Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

Adenosine receptors (ARs) have been identified as promising therapeutic targets for countless pathological conditions, spanning from inflammatory diseases to central nervous system disorders, from cancer to metabolic diseases, from cardiovascular pathologies to respiratory diseases, and beyond. This extraordinary therapeutic potential is mainly due to the plurality of pathophysiological actions of adenosine and the ubiquitous expression of its receptors. This is, however, a double-edged sword that makes the clinical development of effective ligands with tolerable side effects difficult. Evidence of this is the low number of AR agonists or antagonists that have reached the market. An alternative approach is to target allosteric sites via allosteric modulators, compounds endowed with several advantages over orthosteric ligands. In addition to the typical advantages of allosteric modulators, those acting on ARs could benefit from the fact that adenosine levels are elevated in pathological tissues, thus potentially having negligible effects on normal tissues where adenosine levels are maintained low. Several A(1) and various A(3)AR allosteric modulators have been identified so far, and some of them have been validated in different preclinical settings, achieving promising results. Less fruitful, instead, has been the discovery of A(2A) and A(2B)AR allosteric modulators, although the results obtained up to now are encouraging. Collectively, data in the literature suggests that allosteric modulators of ARs could represent valuable pharmacological tools, potentially able to overcome the limitations of orthosteric ligands

Safety evaluations of a synthetic antimicrobial peptide administered intravenously in rats and dogs

The antimicrobial peptide SET-M33 is under study for the development of a new antibiotic against major Gram-negative pathogens. Here we report the toxicological evaluation of SET-M33 administered intravenously to rats and dogs. Dose range finding experiments determined the doses to use in toxicokinetic evaluation, clinical biochemistry analysis, necroscopy and in neurological and respiratory measurements. Clinical laboratory investigations in dogs and rats showed a dose-related increase in creatinine and urea levels, indicating that the kidneys are the target organ. This was also confirmed by necroscopy studies of animal tissues, where signs of degeneration and regeneration were found in kidney when SET-M33 was administered at the highest doses in the two animal species. Neurological toxicity measurements by the Irwin method and respiratory function evaluation in rats did not reveal any toxic effect even at the highest dose. Finally, repeated administration of SET-M33 by short infusion in dogs revealed a no-observed-adverse-effect-level of 0.5 mg/kg/day

Ascomicetes (Fungi: Ascomycota) del Parque Estatal Agua Blanca, Macuspana, Tabasco, México

Background and Aims: The diversity of the macroscopic ascomycetes currently known from the Agua Blanca State Park, Tabasco, is the result of several previous investigations of macromycetes at the state level. As there is no specific study on the ascomycetes of the aforementioned park, in this work the previous records were combined with the results of new explorations within this project.Methods: The Agua Blanca State Park is located in the western and northeastern region of the state of Tabasco, Mexico. Twenty eight explorations were carried out between December 2011 and July 2015. The material collected was deposited in the UJAT herbarium for its preservation and identification. Identification of the samples was carried out following the conventional mycological techniques.Key results: 129 specimens were revised, allowing for the determination of 22 species belonging to two classes, three orders, five families and eight genera. The genera Scutellinia and Rosellinia are reported for the first time for the state. The genus Xylaria is the most diverse with 10 species, while the genera Ophiocordyceps, Scutellinia, Hypoxylon and Rosellinia are the least diverse with one species each.Conclusions: Of the 22 species identified, 12(55%) were new records for Tabasco and 18(22%) were this for the study area, while 10(45%) of the species had previously been found in the state and 4(18%) in the reserve. Finally, this study shows a higher number of species evaluated compared to previous work.Antecedentes y Objetivos: La diversidad de los ascomicetos macroscópicos que se conoce actualmente en el Parque Estatal Agua Blanca, Tabasco, es el resultado de varias investigaciones previas sobre todos los macromicetos a nivel estatal. Como no existe un estudio específico sobre los ascomicetos del parque antes mencionado, en este trabajo se reunieron los registros anteriores con los resultados de nuevas exploraciones de este proyecto.Métodos: El Parque Estatal Agua Blanca se ubica en la región Oeste y Noreste del estado de Tabasco, México. Se realizaron 28 recorridos entre diciembre del 2011 y julio del 2015. El material recolectado se depositó en el herbario UJAT para su preservación e identificación. La identificación de las muestras se realizó siguiendo las técnicas convencionales de micología.Resultados clave: Se revisaron 129 especímenes, los cuales permitieron la determinación de 22 especies pertenecientes a dos clases, tres órdenes, cinco familias y ocho géneros. Los géneros Scutellinia y Rosellinia se reportan por primera vez para el estado. El género Xylaria es el más diverso con 10 especies, mientras que los géneros Ophiocordyceps, Scutellinia, Hypoxylon y Rosellinia son los menos diversos con una especie cada uno.Conclusiones: De las 22 especies determinadas, 12(55%) fueron nuevas citas para Tabasco y 18(82%) lo son para la zona de estudio, mientras que 10(45%) ya se habían encontrado previamente en Tabasco y 4(18%) en el parque. Finalmente, este estudio muestra un mayor número de especies evaluadas en comparación con lo reportado en trabajos previos

Riluzole use in presence of contraindications in adults affected by amyotrophic lateral sclerosis and its off-label use in other motor neuron diseases: Findings from an Italian multicentre study (the {CAESAR} project)

Background: This analysis describes the use of riluzole in amyotrophic lateral sclerosis (ALS) individuals with contraindications and off-label use for subjects with other motor neuron diseases (o-MND) in the Italian regions of Latium, Tuscany and Umbria.Methods: A cohort of adults with ALS prescribed with riluzole during the years 2016–2019 was enrolled from administrative healthcare databases, excluding subjects with o-MND in the preceding 5 years. Being affected by ALS for more than 5 years, presence of tracheostomy, renal or hepatic failure were considered as contraindications to the use of riluzole. A cohort of adults with o-MND was enrolled in 2016–2019 for whom off-label use of riluzole was retrieved up to 4 years, analysing over the time differences related to sex.Results: Among 206 ALS individuals prescribed with riluzole in Latium, 336 in Tuscany and 60 in Umbria, less than 1% were diagnosed with ALS for more than 5 years. Less than 2% were tracheotomised or affected by hepatic failure. Renal failure was documented for 1.9%, 2.7%, and 5.0% of ALS individuals in Latium, Tuscany and Umbria. The o-MND cohort comprised 264 subjects in Latium, 222 in Tuscany, and 66 in Umbria. Non-negligible off-label riluzole use was observed: 8.5%, 33.0%, and 4.2% in females, and 19.9%, 26.5% and 2.4% in males in Latium, Tuscany and Umbria.Discussion: Riluzole use in ALS individuals in the presence of contraindications is rare, with slightly higher numbers in presence of renal failure. Off-label use in o-MND was found to be non-negligible, with variations between sexes

Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy

Progressive myoclonus epilepsy (PME) of Unverricht-Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder with the highest incidence of PME worldwide. Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis in vivo in the developing mouse brain and in vitro in human cerebral organoids (hCOs) derived from EPM1 patients. We find that CSTB (but not one of its pathological variants) is secreted into the mouse cerebral spinal fluid and the conditioned media from hCOs. In embryonic mouse brain, we find that functional CSTB influences progenitors' proliferation and modulates neuronal distribution by attracting interneurons to the site of secretion via cell-non-autonomous mechanisms. Similarly, in patient-derived hCOs, low levels of functional CSTB result in an alteration of progenitor's proliferation, premature differentiation, and changes in interneurons migration. Secretion and extracellular matrix organization are the biological processes particularly affected as suggested by a proteomic analysis in patients' hCOs. Overall, our study sheds new light on the cellular mechanisms underlying the development of EPM1

Producción de basidiomas de Schizophyllum commune (Fungi: Basidiomycota) en subproductos agrícolas de Tabasco, México

Objective: The in vitro mycelial growth rate of Schizophyllum commune Fr. 1815 strainsfrom Tabasco, Mexico and the production of basidiomas in different regional agriculturalsubstrates was evaluated. Four strains were used: CCG003, CGG009, CCG010 andCGG13, and four substrates: cocoa peel (CP), banana leaves (BL), corn leaves (CL)and as a control, mulatto wood (MW). Based on the speed of growth, two strains andthree substrates were selected to evaluate the basidiomas production in two types ofcontainers: plastic bags and rectangular trays. Productivity was assessed based onBiological Efficiency (BE), Yield (Y) and Production Rate (PR). At 12 days of incubation,the highest mycelial growth rate was recorded in CP by CCG003 and CCG013 strains(51.6±22.1, and 64.4±18.1 mm d -1 ) and in HM and HP by CCG009 and CCG010 strains(86.9±17.8, and 58±7.8 mm d -1 ), compared to the control substrate (from 117.2±7.4 to 2120± 0.0 mm d -1 ). High production was recorded in the CC by the CCG009 strain, grownin bags, with BE of 12.8±2.6%, Y of 4.1 ± 0.8% and PR of 0.7±0.1%. The production ofS. commune was better in the bag than in the tray. This study represents an advance inthe production of basidiomas of this important fungus, as a food alternative for thetropical regions of Mexico.Objetivo: se evaluó la tasa de crecimiento micelial in vitro de cepas de Schizophyllum commune Fr. 1815 de Tabasco, México y la producción de basidiomas en diferentes sustratos agrícolas regionales.Diseño/metodología/aproximación: se utilizaron cuatro cepas: CCG003, CGG009, CCG010 y CGG13, y cuatro sustratos: cáscara de cacao (CC), hojas de plátano (HP), hojas de maíz (HM) y comotestigo se utilizó palo mulato (PM). Con base en la velocidad de crecimiento, se seleccionaron dos cepas y tres sustratos para evaluar la producción de basidiomas en dos tipos de contenedores:bolsas plásticas y bandejas rectangulares. La productividad se evaluó mediante la Eficiencia Biológica (EB), el Rendimiento (R) y la Tasa de Producción (TP).Resultados: a los 12 días de incubación, la mayor velocidad de crecimiento micelial se registró en CC por las cepas CCG003 y CCG013 (51.6±22.1 y 64.4±18.1 mm d-1) y en la HM y HP por las cepasCCG009 y CCG010 (86.9±17.8 y 58±7.8 mm d-1), en comparación con el sustrato testigo (de 117.2±7.4 120±0 mm d-1). La producción más alta se registró en la CC por la cepa CCG009 cultivada en bolsa, conuna EB de 12.8±2.6 %, R de 4.1±0.8 % y TP de 0.7±0.1. La producción de S. commune fue mejor en bolsa que en bandeja.Limitaciones del estudio/implicaciones: la escasa retención de humedad del sustrato, así como la plasticidad fenética que presenta la especie, impactan significativamente la producción de los basidiomasal inducir morfologías connadas de un tamaño menor.Hallazgos/conclusiones: este estudio representa un avance en la producción de basidiomas de este importante hongo, como una alternativa alimenticia para las regiones tropicales de México