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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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The Glutamate and the Immune Systems: New Targets for the Pharmacological Treatment of OCD.
Marazziti, D, Albert, U, Mucci, F, Piccinni, A
Current medicinal chemistry. 2018;(41):5731-5738
Abstract
BACKGROUND In the last decades the pharmacological treatment of obsessivecompulsive disorder (OCD) has been significantly promoted by the effectiveness of selective serotonin (5-HT) reuptake inhibitors (SSRIs) and the subsequent development of the 5-HT hypothesis of OCD. However, since a large majority of patients (between 40% and 60 %) do not respond to SSRIs or strategies based on the modulation of the 5-HT system, it is now essential to search for other possible therapeutic targets. AIMS The aim of this paper was to review current literature through a PubMed and Google Scholar search of novel hypotheses and related compounds for the treatment of OCD, with a special focus on the glutammate and the immune systems. DISCUSSION The literature indicates that glutamate, the main excitatory neurotransmitter, might play an important role in the pathophysiology of OCD. In addition, a series of clinical studies also supports the potential efficacy of drugs modulating the glutamate system. The role of the immune system alterations in OCD in both children and adults needs to be more deeply elucidated. In children, a subtype of OCD has been widely described resulting from infections driven by group A streptococcus β-hemolitic and belonging to the so-called "pediatric autoimmune neuropsychiatric disorders associated with streptococcus" (PANDAS). In adults, available findings are meager and controversial, although interesting. CONCLUSION The glutamate and the immune systems represent two intriguing topics of research that hold promise for the development of open novel treatment strategies in OCD.
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Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities.
Macrez, R, Stys, PK, Vivien, D, Lipton, SA, Docagne, F
The Lancet. Neurology. 2016;(10):1089-102
Abstract
Research advances support the idea that excessive activation of the glutamatergic pathway plays an important part in the pathophysiology of multiple sclerosis. Beyond the well established direct toxic effects on neurons, additional sites of glutamate-induced cell damage have been described, including effects in oligodendrocytes, astrocytes, endothelial cells, and immune cells. Such toxic effects could provide a link between various pathological aspects of multiple sclerosis, such as axonal damage, oligodendrocyte cell death, demyelination, autoimmunity, and blood-brain barrier dysfunction. Understanding of the mechanisms underlying glutamate toxicity in multiple sclerosis could help in the development of new approaches for diagnosis, treatment, and follow-up in patients with this debilitating disease. While several clinical trials of glutamatergic modulators have had disappointing results, our growing understanding suggests that there is reason to remain optimistic about the therapeutic potential of these drugs.
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Meningococcal internalization into human endothelial and epithelial cells is triggered by the influx of extracellular L-glutamate via GltT L-glutamate ABC transporter in Neisseria meningitidis.
Takahashi, H, Kim, KS, Watanabe, H
Infection and immunity. 2011;(1):380-92
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Abstract
Meningococcal internalization into human cells is likely to be a consequence of meningococcal adhesion to human epithelial and endothelial cells. Here, we identified three transposon mutants of Neisseria meningitidis that were primarily defective in the internalization of human brain microvascular endothelial cells (HBMEC), with insertions occurring in the gltT (a sodium-independent L-glutamate transporter) gene or its neighboring gene, NMB1964 (unknown function). NMB1964 was tentatively named gltM in this study because of the presence of a mammalian cell entry (MCE)-related domain in the deduced amino acid sequences. The null ΔgltT-ΔgltM N. meningitidis mutant was also defective in the internalization into human umbilical vein endothelial cells and the human lung carcinoma epithelial cell line A549, and the defect was suppressed by transcomplementation of the mutants with gltT(+)-gltM(+) genes. The intracellular survival of the ΔgltT-ΔgltM mutant in HBMEC was not largely different from that of the wild-type strain under our experimental conditions. Introduction of a1-bp deletion and amber or ochre mutations in gltT-gltM genes resulted in the loss of efficient internalization into HBMEC. The defect in meningococcal internalization into HBMEC and L-glutamate uptake in the ΔgltT-ΔgltM mutant were suppressed only in strains expressing both GltT and GltM proteins. The efficiency of meningococcal invasion to HBMEC decreased under L-glutamate-depleted conditions. Furthermore, ezrin, a key membrane-cytoskeleton linker, accumulated beneath colonies of the gltT(+)-gltM(+) N. meningitidis strain but not of the ΔgltT-ΔgltM mutant. These findings suggest that l-glutamate influx via the GltT-GltM L-glutamate ABC transporter serves as a cue for N. meningitidis internalization into host cells.
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Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders.
Blaylock, RL, Strunecka, A
Current medicinal chemistry. 2009;(2):157-70
Abstract
Despite the great number of observations being made concerning cellular and the molecular dysfunctions associated with autism spectrum disorders (ASD), the basic central mechanism of these disorders has not been proposed in the major scientific literature. Our review brings evidence that most heterogeneous symptoms of ASD have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by pro-inflammatory immune cytokines as the underlying mechanism. We suggest that environmental and dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming. In addition, each has effects on cell signaling that can affect neurodevelopment and neuronal function. Our hypothesis opens the door to a number of new treatment modes, including the nutritional factors that naturally reduce excitotoxicity and brain inflammation.
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Pathophysiology of glutamine and glutamate metabolism in premature infants.
Neu, J, Li, N
Current opinion in clinical nutrition and metabolic care. 2007;(1):75-9
Abstract
PURPOSE OF REVIEW The potential efficacy of glutamine and glutamate as nutritional supplements for premature infants was originally met with enthusiasm. Despite no evidence of toxicity in the clinical trials, the use of glutamine has not become routine. In certain studies, the benefits seem clear, whereas in others, benefits have not been demonstrated. Specific designs for studies have been difficult, targets based on mechanistic frameworks have been poorly defined, study populations are heterogeneous and putative mechanisms of glutamine action are multifold. Our purpose is to review recent findings pertaining to (1) the action and mechanisms of glutamine and glutamate in the gastrointestinal tract, and (2) the future directions for glutamine and glutamate research with a focus on the premature neonate. RECENT FINDINGS Studies elucidating mechanisms of glutamine action include tissue protection, immune modulation, preservation of glutathione and antioxidant capacity, preservation of metabolism, decreased intestinal apoptosis, and enhancement of heat shock proteins. The ability to decrease gastrointestinal-derived systemic inflammation appears to have especially significant implications for premature infants. SUMMARY We review recent studies of mechanisms of glutamine and glutamate action, pertinent clinical trials, and suggest areas for future research based on these mechanisms.
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Modulation of voltage-gated potassium channels in human T lymphocytes by extracellular glutamate.
Poulopoulou, C, Markakis, I, Davaki, P, Nikolaou, C, Poulopoulos, A, Raptis, E, Vassilopoulos, D
Molecular pharmacology. 2005;(3):856-67
Abstract
Glutamate is present in the plasma under tightly regulated concentrations. However, under conditions of immune deficiency, such as AIDS and malignancy, its plasma levels are highly elevated. In vitro, glutamate interacts with T lymphocytes, affecting mitogen-induced calcium responses, whereas at high doses, it impairs T lymphocyte proliferation, a process strongly dependent on the activity of voltage-gated potassium channels. In this study, we demonstrate novel dose-related effects of the endogenous ligand glutamate and its metabotropic and non-N-methyl-D-aspartic acid receptor agonists on the electrophysiological properties of native Kv1.3 channels of human T lymphocytes. Glutamate, at concentrations within normal plasma levels, positively modulates Kv1.3 channel gating, causing currents to activate faster and at significantly more hyperpolarized potentials, hence rendering the T lymphocyte readily responsive to immune stimuli. This effect is maximal at 1 microM Glu and is fully mimicked by a 100 microM concentration of the metabotropic receptor agonist trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. Most importantly, Glu, at concentrations > or =100 microM, which in vitro produce suppression of mitogen-induced proliferation, significantly decreases whole-cell potassium currents by increasing current and steady-state inactivation. This effect saturates at 1000 microM and seems to result from the subsequent activation of low-affinity metabotropic Glu receptors, as suggested by specific agonist data. Therefore, the antiproliferative effects of high glutamate may, at least in part, result from its inhibitory effect on the potassium current, suggesting an in vivo immunosuppressive role of elevated plasma glutamate.