Effects of Haloperidol,Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 Microglial Cells

Microglial cells are resident macrophages in the brain that have been implicated in the pathophysiology of schizophrenia. There is a lack of studies covering the effects of antipsychotics on microglial cells. The current literature points to a possible anti-inflammatory action without clear mechanisms of action. The aim of this study is to characterize the effects of haloperidol, risperidone and aripiprazole on BV-2 microglial cells in in vitro conditions. We have used immunofluorescence and flow cytometry to analyze the classical pro and anti-inflammatory markers, while a real-time metabolic assay (Seahorse) was used to assess metabolic function. We analyzed the expression of p70S6K to evaluate the mTOR pathway activity with Western blot. In this study, we demonstrate the varying effects of haloperidol, risperidone and aripiprazole administration in BV-2 microglial cells. All three tested antipsychotics were successful in reducing the pro-inflammatory action of microglial cells, although only aripiprazole increased the expression of anti-inflammatory markers. Most significant differences in the possible mechanisms of action were seen in the real-time metabolic assays and in the mTORC1 signaling pathway activity, with aripiprazole being the only antipsychotic to reduce the mTORC1 activity. Our results shed some new light on the effects of haloperidol, risperidone and aripiprazole action in microglial cells, and reveal a novel possible mechanism of action for aripiprazole.     

Muscle Diversity,Heterogeneity, and Gradients: Learning from Sarcoglycanopathies

Skeletal muscle, the most abundant tissue in the body, is heterogeneous. This heterogeneity forms the basis of muscle diversity, which is reflected in the specialized functions of muscles in different parts of the body. However, these different parts are not always clearly delimitated, and this often gives rise to gradients within the same muscle and even across the body. During the last decade, several studies on muscular disorders both in mice and in humans have observed particular distribution patterns of muscle weakness during disease, indicating that the same mutation can affect muscles differently. Moreover, these phenotypical differences reveal gradients of severity, existing alongside other architectural gradients. These two factors are especially prominent in sarcoglycanopathies. Nevertheless, very little is known about the mechanism(s) driving the phenotypic diversity of the muscles affected by these diseases. Here, we will review the available literature on sarcoglycanopathies, focusing on phenotypic differences among affected muscles and gradients, characterization techniques, molecular signatures, and cell population heterogeneity, highlighting the possibilities opened up by new technologies. This review aims to revive research interest in the diverse disease phenotype affecting different muscles, in order to pave the way for new therapeutic interventions.     

An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram-negative Pathogens and Reduced ex vivo Cochleotoxicity

We describe the convergent synthesis of a 5-O-β-D-ribofuranosyl-based apramycin derivative (apralog) that displays significantly improved antibacterial activity over the parent apramycin against wild-type ESKAPE pathogens. In addition, the new apralog retains excellent antibacterial activity in the presence of the only aminoglycoside modifying enzyme (AAC(3)-IV) acting on the parent, without incurring susceptibility to the APH(3’) mechanism that disables other 5-O-β-D-ribofuranosyl 2-deoxystreptamine type aminoglycosides by phosphorylation at the ribose 5-position. Consistent with this antibacterial activity, the new apralog has excellent 30 nM activity (IC₅₀) for the inhibition of protein synthesis by the bacterial ribosome in a cell-free translation assay, while retaining the excellent across-the-board selectivity of the parent for inhibition of bacterial over eukaryotic ribosomes. Overall, these characteristics translate into excellent in vivo efficacy against E. coli in a mouse thigh infection model and reduced ototoxicity vis à vis the parent in mouse cochlear explants.     

Synthesis of Hydroxylated Biphenyl Derivatives Bearing an α,β-Unsaturated Ketone as a Lead Structure for the Development of Drug Candidates against Malignant Melanoma

A small collection of C₂-symmetric hydroxylated biphenyl derivatives featuring an α,β-unsaturated ketone as a lead structure was prepared, and the capacity of these compounds to act as antiproliferative agents against four human malignant melanoma cell lines was assayed. The prodrug approach was applied in order to improve the delivery of compounds into the cell by modulation of the phenolic hydroxy protecting group. The hydroxylated biphenyl structure bearing an α,β-unsaturated ketone and a phenolic-O-prenylated chain was found to facilitate the delivery of the molecule and interactions with biological targets. Four compounds showed antiproliferative activity resulting in IC₅₀ values in the range of 1.2 to 2.8 μM.     

Long-term lime and phosphogypsum broadcast affects phosphorus cycling in a tropical Oxisol cultivated with soybean under no-till

Nutrient Cycling in Agroecosystems - Broadcast application of lime or phosphogypsum to suppress aluminum (Al) in soils can influence chemistry and fate of phosphorus (P) in natural environments....     

Toxic and genotoxic evaluation of six antibiotics on non-target organisms

The ecotoxicity of the following six antibiotics on aquatic organisms was investigated: Erythromycin, Oxytetracyclin, Sulfamethoxazole, Ofloxacin, Lincomycin and Clarithromycin. Bioassays were performed on bacteria, algae, rotifers, microcrustaceans and fish to assess acute and chronic toxicity, while SOS Chromotest and Ames test were used to detect the genotoxic potential of the investigated drugs. For risk assessment, the environmental impact was calculated by MEC/PNEC ratio using the available data from the literature regarding their occurrence in the aquatic environment and the toxicity data obtained from the bioassays performed. The ecotoxicological results showed that acute toxicity was in the order of mg/L while, for the chronic data the antibiotics were bioactive at concentrations in the order of microg/L, mainly for the algae. Drugs investigated were one or two order of magnitude less active against rotifers and crustaceans. Ofloxacin was the only genotoxic compound and Sulfamethoxazole, Ofloxacin and Lincomycin were mutagenic. As for environmental risk, the macrolides were found to be the most harmful for the aquatic environment.     

Integrated analysis of non-linear loss mechanisms in Yb:YAG ceramics for laser applications

Transparent 9.8 at% Yb:YAG ceramic samples were prepared by reactive sintering of commercial oxides and using 0 or 1 wt% polyethylene glycol (PEG) as dispersant. The optical quality of the samples turns out to be improved by using a dispersant and optical transmittance close to the commercial samples has been obtained. On the other hand the laser characterization evidenced the activation of a non-linear loss mechanism occurring only in the sample containing PEG and despite its better optical quality, at high excitation level. A SEM analysis of material microstructure could not explain this behavior. A state of the art TEM analysis at nanometric scale was performed providing high resolution chemical spectroscopic results that indicate the presence of amorphous and crystalline silicate phases playing different roles in the two samples.     

Development of albendazole sulfoxide-loaded Eudragit microparticles: A potential strategy to improve the drug bioavailability

Albendazole sulfoxide (ABZSO), a broad spectrum anthelmintic drug extensively used in veterinary medicine, exhibits a low and erratic bioavailability due to its poor solubility in biological fluids. The aims of this study were the development, physicochemical characterization, and in vitro release profile evaluation of ABZSO-loaded Eudragit RS PO® microparticles (MPs) in order to improve the rate of dissolution and the dissolved percentage of the drug in pH 7.4. MPs were successfully obtained by the emulsification/solvent evaporation method, achieving entrapment efficiency and process yield of about 60% and mean size of 254 nm. The in vitro release profile study showed that dissolution of ABZSO followed a pseudo-second order kinetics and MPs were able to increase significantly (p < 0.05) the rate of dissolution of ABZSO compared to the micronized and non-micronized free drug, what could lead to an improvement in bioavailability and, consequently, in the antiparasitic activity.     

Word Learning in Very Young Children From Infant‐Directed DVDs

This study examined if babies (6–24 months; n = 60) learn words from a DVD modeled on Baby Einstein?. The study was novel in that it utilized an infant‐directed DVD, but was edited to include low‐frequency words (e.g., medallion) and it utilized the preferential looking method in the posttest so that very young babies could be tested. Results suggested that babies could learn the novel words in the live condition; however, they did not appear to learn them in the video condition. Furthermore, there was no age effect in the video condition. Finally, there was no relationship between visual attention to the video and learning from it. Thus, high attention did not necessarily result in learning.