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Host cell glutamine metabolism as a potential antiviral target.
Hirabara, SM, Gorjao, R, Levada-Pires, AC, Masi, LN, Hatanaka, E, Cury-Boaventura, MF, da Silva, EB, Santos-Oliveira, LCD, Sousa Diniz, VL, Serdan, TAD, et al
Clinical science (London, England : 1979). 2021;(2):305-325
Abstract
A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.
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Vitamin D, zinc and glutamine: Synergistic action with OncoTherad immunomodulator in interferon signaling and COVID‑19 (Review).
Name, JJ, Vasconcelos, AR, Souza, ACR, Fávaro, WJ
International journal of molecular medicine. 2021;(3)
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Abstract
Coronavirus disease 2019 (COVID‑19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), was identified in December, 2019 in Wuhan, China. Since then, it has continued to spread rapidly in numerous countries, while the search for effective therapeutic options persists. Coronaviruses, including SARS‑CoV‑2, are known to suppress and evade the antiviral responses of the host organism mediated by interferon (IFN), a family of cytokines that plays an important role in antiviral defenses associated with innate immunity, and has been used therapeutically for chronic viral diseases and cancer. On the other hand, OncoTherad, a safe and effective immunotherapeutic agent in the treatment of non‑muscle invasive bladder cancer (NMIBC), increases IFN signaling and has been shown to be a promising therapeutic approach for COVID‑19 in a case report that described the rapid recovery of a 78‑year‑old patient with NMIBC with comorbidities. The present review discusses the possible synergistic action of OncoTherad with vitamin D, zinc and glutamine, nutrients that have been shown to facilitate immune responses mediated by IFN signaling, as well as the potential of this combination as a therapeutic option for COVID‑19.
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Effect of Glutamine Supplementation on Muscular Damage Biomarkers in Professional Basketball Players.
Córdova-Martínez, A, Caballero-García, A, Bello, HJ, Pérez-Valdecantos, D, Roche, E
Nutrients. 2021;(6)
Abstract
Scientific evidence supports the role of L-glutamine in improving immune function. This could suggest a possible role of L-glutamine in recovery after intense exercise. To this end, the present report aimed to study if oral L-glutamine supplementation could attenuate muscle damage in a group of players of a mainly eccentric sport discipline such as basketball. Participants (n = 12) were supplemented with 6 g/day of glutamine (G group) or placebo (P group) for 40 days in a crossover study design (20 days with glutamine + 20 days with placebo and vice versa). Blood samples were obtained at the beginning and at the end of each period and markers from exercise-induced muscle damage were determined. The glutamine supplemented group displayed significantly low values of aspartate transaminase, creatine kinase and myoglobin in blood, suggesting less muscle damage compared to the placebo. In addition, adrenocorticotropic hormone levels were lower in the glutamine supplemented group than in the placebo. As a result, the circulating cortisol levels did not increase at the end of the study in the glutamine supplemented group. Altogether, the results indicate that glutamine could help attenuate exercise-induced muscle damage in sport disciplines with predominantly eccentric actions.
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Gastrointestinal Tolerance of Low, Medium and High Dose Acute Oral l-Glutamine Supplementation in Healthy Adults: A Pilot Study.
Ogden, HB, Child, RB, Fallowfield, JL, Delves, SK, Westwood, CS, Millyard, A, Layden, JD
Nutrients. 2020;(10)
Abstract
l-Glutamine (GLN) is a conditionally essential amino acid which supports gastrointestinal (GI) and immune function prior to catabolic stress (e.g., strenuous exercise). Despite potential dose-dependent benefits, GI tolerance of acute high dose oral GLN supplementation is poorly characterised. Fourteen healthy males (25 ± 5 years; 1.79 ± 0.07 cm; 77.7 ± 9.8 kg; 14.8 ± 4.6% body fat) ingested 0.3 (LOW), 0.6 (MED) or 0.9 (HIGH) g·kg·FFM-1 GLN beverages, in a randomised, double-blind, counter-balanced, cross-over trial. Individual and accumulated GI symptoms were recorded using a visual analogue scale at regular intervals up to 24-h post ingestion. GLN beverages were characterised by tonicity measurement and microscopic observations. 24-h accumulated upper- and lower- and total-GI symptoms were all greater in the HIGH, compared to LOW and MED trials (p < 0.05). Specific GI symptoms (discomfort, nausea, belching, upper GI pain) were all more pronounced on the HIGH versus LOW GLN trial (p < 0.05). Nevertheless, most symptoms were still rated as mild. In comparison, the remaining GI symptoms were either comparable (flatulence, urge to regurgitate, bloating, lower GI pain) or absent (heart burn, vomiting, urge to defecate, abnormal stools, stitch, dizziness) between trials (p > 0.05). All beverages were isotonic and contained a dose-dependent number of GLN crystals. Acute oral GLN ingestion in dosages up to 0.9 g·kg·FFM-1 are generally well-tolerated. However, the severity of mild GI symptoms appeared dose-dependent during the first two hours post prandial and may be due to high-concentrations of GLN crystals.
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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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Glutamine supported early enteral therapy for severe acute pancreatitis: A systematic review and meta-analysis.
Jiang, X, Pei, LY, Guo, WX, Qi, X, Lu, XG
Asia Pacific journal of clinical nutrition. 2020;(2):253-261
Abstract
BACKGROUND AND OBJECTIVES Several studies have shown that glutamine (Gln) may play an important role in energy metabolism, inflammatory reactions, and immune processes in patients with severe acute pancreatitis (SAP). Nevertheless, the results of individual randomized controlled trials (RCTs) on Gln nutrition support for SAP are contradictory. This systematic review and meta-analysis evaluated the clinical benefit of Gln-supported early enteral nutrition (G+EEN) in patients with SAP. METHODS AND STUDY DESIGN Cochrane Library, PubMed, Embase, CNKI, Wan Fang, and Chinese Biomedical Literature Database were searched for relevant studies published before December 2018. RCTs of G+EEN versus standard early enteral nutrition (EEN) for SAP were selected, with both started within 48 h of admission. RESULTS Seven clinical RCTs including a total of 433 patients (EEN group: 218 patients; G+EEN group: 215 patients) were included. Compared with EEN, G+EEN increased serum albumin (standard mean difference [SMD]=0.74; 95% confidence interval [CI], 0.33-1.15; p<0.01), reduced serum hypersensitive C-reactive protein (SMD=-1.62; 95% CI, -1.98 to -1.26; p<0.01) and risks of mortality risk (risk ratio= 0.38; 95% CI, 0.16-0.90; p=0.03) and multiple organ dysfunction syndrome (MODS)(risk ratio=0.37; 95% CI, 0.15-0.94; p<0.01), and shortened length of hospital stay (SMD=-1.19; 95% CI, -1.88 to 0.49; p<0.01); moreover, it did not significantly increase the incidence of infection-related complications, operative interventions, or APACHE II scores. CONCLUSIONS G+EEN is beneficial in SAP management.
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Role of heat shock protein and cytokine expression as markers of clinical outcomes with glutamine-supplemented parenteral nutrition in surgical ICU patients.
Wischmeyer, PE, Mintz-Cole, RA, Baird, CH, Easley, KA, May, AK, Sax, HC, Kudsk, KA, Hao, L, Tran, PH, Jones, DP, et al
Clinical nutrition (Edinburgh, Scotland). 2020;(2):563-573
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Abstract
BACKGROUND Nutrients, such as glutamine (GLN), have been shown to effect levels of a family of protective proteins termed heat shock proteins (HSPs) in experimental and clinical critical illness. HSPs are believed to serve as extracellular inflammatory messengers and intracellular cytoprotective molecules. Extracellular HSP70 (eHSP70) has been termed a chaperokine due to ability to modulate the immune response. Altered levels of eHSP70 are associated with various disease states. Larger clinical trial data on GLN effect on eHSP expression and eHSP70's association with inflammatory mediators and clinical outcomes in critical illness are limited. OBJECTIVE Explore effect of longitudinal change in serum eHSP70, eHSP27 and inflammatory cytokine levels on clinical outcomes such as pneumonia and mortality in adult surgical intensive care unit (SICU) patients. Further, evaluate effect of parenteral nutrition (PN) supplemented with GLN (GLN-PN) versus GLN-free, standard PN (STD-PN) on serum eHSP70 and eHSP27 concentrations. METHODS Secondary observational analysis of a multicenter clinical trial in 150 adults after cardiac, vascular, or gastrointestinal surgery requiring PN support and SICU care conducted at five academic medical centers. Patients received isocaloric, isonitrogenous PN, with or without GLN dipeptide. Serum eHSP70 and eHSP27, interleukin-6 (IL-6), and 8 (IL-8) concentrations were analyzed in patient serum at baseline (prior to study PN) and over 28 days of follow up. RESULTS eHSP70 declined over time in survivors during 28 days follow-up, but non-survivors had significantly higher eHSP70 concentrations compared to survivors. In patients developing pneumonia, eHSP70, eHSP27, IL-8, and IL-6 were significantly elevated. Adjusted relative risk for hospital mortality was reduced 75% (RR = 0.25, p = 0.001) for SICU patients with a faster decline in eHSP70. The area under the receiver operating characteristic curve was 0.85 (95% CI: 0.76 to 0.94) for the final model suggesting excellent discrimination between SICU survivors and non-survivors. GLN-PN did not alter eHSP70 or eHSP27 serum concentrations over time compared to STD-PN. CONCLUSION Our results suggest that serum HSP70 concentration may be an important marker for severity of illness and likelihood of recovery in the SICU. GLN-supplemented-PN did not increase eHSP70.
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Free Amino Acids in Human Milk: A Potential Role for Glutamine and Glutamate in the Protection Against Neonatal Allergies and Infections.
van Sadelhoff, JHJ, Wiertsema, SP, Garssen, J, Hogenkamp, A
Frontiers in immunology. 2020;:1007
Abstract
Breastfeeding is indicated to support neonatal immune development and to protect against neonatal infections and allergies. Human milk composition is widely studied in relation to these unique abilities, which has led to the identification of various immunomodulating components in human milk, including various bioactive proteins. In addition to proteins, human milk contains free amino acids (FAAs), which have not been well-studied. Of those, the FAAs glutamate and glutamine are by far the most abundant. Levels of these FAAs in human milk sharply increase during the first months of lactation, in contrast to most other FAAs. These unique dynamics are globally consistent, suggesting that their levels in human milk are tightly regulated throughout lactation and, consequently, that they might have specific roles in the developing neonate. Interestingly, free glutamine and glutamate are reported to exhibit immunomodulating capacities, indicating that these FAAs could contribute to neonatal immune development and to the unique protective effects of breastfeeding. This review describes the current understanding of the FAA composition in human milk. Moreover, it provides an overview of the effects of free glutamine and glutamate on immune parameters relevant for allergic sensitization and infections in early life. The data reviewed provide rationale to study the role of free glutamine and glutamate in human milk in the protection against neonatal allergies and infections.
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Glutamine in Burn Injury.
Wischmeyer, PE
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2019;(5):681-687
Abstract
Burn injury is the most devastating of survivable injuries and is a worldwide public health crisis. Burn injury is among the most severe metabolic stresses a patient can sustain. A major burn leads to an inflammatory response and catabolism that, when compounded by burn wound nutrient losses, can lead to severe nutrition losses and deficiencies. These losses can impair immune function and wound healing and place burn patients at high risk for organ injury and mortality. Experimental data indicate glutamine (GLN) is well positioned mechanistically, perhaps above and beyond in any other intensive care unit setting, to improve outcome in burn-injured patients. Initial clinical trial data have also shown a consistent signal of reduced mortality and reduced hospital length of stay in burn-injured subjects, without signals of clinical risk. A number of GLN clinical trials demonstrate significant reductions of gram-negative bacteremia in burn injury, perhaps via maintenance of the gut barrier or gut immune function. Current societal recommendations continue to suggest the use of GLN in burn injury. The promising clinical data in burn-injured patients, with no signals of harm, have warranted study of GLN in the definitive RE-ENERGIZE trial, which is now ongoing.
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Combination of arginine, glutamine, and omega-3 fatty acid supplements for perioperative enteral nutrition in surgical patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST): A prospective, randomized, double-blind study.
Ma, C, Tsai, H, Su, W, Sun, L, Shih, Y, Wang, J
Journal of postgraduate medicine. 2018;(3):155-163
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BACKGROUND Perioperative enteral nutrition (EN) enriched with immune-modulating substrates is preferable for patients undergoing major abdominal cancer surgery. In this study, perioperative EN enriched with immune-modulating nutrients such as arginine, glutamine, and omega-3 fatty acids was evaluated for its anti-inflammatory efficacy in patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST) receiving curative surgery. MATERIALS AND METHODS This prospective, randomized, double-blind study recruited 34 patients with gastric adenocarcinoma or gastric GIST undergoing elective curative surgery. These patients were randomly assigned to the study group, receiving immune-modulating nutrient-enriched EN, or the control group, receiving standard EN from 3 days before surgery (preoperative day 3) to up to postoperative day 14 or discharge. Laboratory and inflammatory parameters were assessed on preoperative day 3 and postoperative day 14 or at discharge. Adverse events (AEs) and clinical outcomes were documented daily and compared between groups. RESULTS No significant differences were observed between the two groups in selected laboratory and inflammatory parameters, or in their net change, before and after treatment. AEs and clinical outcomes, including infectious complications, overall complications, time to first bowel action, and length of hospital stay after surgery, were comparable between treatment groups (all P > 0.05). CONCLUSION Immune-modulating nutrient-enriched EN had no prominent immunomodulation effect compared with that of standard EN.