BMC Pharmacology & Toxicology最新文献

Objective: Bisphenol A (BPA), a pervasive environmental pollutant, is increasingly associated with osteoarthritis (OA) development, yet its molecular mechanisms remain unknown. Currently, there is no definitive cure for OA.

Methods: BPA targets were predicted using STITCH and Swiss Target Prediction, while OA-related targets were collected from GeneCards, OMIM, and the Therapeutic Target Database (TTD). Protein-protein interaction (PPI) networks were constructed using STRING and visualized in Cytoscape to identify hub targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed, and molecular docking with AutoDock evaluated BPA-core target interactions. We employed our Computational Analysis of Novel Drug Opportunities (CANDO) platform for de novo drug prediction.

Results: Systematic bioinformatics analysis identified 26 candidate targets, with ESR1, PTGS2, CCL2, FLNA, and TRPV1 as key hubs. Pathway analysis revealed involvement in calcium ion transport, muscle contraction, IL-17 signaling, and estrogen signaling. Molecular docking confirmed strong BPA-target binding affinities. CANDO predicted 14 potential OA treatments, including glucosamine, ibuprofen, celecoxib, indomethacin, palmitic acid, and linoleic acid. Notably, qRT-PCR validation revealed that ESR1, PTGS2, CCL2, and TRPV1 were highly expressed, whereas FLNA was expressed at lower levels in the osteoarthritis blood samples.

Conclusions: This study elucidates BPA's molecular mechanisms in OA and identifies promising therapeutic candidates. The integration of network toxicology, molecular docking, and computational drug discovery provides a robust framework for understanding environmental toxicants and advancing OA therapies.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder marked by exocrine gland impairment and systemic manifestations. Environmental endocrine disruptors, including bisphenol A (BPA), have been associated with immunological dysregulation; however, their involvement in pSS is not well-defined. This study integrated network toxicology, molecular docking, molecular dynamics simulation, and in vitro validation to examine the potential effects of BPA on pSS. Bioinformatics investigation revealed 25 overlapping targets between BPA-associated genes and differentially expressed genes related to pSS, with CASP3, PTGS1, and PTGS2 identified as main possibilities. Molecular docking and molecular dynamics simulations validated robust and stable interactions of BPA with these proteins. Cellular studies with human submandibular gland epithelial cells demonstrated dose-dependent cytotoxicity of BPA, accompanied by substantial overexpression of CASP3, PTGS1, and PTGS2 at 1 µM exposure. The data indicate that BPA enhances apoptosis and inflammatory signaling in salivary gland cells, potentially contributing to pSS progression. This study provides mechanistic insight into how BPA may contribute to autoimmune disease development, highlighting its potential role in pSS.

Background: Myasthenia gravis is a rare autoimmune disease mediated by autoantibodies directed against acetylcholine receptors (AChRs) at the neuromuscular junction. These autoantibodies cause dysfunction through AChR blockade, AChR degradation due to crosslinking and internalisation, and complement activation.

Methods: A novel in vitro model of the human neuromuscular junction was established on a microfluidic platform to investigate the effect of anti-AChR autoantibodies on complement activation and neuromuscular transmission and the mechanism of action of complement inhibition in myasthenia gravis. The NeuroMuscle^TM platform enabled the connection of human induced pluripotent stem-cell-derived motor neuron spheroids with three-dimensional cultures of skeletal muscle fibres, forming functional neuromuscular junctions. Functional connectivity was assessed by glutamate stimulation of motor neuron spheroids and monitoring of calcium transients in genetically encoded calcium indicator protein 6 (GCaMP6)-transduced muscle fibres.

Results: Incubation of in vitro neuromuscular junction tissues with sera from patients with anti-AChR autoantibody-positive myasthenia gravis, in contrast to healthy controls, induced a significant increase in membrane attack complex (MAC) deposition and complement split products, accompanied by a notable reduction in calcium transients. Treatment with zilucoplan, a complement component 5 (C5) inhibitor, prevented complement activation and preserved neuromuscular junction functional integrity. The model demonstrated that complement-mediated damage is a major driver of neuromuscular junction functional impairment in the myasthenia gravis patient sera tested in this study. Furthermore, the study explored the reversibility of neuromuscular junction damage, revealing that shortening the delay before initiating complement inhibitor treatment in the in vitro neuromuscular junction tissues enhances the reversibility of neuromuscular transmission.

Conclusions: These findings offer a mechanistic rationale for the observed clinical response in patients with anti-AChR autoantibody-positive myasthenia gravis treated with C5 inhibitors. The in vitro neuromuscular junction model provides a robust platform for studying the mechanistic pathways of complement-mediated damage and evaluating therapeutic interventions for myasthenia gravis.

Background: Neutrophilic chronic rhinosinusitis (CRS) is characterized by persistent inflammation and often responds poorly to corticosteroid therapy. In this disease, neutrophil extracellular traps (NETs) are increasingly recognized as key mediators of mucosal damage and polypogenesis. The removal of NETs by deoxyribonuclease 1 could be a potential therapeutic approach to overcome steroid resistance in neutrophilic CRS. In this study, we established a mouse model of neutrophilic CRS and evaluated the effect of a genetically engineered deoxyribonuclease 1 'AR-CR8 Dnase1' on NETs and polyp formation in the mice.

Methods: Human neutrophils were isolated and treated with LPS to induce NET formation. An animal model for neutrophilic CRS and polyps was developed by intranasal administration of LPS and Staphylococcal toxin. H&E staining and immunofluorescence were performed to identify polyps, NETs, and immune cells in nasal cavities.

Results: AR-CR8 Dnase1 effectively degraded NET-like structures in LPS-stimulated human neutrophils. In the mouse CRS model, the intranasal administration of AR-CR8 Dnase1 noticeably reduced the burden of nasal polyps. The intranasal treatment of Dnase1 was effective as much as an injection of dexamethasone in reducing polyp number and NET accumulation in this model.

Conclusions: These results suggest that an engineered deoxyribonuclease 1 like AR-CR8 Dnase1 be an emerging bio-drug to inhibit inflammatory reaction and polyp formation in patients with neutrophilic CRS. AR-CR8 Dnase1 may be an alternative therapeutic for patients with CRS who are not suitable for steroid therapy, and further studies comparing dosing, durability, and safety are needed before considering clinical use.

Trial registration: Not applicable.

Background: Tremors and rigid muscles are symptoms of Parkinson's disease (PD), which affects about 1% of the global population.

Purpose: To investigate the integrated therapeutic benefits of the phytopharmaceutical berberine and mucoadhesive nanoliposomes, administered via the nose-to-brain route, to enhance bioavailability, facilitate blood-brain barrier penetration, and augment efficacy against neurodegenerative progression in Parkinson's disease (PD).

Study design: This study aimed to develop and characterize chitosan-decorated liposomes (chitosomes) loaded with berberine (BER) for targeted brain delivery via the intranasal route.

Methods: In vitro characterization of BER loaded chitosomes was conducted including measurement of particle size, zeta potential, EE % and in vitro drug release. The optimized formulation was intranasally administered in rats with rotenone-induced PD animal model, motor function and coordination were investigated besides testing the levels of different biomarkers and histopathological examination.

Results: The prepared chitosomes had a particle size of 312 nm, zeta potential of 34 mV, and high encapsulation efficiency (89.3%) and sustained drug release. In vivo assessments conducted in a rotenone-induced PD animal model revealed notable improvements in motor function and coordination. Biochemical evaluations showed that BER chitosomes reduced α-synuclein by 49% and raised dopamine levels by 55% as compared to the model group. Additionally, BER chitosomes significantly decreased oxidative stress markers by a 67% decrease in NF-κB levels and a one-fold increase in Nrf2. Histological examination showed a noticeable reduction in neuronal degeneration and Lewy body formation.

Conclusion: Our findings imply that BER chitosomes are a viable intranasal delivery tool for the efficient treatment of PD due to their enhanced bioavailability. and greater nasal mucosa penetration.