International Journal of Molecular Sciences

Thioester-containing proteins (TEPs), which are distinguished by the thioester motif (GCGEQ), are essential to arthropods’ defense against infections. Although TEPs have been extensively investigated in Anopheles, Aedes, and Drosophila, their functions in Culex mosquitoes remain inadequately explored. Interestingly, we discovered that Culex TEPs exhibit functional antagonism to their orthologs in other species, actively facilitating viral infection in this vector. In this study, we identified nine TEP genes in Culex quinquefasciatus, three of which were found to critically facilitate Japanese encephalitis virus (JEV) infection, with CqTEP27 exhibiting the most pronounced proviral effect. Mechanistically, CqTEP27 may have suppressed the production of several antimicrobial peptides (AMPs), which increased JEV replication. Our work also highlights the potential of targeting susceptibility factors such as CqTEP27 to block pathogen acquisition. Notably, the rate of mosquito infection was significantly decreased by membrane blood feeding antisera against CqTEP27. Therefore, vaccination against CqTEP27 offers a workable method of avoiding JEV infection. According to our research, CqTEP27 is a promising target for the development of vaccines that prevent JEV transmission. By preventing viral infection in mosquitoes that feed on immunized hosts, this approach can directly disrupt the natural transmission cycle, offering a novel strategy to reduce the disease burden.

L-DOPA-induced dyskinesia (LID) remains the most challenging complication of dopamine replacement therapy in Parkinson’s disease, correlated with maladaptive plasticity within corticostriatal circuits. Perineuronal nets (PNNs), extracellular matrix structures enwrapping mainly parvalbumin interneurons (PV-INs), are key regulators of neuronal stability and plasticity, yet their contribution to LID is unknown. Using a unilateral 6-hydroxydopamine rat model of Parkinsonism followed by chronic L-DOPA administration, we quantified PNN–PV associations by Wisteria floribunda agglutinin (WFA) and PV immunolabeling across striatal and motor cortical territories. Dopamine loss markedly reduced PNN density and intensity in the dorsolateral striatum (DLS), which only partially recovered after L-DOPA. In LID, canonical WFA⁺/PV⁺ cells remained low, whereas non-canonical WFA⁻/PV⁺ populations expanded in both DLS and M1 motor cortex (M1), indicating region-specific remodeling toward a high-plasticity state. To assess causality, we used Chondroitinase ABC (ChABC) for PNN degradation. DLS-targeted ChABC exacerbated abnormal involuntary movements and increased local PV density, while M1-ChABC had no behavioral effect but altered PV metrics within the DLS–M1 axis. These findings identify the DLS as a critical node where PNN fragility amplifies dyskinesia, highlight a functional coupling between striatal and cortical PNN–PV remodeling, and suggest that stabilizing extracellular matrix integrity could mitigate maladaptive plasticity underlying LID.

Endothelial-to-mesenchymal transition (EndMT) is a cellular program implicated in fibrosis, vascular remodeling, and the tumor microenvironment across multiple organs. We synthesize mechanistic pathways including TGF-β/SMAD, non-canonical (MAPK, PI3K/AKT, Rho/ROCK), Notch, and Wnt/β-catenin cascades. Their crosstalk with hypoxia, inflammatory cues, and epigenetic mechanisms can drive loss of endothelial identity and acquisition of mesenchymal characteristics. We outline disease contexts in the heart, lungs, kidneys, liver, central nervous system, and cancer, highlighting context-dependent contributory roles of EndMT. Therapeutically, we review pathway-targeted agents, epigenetic inhibitors, microRNA-based strategies, antibodies/biologics, small molecules and natural compounds, and cell- and gene-based interventions. Finally, we outline a translational roadmap that pairs patient-derived iPSC/organoid and organ-on-a-chip platforms to stratify EndMT states and prioritize targets. We also explore combination regimens that integrate multi-pathway modulation with epigenetic and immune approaches, aiming to deliver clinically meaningful anti-fibrotic benefits while better preserving physiological signaling.