Neuroinflammation is a key process in Alzheimer’s disease (AD). We aimed to examine the development and evaluation of a comprehensive in vitro model that captures the complex interplay between neurons and immune cell types. Retinoic acid-differentiated SH-SY5Y neuroblastoma cells exposed to LPS-conditioned media (CM) from RAW264.7 macrophages, BV2 microglia, and HL60 promyelocytic cells differentiated into neutrophil- or monocyte-like phenotypes were analyzed. The effects of CM containing inflammatory factors on neuronal viability and function were systematically evaluated. Neuronal oxidative stress, mitochondrial function, autophagy and protein aggregates were analyzed. The involvement of insulin resistance was studied by assaying glucose uptake and determining its IC₅₀ values for cell viability improvement and GSK3β phosphorylation. After short-term exposure (3 h), most inflammatory CMs induced peroxide production in neurons, with the strongest effect observed in media from DMSO- or RA-differentiated HL60 cells. Mitochondrial membrane potential was markedly reduced by LPS-stimulated BV2 and HL60-derived CMs. Prolonged exposure (72 h) revealed partial normalization of oxidative stress and mitochondrial membrane potential. Glucose uptake was significantly impaired in cells treated with LPS-activated RAW264.7, BV2, and DMSO-differentiated HL60 cell media, while insulin partially rescued this effect, except for the CM of BV2 cells. Notably, insulin IC₅₀ increased dramatically under LPS-treated BV2 cells induced inflammation (35 vs. 198 pM), confirming the development of insulin resistance. Immune cell-specific inflammation causes distinct effects on neuronal oxidative stress, mitochondrial function, protein aggregation, insulin signaling and viability. LPS-activated BV2-derived CM best recapitulates AD-related pathology, offering a relevant in vitro model for further studies.

Alzheimer’s disease (AD) is characterized by mitochondrial dysfunction, oxidative stress, insulin resistance, and aberrant protein aggregation. Neurodegeneration model with neuronal insulin resistance was induced in SH-SY5Y human neuroblastoma cells by streptozotocin (STZ). We evaluated the neuroprotective effects of resveratrol (RZV) and three structural analogs: oxyresveratrol (OXI), monomethyl resveratrol (MONO), and trimethyl resveratrol (TRI). Mitochondrial function, plasma membrane integrity, oxidative stress) and autophagy were studied by fluorescent assays. Phosphorylated GSK3 levels were measured by ELISA as an indicator of insulin sensitivity. TRI exhibited significant mitochondrial protective effects and strongly induced autophagy. OXI demonstrated excellent antioxidant activity but showed no detectable mitochondrial protective or autophagy-inducing effects. RZV and MONO exhibited moderate antioxidant effects along with strong insulin-sensitizing and autophagy-inducing properties. Insulin sensitivity was most potently restored by RZV (IC₅₀ = 54 pM) and MONO (IC₅₀ = 50 pM), whereas TRI (IC₅₀ = 160 pM) was less potent, and OXI (IC₅₀ = 97 pM) showed moderate potency. Our findings suggest that the neuroprotective effects of resveratrol analogs significantly depend on their molecular structure and that they exert their beneficial effects through distinct mechanisms. This research may contribute to the development of novel, multi-target compounds for the treatment of neurodegenerative diseases.

Background/Objectives: Stereochemistry can substantially influence the biological activity and pharmaceutical properties of small molecules. This study investigated the stereochemistry-dependent biological activity and chiral recognition of novel naphthylethyl thiourea enantiomers using an integrated biological, chromatographic, and computational approach. Methods: Ten pairs of naphthylethyl thiourea enantiomers were synthesized from enantiomerically pure precursors and characterized. Antiproliferative and antibacterial activity, chiral HPLC behavior on polysaccharide- and protein-based stationary phases, molecular docking, and multivariate relationships were evaluated. Results: Target-dependent enantioselectivity and substituent-dependent activity patterns were observed. All enantiomeric pairs were chromatographically distinguished under at least one condition, and selected compounds showed selector- and mobile-phase-dependent changes in elution order. AGP-based chromatography showed stereoselective recognition for a subset of compounds, while computational analyses provided complementary support for the experimental trends. Conclusions: Stereochemistry and substitution jointly influence biological and chromatographic behavior in this thiourea series. Integrated biological, chromatographic, and computational profiling provides a useful framework for early enantiomer-resolved developability assessment.

Chromosomal abnormalities are among the most common molecular characteristics of human cancer cells and are believed to play an essential role in the genesis of tumor driver molecules. Chromosome translocations are one of the first recognized tumor-related chromatin alterations; many of them are so typical to certain neoplasms that they are used as diagnostic biomarkers in contemporary clinical histopathology. Understanding their molecular roles in carcinogenesis is essential to the development of novel targeted therapeutics but this has been hindered by the difficulties in establishing appropriate in vitro models. Here, we review the recent advances of the field covering its historical background, medical relevance and most recent technological breakthroughs in chromosomal translocation modeling that may facilitate the innovations of related tumor-agnostic therapeutic modalities.

Dendritic cells (DCs) are a heterogeneous population known for antigen presentation and immune modulation, playing a key role in priming a T cell response against pathogens and tumor cells. Despite their putative therapeutic value, their scarcity in peripheral blood limited their direct use in therapeutic applications until recently. The discovery that DCs can be generated from circulating monocytes ex vivo, however, gave a boost of extensive research in the use of DCs in clinical applications. Still, despite the numerous clinical trials, the introduction of DCs in the everyday clinical oncology practice is delayed. In this narrative review, we provide an updated summary of the field covering the theoretical and practical aspects of the concept of the use of DCs in adoptive cellular immunotherapy and the completed or ongoing clinical trials for the use of these species in clinical oncology practice. To better understand the current developments of the field, we included those clinical trial reports that published evaluable data to date. Based on our literature survey, DC-based adoptive cellular therapy is a safe therapeutic intervention with valuable clinical potential. Its widespread implementation, however, is likely delayed due to a number of factors that make meaningful evaluation of clinical trial results complicated. These include the great variety of preclinical trial concepts, difficult and heterogenous patient cohorts, and the diversity of intervention techniques applied. Since these factors might hinder the routine implementation of DC-based applications in the more widespread forms of immunotherapy, one of the urgent short-term future directions seems to be the standardization of the DC-based methodologies.