Structural Exploration around 4-Cyclopropyl-Substituted 1,2,4-Benzothiadiazine 1,1-Dioxides: Impact of the Dihalo-Substitution of the Benzene Ring on α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Receptor Potentiation.

The present study investigates the AMPA receptor potentiation and cognitive-enhancing effects of novel halosubstituted 3,4-dihydro-2-1,2,4-benzothiadiazine 1,1-dioxides. Monohalosubstituted 4-cyclopropyl-3,4-dihydro-2-1,2,4-benzothiadiazine 1,1-dioxides were initially identified for their promising activity. In this article, a new pharmacomodulation explored the addition of a second halogen atom on the benzene nucleus and the variation of the cycloalkyl group at the 4-position.

Blood glucose measurement inside and outside the laboratory: both preanalytical and analytical challenges.

Glucose measurement is a critical investigation in metabolic disease management, especially in diabetes and inherited disorders. However, both laboratory-based and handheld point-of-care (HPOC) (glucometers) glucose testing face significant preanalytical and analytical challenges. In central laboratories, glycolysis in uncentrifuged samples leads to glucose consumption, which may compromise diagnostic accuracy.

Exploration of the Isosteric Concept Applied to 1,2,4-Benzothiadiazine 1,1-Dioxides in the Discovery of Novel AMPA Receptor Positive Allosteric Modulators.

The present study aims to highlight the impact on biological activity of the application of the isosteric concept to 1,2,4-benzothiadiazine 1,1-dioxides (BTDs) reported as AMPA receptor positive allosteric modulators (AMPAR PAMs). In a previous work, thiochroman 1,1-dioxides were designed as AMPAR PAMs by removing the two nitrogen atoms of the thiadiazine ring, a first pharmacomodulation process that led to encouraging results. In this study, another pharmacomodulation approach was employed to assess the impact of removing only one of the two nitrogen atoms of the thiadiazine ring providing two new series of candidates: 1,2-benzothiazine 1,1-dioxides and 1,4-benzothiazine 1,1-dioxides.

Longitudinal NMR-based Metabolomics Analysis of Male Mountain Ultramarathon Runners: New Perspectives for Athletes Monitoring and Injury Prevention.

Background: The aim of this study was to explore how a metabolomic approach could provide valuable information on changes in the athletes' metabolome during a mountain ultramarathon race. To achieve this goal, we established a longitudinal cohort of athletes enrolled in the TOR des Géants, a 330 km mountain ultramarathon with 24,000 m of elevation gain. Sixteen healthy male athletes (43.

Metabolite profiling of Artemisia afra and Artemisia annua extracts reveals divergent effects on Plasmodium falciparum.

Background: Artemisia spp. have been used for millennia in traditional medicine to treat a variety of ailments, including malaria. Extracts of Artemisia afra and A.

[Clinical metabolomics : an innovative approach towards preventive and personalized medicine].

In order to improve our healthcare system, it is undeniable that the future of modern medicine must focus on a more preventive and personalized approach, notably based on the individual characteristics specific to each patient. In this perspective, clinical metabolomics, which focuses on metabolites, emerges as a particularly interesting and promising approach. Indeed, this science reflects the internal and external stimuli received by an individual, thus capturing their physiological and/or pathological state.

Comparison of Three Widely Employed Extraction Methods for Metabolomic Analysis of Trypanosoma brucei.

Trypanosoma brucei (Tb) is the causative agent of human African trypanosomiasis (HAT), also known as sleeping sickness, which can be fatal if left untreated. An understanding of the parasite's cellular metabolism is vital for the discovery of new antitrypanosomal drugs and for disease eradication. Metabolomics can be used to analyze numerous metabolic pathways described as essential to Tb.

Comparison of extraction methods in vitro Plasmodium falciparum: A H NMR and LC-MS joined approach.

Malaria is a parasitic disease that remains a global concern and the subject of many studies. Metabolomics has emerged as an approach to better comprehend complex pathogens and discover possible drug targets, thus giving new insights that can aid in the development of antimalarial therapies. However, there is no standardized method to extract metabolites from in vitro Plasmodium falciparum intraerythrocytic parasites, the stage that causes malaria.

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators.

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344).

Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid.

In obesity, adipose tissue infiltrating macrophages acquire a unique pro-inflammatory polarization, thereby playing a key role in the development of chronic inflammation and Type 2 diabetes. Increased saturated fatty acids (SFAs) levels have been proposed to drive this specific polarization. Accordingly, we investigated the immunometabolic reprogramming in SFA-treated human macrophages.

Recent metabolomic developments for antimalarial drug discovery.

Malaria is a parasitic disease that remains a global health issue, responsible for a significant death and morbidity toll. Various factors have impacted the use and delayed the development of antimalarial therapies, such as the associated financial cost and parasitic resistance. In order to discover new drugs and validate parasitic targets, a powerful omics tool, metabolomics, emerged as a reliable approach.

Design, Synthesis, and Evaluation of Novel Pyruvate Dehydrogenase Kinase Inhibitors.

Aims: The present work describes the synthesis and the biological evaluation of novel compounds acting as pyruvate dehydrogenase kinase (PDK) inhibitors. These drugs should become a new therapeutic approach for the treatment of pathologies improved by the control of the blood lactate level.

Methods: Four series of compounds belonging to N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2- methylpropanamides and 1,2,4-benzothiadiazine 1,1-dioxides were prepared and evaluated as PDK inhibitors.

Kidney-targeted irradiation triggers renal ischemic preconditioning in mice.

Renal ischemia-reperfusion (I/R) causes acute kidney injury (AKI). Ischemic preconditioning (IPC) attenuates I/R-associated AKI. Whole body irradiation induces renal IPC in mice.

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells.

Myoferlin, an emerging oncoprotein, has been associated with a low survival in several cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated cancer cells to iron-dependent cell death, ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death.

Trypanosoma brucei: Metabolomics for analysis of cellular metabolism and drug discovery.

Background: Trypanosoma brucei is the causative agent of Human African Trypanosomiasis (also known as sleeping sickness), a disease causing serious neurological disorders and fatal if left untreated. Due to its lethal pathogenicity, a variety of treatments have been developed over the years, but which have some important limitations such as acute toxicity and parasite resistance. Metabolomics is an innovative tool used to better understand the parasite's cellular metabolism, and identify new potential targets, modes of action and resistance mechanisms.

MISpheroID: a knowledgebase and transparency tool for minimum information in spheroid identity.

Spheroids are three-dimensional cellular models with widespread basic and translational application across academia and industry. However, methodological transparency and guidelines for spheroid research have not yet been established. The MISpheroID Consortium developed a crowdsourcing knowledgebase that assembles the experimental parameters of 3,058 published spheroid-related experiments.

Metabolomic Signatures Discriminate Horses with Clinical Signs of Atypical Myopathy from Healthy Co-grazing Horses.

Atypical myopathy (AM) is a severe rhabdomyolysis syndrome that occurs in grazing horses. Despite the presence of toxins in their blood, all horses from the same pasture are not prone to display clinical signs of AM. The objective of this study was to compare the blood metabolomic profiles of horses with AM clinical signs with those of healthy co-grazing (Co-G) horses.