Multitarget 2'-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities.

The complex nature of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD) calls for multidirectional treatment. Restoring neurotransmitter levels by combined inhibition of cholinesterases (ChEs) and monoamine oxidases (MAOs, MAO-A and MAO-B), in conjunction with strategies to counteract amyloid ß (Aß) aggregation, may constitute a therapeutically strong multi-target approach for the treatment of NDDs. Chalcones are a subgroup of flavonoids with a broad spectrum of biological activity. We report here the synthesis of 2'-hydroxychalcones as MAO-A and MAO-B inhibitors. Compounds 5c (IC50 = 0.031 ± 0.001 µM), 5a (IC50 = 0.084 ± 0.003 µM), 2c (IC50 = 0.095 ± 0.019 µM) and 2a (IC50 = 0.111 ± 0.006 µM) were the most potent, selective and reversible inhibitors of human (h)MAO-B isoform. hMAO-B inhibitors 1a, 2a and 5a also inhibited murine MAO-B in vivo in mouse brain homogenates. Molecular modelling rationalised the binding mode of 2'-hydroxychalcones in the active site of hMAO-B. Additionally, several derivatives inhibited murine acetylcholinesterase (mAChE) (IC50 values from 4.37 ± 0.83 µM to 15.17 ± 6.03 µM) and reduced the aggregation propensity of Aß. Moreover, some derivatives bound to the benzodiazepine binding site (BDZ-bs) of the γ-aminobutyric acid A (GABAA) receptors (1a and 2a with Ki = 4.9 ± 1.1 µM and 5.0 ± 1.1 µM, respectively), and exerted sedative and/or anxiolytic like effects on mice. The biological results reported here on 2'-hydroxychalcones provide an extension to previous studies on chalcone scaffold and show them as a potential treatment strategy for NDDs and their associated comorbidities.

The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid homeostasis.

Mutations in the ATP13A2 gene (PARK9, CLN12, OMIM 610513) were initially associated with a form of Parkinson's Disease (PD) known as Kufor Rakeb Syndrome (KRS). However, the genetic spectrum of ATP13A2-associated disorders was expanded in the last years, because it has been found to underlay variants of neuronal ceroid-lipofuscinoses (NCLs) and hereditary spastic paraplegia. As ATP13A2 seems to be a key component of the endo-lysosome pathway, the fact that these pathologies are commonly characterized by endo-lysosomal dysfunction is not surprising. Here we report that increasing the level of functional ATP13A2 in a stable SH-SY5Y cell line disrupts lipid homeostasis. ATP13A2 overexpression increases the fluorescence intensity of the fluorescent analog phosphatidylethanolamine (NBD-PE) and the formation of multilamellar bodies, resembling the so-called "drug-induced phospholipidosis". We also found that expression of ATP13A2 reduces the ceramide-fluorescence intensity and the content of bis(monoacylglyceryl)phosphate (BMP). BMP is required for lipid degradation and exosome biogenesis inside acidic compartments, so this result suggests that ATP13A2 may be modifying the lipid digestion capacity and/or the redistribution of lipids in these subcellular organelles. In addition, ATP13A2-overexpression decreased the total content of triglycerides (TGs), cholesterol and lipid droplets. As TGs are necessary for the synthesis of new membranes, this observation suggests that increasing the function of ATP13A2 switches the endo-lysosomal system towards vesicle secretion.

Chalcone derivatives: synthesis, in vitro and in vivo evaluation of their anti-anxiety, anti-depression and analgesic effects.

Anxiety disorders, depression and pain are highly prevalent pathologies. Their pharmacotherapy is associated with unwanted side effects; hence there is a clinical need to develop more effective drugs with fewer adverse reactions. Chalcones are one of the major classes of naturally occurring compounds. Chalcones and their derivatives have a huge importance in medicinal chemistry, displaying a wide range of pharmacological activities including anti-inflammatory, antimicrobial, antioxidant, cytotoxic and antitumor actions. The aim of this work was to evaluate chalcone effects on different targets involved in these pathologies. We have synthesized a series of simple chalcone derivatives taking common structural requirements described in literature related to their anxiolytic-like, antidepressant-like and/or antinociceptive properties into account. Furthermore, their potential in vitro effects towards different targets involved in these pathologies were evaluated. We have obtained twenty chalcones with moderate to high yields and assessed their ability to bind distinctive receptors, from rat brain homogenates, by displacement of labelled specific ligands: [3H] FNZ (binding site of benzodiazepines/GABAA), [3H] 8-OH-DPAT (serotonin 5-HT1A) and [3H] DAMGO (µ-opioid). Those compounds that showed the better in vitro activities were evaluated in mice using different behavioural tasks. In vivo results showed that 5'-methyl-2'-hydroxychalcone (9) exerted anxiolytic-like effects in mice in the plus maze test. While chalcone nuclei (1) revealed antidepressant-like activities in the tail suspension test. In addition, the novel 5'-methyl-2'-hydroxy-3'-nitrochalcone (12) exhibited antinociceptive activity in acute chemical and thermal nociception tests (writhing and hot plate tests). In conclusion, chalcones are thus promising compounds for the development of novel drugs with central nervous system (CNS) actions.

Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys.

Leydig-cell tumours (LCTs) are rare endocrine tumours of the testicular interstitium, with recent increased incidence. Symptoms include precocious puberty in children; and erectile dysfunction, infertility and/or gynaecomastia, in adults. So far, scientific evidence points to aromatase (CYP19) overexpression and excessive oestrogen and insulin-like growth factor (IGF) -1 production as responsible for Leydig-cell tumourigenesis. LCTs are usually benign; however, malignant LCTs respond poorly to chemo/radiotherapy, highlighting the need to identify novel targets for treatment. Herein, we investigated the potential role of the histamine receptor H4 (HRH4) as a therapeutic target for LCTs using R2C rat Leydig tumour cells, a well-documented in vitro model for Leydigioma. Also, we studied for the first time the expression of CYP19, IGF-1R, oestrogen receptor (ER) α, ERß, androgen receptor (AR) and HRH4 in human prepubertal LCTs versus normal prepubertal testes (NPTs). HRH4 agonist treatment inhibited steroidogenesis and proliferation in R2C cells and also negatively affected their pro-angiogenic capacity in vitro and in vivo, as assessed by evaluating the proliferative activity of human umbilical vein endothelial cells and by means of the quail chorioallantoic membrane assay, respectively. Moreover, E2 and IGF-1 inhibited HRH4 mRNA and protein levels. In human prepubertal LCTs, CYP19, IGF-1R, ERα and ERß were overexpressed compared with NPTs. In contrast, HRH4 staining was weak in LCTs, but moderate/strong and confined to the interstitium in NPTs. Importantly, HRH4 was absent or barely detectable in seminiferous tubules or germ cells. Overall, our results point to HRH4 as a novel therapeutic target in LCTs.

Seasonality of respiratory syncytial virus in Buenos Aires. Relationship with global climate change.

INTRODUCTION: Global climate change circulation pattern respiratory syncytial virus (RSV). We assessed whether RSV season has changed over the past 20 years and its correlation with mean annual temperature. METHODS: Cross-sectional study that included records of RSV and temperatures from Buenos Aires (1995-2014). RSV season onset, offset and duration, and its correlation with mean annual temperature were described for each year. RESULTS: A total of 8109 RSV infections were identified. The duration of RSV season reduced significantly (1995: 29 weeks vs. 2014: 17 weeks; R: 0.6; p < 0.001) due to an early ending (1995: week 45 vs. 2014: week 33; R: 0.6; p < 0.001). No correlation was observed between mean annual temperature and RSV season start, end and duration. CONCLUSIONS: Over the past 20 years, RSV season shortened significantly, but no correlation with temperature was observed.

INTRODUCTION: El cambio climático global podría modificar la circulación del virus sincicial respiratorio (VSR). Evaluamos si la temporada de VSR se modificó en los últimos 20 años y su correlación con la temperatura media anual. METHODS: Estudio transversal, en el que se utilizaron registros de VSR y temperatura de la Ciudad de Buenos Aires (19952014). Para cada año, describimos el inicio, el fin y la duración de la temporada de VSR y su correlación con la temperatura media anual. RESULTS: Se identificaron 8109 infecciones por VSR. La duración de la temporada disminuyó significativamente (1995: 29 semanas vs. 2014: 17 semanas; R: 0,6; p < 0,001), debido a una finalización más precoz (1995: semana 45 vs. 2014: semana 33; R: 0,6; p < 0,001). No se observó correlación entre la temperatura media anual y la duración, el comienzo ni la finalización de la temporada de VSR. CONCLUSIONS: En los últimos 20 años, la duración de la temporada de VSR se acortó significativamente, sin correlación con la temperatura.

Sexual selection in a polygynous rodent (Ctenomys talarum): an analysis of fighting capacity.

The South American subterranean rodent genus Ctenomys (Caviomorpha: Octodontoidea), which uses both claws and teeth to dig, shows striking morphological adaptations to its specialized mode of life. Among other traits, the genus has evolved a powerful jaw musculature and procumbent incisors that are used for dento-excavation. Behavioral observations indicate that these traits are also used during male aggressive encounters, which characterize the polygynous mating system of one of the species of the genus, Ctenomys talarum. A question emerges about sexual selection: could it have induced further changes in traits primarily evolved as adaptations for digging? To address this issue, we studied functional and morphological attributes of the jaw and incisors in specimens of C. talarum. Incisor bite forces were measured on wild females and males from a local population (Mar de Cobo; Buenos Aires Province) by means of a strain gauge load cell force transducer. Museum specimens coming from the same population were studied to assess anatomical attributes of both sexes. Since this species exhibits dimorphism in body size, the possible effect of body mass on the studied traits was analyzed. Males and females showed significant differences in biting performance and mandibular width, but when size was taken into account these differences disappeared. However, other dimorphic traits can vary with a certain independence with respect to size, particularly the 2nd moment of area of the incisors and, to a lesser extent, incisor procumbency. The former geometrical parameter, which is proportional to the bending strength, was highly dimorphic. This fact suggests that, during aggressive encounters between males, biting would place large bending loads on the incisors.

[Antipoliomyelitic vaccination in children living in Buenos Aires City]. / Vacunación antipoliomielítica en niños de la Ciudad de Buenos Aires.

Following the presentation of a confirmed case of paralytic polio Sabin-derived virus (VSD) in a child of 15 months we analyzed the coverage of poliomyelitis vaccination in children living in the City of Buenos Aires, in the 2006/2008 triennium. There was an improvement over the period analyzed, but values above 95% were reached only for the first dose. The proportion of inactivated vaccine (IPV) increased at the expense of live oral vaccine (OPV); in 2008, the first dose IPV coverage was 37.64% and 19.48% for the school entrance. The lack of intestinal immunity that occurs in children immunized with IPV, plus a poor coverage with OPV, allows the circulation of wild virus or VSD favoring the occurrence of paralytic poliomyelitis in unvaccinated or immunocompromised children.

Vacunación antipoliomielítica en niños de la Ciudad de Buenos Aires / Antipoliomyelitic vaccination in children living in Buenos Aires City

A raíz de la presentación de un caso confirmado de poliomielitis paralítica por virus Sabin derivado (VSD) en niños de 15 meses se analizó la cobertura de vacunación antipoliomielítica en niños residentes en la Ciudad de Buenos Aires, durante el trienio 2006/2008. Se observó una mejora a lo largo del período analizado, pero sólo hubo valores superiores al 95 por ciento para la primera dosis. Aumentó la proporción de vacuna inactivada (IPV) en desmedro de la vacuna oral viva (OPV); en 2008, la cobertura con IPV primera dosis fue del 37,64 por ciento y del 19,48 por ciento para el ingreso escolar. La falta de inmunidad intestinal que se presenta en los niños vacunados con IPV, asociada a coberturas insatisfactorias condiciona un terreno propicio para la circulación de virus salvaje o VSD, lo cual favorece la aparición de casos de poliomielitis paralítica en niños no vacunados o inmunodeficientes.

Vacunación antipoliomielítica en niños de la Ciudad de Buenos Aires / Antipoliomyelitic vaccination in children living in Buenos Aires City

A raíz de la presentación de un caso confirmado de poliomielitis paralítica por virus Sabin derivado (VSD) en niños de 15 meses se analizó la cobertura de vacunación antipoliomielítica en niños residentes en la Ciudad de Buenos Aires, durante el trienio 2006/2008. Se observó una mejora a lo largo del período analizado, pero sólo hubo valores superiores al 95 por ciento para la primera dosis. Aumentó la proporción de vacuna inactivada (IPV) en desmedro de la vacuna oral viva (OPV); en 2008, la cobertura con IPV primera dosis fue del 37,64 por ciento y del 19,48 por ciento para el ingreso escolar. La falta de inmunidad intestinal que se presenta en los niños vacunados con IPV, asociada a coberturas insatisfactorias condiciona un terreno propicio para la circulación de virus salvaje o VSD, lo cual favorece la aparición de casos de poliomielitis paralítica en niños no vacunados o inmunodeficientes.(AU)

Photocatalytic printing of inorganic nanopatterns via poly(styrene-block-carbosilane) copolymer thin films on titania substrates.

Well-defined, ordered arrays of nanoscale depressions were obtained in linear-brush-type polystyrene-block-polycarbosilane (PS-b-PCS) diblock copolymer thin films by acetone vapor annealing and silica nanodot arrays were directly obtained from such thin films deposited on a titania substrate by one-step exposure to UV light as a result of transformation of the PCS units to silica, driven by the photocatalytic activity of titania concurrent with removal of the organic matrix.