Influenza A virus (IAV) infections continue to threaten public health. Current strategies, such as vaccines and antiviral drugs, are limited due to their time-consuming development and drug-resistant strains. Therefore, new effective treatments are needed. Here, virus-supportive cellular factors are promising drug targets, and the encapsulation of candidate substances in poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) is intended to improve their bioavailability. This study investigates the potential of the indirubin derivative 6-bromoindirubin-3′-glycerol-oxime ether (6BIGOE), a glycogen synthase kinase 3 (GSK-3)β inhibitor, for its potential to regulate IAV replication in vitro. The effects of 6BIGOE-loaded PLGA NPs on cell metabolism were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays in A549 and Calu-3 cells. Viral replication and spread were monitored in various IAV-infected cell lines in the absence and presence of free and 6BIGOE-loaded PLGA NPs via plaque assays and Western blot analysis. The encapsulation of 6BIGOE in PLGA NPs resulted in reduced negative side effects on cell viability while maintaining antiviral efficacy. Both encapsulated and free 6BIGOE exhibited antiviral activity, potentially through GSK-3β inhibition and the disruption of key signaling pathways required for viral replication. The data indicate 6BIGOE, particularly after encapsulation in NPs, as a potential candidate for further investigation and development as an antiviral agent to treat IAV infections.

The efficient delivery of lipophilic drugs still remains a major challenge in pharmaceutical nanotechnology, particularly due to limitations in drug loading, drug stability, and the biocompatibility of polymeric nanocarriers. Poly(ester amide)s represent a promising class of biodegradable materials and were investigated in the present study for the delivery of the anti-inflammatory, lipophilic drug 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE). Poly(ester amide)s incorporating the aromatic and non-aromatic α-amino acids l-phenylalanine or l-valine, next to glycolic acid as ester component, were synthesized by ring-opening polymerization and used to prepare nanoparticles via nanoemulsification in comparison to the widely used poly(lactic-co-glycolic acid) (PLGA). All polymers formed monodisperse nanoparticles of around 200 nm with anionic surfaces (ca. -20 mV) and comparable drug release profiles. Advantageously, the encapsulation efficiency of 6BIGOE was significantly improved to 63-78 % using poly(ester amide)s compared to 42 % for PLGA, confirmed by molecular dynamic simulations revealing enhanced interactions and miscibility between poly(ester amide)s and 6BIGOE. Poly(ester amide) nanoparticles showed higher glass transition temperatures compared to PLGA, indicating an improved thermo-mechanical stability. In human monocytes, 6BIGOE-loaded poly(ester amide) nanoparticles demonstrated excellent biocompatibility with pronounced anti-inflammatory activity by modulating pro- and anti-inflammatory mediators which highlights their potential as a versatile and tunable platform for the delivery of lipophilic anti-inflammatory drugs.

Despite extensive characterisation of immune responses across peripheral organs, the immunological landscape of the central nervous system (CNS) remains incompletely defined. Among the resident immune cell populations in the brain, mast cells and microglia have emerged as key modulators of neuroinflammatory processes. Research has increasingly also shown that these cells contribute to fundamental homeostatic functions, including regulation of sleep, affective states, and energy balance. These cells engage in complex bidirectional communication, mediated in part by the biogenic amine histamine. Although histamine was first identified over a century ago, its multifaceted roles in CNS homeostasis, immune surveillance, and neuropathophysiology remain poorly delineated. This review examines the biosynthesis, receptor-mediated signalling, and functional consequences of histaminergic activity within the brain, with a particular focus on microglial dynamics. We discuss crosstalk between mast cells and microglia via histamine signalling pathways, and the potential implications of this interaction in the etiology of neurodevelopmental disorders. Furthermore, we evaluate the emerging evidence on the capacity of centrally acting antihistamines, especially those capable of penetrating the blood–brain barrier, to modulate microglial phenotypes. Collectively, these insights underscore the urgent need for deeper mechanistic studies to elucidate histamine's role in CNS immunophysiology.

Influenza A virus (IAV) infections continue to threaten public health. Current strategies, such as vaccines and antiviral drugs, are limited due to time-consuming development and drug-resistant strains. Therefore, new effective treatments are needed. Here, virus-supportive cellular factors are promising drug targets, and encapsulation of candidate substances in PLGA nanoparticles (NPs) is intended to improve their bioavailability. This study investigates the potential of the indirubin derivative 6BIGOE, a GSK-3β inhibitor, for its potential to regulate IAV replication in vitro. The effects of 6BIGOE-loaded PLGA NPs on cell metabolism were assessed by MTT and LDH assays in A549 and Calu-3 cells. Viral replication and spread were monitored in various IAV-infected cell lines in absence and presence of free and 6BIGOE-loaded PLGA NPs via plaque assays and Western blot analysis. Encapsulation of 6BIGOE in PLGA NPs resulted in reduced negative side effects on cell viability while maintaining antiviral efficacy. Both encapsulated and free 6BIGOE exhibited antiviral activity, potentially through GSK-3β inhibition and disruption of key signaling pathways required for viral replication. The data indicate 6BIGOE, particularly after encapsulation in NPs, as a potential candidate for further investigation and development as an antiviral agent to treat IAV infections.