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1.
Gut microbiota-dependent phenylacetylglutamine in cardiovascular disease: current knowledge and new insights.
Song, Y, Wei, H, Zhou, Z, Wang, H, Hang, W, Wu, J, Wang, DW
Frontiers of medicine. 2024;(1):31-45
Abstract
Phenylacetylglutamine (PAGln) is an amino acid derivate that comes from the amino acid phenylalanine. There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular diseases. In this review, we discussed the metabolic pathway of PAGln production and the quantitative measurement methods of PAGln. We summarized the epidemiological evidence to show the role of PAGln in diagnostic and prognostic value in several cardiovascular diseases, such as heart failure, coronary heart disease/atherosclerosis, and cardiac arrhythmia. The underlying mechanism of PAGln is now considered to be related to the thrombotic potential of platelets via adrenergic receptors. Besides, other possible mechanisms such as inflammatory response and oxidative stress could also be induced by PAGln. Moreover, since PAGln is produced across different organs including the intestine, liver, and kidney, the cross-talk among multiple organs focused on the function of this uremic toxic metabolite. Finally, the prognostic value of PAGln compared to the classical biomarker was discussed and we also highlighted important gaps in knowledge and areas requiring future investigation of PAGln in cardiovascular diseases.
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2.
The effects of glutamine supplementation on markers of apoptosis and autophagy in sickle cell disease peripheral blood mononuclear cells.
Walter, PB, Hohman, LS, Rokeby, A, Lum, JJ, Hagar, R, Lavrisha, L, Saulys, A, Kuypers, FA, Vichinsky, E, Morris, CR
Complementary therapies in medicine. 2022;:102856
Abstract
OBJECTIVES L-Glutamine was FDA-approved for sickle cell disease (SCD) in 2017, yet the mechanism(s)-of-action are poorly understood. This study investigates the potential activation of autophagy as a previously unexplored mechanism-of-benefit. DESIGN Prospective, open-label, 8-week, phase-2 trial of oral L-glutamine (10 g TID) in patients with SCD at risk for pulmonary hypertension identified by Doppler-echocardiography by an elevated tricuspid-regurgitant-jet-velocity (TRV)≥ 2.5 m/s. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples taken from SCD patients at baseline, two, four, six and eight weeks of glutamine therapy, and from controls at baseline; BAX (pro-apoptotic marker) and LC3-II/LC3-I (autophagy marker) were measured via western blot analysis to assess apoptosis and autophagy respectively. SETTING Comprehensive SCD Center in Oakland, California. RESULTS Patients with SCD (n = 8) had a mean age of 44 ± 16, 50% were male; 63% Hb-SS, and mean TRV= 3.1 ± 0.7 m/s. Controls' mean age (n = 5) was 32 ± 12% and 57% were male; all were Hb-AA with a mean TRV= 1.8 ± 0.6. At baseline, SCD-PBMCs had 2-times higher levels of BAX and LC3-I versus controls (both p = 0.03). Levels of BAX expression increased by 300% after 8-weeks of glutamine supplementation (p = 0.005); LC3-I protein levels decreased while LC3-II levels increased by 70%, giving a significant increase in the LC3-II/LC3-I ratio (p = 0.02). CONCLUSION PBMCs from glutamine-supplemented SCD patients have upregulated apoptotic and autophagy proteins. The parallel increase in BAX and the LC3-II / LC3-I ratio with glutamine supplementation suggest a possible role of autophagic cell death. The increase in apoptotic markers provide insight into a possible mechanism used by peripheral PBMCs during glutamine supplementation in patients with SCD.
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3.
Metformin Treatment or PRODH/POX-Knock out Similarly Induces Apoptosis by Reprograming of Amino Acid Metabolism, TCA, Urea Cycle and Pentose Phosphate Pathway in MCF-7 Breast Cancer Cells.
Huynh, TYL, Oscilowska, I, Sáiz, J, Nizioł, M, Baszanowska, W, Barbas, C, Palka, J
Biomolecules. 2021;(12)
Abstract
It has been considered that proline dehydrogenase/proline oxidase (PRODH/POX) is involved in antineoplastic activity of metformin (MET). The aim of this study is identification of key metabolites of glycolysis, pentose phosphate pathway (PPP), tricarboxylic acids (TCA), urea cycles (UC) and some amino acids in MET-treated MCF-7 cells and PRODH/POX-knocked out MCF-7 (MCF-7crPOX) cells. MCF-7crPOX cells were generated by using CRISPR-Cas9. Targeted metabolomics was performed by LC-MS/MS/QqQ. Expression of pro-apoptotic proteins was evaluated by Western blot. In the absence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to similar inhibition of glycolysis (drastic increase in intracellular glucose and pyruvate) and increase in the utilization of phospho-enol-pyruvic acid, glucose-6-phosphate and some metabolites of TCA and UC, contributing to apoptosis. However, in the presence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to utilization of some studied metabolites (except glucose), facilitating pro-survival phenotype of MCF-7 cells in these conditions. It suggests that MET treatment or PRODH/POX-knock out induce similar metabolic effects (glucose starvation) and glycolysis is tightly linked to glutamine metabolism in MCF-7 breast cancer cells. The data provide insight into mechanism of anticancer activity of MET as an approach to further studies on experimental breast cancer therapy.
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4.
L-Glutamine Supplementation Enhances Strength and Power of Knee Muscles and Improves Glycemia Control and Plasma Redox Balance in Exercising Elderly Women.
Amirato, GR, Borges, JO, Marques, DL, Santos, JMB, Santos, CAF, Andrade, MS, Furtado, GE, Rossi, M, Luis, LN, Zambonatto, RF, et al
Nutrients. 2021;(3)
Abstract
We investigated the effects of oral L-glutamine (Gln) supplementation, associated or not with physical exercises, in control of glycemia, oxidative stress, and strength/power of knee muscles in elderly women. Physically active (n = 21) and sedentary (n = 23) elderly women aged 60 to 80 years were enrolled in the study. Plasma levels of D-fructosamine, insulin, reduced (GSH) and oxidized (GSSG) glutathione, iron, uric acid, and thiobarbituric acid-reactive substances (TBARs) (lipoperoxidation product), as well as knee extensor/flexor muscle torque peak and average power (isokinetic test), were assessed pre- and post-supplementation with Gln or placebo (30 days). Higher plasma D-fructosamine, insulin, and iron levels, and lower strength/power of knee muscles were found pre-supplementation in the NPE group than in the PE group. Post-supplementation, Gln subgroups showed higher levels of GSH, GSSG, and torque peak, besides lower D-fructosamine than pre-supplementation values. Higher muscle average power and plasma uric acid levels were reported in the PE + Gln group, whereas lower insulin levels were found in the NPE + Gln than pre-supplementation values. TBARs levels were diminished post-supplementation in all groups. Gln supplementation, mainly when associated with physical exercises, improves strength and power of knee muscles and glycemia control, besides boosting plasma antioxidant capacity of elderly women.
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5.
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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6.
A Narrative Review about Nutritional Management and Prevention of Oral Mucositis in Haematology and Oncology Cancer Patients Undergoing Antineoplastic Treatments.
García-Gozalbo, B, Cabañas-Alite, L
Nutrients. 2021;(11)
Abstract
Cancer is a prevalent disease worldwide, and treatments such as radiotherapy and chemotherapy sometimes lead to adverse events. Oral mucositis is one of the most disabling adverse events, and clinical guidelines do not take into account nutritional interventions. The primary endpoint was to gather the evidence about the efficacy of nutritional interventions in the prevention and/or treatment of antineoplastic-induced oral mucositis in oncological patients. A bibliographic review was carried out in the PubMed data base by combining MeSH terms with Boolean operators. Articles were selected based on inclusion and exclusion criteria; 50 final articles were found. Although further evidence is needed, glutamine, honey, and vitamins appear to be good therapeutic options. The rest of the compounds presented controversial or insufficient results, making it difficult to draw conclusions over their utilization as prevention or treatment options. Little evidence is reported about oral mucositis nutritional interventions in spite of them being attainable and affordable compounds. Scarce evidence is shown in paediatric patients compared with adults. Developing higher quality studies and combinations with the compounds researched is necessary for creating a stronger body of evidence.
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7.
Targeting GLS1 to cancer therapy through glutamine metabolism.
Yu, W, Yang, X, Zhang, Q, Sun, L, Yuan, S, Xin, Y
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2021;(11):2253-2268
Abstract
Glutamine metabolism is one of the hallmarks of cancers which is described as an essential role in serving as a major energy and building blocks supply to cell proliferation in cancer cells. Many malignant tumor cells always display glutamine addiction. The "kidney-type" glutaminase (GLS1) is a metabolism enzyme which plays a significant part in glutaminolysis. Interestingly, GLS1 is often overexpressed in highly proliferative cancer cells to fulfill enhanced glutamine demand. So far, GLS1 has been proved to be a significant target during the carcinogenesis process, and emerging evidence reveals that its inhibitors could provide a benefit strategy for cancer therapy. Herein, we summarize the prognostic value of GLS1 in multiple cancer type and its related regulatory factors which are associated with antitumor activity. Moreover, this review article highlights the remarkable reform of discovery and development for GLS1 inhibitors. On the basis of case studies, our perspectives for targeting GLS1 and development of GLS1 antagonist are discussed in the final part.
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8.
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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Abstract
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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Possibility that the Onset of Autism Spectrum Disorder is Induced by Failure of the Glutamine-Glutamate Cycle.
Kawada, K, Kuramoto, N, Mimori, S
Current molecular pharmacology. 2021;(2):170-174
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disease, and the number of patients has increased rapidly in recent years. The causes of ASD involve both genetic and environmental factors, but the details of causation have not yet been fully elucidated. Many reports have investigated genetic factors related to synapse formation, and alcohol and tobacco have been reported as environmental factors. This review focuses on endoplasmic reticulum stress and amino acid cycle abnormalities (particularly glutamine and glutamate) induced by many environmental factors. In the ASD model, since endoplasmic reticulum stress is high in the brain from before birth, it is clear that endoplasmic reticulum stress is involved in the development of ASD. On the other hand, one report states that excessive excitation of neurons is caused by the onset of ASD. The glutamine- glutamate cycle is performed between neurons and glial cells and controls the concentration of glutamate and GABA in the brain. These neurotransmitters are also known to control synapse formation and are important in constructing neural circuits. Theanine is a derivative of glutamine and a natural component of green tea. Theanine inhibits glutamine uptake in the glutamine-glutamate cycle via slc38a1 without affecting glutamate; therefore, we believe that theanine may prevent the onset of ASD by changing the balance of glutamine and glutamate in the brain.
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The effect of glutamine supplementation on serum levels of some inflammatory factors, oxidative stress, and appetite in COVID-19 patients: a case-control study.
Mohajeri, M, Horriatkhah, E, Mohajery, R
Inflammopharmacology. 2021;(6):1769-1776
Abstract
BACKGROUND Malnutrition is seen in COVID-19 patients, and reducing malnutrition with appropriate therapies may improve these patients' health. This case-control study aimed to assess and compare serum levels of some inflammatory factors, oxidative stress, and appetite in COVID-19 patients with respiratory infections that receive glutamine treatment with a control group. METHODS In this study, patients who consented to use glutamine were considered as the case group and other patients who did not use glutamine were considered as a control group. Two hundred twenty-two COVID-19 patients (51.2 ± 6.7) using L-Glutamine and 230 COVID-19 patients (51.3 ± 8.2) with similar age, gender, and clinical status, as the control group, were included in the study. For 5 days, the case group consumed 10 g of glutamine supplement three times per day. At the end of the 5 days, blood samples were taken again to test for serum levels of IL1β, tumor necrosis factor-α, malondialdehyde, and total antioxidant capacity, then all data were analyzed. RESULTS Serum levels of β-1 interleukin, tumor necrosis factor-α and hs-CRP were significantly reduced with five days of glutamine supplementation (p < 0.05), and patients' appetite during 5 days of glutamine supplementation compared with the control group had a significant increase (p < 0.05). CONCLUSION Glutamine supplementation in COVID-19 patients with respiratory infection significantly reduces serum levels of interleukin-1 β, hs-CRP, and tumor necrosis factor-α and significantly increases appetite, so glutamine supplementation may be useful for COVID-19 patients in the hospital.