Glyphosate is the most used herbicide in agriculture. Its major metabolite is AMPA (aminomethylphosphonic acid), but N-acetyl-AMPA and N-acetylglyphosate are also metabolites of interest. For risk assessment, a general residue definition was proposed as the sum of glyphosate, AMPA, N-acetyl-glyphosate and N-acetyl-AMPA, expressed as glyphosate. A confirmatory method for glyphosate in fat, liver and kidneys, as well as a confirmatory method for AMPA and N-acetyl-glyphosate in all matrices, are still missing. In this paper, we present a method for the quantitative determination of glyphosate residues and its metabolites AMPA, N-acetyl-AMPA and N-acetyl-glyphosate by liquid chromatography-mass spectrometry (LC-MS/MS) in adipose tissue, liver, eggs, milk and honey without derivatization. Different chromatographic columns were tested, with the Hypercarb column providing the best results. The analytes were eluted with mobile phases of acidified water with 1.2% formic acid and 0.5% formic acid in acetonitrile. Sample purification procedures were also optimized by varying the solvent extraction mixtures (water, methanol and mixture ψ (methanol, water) = 1:1, each with the addition of 1% formic acid (v/v)), using different sorbents in solid phase extraction (SPE) (polymeric cationic (PCX) and anionic (PAX)) and using dispersive solid phase extraction (dSPE) (C18 and PSA) by modifying the extraction procedures. Finally, the analytes were extracted from the samples with 1% formic acid in water (v/v). Milk and adipose tissue were purified by the addition of dichloromethane, while liver and egg samples were purified by SPE with a mixed cation exchange sorbent and ultrafiltration with cut-off filters. The proposed analytical procedures were validated according to SANTE/11312/2021 guidelines: linearity, limits of quantification, precision and accuracy were determined for all matrices. The limits of quantification (LOQs) ranged from 0.025 to 0.2 mg kg-1. Precision, expressed as relative standard deviation, was <20%, while accuracy, expressed as analytical recovery, ranged from 70% to 120%. During method validation, the measurement uncertainty was estimated to be <50% for all analytes. Good validation parameters according to the SANTE document were achieved for all analytes. Therefore, the method can be considered reliable and sensitive enough for routine monitoring of polar pesticides. The application of the accredited method in routine analysis will provide data that are useful for the re-evaluation of risk assessment studies in foods of animal origin.

Parkinson\'s disease (PD) is the second most frequent neurodegenerative disorder, affecting millions of people and rapidly increasing over the last decades. Even though there is no intervention yet to stop the neurodegenerative pathology, many efficient treatment methods are available, including for patients with advanced PD. Neuroplasticity is a fundamental property of the human brain to adapt both to external changes and internal insults and pathological processes. In this paper we examine the current knowledge and concepts concerning changes at network level, cellular level and molecular level as parts of the neuroplastic response to protein aggregation pathology, synapse loss and neuronal loss in PD. We analyse the beneficial, compensatory effects, such as augmentation of nigral neurons efficacy, as well as negative, maladaptive effects, such as levodopa-induced dyskinesia. Effects of physical activity and different treatments on neuroplasticity are considered and the opportunity of biomarkers identification and use is discussed.

Fish reared under seminatural conditions can be challenged by exposure to herbicides. Farming facilities relying on the surrounding area\'s water quality can be affected by glyphosate and aminomethylphosphonic acid (AMPA) contamination. This review summarizes findings on how glyphosate and AMPA in the amounts registered in surface waterbodies affect redox status and biotransformation in fish and covers the aspect of diet supplementation for oxidative stress relief. Environmentally relevant concentrations of glyphosate and AMPA can alter the transcription and catalytic activities of antioxidant enzymes, decrease the content of reduced glutathione, and increase the accumulation of lipid peroxidation products, all of which are signs of a redox imbalance. Glyphosate has been shown to affect complex I in the mitochondrial respiratory chain and dysregulate iron transport-related genes, causing redox disturbance. Relatively high but environmentally realistic glyphosate concentrations can initiate the induction of cytochrome P450 biotransformation enzymes, alter the regulation of ABC exporters, and cause the inhibition of the redox-sensitive Nrf2 signaling pathway. Studies on reducing herbicide toxicity through dietary supplementation are a promising area of research. Natural functional supplements have been proven to have great potential for mitigating glyphosate-induced oxidative stress and thereby improving fish health, which in turn means maintaining productivity in fish farms that use natural water. However, data on the effects of AMPA on fish are scarce, and studies on the alleviation of its toxicity in fish are lacking. Considering the variety of AMPA contamination routes, one cannot underestimate the need for further research.

Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis is a rare form of autoimmune encephalitis. We report a case of a patient with myasthenia gravis post-thymoma treatment who presented with deteriorating mental status. She was found to have positive AMPA receptor titers in her cerebrospinal fluid and subsequently attained full recovery. Of the limited number of cases that were documented, we report the only case of a patient who was previously immunocompromised to develop the condition. Even though autoimmune encephalitis is an emerging condition, its early differentiation from other causes of encephalitis is crucial in the prognosis of the patient.

Accumulation of hyper-phosphorylated tau and amyloid beta (Aβ) are key pathological hallmarks of Alzheimer\'s disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid β. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.

Glyphosate is widely used in agriculture for weed control; however, it may pollute water systems with its by-product, aminomethylphosphonic acid (AMPA). Therefore, a better understanding of the flows of glyphosate and AMPA from soils into rivers is required. We developed the spatially explicit MARINA-Pesticides model to estimate the annual inputs of glyphosate and AMPA into rivers, considering 10 crops in 10,226 sub-basins globally for 2020. Our model results show that, globally, 880 tonnes of glyphosate and 4,090 tonnes of AMPA entered rivers. This implies that 82 % of the river inputs were from AMPA, with glyphosate accounting for the remainder. Over half of AMPA and glyphosate in rivers globally originated from corn and soybean production; however, there were differences among sub-basins. Asian sub-basins accounted for over half of glyphosate in rivers globally, with the contribution from corn production being dominant. South American sub-basins accounted for approximately two-thirds of AMPA in rivers globally, originating largely from soybean production. Our findings constitute a reference for implementing and supporting effective control strategies to achieve Sustainable Development Goals 2 and 6 (food production and clean water, respectively) simultaneously in the future.

Depression is a leading cause of disability and reduced work capacity worldwide. The monoamine theory of the pathogenesis of depression has remained dominant for many decades, however, drugs developed on its basis have limited efficacy. Exploring alternative mechanisms underlying this pathology could illuminate new avenues for pharmacological intervention. Targeting glutamatergic pathways in the CNS, particularly through modulation of NMDA and AMPA receptors, demonstrates promising results. This review presents some existing drugs with glutamatergic activity and novel developments based on it to enhance the efficacy of pharmacotherapy for depressive disorders.
Депрессия является одной из лидирующих причин инвалидизации и снижения трудоспособности во всем мире. Моноаминовая теория патогенеза депрессии оставалась главенствующей на протяжении многих десятилетий, однако препараты, разработанные на ее основе, имеют ограниченную эффективность. Изучение иных механизмов возникновения данной патологии может пролить свет на новые пути фармакокоррекции этого заболевания. Влияние на глутаматергические пути в центральной нервной системе, в частности модуляция рецепторов N-метил-D-аспартата и α-амино-3-гидрокси-5-метил-4-изоксазолпропионовой кислоты, показывает многообещающие результаты. В данном обзоре представлены некоторые существующие препараты с глутаматергической активностью, а также новые разработки на ее основе для повышения эффективности лекарственной терапии депрессивных заболеваний.

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Familial Alzheimer\'s disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD.

Functions of the cerebellar cortex, from motor learning to emotion and cognition, depend on the appropriate molecular composition at diverse synapse types. Glutamate receptor distributions have been partially mapped using immunogold electron microscopy. However, information is lacking on the distribution of many other components, such as Shank2, a postsynaptic scaffolding protein whose cerebellar dysfunction is associated with autism spectrum disorders. Here, we used an adapted Magnified Analysis of the Proteome, an expansion microscopy approach, to map multiple glutamate receptors, scaffolding and signaling proteins at single synapse resolution in the cerebellar cortex. Multiple distinct synapse-selective distribution patterns were observed. For example, AMPA receptors were most concentrated at synapses on molecular layer interneurons and at climbing fiber synapses, Shank1 was most concentrated at parallel fiber synapses on Purkinje cells, and Shank2 at both climbing fiber and parallel fiber synapses on Purkinje cells but little on molecular layer interneurons. Our results are consistent with gene expression data but also reveal input-selective targeting within Purkinje cells. In specialized glomerular structures of the granule cell layer, AMPA receptors as well as most other synaptic components preferentially targeted to synapses. However, NMDA receptors and the synaptic GTPase activating protein SynGAP preferentially targeted to extrasynaptic sites. Thus, glomeruli may be considered integrative signaling units through which mossy fibers differentially activate synaptic AMPA and extrasynaptic NMDA receptor complexes. Furthermore, we observed NMDA receptors and SynGAP at adherens junctions, suggesting a role in structural plasticity of glomeruli. Altogether, these data contribute to mapping the cerebellar \'synaptome\'.