúdos totais do receptor beta (IR-ß) e do substrato do receptor de insulina (IRS-1), e diminuindo a fosforilação de IRS-1, AKT e P44/42 MAPK. Adicionalmente, houve redução na expressão do transportador de glicose (GLUT4) e HSP70, redução da viabilidade celular e menor fosforilação de p70S6k e S6, proteínas relacionadas à síntese proteica. Em contraste, a suplementação com DIP aumentou os conteúdos totais de IR-ß e IRS-1 e a fosforilação de IRS-1 e AKT. A glicólise anaeróbia e a capacidade glicolítica, além da fosforilação de p70S6k e S6, foram aumentadas pelo DIP em condições normais e na resistência à insulina. Nestas condições experimentais, nossos resultados sugerem que a suplementação com DIP melhorou as vias de sinalizações da insulina e da mTOR/S6K, aumentou a captação e metabolização da glicose, independente da estimulação com insulina e, finalmente, promoveu citoproteção resgatando parcialmente as células de um estado resistente à insulina, por meio do aumento de HSP70 e ativação das etapas finais da via mTOR/S6K.

Subproject 1: Determination of the anti-inflammatory and cytoprotective effects of supplementation with L-glutamine and L-alanine, or with L-alanyl-L-glutamine in rats submitted to resistance training. Intense exercise reduces glutamine availability, compromising immune function and recovery of athletes. The objective of the study was to evaluate the effects of chronic oral supplementation with L-glutamine and L-alanine, in their free form or as dipeptide (DIP), on muscle damage, inflammation and cytoprotection in adult Wistar rats submitted to resistance training (RT). In this study, RT reduced glutamine concentration in plasma and EDL muscle. However, this effect was attenuated by supplements containing L-glutamine, which increased the contents of the stress response protein (HSP70) in immune system cells (PBMC) and EDL, concomitantly with the reduction of NF-kB activation and the concentration of cytokines in EDL. The protective effect of supplementation was also evidenced by attenuation of lesion markers (CK and LDH) and inflammation (TNF-α and IL-1ß), as well as by the increase in anti-inflammatory plasma markers (IL-6, IL-10 and MCP-1). Our results suggest that chronic oral supplementation with L-glutamine (administered along with free L-alanine or as DIP) promoted HSP70-mediated cytoprotective effects in response to RT-induced injury and inflammation. Subproject 2: Effects of L-alanyl-L-glutamine on the components of insulin and mTOR/ S6K signaling pathways and cytoprotection in C2C12 musculoskeletal cells. The dipeptide L-alanyl-L-glutamine is known to modulate metabolism and cell viability. However, the effects on the classical components of insulin and mTOR/ S6K signaling pathways, as well as the cytoprotective effect on muscle cells, are poorly understood. The aim of this study was to investigate the effect of DIP on insulin and mTOR/ S6K signaling pathways in C2C12 myotubes, under normal or insulin resistant conditions. Chronic insulin exposure (24h) promoted insulin resistance, reducing the total contents of the insulin receptor (IR-ß) and the insulin receptor substrate (IRS-1), and decreasing the phosphorylation of IRS-1, AKT and P44/ 42 MAPK. In addition, there was a reduction in the expression of glucose transporter (GLUT4) and HSP70, reduction of cell viability and defective phosphorylation of p70S6k and S6, which are related to protein synthesis. On the other hand, DIP supplementation increased the total contents of IR-ß and IRS-1 and the phosphorylation of IRS-1 and AKT. Anaerobic glycolysis and glycolytic capacity, in addition to phosphorylation of p70S6k and S6, were increased by DIP under normal conditions and in insulin resistance. In our experimental conditions, our results suggest that DIP supplementation improved the signaling pathways of insulin and mTOR/ S6K, increased glucose uptake and metabolism, independent of insulin stimulation, and finally promoted cytoprotection by partially rescuing the cells of an insulin resistant state, by increasing HSP70 and activating the final stages of the mTOR/ S6K pathway.

Avaliação do controle da expressão gênica de citocinas pró inflamatórias mediado pela IL-10. Participação da IL-10 na modulação da resposta inflamatória exercida pela glutamina e na restrição alimentar / Proinflammatory cytokines gene expression control mediated by IL-10. Participation of IL-10 on inflammatory response exerted by glutamine and dietary restriction

O desenvolvimento de uma resposta imune adequada é um processo extremamente importante para a manutenção da homeostase do organismo. Uma série de processos são desencadeados a partir do primeiro contato com micro-organismos patógenos até a efetivação da resposta imune de memória. Todos esses processos envolvem a participação e a complexa atuação de mediadores como as citocinas inflamatórias e também citocinas regulatórias, que exercerão efeitos controlando o processo inflamatório. Diversos mecanismos moleculares, subjacentes à resposta inflamatória, ainda não estão totalmente compreendidos, como por exemplo o controle da expressão de genes inflamatórios exercido pela IL-10. Os processos envolvidos na resposta inflamatória são mantidos às custas do consumo de nutrientes, dentre eles podemos destacar o aminoácido glutamina, que atua em nível molecular, fornecendo nitrogênio para a formação do material genético e fonte energética para determinadas células do sistema imunológico como os macrófagos. Portanto, neste trabalho, investigamos os efeitos da IL-10 na modificação de nucleossomos, evidenciando o papel dessa citocina em regular a expressão de genes inflamatórios em macrófagos. Avaliamos também a função da glutamina, modulando a expressão de RNAm de citocinas inflamatórias e regulatórias dessas células. E por último, desenvolvemos um modelo de restrição alimentar em camundongos, nos quais avaliamos os efeitos desse modelo considerando-se alguns aspectos hematológicos e estudamos as alterações na resposta inflamatória em células esplênicas e do peritônio, bem como avaliamos a suplementação de glutamina in vitro na produção das citocinas (IL-12, TNF-alfa, IL-10) e a expressão do fator de transcrição NFkB. Os resultados compilados mostraram que a IL-10 leva a uma rápida redução da acetilação de nucleossomos, modulando a arquitetura da cromatina de genes inflamatórios como a IL-12. A glutamina modula a expressão de citocinas inflamatórias, regulando positivamente a expressão de IL-10 e Interferon beta. E a restrição alimentar induz a redução de citocinas proinflamatórias (IL-12 e TNF-α), influenciadas pelo aumento da produção de IL-10 e finalmente a suplementação com glutamina não interfere nesses parâmetros nas células peritoneiais e esplênicas do grupo submetido à restrição alimentar. Conclusão: a IL-10 modula a expressão gênica através da modificação de nucleossomos em macrófagos derivados da medula; a glutamina modula a expressão de IL-10 inibindo a resposta inflamatória, e a restrição alimentar modula alguns aspectos hematológicos e possui propriedades anti-inflamatórias

The development of an appropriate immune response is an important process to the organism's homeostatic maintenance. A series of processes are triggered upon the very first contact with pathogens, up to the immunological memory establishment. These processes implicate in the participation of complex mediators, such as inflammatory and regulatory cytokines that will control the inflammatory process. Some mechanisms underlying the inflammatory response are not totally understood, the control of inflammatory genes exerted by IL-10 is an example. The processes involved in the inflammatory response are kept with nutrients expense, among these nutrients we can highlight the amino acid glutamine. It acts in a molecular level, supplying nitrogen to genetic material formation and as an energy supply for immune cells such as macrophages. Thus, we investigated the IL-10 effects on nucleosome modifications evidencing this cytokine role regulating inflammatory genes expression in macrophages. We also evaluated glutamine functions modulating inflammatory and regulatory cytokines mRNA expression on these cells. Ultimately, we developed a dietary restriction animal model where we evaluated it's effects on selected haematological aspects, analyzing the alteration in the inflammatory response of splenic and peritoneal cells. We also evaluated in vitro glutamine supplementation assessing cytokines production (IL-12, TNF-α, and IL-10) and the expression of NFkB transcription factor. The compiled results a expressive reduction in nucleosome acetylation modifying the chromatin architecture of inflammatory genes such as IL-12 and IL-6. Glutamine modulates inflammatory cytokines gene expression upregulating the expression of IL-10 and interferon beta. The dietary restriction reduces proinflammatory cytokines production (IL-12 and TNF-α), these results are influenced by the upregulated IL-10 production, glutamine supplementation have no effect on these parameters in the dietary restriction group. In conclusion, we can infer that IL-10 modulates gene expression trough nucleosome modification in bone marrow derived macrophages, glutamine has a potential effect on IL-10 expression, inhibiting the inflammatory response and dietary restriction modifies hematological parameters, presenting anti-inflammatory properties