Search Results (65)

Remote alpine lakes on the Xizang Plateau are important archives for tracing the long-range atmospheric transport (LRAT) of persistent organic pollutants, yet historical records of polybrominated diphenyl ethers (PBDEs) from this region remain scarce. The main objective of this study was to reconstruct the historical record of PBDEs in Yamzho Yumco sediments and to evaluate whether this record reflects source evolution, atmospheric transport, deposition, and post-emission environmental fractionation in a remote alpine receptor system. To achieve this objective, 17 PBDE congeners were determined in a ²¹⁰Pb- and ¹³⁷Cs-dated sediment core spanning 1930–2023. Σ₁₇PBDE concentrations ranged from 5.80 to 263.13 pg/g dw, and depositional fluxes ranged from 2.67 to 121.04 pg/cm²/yr, both showing a marked increase after the 1970s and remaining elevated after 2000. Lower-brominated congeners, especially BDE-47, dominated the core, whereas nona- and deca-BDEs appeared mainly in recent sediments, indicating progressive source evolution in recent decades. Tri- to penta-BDEs remained the dominant homologue fraction throughout the record, while elevated post-2000 BDE-47/BDE-99 ratios point to congener-selective environmental fractionation during atmospheric transport and deposition. Together, these results suggest that Yamzho Yumco sediments preserve not only the history of regional PBDE input, but also the coupled imprint of source evolution, transport-related fractionation, and delayed environmental response in a remote high-altitude receptor system. This study highlights the value of Xizang Plateau Lake sediments for process-based interpretation of POP fate in mountain environments. Full article

The emergence of variant strains of Avian orthoreovirus (ARV) has caused substantial economic losses in the poultry industry worldwide, but the molecular features of goose-origin strains and viral transmission among different avian species remain poorly understood. Here, we describe a goose-origin avian orthoreovirus strain, SD0407, associated with growth retardation and joint swelling. Complete genome analysis identified ten double-stranded RNA segments. Sequence comparison indicated that SD0407 is closely related to previously reported duck-origin reovirus strains. Phylogenetic and recombination analyses showed that most segments clustered with duck-origin strains, indicating close genetic relatedness among waterfowl-origin orthoreoviruses. Sequence and structural analysis of the σC attachment protein revealed ten unique amino acid substitutions, including D250 within the DE-loop region involved in receptor-binding. Molecular docking suggested that σC interacts with the conserved AnxA2-S100A10 heterotetrameric receptor complex, providing a possible structural basis for receptor compatibility across avian species. Although SD0407 replicated efficiently in goose embryo fibroblasts, it did not induce expression of type I, II or III interferons. Transcriptome profiling revealed weak activation of innate immune signaling and downregulation of metabolic and cytoskeletal genes, consistent with effective suppression of antiviral responses. These findings demonstrate that SD0407 combines structural variability with immune evasion to enhance host adaptability and underscore the importance of sustained ARV surveillance in waterfowl populations. Full article

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

Avian reovirus (ARV) is a major poultry pathogen recently recognized for its potential as an oncolytic virus that selectively infects and kills cancer cells without harming healthy human cells. However, the receptors mediating ARV entry into cancer cells remain unclear. Using mouse melanoma B16-F10 cells as a model, this study identified ARV-binding receptor candidates through viral overlay protein binding assay (VOPBA), SDS-PAGE, and LC-MS/MS analysis. Plaque-forming assays (PFAs) evaluated viral replication efficiency, while co-immunoprecipitation (Co-IP) and proximity ligation assay (PLA) confirmed direct interactions between viral σC and host receptor proteins. Functional assays using shRNA knockdown and antibody blocking demonstrated that inhibition of Plg-RKT expression markedly reduced ARV infection. Western blot analysis revealed that ARV binding to Plg-RKT activates Src and p38 MAPK signaling pathways, which promote caveolin-1 phosphorylation and caveolae-mediated endocytosis. These findings identify Plg-RKT as a crucial receptor mediating ARV σC binding and entry into B16-F10 melanoma cells. Furthermore, activation of Src-p38 MAPK signaling was shown to be essential for viral internalization. This study elucidates the molecular mechanism underlying ARV entry into melanoma cells and provides valuable insight for improving the selectivity and therapeutic potential of ARV as an oncolytic virus. Full article

Background: The tumor microenvironment (TME) poses significant challenges to effective therapy, with cancer-associated fibroblasts (CAFs) playing a key role in tumor progression and drug resistance in triple-negative breast cancer (TNBC). Herein, a TME responsive nanocapsule, NPC-ABS/FDS, was developed utilizing baicalein, a CAFs modulator, and the cytotoxic drug doxorubicin to selectively target CAFs and tumor cells, respectively, in a stepwise manner. Methods: NPC-ABS/FDS was designed with CD13-mediated primary targeting for tumor accumulation and secondary targeting via σ-receptor binding (ABS nanoparticles) for CAFs and folate modification (FDS nanoparticles) for cancer cells. Physicochemical properties were assessed using TEM, particle size, and ζ-potential analyses. Fluorescence imaging evaluated tumor retention, while cellular uptake and TME modulation were analyzed in vitro and in vivo. Results: The successful preparation of NPC-ABS/FDS was demonstrated by its uniform morphology, stable characteristics, charge reversal, and increased particle size. Fluorescence imaging confirmed prolonged peritumoral retention. Cellular uptake increased 2.5-fold for baicalein in CAFs and 4.3-fold for doxorubicin in cancer cells. NPC-ABS/FDS downregulated α-SMA and FAP, reducing CAFs activation, improving intratumoral drug penetration, and enhancing CD8⁺ and CD4⁺ T cell infiltration while decreasing regulatory T cells. Conclusions: NPC-ABS/FDS effectively modulates multiple TME components, including CAFs and immune cells, and improves drug delivery in TNBC. These findings may support the development of improved therapeutic approaches for TNBC. Full article

Neutral and protonated histamine tautomers, mono-substituted with twelve functional groups, were studied theoretically as isolated molecules and complexes with the H₁ receptor. Geometry and energy of tautomers were optimized using the DFT method with the B3LYP functional and the aug-cc-pVTZ basis set. The approach was based on the charge of the substituent active region (cSAR) parameters and the Harmonic Oscillator Model of Aromaticity (HOMA) indices. The cSAR parameters characterized the electron density better than the conventional Hammett’s constants σ. In general, the cSAR parameters correlate with other characteristics of the charge distribution, particularly those for substituents at the carbon atom in the ring adjacent to the side chain. Substituents at this atom affected the aromaticity less strongly than those located between two nitrogen atoms, which confirmed recent reports. Our results suggest that the 3H tautomer isomerizes into the 1H one after binding to the H₁ receptor. Moreover, the electron structure of the molecule hydrogen-bonded to the receptor may significantly depend on the electron donor-acceptor properties of the substituent. The strong electron-accepting substituents, e.g., NO₂, favor the imidazole configuration of the ring in the bonded molecule, while the strong electron-donating ones, e.g., NH₂, promote the imidazolium one. Full article

Background/Objectives: Ligands blocking σ₁ receptors or NMDA receptors show promising pharmacological properties, such as analgesia or neuroprotection. It had been shown that depending on the stereochemistry and substitution pattern, 1,3-dioxnaes can selectively interact with either σ₁ receptors or the phencyclidine binding site of NMDA receptors. Herein, systematic modifications of homologous aminobutyl substituted 1,3-dioxanes were conducted in order to identify ligands selectively addressing σ receptors or NMDA receptors. Methods: The first step of the synthesis, i.e., the acetalization of benzaldehyde (7a) or propiophenone (7b) with pentane-1,3,5-triol (6), determined the relative configuration of the envisaged 1,3-dioxanes bearing 4-aminobutyl substituents in 4-position. Multi-step homologation of ethanols 8 provided various primary, secondary and tertiary amines 14, 16–19, and 24–27. The affinity towards σ₁ and σ₂ receptors as well as the PCP and ifenprodil binding sites of the NMDA receptor was systematically evaluated in radioligand receptor binding studies. Results: Only the primary amines 14b and 24b derived from propiophenone interacted moderately with the PCP binding site of the NMDA receptor. Within this class of compounds, the N-benzylamines 17 and 18 showed the highest σ₁ affinity with high selectivity over the PCP binding site and at least preference over the σ₂ receptor. The benzylamine 17a (K_i(σ₁) = 31 nM, LLE = 6.19) and the pyrrolidine 19a (K_i(σ₁) = 154 nM, LLE = 6.72) represent the most promising σ₁ ligands of this compound series, when taking the lipophilicity and receptor selectivity into account. Conclusions: Both compounds showed medium metabolic stability in vitro rendering them promising candidates for further studies. Full article

Age-related macular degeneration (AMD) is a common eye disease that significantly affects daily activities and impedes the quality of life in aging adults, yet effective treatments to halt or reverse disease progression are currently lacking. Ongoing research aims at understanding the complex mechanisms underlying AMD pathophysiology involving retinal pigment epithelium (RPE) dysfunction, drusen formation, inflammation, neovascularization, and RPE/photoreceptor degeneration. Sigma 2 receptor/transmembrane protein 97 (σ₂R/TMEM97) is a multifunctional protein implicated in cellular processes including cholesterol homeostasis, lysosome-dependent autophagy, calcium homeostasis, and integrated stress response (ISR). Recent genome-wide association studies (GWASs) have identified σ₂R/TMEM97 as a novel genetic risk factor strongly associated with AMD development. In this review, we summarize recent research progress on σ₂R/TMEM97 in age-related neurodegenerative diseases, highlighting its implication as a molecular target in AMD via regulating oxidative stress, inflammation, lipid uptake, drusen formation, and epithelial–mesenchymal transition (EMT). We also discuss the potential of modulating σ₂R/TMEM97 function with novel small-molecule drugs as a promising treatment for dry AMD and the unresolved questions in understanding the mechanistic basis of their actions. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

Background/Objectives: The purpose of this research was to investigate the effects of bisphenol A (BPA) exposure on neurobehavioral testing in young Wistar rats and to evaluate the therapeutic potential of Thymus ciliatus (TEO) essential oil to attenuate the damage induced by this chemical toxin. Methods: The essential oil was extracted by hydro-distillation (yield of 2.26%), and the characterization by GC-MS indicates that the major components of Thymus ciliatus oil are thymol (63.33%), p-cymene (13.4%), and σ-terpinene (6.69%). Acute BPA intoxication was induced with a dose of 50 mg/kg orally for 60 days. The neurobehavioral evaluation, performed using a comprehensive set of tests including the forced swim test, dark/light box, Morris water maze, open field test, and sucrose preference test, clearly demonstrated that bisphenol A (BPA) exposure induced significant neurobehavioral impairments. Results: These impairments included reduced exploratory behavior indicative of heightened stress, anxiety, and depressive-like states, as well as deficits in memory and learning. Furthermore, BPA intoxication was associated with metabolic disturbances such as hyperglycemia along with histopathological evidence of brain tissue damage. However, TEO treatment attenuated these adverse effects by restoring neurobehavioral function. Molecular docking analysis revealed an affinity between the major essential oils identified in T. ciliatus, BPA, and the 5HT2C receptor and the MAO, AChE, and BChE enzymes, suggesting a potential mechanism underlying BPA’s effects on behavior and memory. In addition, TEO also showed an interaction with these molecules, suggesting a therapeutic potential against BPA. These findings underscore the promising role of TEO in mitigating the poisonous effects of BPA and pave the way for additional research into the molecular mechanisms and therapeutic uses of natural bioactive compounds for the prevention and treatment of toxic diseases. Thymol, the major compound in TEO, exhibited activity related to the dopamine and serotonin pathways, so it could have potential antidepressant properties. Conclusions: Thymol might be a promising candidate for the treatment of neurodegenerative and neurological disorders such as depression, Parkinson’s disease, and Alzheimer’s disease while also preventing histological damage in the brain. Full article

Background/Objectives: The novel pyrazoloquinolinone ligand CW-02-79 shows a unique profile of selective binding to σ2 receptors, but its poor solubility in both water and lipids makes its research and development a burdensome task. We aimed to develop a phospholipid-complex-based nanoemulsion formulation containing CW-02-79 suitable for intravenous administration in preclinical research. Methods: The decorated and undecorated nanoemulsions were formulated and subjected to detailed physiochemical characterization. The delivery and exposure to CW-02-79 from selected nanoemulsions were examined in the in vitro blood–brain barrier model based on human-induced pluripotent stem-cell-derived microvascular endothelial cells, astrocytes, and pericytes, and in vivo neuropharmacokinetic study in rats, respectively. Results: The developed biocompatible nanoemulsions loaded with a CW-02-79—phospholipid complex at a mass ratio of 1:10 exhibited a small droplet size and narrow size distribution, with satisfactory physicochemical stability during steam sterilization and short-term storage at 25 °C. The analysis of protein binding interactions revealed that the PEGylated nanoemulsions had fewer observable interactions compared to the undecorated nanoemulsions, especially when 0.2% DSPE-PEG2000 and 0.1% DSPE-PEG2000-mannose were combined. An in vitro BBB study demonstrated that a substantial part of CW-02-79 present in the applied nanoemulsion is able to permeate the barrier. The quantification of CW-02-79 in plasma/brain homogenate and calculated pharmacokinetic parameters confirmed good systemic and brain availability after intravenous administration. There were subtle differences in the pharmacokinetic parameters in favor of a dual surface-functionalized nanoemulson containing the glucose transporter-1-targeting ligand (mannose). Conclusions: The developed and characterized nanoemulsions enable substantial brain exposure to CW-02-79 as a prerequisite for a pharmacologically and clinically relevant selective modulation of σ2 receptors. Full article

The complexity of Alzheimer’s disease (AD) pathophysiology represents a significant challenge in the development of effective therapeutic agents for its treatment. CNEURO-201 (CN, also Amylovis-201) is a novel pharmaceutical agent with dual activity as an anti-amyloid-β (Aβ) agent and σ1 receptor agonist. CN exhibits great efficacy at very low doses, delaying cognitive impairment and alleviating Aβ load in animal models of AD. However, CN functions on other remains related to this pathology remain to be investigated. The present study sought to evaluate the effects of CN treatment at a dosage of 0.1 mg kg⁻¹ (p.o) over an eight-week period in the 3xTg-AD mouse model. In silico studies, as well as biochemical and immunofluorescence assays, were conducted on brain tissue to investigate the CN effects on acetylcholine metabolism, redox system, and glial cell activation-related biomarkers in brain regions that are relevant for memory. The results demonstrated that CN effectively rescues cognitive impairment of 3xTg-AD mice by influencing glial activity to reduce existing Aβ plaques but also modulating acetylcholine metabolism and the enzymatic response of proteins involved in the redox system. Our outcomes reinforced the potential of CN in treating AD by acting on multiple pathways altered in this disease. Full article

Sigma receptors (σRs) represent very attractive biological targets for the development of potential agents for the treatment of several neurological disorders. In the search for new small molecule drugs against neuropathic pain, we identified 2-{[2-(1-benzylpiperidin-4-yl)ethyl]amino}-6-[methyl(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitrile (5) as a polyfunctionalized small pyridine with potent dual-target activities against acetylcholinesterase (AChE) (IC₅₀ = 13 nM) and butyrylcholinesterase (BuChE) (IC₅₀ = 3.1 µM), exhibiting high σ₁R affinity (K_i(hσ₁R) = 1.45 nM) and 290-fold selectivity over the σ₂R subtype. These results are in good agreement with those found in the molecular modeling of compound 5. This is possibly due to the preferred combination in this molecule of a linker n = 2 connecting the N-Bn-piperidine motif to the C2 pyridine, without a phenyl group at C4, and a N-Me-substituted propargyl amine in the chain located at C6. Full article

Background: In melanoma, multiligand drug strategies to disrupt cancer-associated epigenetic alterations and angiogenesis are particularly promising. Here, a novel dual-ligand with a single shared pharmacophore capable of simultaneously targeting histone deacetylases (HDACs) and sigma receptors (σRs) was synthesized and subjected to phenotypic in vitro screening. Methods: Tumor cell proliferation and spreading were investigated using immortalized human cancer and normal cell lines. Angiogenesis was also evaluated in mouse endothelial cells using a tube formation assay. Results: The dual-ligand compound exhibited superior potency in suppressing both uveal and cutaneous melanoma cell viability compared to other cancer cell types or normal cells. Melanoma selectivity reflected inhibition of the HDAC-dependent epigenetic regulation of tumor proliferative kinetics, without involvement of σR signaling. In contrast, the bifunctional compound inhibited the formation of capillary-like structures, formed by endothelial cells, and tumor cell spreading through the specific regulation of σ₁R signaling, but not HDAC activity. Conclusions: Together, the present findings suggest that dual-targeted HDAC/σ₁R ligands might efficiently and simultaneously disrupt tumor growth, dissemination and angiogenesis in melanoma, a strategy amenable to future clinical applications in precision cancer treatment. Full article

The hydroxylated perhydroquinoxaline 14 was designed by conformational restriction of the prototypical κ receptor agonist U-50,488 and the introduction of an additional polar group. The synthesis of 14 comprised ten reaction steps starting from diethyl 3-hydroxyglutarate (4). The first key step was the diastereoselective establishment of the tetrasubstituted cyclohexane 7 by the reaction of dialdehyde 6 with benzylamine and nitromethane. The piperazine ring was annulated by the reaction of silyloxy-substituted cyclohexanetriamine 8 with dimethyl oxalate. The pharmacophoric structural elements characteristic for κ receptor agonists were finally introduced by functional group modifications. The structure including the relative configuration of the tetrasubstituted cyclohexane derivative (2r,5s)-7a and the perhydroquinoxaline 9 was determined unequivocally by X-ray crystal structure analysis. The hydroxylated perhydroquinoxaline 14 showed moderate κ receptor affinity (K_i = 599 nM) and high selectivity over μ, δ, σ₁, and σ₂ receptors. An ionic interaction between the protonated pyrrolidine of 14 and D138 of κ receptor anchors 14 in the κ receptor binding pocket. Full article