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1.
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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2.
Oxidative stress and glutamate excretion in alcoholic steatosis: Metabolic synapse between hepatocyte and stellate cell.
Kim, HH, Choi, SE, Jeong, WI
Clinical and molecular hepatology. 2020;(4):697-704
Abstract
Chronic alcohol consumption induces the development of alcoholic steatosis in the liver, which is one of the most widespread liver diseases worldwide. During general alcohol metabolism, hepatocytes generate mitochondria- and cytochrome P450 2E1 (CYP2E1)-mediated reactive oxygen species (ROS) whose accumulation elicits activation of the hepatic anti-oxidant system, including glutathione (GSH). However, chronic alcohol consumption decreases GSH generation through cysteine deficiency by suppressing the methionine cycle and trans-sulfuration system, whereas it turns on an alternative defense pathway, such as the xCT transporter, to compensate for GSH shortage. The xCT transporter mediates the uptake of cystine coupled to the efflux of glutamate, leading to an increase in blood glutamate. In response to the elevated glutamate in the liver, the expression of metabotropic glutamate receptor 5 (mGluR5) is up-regulated in hepatic stellate cells (HSCs) along with enhanced production of 2-arachidonoylglycerol, which in turn stimulates cannabinoid receptor 1 (CB1R) on neighboring hepatocytes to increase de novo lipogenesis. On the other hand, blockade of mGluR5 and CB1R attenuates alcoholic steatosis. Interestingly, although the increased expression of CYP2E1-mediated xCT and ROS generation are mainly observed at the perivenous area (zone 3), fat accumulation is mostly detected at hepatic zone 2. To resolve this discrepancy, this review summarizes recent advances on glutamate/mGluR5-derived alcoholic steatosis and zone-dependently different responses to alcohol intake. In addition, the bidirectional loop pathway and its unique metabolic synapse between hepatocytes and HSCs are discussed.
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3.
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.
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4.
Nanoparticles and neurotoxicity: Dual response of glutamatergic receptors.
Engin, AB, Engin, A
Progress in brain research. 2019;:281-303
Abstract
Although the use of nanoparticles for neuro-diagnostic and neurotherapeutic purposes provides superior benefits than the conventional approaches, it may be potentially toxic in central nervous system. In this respect, nanotechnological research focuses on nanoneurotoxicity-nanoneurosafety concepts. Despite these efforts, nanoparticles (NPs) may cause neurotoxicity, neuroinflammation, and neurodegeneration by penetrating the brain-olfactory route and blood-brain barrier (BBB). Indeed, due to their unique structures nanomaterials can easily cross biological barriers, thus avoid drug delivery problems. Despite the advancement of nanotechnology for designing therapeutic agents, toxicity of these nanomaterials is still a concern. Activation of neurons by astrocytic glutamate is a result of NPs-mediated astrocyte-neuron crosstalk. Increased extracellular glutamate levels due to enhanced synthesis and reduced reuptake may induce neuronal damage by abnormal activation of extrasynaptic N-methyl d-aspartate receptor (NMDAR) subunits. NMDAR is the key factor that mediates the disturbances in intracellular calcium homeostasis, mitochondrial dysfunction and generation of reactive oxygen species in NPs exposed neurons. While some NPs cause neuronal death by inducing NMDARs, others may be neurotoxic through the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or protect the neurons via blocking NMDARs. However, mechanisms of dual effects of NPs, neurotoxicity or neuroprotection are not precisely known. Some NPs present neuroprotective effect either by selectively inhibiting extrasynaptic subunit of NMDARs or by attenuating oxidative stress. NPs-related proinflammatory activation of microglia contributes to the dysfunction and cytotoxicity in neurons. Therefore, investigation of the interaction of NPs with the neuronal signaling molecules and neuronal receptors is necessary for the better understanding of the neurotoxicity or neurosafety of nanomaterials.
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5.
Mitochondrial Carriers for Aspartate, Glutamate and Other Amino Acids: A Review.
Monné, M, Vozza, A, Lasorsa, FM, Porcelli, V, Palmieri, F
International journal of molecular sciences. 2019;(18)
Abstract
Members of the mitochondrial carrier (MC) protein family transport various molecules across the mitochondrial inner membrane to interlink steps of metabolic pathways and biochemical processes that take place in different compartments; i.e., are localized partly inside and outside the mitochondrial matrix. MC substrates consist of metabolites, inorganic anions (such as phosphate and sulfate), nucleotides, cofactors and amino acids. These compounds have been identified by in vitro transport assays based on the uptake of radioactively labeled substrates into liposomes reconstituted with recombinant purified MCs. By using this approach, 18 human, plant and yeast MCs for amino acids have been characterized and shown to transport aspartate, glutamate, ornithine, arginine, lysine, histidine, citrulline and glycine with varying substrate specificities, kinetics, influences of the pH gradient, and capacities for the antiport and uniport mode of transport. Aside from providing amino acids for mitochondrial translation, the transport reactions catalyzed by these MCs are crucial in energy, nitrogen, nucleotide and amino acid metabolism. In this review we dissect the transport properties, phylogeny, regulation and expression levels in different tissues of MCs for amino acids, and summarize the main structural aspects known until now about MCs. The effects of their disease-causing mutations and manipulation of their expression levels in cells are also considered as clues for understanding their physiological functions.
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6.
The neurophysiology of hyperarousal in restless legs syndrome: Hints for a role of glutamate/GABA.
Lanza, G, Ferri, R
Advances in pharmacology (San Diego, Calif.). 2019;:101-119
Abstract
Restless legs syndrome (RLS) is a common sensory-motor circadian disorder, whose basic components include urge to move the legs, unpleasant sensory experience, and periodic leg movements during sleep, all associated with an enhancement of the individual's arousal state. Brain iron deficiency (BID) is considered to be a key initial pathobiological factor, based on alterations of iron acquisition by the brain, also moderated by genetic factors. In addition to the well-known dopaminergic involvement in RLS, previous studies pointed out that BID brings also a hyperglutamatergic state that influences a dysfunctional cortico-striatal-thalamic-cortical circuit in genetically vulnerable individuals. However, the enhancement of arousal mechanisms in RLS may also be explained by functional changes of the ascending arousal systems and by deficitary GABA-mediated inhibitory control. Very recently, it was also suggested that BID induces a hypoadenosinergic state in RLS, thus possibly providing a link for a putative unified pathophysiological mechanism accounting for both hyperarousal and sensory-motor signs. Consequently, RLS might be viewed as a multitransmitter neurochemical disorder, globally resulting in enhanced excitability and decreased inhibition. In this framework, understanding the complex interaction of different neuronal circuits in generating the symptoms of RLS is mandatory both for a better diagnostic refinement and for an innovative therapeutic support. Notably, multiple neurotransmission dysfunction, either primary or triggered by BID, may also bridge the gap between RLS and other chronic pain disorders. This chapter summarizes the current experimental and clinical findings into a heuristic model of the electrophysiology and neurochemistry underlying RLS.
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7.
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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8.
Perspective of ions and messengers: an intricate link between potassium, glutamate, and cyclic di-AMP.
Gundlach, J, Commichau, FM, Stülke, J
Current genetics. 2018;(1):191-195
Abstract
Potassium and glutamate are the most abundant ions in every living cell. Whereas potassium plays a major role to keep the cellular turgor and to buffer the negative charges of the nucleic acids, the major function of glutamate is to serve as the universal amino group donor. In addition, both ions are involved in osmoprotection in bacterial cells. Here, we discuss how bacterial cells maintain the homeostasis of both ions and how adaptive evolution allows them to live even at extreme potassium limitation. Interestingly, positively charged amino acids are able to partially replace potassium, likely by buffering the negative charge of DNA. A major factor involved in the control of potassium homeostasis in Gram-positive bacteria is the essential second messenger cyclic di-AMP. This nucleotide is synthesized in response to the potassium concentration and in turn controls the expression and activity of potassium transporters. We discuss the link between the two major ions, DNA and the second messenger c-di-AMP.
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9.
[Memantine: from the original brand to generics].
Titova, NV
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2017;(10):136-143
Abstract
Memantine is the first clinically available glutamate antagonist, with an antagonist action at the N-methyl-D-aspartate receptors in the brain, for correction of cognitive and behavioral functions in neurodegenerative disorders. Glutamate mediated excitotoxic neuronal damage has been implicated in Alzheimer's disease (AD) and other parkinsonism-related dementias and, therefore, memantine represents a novel mode of action to counteract the glutamate-mediated excitotoxicity. In moderate to severe AD, 20 mg of memantine shows a positive effect on cognition, mood, behavior and the ability to perform activities of daily living. Long-term studies show good tolerability of memantine with an acceptable side-effect profile. In recent years, there have been a proliferation of a number of companies producing generic memantine with different trade names. In Russia, the first memantine generic drug noojerone was approved in 2010 and its use has since been supported by a growing evidence base of efficacy in real-life clinical practice. Postmarketing studies show that noojerone provides long-term and effective therapy in patients with moderate and severe Alzheimer's dementia. This observation is supported by the clinically significant therapeutic effect of noojerone on cognitive and daily functioning, behavioral and psychotic symptoms of dementia and a reduction of the burden on caregivers. This generic version of memantine is affordable and, therefore, reduces financial burden on patients and improves compliance with treatment.
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10.
Glutamate Excitotoxicity and Oxidative Stress in Epilepsy: Modulatory Role of Melatonin.
Vishnoi, S, Raisuddin, S, Parvez, S
Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 2016;(4):365-374
Abstract
Epilepsy is thought to be associated with oxidative stress, glutamate excitotoxicity, and mitochondrial dysfunction. The enhanced synthesis and release of oxygen free radicals is linked to the low and oxidative potential of the central nervous system. Glutamate excitotoxicity also contributes significantly to the production of reactive nitrogen species that cause nitrosative stress. A decrease in adenosine triphosphate synthesis, which leads to free radical formation, is associated with mitochondrial dysfunction. The brain is very much susceptible to degeneration and oxidative stress because of its low antioxidant enzyme activity. Melatonin, a hormone secreted by the pineal gland, has remarkable antioxidant properties. Melatonin and its analogs that bind to melatonin receptors have a significant role in suppressing seizures. Melatonin scavenges oxygen free radicals such as hydroxyl radical, peroxy radical, peroxynitrite anion, and superoxide radical and stimulates synthesis of superoxide dismutase and glutathione peroxidase, which are potent antioxidant enzymes. Melatonin administration has been shown to be effective in both experimental models and patients suffering from epilepsy. In this review, we compile the literature supporting consequences of seizures and the protective role of melatonin during seizures.