Roles of the Unsaturated Fatty Acid Docosahexaenoic Acid in the Central Nervous System: Molecular and Cellular Insights

Fatty acids (FAs) are essential components of the central nervous system (CNS), where they exert multiple roles in health and disease. Among the FAs, docosahexaenoic acid (DHA) has been widely recognized as a key molecule for neuronal function and cell signaling. Despite its relevance, the molecular pathways underlying the beneficial effects of DHA on the cells of the CNS are still unclear. Here, we summarize and discuss the molecular mechanisms underlying the actions of DHA in neural cells with a special focus on processes of survival, morphological development, and synaptic maturation. In addition, we examine the evidence supporting a potential therapeutic role of DHA against CNS tumor diseases and tumorigenesis. The current results suggest that DHA exerts its actions on neural cells mainly through the modulation of signaling cascades involving the activation of diverse types of receptors. In addition, we found evidence connecting brain DHA and ω-3 PUFA levels with CNS diseases, such as depression, autism spectrum disorders, obesity, and neurodegenerative diseases. In the context of cancer, the existing data have shown that DHA exerts positive actions as a coadjuvant in antitumoral therapy. Although many questions in the field remain only partially resolved, we hope that future research may soon define specific pathways and receptor systems involved in the beneficial effects of DHA in cells of the CNS, opening new avenues for innovative therapeutic strategies for CNS diseases.     

Reactions with 5-substituted 4-arylimino-2-thiazolidinones

The reaction of 5-arylidene-4-arylimino-2-thiazolidinones 4 with GRIGNARD reagents effected 1,4-addition to the exocyclic  CC bond with the formation of 5 . Alkylation of the arylidene derivatives 4 with diazomethane or methyl iodide results in the formation of the N-methyl derivatives 6 . Treatment of 6 with phenylmagnesium bromide effects addition of the reagent to the double bond of the lateral chain to yield products, proved to have structure 8 . The 5-arylazo derivatives 9 of 4-arylimino-2-thiazolidinones were obtained by coupling 4 with aromatic diazonium chlorides. Compounds 9 were N-methylated with diazomethane to yield 10 .     

An approach to accidents modeling based on compounds road environments

The most common approach to study the influence of certain road features on accidents has been the consideration of uniform road segments characterized by a unique feature. However, when an accident is related to the road infrastructure, its cause is usually not a single characteristic but rather a complex combination of several characteristics. The main objective of this paper is to describe a methodology developed in order to consider the road as a complete environment by using compound road environments, overcoming the limitations inherented in considering only uniform road segments. The methodology consists of: dividing a sample of roads into segments; grouping them into quite homogeneous road environments using cluster analysis; and identifying the influence of skid resistance and texture depth on road accidents in each environment by using generalized linear models. The application of this methodology is demonstrated for eight roads. Based on real data from accidents and road characteristics, three compound road environments were established where the pavement surface properties significantly influence the occurrence of accidents. Results have showed clearly that road environments where braking maneuvers are more common or those with small radii of curvature and high speeds require higher skid resistance and texture depth as an important contribution to the accident prevention.     

Green Synthesis of Silymarin–Chitosan Nanoparticles as a New Nano Formulation with Enhanced Anti-Fibrotic Effects against Liver Fibrosis

Background: Silymarin (SIL) has long been utilized to treat a variety of liver illnesses, but due to its poor water solubility and low membrane permeability, it has a low oral bioavailability, limiting its therapeutic potential. Aim: Design and evaluate hepatic-targeted delivery of safe biocompatible formulated SIL-loaded chitosan nanoparticles (SCNPs) to enhance SIL’s anti-fibrotic effectiveness in rats with CCl₄-induced liver fibrosis. Methods: The SCNPs and chitosan nanoparticles (CNPs) were prepared by ionotropic gelation technique and are characterized by physicochemical parameters such as particle size, morphology, zeta potential, and in vitro release studies. The therapeutic efficacy of successfully formulated SCNPs and CNPs were subjected to in vivo evaluation studies. Rats were daily administered SIL, SCNPs, and CNPs orally for 30 days. Results: The in vivo study revealed that the synthesized SCNPs demonstrated a significant antifibrotic therapeutic action against CCl₄-induced hepatic injury in rats when compared to treated groups of SIL and CNPs. SCNP-treated rats had a healthy body weight, with normal values for liver weight and liver index, as well as significant improvements in liver functions, inflammatory indicators, antioxidant pathway activation, and lipid peroxidation reduction. The antifibrotic activities of SCNPs were mediated by suppressing the expression of the main fibrosis mediators TGFβR1, COL3A1, and TGFβR2 by boosting the hepatic expression of protective miRNAs; miR-22, miR-29c, and miR-219a, respectively. The anti-fibrotic effects of SCNPs were supported by histopathology and immunohistochemistry (IHC) study. Conclusions: According to the above results, SCNPs might be the best suitable carrier to target liver cells in the treatment of liver fibrosis.     

Selective Recovery of Cadmium,Cobalt, and Nickel from Spent Ni–Cd Batteries Using Adogen® 464 and Mesoporous Silica Derivatives

Spent Ni–Cd batteries are now considered an important source for many valuable metals. The recovery of cadmium, cobalt, and nickel from spent Ni–Cd Batteries has been performed in this study. The optimum leaching process was achieved using 20% H₂SO₄, solid/liquid (S/L) 1/5 at 80 °C for 6 h. The leaching efficiency of Fe, Cd, and Co was nearly 100%, whereas the leaching efficiency of Ni was 95%. The recovery of the concerned elements was attained using successive different separation techniques. Cd(II) ions were extracted by a solvent, namely, Adogen^® 464, and precipitated as CdS with 0.5% Na₂S solution at pH of 1.25 and room temperature. The extraction process corresponded to pseudo-2nd-order. The prepared PTU-MS silica was applied for adsorption of Co(II) ions from aqueous solution, while the desorption process was performed using 0.3 M H₂SO₄. Cobalt was precipitated at pH 9.0 as Co(OH)₂ using NH₄OH. The kinetic and thermodynamic parameters were also investigated. Nickel was directly precipitated at pH 8.25 using a 10% NaOH solution at ambient temperature. FTIR, SEM, and EDX confirm the structure of the products.     

Genetic LGALS1 Variants Are Associated with Heterogeneity in Galectin-1 Serum Levels in Patients with Early Arthritis

Galectin 1 (Gal1) exerts immunomodulatory effects leading to therapeutic effects in autoimmune animal models. Patients with rheumatoid arthritis have been reported to show higher Gal1 serum levels than the healthy population. Our study aimed to find genetic variants on the Gal1 gene (LGALS1) modulating its expression and/or clinical features in patients with early arthritis (EA). LGALS1 was sequenced in 53 EA patients to characterize all genetic variants. Then, we genotyped rs9622682, rs929039, and rs4820293, which covered the main genetic variation in LGALS1, in 532 EA patients. Gal1 and IL-6 serum levels were measured by ELISA and Gal1 also by western blot (WB) in lymphocytes from patients with specific genotypes. Once disease activity improved with treatment, patients with at least one copy of the minor allele in rs9622682 and rs929039 or those with GG genotype in rs4820293 showed significantly higher Gal1 serum levels (p < 0.05). These genotypic combinations were also associated with higher Gal1 expression in lymphocytes by WB and lower IL-6 serum levels in EA patients. In summary, our study suggests that genetic variants studied in LGALS1 can explain heterogeneity in Gal1 serum levels showing that patients with higher Gal1 levels have lower serum IL-6 levels.     

Effects of Dietary n-3 LCPUFA Supplementation on the Hippocampus of Aging Female Mice: Impact on Memory,Lipid Raft-Associated Glutamatergic Receptors and Neuroinflammation

Long-chain polyunsaturated fatty acids (LCPUFA), essential molecules whose precursors must be dietary supplied, are highly represented in the brain contributing to numerous neuronal processes. Recent findings have demonstrated that LCPUFA are represented in lipid raft microstructures, where they favor molecular interactions of signaling complexes underlying neuronal functionality. During aging, the brain lipid composition changes affecting the lipid rafts’ integrity and protein signaling, which may induce memory detriment. We investigated the effect of a n-3 LCPUFA-enriched diet on the cognitive function of 6- and 15-months-old female mice. Likewise, we explored the impact of dietary n-3 LCPUFAs on hippocampal lipid rafts, and their potential correlation with aging-induced neuroinflammation. Our results demonstrate that n-3 LCPUFA supplementation improves spatial and recognition memory and restores the expression of glutamate and estrogen receptors in the hippocampal lipid rafts of aged mice to similar profiles than young ones. Additionally, the n-3 LCPUFA-enriched diet stabilized the lipid composition of the old mice’s hippocampal lipid rafts to the levels of young ones and reduced the aged-induced neuroinflammatory markers. Hence, we propose that n-3 LCPUFA supplementation leads to beneficial cognitive performance by “rejuvenating” the lipid raft microenvironment that stabilizes the integrity and interactions of memory protein players embedded in these microdomains.     

Identification of Spliceogenic Variants beyond Canonical GT-AG Splice Sites in Hereditary Cancer Genes

Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.     

Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15–20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.