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The Emerging Role of l-Glutamine in Cardiovascular Health and Disease.
Durante, W
Nutrients. 2019;(9)
Abstract
Emerging evidence indicates that l-glutamine (Gln) plays a fundamental role in cardiovascular physiology and pathology. By serving as a substrate for the synthesis of DNA, ATP, proteins, and lipids, Gln drives critical processes in vascular cells, including proliferation, migration, apoptosis, senescence, and extracellular matrix deposition. Furthermore, Gln exerts potent antioxidant and anti-inflammatory effects in the circulation by inducing the expression of heme oxygenase-1, heat shock proteins, and glutathione. Gln also promotes cardiovascular health by serving as an l-arginine precursor to optimize nitric oxide synthesis. Importantly, Gln mitigates numerous risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, glucose intolerance, obesity, and diabetes. Many studies demonstrate that Gln supplementation protects against cardiometabolic disease, ischemia-reperfusion injury, sickle cell disease, cardiac injury by inimical stimuli, and may be beneficial in patients with heart failure. However, excessive shunting of Gln to the Krebs cycle can precipitate aberrant angiogenic responses and the development of pulmonary arterial hypertension. In these instances, therapeutic targeting of the enzymes involved in glutaminolysis such as glutaminase-1, Gln synthetase, glutamate dehydrogenase, and amino acid transaminase has shown promise in preclinical models. Future translation studies employing Gln delivery approaches and/or glutaminolysis inhibitors will determine the success of targeting Gln in cardiovascular disease.
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Deciphering the galectin-12 protein interactome reveals a major impact of galectin-12 on glutamine anaplerosis in colon cancer cells.
Katzenmaier, EM, Fuchs, V, Warnken, U, Schnölzer, M, Gebert, J, Kopitz, J
Experimental cell research. 2019;(2):129-139
Abstract
Galectins are β-galactoside binding proteins which possess a variety of functions including modulation of apoptosis, growth and differentiation. Hence, alterations in the expression profile have been associated with loss of cellular homeostasis contributing to tumor growth and progression. Though galectin-12 is significantly downregulated in several tumor entities, including colon cancer, its impact on cellular homeostasis as well as galectin-12 specific binding partners have not been identified so far. We therefore established an experimental strategy which is based on reversible cross-link immunoprecipitation to capture the galectin-12 protein interactome in colon cancer cells. By applying this approach, we identified 10 novel candidates of galectin-12 interacting proteins including the neutral amino acid exchanger SLC1A5. Remarkably, we uncovered that binding of galectin-12 to SLC1A5 significantly reduced glutamine uptake in our model cell line. Consequently, utilization of glutamine carbon for biomass synthesis was profoundly affected, suggesting galectin-12 as a novel inhibitor of glutamine anaplerosis in colon cancer cells. More detailed analysis revealed that colon cancer cells can counteract galectin-12 mediated glutamine deprivation by induction of compensatory mechanisms which facilitate adaption to low-glutamine conditions and thus survival.
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Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy in hematologic malignancies.
Al-Zebeeby, A, Vogler, M, Milani, M, Richards, C, Alotibi, A, Greaves, G, Dyer, MJS, Cohen, GM, Varadarajan, S
Haematologica. 2019;(5):1016-1025
Abstract
BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-XL (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines. In these models, resistance could not be attributed to either consistent changes in expression levels of the anti-apoptotic proteins or interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we found that targeting glutamine uptake and its downstream signaling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mammalian target of rapamycin signaling resulted in marked sensitization of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy.
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Reduced excitatory neurotransmitter levels in anterior insulae are associated with abdominal pain in irritable bowel syndrome.
Bednarska, O, Icenhour, A, Tapper, S, Witt, ST, Tisell, A, Lundberg, P, Elsenbruch, S, Engström, M, Walter, S
Pain. 2019;(9):2004-2012
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Abstract
Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstrate altered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However, alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changes remain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthy controls [HC]) with respect to aINS glutamate + glutamine (Glx) and γ-aminobutyric acid (GABA+) concentrations and addressed possible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonance spectroscopy of bilateral aINS to assess Glx and GABA+ concentrations. Questionnaire data from all participants and prospective symptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related and psychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P < 0.05, right aINS P < 0.001), whereas no group differences were detected for GABA+ concentrations. Lower right-lateralized Glx concentrations in patients were substantially predicted by longer pain duration, while less frequent use of adaptive pain-coping predicted lower Glx in left aINS. Our findings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results also indicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and of the left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.
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Cerebrospinal Fluid Spermidine, Glutamine and Putrescine Predict Postoperative Delirium Following Elective Orthopaedic Surgery.
Pan, X, Cunningham, EL, Passmore, AP, McGuinness, B, McAuley, DF, Beverland, D, O'Brien, S, Mawhinney, T, Schott, JM, Zetterberg, H, et al
Scientific reports. 2019;(1):4191
Abstract
Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (≥65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 ≤ 0.56; Q2 ≤ 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P < 0.05; FDR < 0.07), and performed well as CSF biomarkers (ROC > 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF Aβ42 (ROC > 0.8), and spermidine significantly correlated with Aβ42 (pearson r = -0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with Aβ42, and this requires further investigation.
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Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome.
Zhou, Q, Verne, ML, Fields, JZ, Lefante, JJ, Basra, S, Salameh, H, Verne, GN
Gut. 2019;(6):996-1002
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Abstract
BACKGROUND More effective treatments are needed for patients with postinfectious, diarrhoea-predominant, irritable bowel syndrome (IBS-D). Accordingly, we conducted a randomised, double-blind, placebo-controlled, 8-week-long trial to assess the efficacy and safety of oral glutamine therapy in patients who developed IBS-D with increased intestinal permeability following an enteric infection. METHODS Eligible adults were randomised to glutamine (5 g/t.i.d.) or placebo for 8 weeks. The primary end point was a reduction of ≥50 points on the Irritable Bowel Syndrome Severity Scoring System (IBS-SS). Secondary endpoints included: raw IBS-SS scores, changes in daily bowel movement frequency, stool form (Bristol Stool Scale) and intestinal permeability. RESULTS Fifty-four glutamine and 52 placebo subjects completed the 8-week study. The primary endpoint occurred in 43 (79.6%) in the glutamine group and 3 (5.8%) in the placebo group (a 14-fold difference). Glutamine also reduced all secondary endpoint means: IBS-SS score at 8 weeks (301 vs 181, p<0.0001), daily bowel movement frequency (5.4 vs 2.9±1.0, p<0.0001), Bristol Stool Scale (6.5 vs 3.9, p<0.0001) and intestinal permeability (0.11 vs 0.05; p<0.0001). 'Intestinal hyperpermeability' (elevated urinary lactulose/mannitol ratios) was normalised in the glutamine but not the control group. Adverse events and rates of study-drug discontinuation were low and similar in the two groups. No serious adverse events were observed. CONCLUSIONS In patients with IBS-D with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements dramatically and safely reduced all major IBS-related endpoints. Large randomised clinical trials (RCTs) should now be done to validate these findings, assess quality of life benefits and explore pharmacological mechanisms. TRIAL REGISTRATION NUMBER NCT01414244; Results.
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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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The Effect of Acute Glutamine Supplementation on Markers of Inflammation and Fatigue During Consecutive Days of Simulated Wildland Firefighting.
Nava, RC, Zuhl, MN, Moriarty, TA, Amorim, FT, Bourbeau, KC, Welch, AM, McCormick, JJ, King, KE, Mermier, CM
Journal of occupational and environmental medicine. 2019;(2):e33-e42
Abstract
OBJECTIVE To examine the effect of oral glutamine supplementation on inflammation and fatigue during and after simulated wildland firefighting (WLFF) tasks in hot conditions over 2 consecutive days. METHODS Eleven men and women ingested a glutamine supplement or a placebo before and after simulated wildland firefighting in an environmental chamber (38 °C, 35% relative humidity). Subjective fatigue, markers of inflammation, and cellular stress were measured pre, post and 4 hours post-exercise on both days. RESULTS Gastrointestinal damage, subjective fatigue, and ratings of perceived exertion were lower after glutamine supplementation compared with placebo. Heat shock protein 70 (HSP70) and nuclear factor kappa-inhibitor alpha (IκBα) levels were higher on both days of the glutamine trial compared with placebo. CONCLUSIONS Glutamine supplementation may improve recovery after fire suppression in WLFFs. This may result from the upregulation of HSP70 which inhibits inflammation and protects against gastrointestinal (GI) barrier damage.
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High plasma glutamate and low glutamine-to-glutamate ratio are associated with type 2 diabetes: Case-cohort study within the PREDIMED trial.
Liu, X, Zheng, Y, Guasch-Ferré, M, Ruiz-Canela, M, Toledo, E, Clish, C, Liang, L, Razquin, C, Corella, D, Estruch, R, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2019;(10):1040-1049
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Abstract
BACKGROUND AND AIMS Glutamate, glutamine are involved in energy metabolism, and have been related to cardiometabolic disorders. However, their roles in the development of type-2 diabetes (T2D) remain unclear. The aim of this study was to examine the effects of Mediterranean diet on associations between glutamine, glutamate, glutamine-to-glutamate ratio, and risk of new-onset T2D in a Spanish population at high risk for cardiovascular disease (CVD). METHODS AND RESULTS The present study was built within the PREDIMED trial using a case-cohort design including 892 participants with 251 incident T2D cases and 641 non-cases. Participants (mean age 66.3 years; female 62.8%) were non diabetic and at high risk for CVD at baseline. Plasma levels of glutamine and glutamate were measured at baseline and after 1-year of intervention. Higher glutamate levels at baseline were associated with increased risk of T2D with a hazard ratio (HR) of 2.78 (95% CI, 1.43-5.41, P for trend = 0.0002). In contrast, baseline levels of glutamine (HR: 0.64, 95% CI, 0.36-1.12; P for trend = 0.04) and glutamine-to-glutamate ratio (HR: 0.31, 95% CI, 0.16-0.57; P for trend = 0.0001) were inversely associated with T2D risk when comparing extreme quartiles. The two Mediterranean diets (MedDiet + EVOO and MedDiet + mixed nuts) did not alter levels of glutamine and glutamate after intervention for 1 year. However, MedDiet mitigated the positive association between higher baseline plasma glutamate and T2D risk (P for interaction = 0.01). CONCLUSION Higher levels of glutamate and lower levels of glutamine were associated with increased risk of T2D in a Spanish population at high risk for CVD. Mediterranean diet might mitigate the association between the imbalance of glutamine and glutamate and T2D risk. This trial is registered at http://www.controlled-trials.com, ISRCTN35739639.
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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.