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1.
Dietary glutamic acid and aspartic acid as biomarkers for predicting diabetic retinopathy.
Park, SY, Kim, J, Son, JI, Rhee, SY, Kim, DY, Chon, S, Lim, H, Woo, JT
Scientific reports. 2021;(1):7244
Abstract
The screening rate of diabetic retinopathy (DR) is low despite the importance of early diagnosis. We investigated the predictive value of dietary glutamic acid and aspartic acid for diagnosis of DR using the Korea National Diabetes Program cohort study. The 2067 patients with type 2 diabetes without DR were included. The baseline intakes of energy, glutamic acid and aspartic acid were assessed using a 3-day food records. The risk of DR incidence based on intake of glutamic acid and aspartic acid was analyzed. The DR group was older, and had higher HbA1c, longer DM duration, lower education level and income than non-DR group (all p < 0.05). The intake of total energy, glutamic acid and aspartic acid were lower in DR group than non-DR group (p = 0.010, p = 0.025 and p = 0.042, respectively). There was no difference in the risk of developing DR according to the intake of glutamic acid and ascorbic acid. But, aspartic acid intake had a negative correlation with PDR. Hence, the intake of glutamic acid and aspartic acid did not affect in DR incidence. However, lower aspartic acid intake affected the PDR incidence.
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2.
Mitochondrial dysfunction as a critical event in the pathophysiology of bipolar disorder.
Scaini, G, Andrews, T, Lima, CNC, Benevenuto, D, Streck, EL, Quevedo, J
Mitochondrion. 2021;:23-36
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Abstract
The understanding of the pathophysiology of bipolar disorder (BD) remains modest, despite recent advances in neurobiological research. The mitochondrial dysfunction hypothesis of bipolar disorder has been corroborated by several studies involving postmortem brain analysis, neuroimaging, and specific biomarkers in both rodent models and humans. Evidence suggests that BD might be related to abnormal mitochondrial morphology and dynamics, neuroimmune dysfunction, and atypical mitochondrial metabolism and oxidative stress pathways. Mitochondrial dysfunction in mood disorders is also associated with abnormal Ca2+ levels, glutamate excitotoxicity, an imbalance between pro- and antiapoptotic proteins towards apoptosis, abnormal gene expression of electron transport chain complexes, and decreased ATP synthesis. This paper aims to review and discuss the implications of mitochondrial dysfunction in BD etiology and to explore mitochondria as a potential target for novel therapeutic agents.
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3.
Perisynaptic astrocytes as a potential target for novel antidepressant drugs.
Frizzo, ME, Ohno, Y
Journal of pharmacological sciences. 2021;(1):60-68
Abstract
Emerging evidence suggests that dysfunctions in glutamatergic signaling are associated with the pathophysiology of depression. Several molecules that act on glutamate binding sites, so-called glutamatergic modulators, are rapid-acting antidepressants that stimulate synaptogenesis. Their antidepressant response involves the elevation of both extracellular glutamate and brain-derived neurotrophic factor (BDNF) levels, as well as the postsynaptic activation of the mammalian target of rapamycin complex 1. The mechanisms involved in the antidepressant outcomes of glutamatergic modulators, including ketamine, suggest that astrocytes must be considered a cellular target for developing rapid-acting antidepressants. It is well known that extracellular glutamate levels and glutamate intrasynaptic time-coursing are maintained by perisynaptic astrocytes, where inwardly rectifying potassium channels 4.1 (Kir4.1 channels) regulate both potassium and glutamate uptake. In addition, ketamine reduces membrane expression of Kir4.1 channels, which raises extracellular potassium and glutamate levels, increasing postsynaptic neural activities. Furthermore, inhibition of Kir4.1 channels stimulates BDNF expression in astrocytes, which may enhance synaptic connectivity. In this review, we discuss glutamatergic modulators' actions in regulating extracellular glutamate and BDNF levels, and reinforce the importance of perisynaptic astrocytes for the development of novel antidepressant drugs.
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Novel Glutamate-Putrescine Ligase Activity in Haloferax mediterranei: A New Function for glnA-2 Gene.
Rodríguez-Herrero, V, Peris, A, Camacho, M, Bautista, V, Esclapez, J, Bonete, MJ
Biomolecules. 2021;(8)
Abstract
The genome of the halophilic archaea Haloferax mediterranei contains three ORFs that show homology with glutamine synthetase (GS) (glnA-1, glnA-2, and glnA-3). Previous studies have focused on the role of GlnA-1, suggesting that proteins GlnA-2 and GlnA-3 could play a different role to that of GS. Glutamine synthetase (EC 6.3.1.2) belongs to the class of ligases, including 20 subclasses of other different enzymes, such as aspartate-ammonia ligase (EC 6.3.1.1), glutamate-ethylamine ligase (EC 6.3.1.6), and glutamate-putrescine ligase (EC 6.3.1.11). The reaction catalyzed by glutamate-putrescine ligase is comparable to the reaction catalyzed by glutamine synthetase (GS). Both enzymes can bind a glutamate molecule to an amino group: ammonium (GS) or putrescine (glutamate-putrescine ligase). In addition, they present the characteristic catalytic domain of GS, showing significant similarities in their structure. Although these proteins are annotated as GS, the bioinformatics and experimental results obtained in this work indicate that the GlnA-2 protein (HFX_1688) is a glutamate-putrescine ligase, involved in polyamine catabolism. The most significant results are those related to glutamate-putrescine ligase's activity and the analysis of the transcriptional and translational expression of the glnA-2 gene in the presence of different nitrogen sources. This work confirms a new metabolic pathway in the Archaea domain which extends the knowledge regarding the utilization of alternative nitrogen sources in this domain.
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5.
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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Unveiling a key role of oxaloacetate-glutamate interaction in regulation of respiration and ROS generation in nonsynaptic brain mitochondria using a kinetic model.
Selivanov, VA, Zagubnaya, OA, Nartsissov, YR, Cascante, M
PloS one. 2021;(8):e0255164
Abstract
Glutamate plays diverse roles in neuronal cells, affecting cell energetics and reactive oxygen species (ROS) generation. These roles are especially vital for neuronal cells, which deal with high amounts of glutamate as a neurotransmitter. Our analysis explored neuronal glutamate implication in cellular energy metabolism and ROS generation, using a kinetic model that simulates electron transport details in respiratory complexes, linked ROS generation and metabolic reactions. The analysis focused on the fact that glutamate attenuates complex II inhibition by oxaloacetate, stimulating the latter's transformation into aspartate. Such a mechanism of complex II activation by glutamate could cause almost complete reduction of ubiquinone and deficiency of oxidized form (Q), which closes the main stream of electron transport and opens a way to massive ROS generating transfer in complex III from semiquinone radicals to molecular oxygen. In this way, under low workload, glutamate triggers the respiratory chain (RC) into a different steady state characterized by high ROS generation rate. The observed stepwise dependence of ROS generation on glutamate concentration experimentally validated this prediction. However, glutamate's attenuation of oxaloacetate's inhibition accelerates electron transport under high workload. Glutamate-oxaloacetate interaction in complex II regulation underlies the observed effects of uncouplers and inhibitors and acceleration of Ca2+ uptake. Thus, this theoretical analysis uncovered the previously unknown roles of oxaloacetate as a regulator of ROS generation and glutamate as a modifier of this regulation. The model predicted that this mechanism of complex II activation by glutamate might be operative in situ and responsible for excitotoxicity. Spatial-time gradients of synthesized hydrogen peroxide concentration, calculated in the reaction-diffusion model with convection under a non-uniform local approximation of nervous tissue, have shown that overproduction of H2O2 in a cell causes excess of its level in neighbor cells.
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7.
Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study.
Lehn-Stefan, A, Peter, A, Machann, J, Schick, F, Randrianarisoa, E, Heni, M, Wagner, R, Birkenfeld, AL, Fritsche, A, Häring, HU, et al
The Journal of clinical endocrinology and metabolism. 2021;(2):e982-e989
Abstract
OBJECTIVE Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis. METHODS Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT). RESULTS Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ -.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05). CONCLUSIONS Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.
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8.
Glutamate levels and perfusion in pons during migraine attacks: A 3T MRI study using proton spectroscopy and arterial spin labeling.
Younis, S, Christensen, CE, Vestergaard, MB, Lindberg, U, Tolnai, D, Paulson, OB, Larsson, HB, Hougaard, A, Ashina, M
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021;(3):604-616
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Abstract
Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.
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The Low Glutamate Diet Effectively Improves Pain and Other Symptoms of Gulf War Illness.
Holton, KF, Kirkland, AE, Baron, M, Ramachandra, SS, Langan, MT, Brandley, ET, Baraniuk, JN
Nutrients. 2020;(9)
Abstract
Gulf War Illness (GWI) is a multisymptom disorder including widespread chronic pain, fatigue and gastrointestinal problems. The objective of this study was to examine the low glutamate diet as a treatment for GWI. Forty veterans with GWI were recruited from across the US. Outcomes included symptom score, myalgic score, tender point count, dolorimetry and the Chalder Fatigue Scale. Subjects were randomized to the low glutamate diet or a wait-listed control group, with symptom score being compared after one month. Subjects then went onto a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG)/placebo to test for return of symptoms. Symptom score was compared between diet intervention and wait-listed controls with an independent t-test and effect size was calculated with Cohen's d. Change scores were analyzed with Wilcoxon Signed Rank tests. Crossover challenge results were analyzed with General Linear Models and cluster analysis. The diet intervention group reported significantly less symptoms (p = 0.0009) than wait-listed controls, with a very large effect size, d = 1.16. Significant improvements in average dolorimetry (p = 0.0006), symptom score, tender point number, myalgic score and the Chalder Fatigue Scale (all p < 0.0001) were observed after the 1-month diet. Challenge with MSG/placebo resulted in significant variability in individual response. These results suggest that the low glutamate diet can effectively reduce overall symptoms, pain and fatigue in GWI, but differential results upon challenge suggest that other aspects of the diet, or underlying differences within the population, may be driving these changes. Future research is needed to identify potential nutrient effects, biomarkers, and underlying metabolic differences between responders and non-responders.
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Mechanosensitive channels of Corynebacterium glutamicum functioning as exporters of l-glutamate and other valuable metabolites.
Kawasaki, H, Martinac, B
Current opinion in chemical biology. 2020;:77-83
Abstract
In the industrial l-glutamate production established on the use of Corynebacterium glutamicum, l-glutamate synthesized intracellularly is exported through mechanosensitive transmembrane channel proteins (MscCG and MscCG2) activated by the force-from-lipids. The involvement of MscCG2 in l-glutamate export by C. glutamicum was demonstrated in 2018; however, MscCG was previously found to be the major exporter of l-glutamate. Recent advances in research methods, such as development of the microbial patch clamp, revealed unique characteristics of MscCG, including its conductance, opening and closing thresholds, and gating hysteresis, as well as the significant effect of membrane lipids on the channel properties. In addition, the cryoelectron microscopic structure of Escherichia coli MscS, the canonical representative of the mechanosensitive channel family to which MscCG and MscCG2 belong, revealed its new membrane-interacting region, new position within the lipid bilayer, and hook lipids in a newly defined cavity between subunits. In this short review, the applications of bacterial mechanosensitive channels in the development of effective microbial cell factories, which will contribute to sustainable development, are discussed.