TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

Abstract Ligands addressed to the mitochondrial Translocator Protein (TSPO) have been suggested as cell death/life and steroidogenesis modulators. Thus, TSPO ligands have been proposed as drug candidates in several diseases; nevertheless, a correlation between their binding affinity and in vitro efficacy has not been demonstrated yet, questioning the specificity of the observed effects. Since drug-target residence time is an emerging parameter able to influence drug pharmacological features, herein, the interaction between TSPO and irDE-MPIGA, a covalent TSPO ligand, was investigated in order to explore TSPO control on death/life processes in a standardized glioblastoma cell setting. After 90 min irDE-MPIGA cell treatment, 25 nM ligand concentration saturated irreversibly all TSPO binding sites; after 24 h, TSPO de-novo synthesis occurred and about 40 % TSPO binding sites resulted covalently bound to irDE-MPIGA. During cell culture treatments, several dynamic events were observed: (a) early apoptotic markers appeared, such as mitochondrial membrane potential collapse (at 3 h) and externalization of phosphatidylserine (at 6 h); (b) cell viability was reduced (at 6 h), without cell cycle arrest. After digitonin-permeabilized cell suspension treatment, a modulation of mitochondrial permeability transition pore was evidenced. Similar effects were elicited by the reversible TSPO ligand PIGA only when applied at micromolar dose. Interestingly, after 6 h, irDE-MPIGA cell exposure restored cell survival parameters. These results highlighted the ligand-target residence time and the cellular setting are crucial parameters that should be taken into account to understand the drug binding affinity and efficacy correlation and, above all, to translate efficiently cellular drug responses from bench to bedside

Examination of sleep in relation to dietary and lifestyle behaviors during Ramadan: A multi-national study using structural equation modeling among 24,500 adults amid COVID-19

Background Of around 2 billion Muslims worldwide, approximately 1.5 billion observe Ramadan fasting (RF) month. Those that observe RF have diverse cultural, ethnic, social, and economic backgrounds and are distributed over a wide geographical area. Sleep is known to be significantly altered during the month of Ramadan, which has a profound impact on human health. Moreover, sleep is closely connected to dietary and lifestyle behaviors. Methods This cross-sectional study collected data using a structured, self-administered electronic questionnaire that was translated into 13 languages and disseminated to Muslim populations across 27 countries. The questionnaire assessed dietary and lifestyle factors as independent variables, and three sleep parameters (quality, duration, and disturbance) as dependent variables. We performed structural equation modeling (SEM) to examine how dietary and lifestyle factors affected these sleep parameters. Results In total, 24,541 adults were enrolled in this study. SEM analysis revealed that during RF, optimum sleep duration (7–9 h) was significantly associated with sufficient physical activity (PA) and consuming plant-based proteins. In addition, smoking was significantly associated with greater sleep disturbance and lower sleep quality. Participants that consumed vegetables, fruits, dates, and plant-based proteins reported better sleep quality. Infrequent consumption of delivered food and infrequent screen time were also associated with better sleep quality. Conflicting results were found regarding the impact of dining at home versus dining out on the three sleep parameters. Conclusion Increasing the intake of fruits, vegetables, and plant-based proteins are important factors that could help improve healthy sleep for those observing RF. In addition, regular PA and avoiding smoking may contribute to improving sleep during RF

Translocator protein ligands as promising therapeutic tools for anxiety disorders

The Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is an 18 kDa mitochondrial protein primarily involved in steroid biosynthesis in both peripheral and glial cells. It has been extensively reported that TSPO regulates the rate-limiting translocation of cholesterol from the outer to the inner mitochondrial membrane before its transformation by cytochrome P450scc into pregnenolone, which is further converted into an array of different steroids. In the brain, neurosteroids such as allopregnanolone and pregnenolone, acting as positive modulators of γ-aminobutyric type A (GABAA) receptors, exert anxiolytic activity. Specific ligands targeting TSPO increase neurosteroid production and for this reason they have been suggested to play an important role in anxiety modulation. Unlike benzodiazepines (Bzs), which represent the most common anti-anxiety drugs administered around the world, selective TSPO ligands have shown anxiolytic effects in animal models without any of the side effects associated with Bzs. Therefore, specific TSPO ligands that are able to promote neurosteroidogenesis may represent the future of therapeutic treatment of anxiety disorders. Furthermore, TSPO expression levels are altered in several different psychiatric disorders in which anxiety is the main symptom. This article reviews the primary and patent literature over the last decade concerning the development of novel TSPO ligands that have resulted effective in various models of anxiety, taking into special consideration their structure-activity relationships

New data on the distribution area of the Atlas foxglove Digitalis atlantica (Pomel) / Nouvelles données sur l’aire de distribution de la Digitale de l’Atlas Digitalis atlantica (Pomel)

This study is a first aimed at searching for a plant strictly endemic to Algeria, Digitalis atlantica Pomel, for a possible evaluation of its conservation status. The research was conducted from March to July 2019 in the forests of the Babor mountains, in the north-eastern area of Kabylia, likely to contain this species. The discovery of three new locations of the Atlas foxglove, outside its historical occurrence, has allowed the collection of new data on this species and its range. The conservation of the species is expected to be problematic because the three new forests sites do not benefit from protected area status.Cette étude est une première exploration visant la recherche d’une plante endémique stricte d’Algérie la Digitale de l’Atlas, Digitalis atlantica Pomel pour une éventuelle évaluation de son état de conservation. Les recherches se sont déroulées durant la période allant de mars à juillet 2019 dans les forêts de montagne de la Kabylie des Babors susceptibles d’abriter cette espèce. La découverte de trois nouvelles stations de la Digitale de l’Atlas, en dehors de sa présence dans les sites historiques, a permis de recueillir de nouvelles données sur cette espèce et sur son aire de distribution. La conservation de l’espèce est problématique car les trois forêts échantillonnées ne bénéficient pas du statut de zone protégée.Chelli-Tabti Dalila, Markhouf Sabrina, Derradji Soria, Hamitouche Souad, Bouchareb Abdelouhab, Bougaham Abdelazize Franck. New data on the distribution area of the Atlas foxglove Digitalis atlantica (Pomel) / Nouvelles données sur l’aire de distribution de la Digitale de l’Atlas Digitalis atlantica (Pomel). In: Ecologia mediterranea, tome 46 n°1, 2020. pp. 41-47

Anxiolytic properties of a 2-phenylindolglyoxylamide TSPO ligand: Stimulation of in vitro neurosteroid production affecting GABA(A) receptor activity

A number of neurosteroids have been demonstrated to exert anxiolytic properties by means of a positive modulation of inhibitory GABAergic neurotransmission. The observation that neurosteroid synthesis can be pharmacologically regulated by ligands to the mitochondrial translocator protein (TSPO) has prompted the search for new, more selective TSPO ligands able to stimulate steroidogenesis with great efficacy. In the present study, the potential anxiolytic activity of a selective TSPO ligand, N,N-di-n-propyl-2-(4-methylphenyl)indol-3-ylglyoxylamide (MPIGA), was tested by means of the elevated plus maze paradigm. Moreover, the in vitro effects on synaptoneurosomal GABAA receptor (GABAAR) activity exerted by the conditioned salt medium from MPIGA-treated ADF human glial cells were investigated. MPIGA (30 mg/kg) was found to affect rats’ performance in the elevated plus maze test significantly, leading to an increase in both entries and time spent in the open arms. This same dose of MPIGA had no effect on rats’ spontaneous exploratory activity. The conditioned salt medium from MPIGA-treated ADF cells potentiated the 36Cl uptake into cerebral cortical synaptoneurosomes. The exposure of ADF cells to MPIGA stimulated the production of pregnelonone derivatives including allopregnanolone, one of the major positive GABAAR allosteric modulator. In conclusion, the TSPO ligand MPIGA is a promising anxiolytic drug. The mechanism of action by which MPIGA exerts its anxiolytic activity was identified in the stimulation of endogenous neurosteroid production, which in turn determined a positive modulation of GABAAR activity, thus opening the way to the potential use of this TSPO ligand in anxiety and depressive disorders

New Fluorescent 2-Phenylindoleglyoxylamide Derivatives as Probes Targeting the Peripheral-Type Benzodiazepine Receptor: Design, Synthesis, and Biological Evaluation

Fluorescent ligands for the peripheral-type benzodiazepine receptor (PBR) featuring the 7-nitrobenz-2-oxa-1,3-diazol-4-yl moiety were synthesized, based on N,N-dialkyl-2-phenylindol-3-ylglyoxylamides, a potent, selective class of PBR ligands previously described by us. All the new ligands are moderately to highly potent at the PBR, with a complete selectivity over the central benzodiazepine receptor. Results from fluorescence microscopy showed that these probes specifically labeled the PBR at the mitochondrial level in C6 glioma cells