BMC Pharmacology & Toxicology最新文献

Background: The present investigation assessed the potential ameliorating effect of zinc oxide resveratrol nanoparticles against Levofloxacin-induced liver damage in rats.

Methods: Fifty adult Wistar rats were split up into five groups at random. (n = 10). GI, (control): was orally gavaged with distilled water; G II (LFX): was orally given levofloxacin (LFX) (40 mg/kg BW). G III was orally administered zinc oxide resveratrol nanoparticles (Zn- RSV) (20 mg/kg BW). G IV: was given Zn-RSV as GIII and LFX as GII simultaneously (LFX + Zn-RSV). GV: was given LFX as GII and zinc oxide (20 mg/kg BW) (LFX + Zn). All treatments were given every other day for two months.

Results: Administration of zinc oxide resveratrol nanoparticles (Zn-RSV NPs) significantly mitigated levofloxacin (LFX)-induced hepatotoxicity in rats. Compared to LFX-treated groups through improved liver function via lowered serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine levels. Also, reduced oxidative stress markers, decreased malondialdehyde (MDA) and nitric oxide (NO) levels in hepatic tissue and enhanced antioxidant defenses, increased superoxide dismutase (SOD) and catalase activities, restoring them to near-normal levels. Modulated apoptosis: Downregulated pro-apoptotic BAX expression and upregulated anti-apoptotic Bcl-2 expression, promoting cell survival. Zn-RSV NPs alleviated histopathological changes through mitigated LFX-induced degenerative and necrotic changes in hepatic tissue, preserving tissue architecture.

Conclusions: This study revealed that zinc oxide resveratrol nanoparticles modulated levofloxacin-induced hepatic damage by lowering inflammation and oxidative stress while increasing the activity of antioxidant enzymes in rat hepatic tissue.

Background: Parabens (PBs) are associated with an increased risk of breast cancer, yet their underlying molecular mechanisms remain poorly understood. This study aimed to comprehensively elucidate the targets and mechanisms of PBs in breast cancer by integrating network toxicology, bioinformatics, Mendelian randomization (MR), molecular docking, and other complementary methodologies.

Results: Network toxicology analysis identified 2,851 potential PB targets, with 172 significantly linked to breast cancer. Pathway enrichment revealed that PBs predominantly influence the Phosphatidylinositol 3-kinase-Akt (PI3K-Akt) signaling pathway and the cell cycle pathway. Two-sample MR identified TELO2 as a significant risk factor for both malignant and benign breast cancer (malignant: IVW OR = 1.06, 95% CI: 1.001-1.126, p = 0.047; benign: IVW OR = 1.13, 95% CI: 1.009-1.270, p = 0.034). Bioinformatics analysis demonstrated that TELO2 expression was significantly elevated in breast cancer tissues (p < 0.05) and exhibited high diagnostic accuracy (AUC: 0.803 in TCGA and 0.876 in GSE20685). Furthermore, mediation analysis revealed that modulating natural killer T (NKT) cells significantly mediated the TELO2-breast cancer link, with a mediation proportion of 20.46%. Molecular docking confirmed stable binding interactions between PBs and the TELO2 protein. Moreover, an mRNA-microRNA (miRNA)-long non-coding RNA (lncRNA) regulatory network centered on TELO2 identified 19 miRNAs and 189 lncRNAs as potential regulators of its expression.

Conclusions: Our integrative findings suggest that parabens may exert deleterious effects in the context of breast cancer by specifically targeting the TELO2 gene and its associated regulatory networks and pathways. These findings not only advance our understanding of the environmental drivers of BC but also pave the way for future research aimed at mitigating the disease's health burden through targeted interventions against harmful environmental exposures.

Background: Nickel exposure is a recognized environmental and occupational hazard that contributes to pulmonary oxidative stress and inflammation, potentially leading to chronic respiratory conditions. Probiotics, known for their antioxidant and anti-inflammatory effects, offer a promising strategy to combat oxidative stress caused by nickel exposure. This research will investigate how native probiotics can reduce inflammatory responses and oxidative damage in lung tissues, improving strategies for lung protection against heavy metal toxicity.

Methods: In this study, male NMRI mice were subjected to Nickel exposure to induce oxidative stress and inflammation for a duration of 60 days, after which they received probiotic treatment with a concentration of 1.6 * 10⁹ CFU/ml. To assess the impact of these interventions on the antioxidant system and inflammatory responses, Real-Time PCR analysis was performed to evaluate the gene expression profiles in the lung tissue of the mice.

Results: The study revealed that native probiotic strains significantly upregulated antioxidant gene expression while concurrently enhancing genes linked to the inflammatory signaling pathway. Although Nickel exposure diminished the expression of these genes, the administration of probiotics after Nickel exposure led to a marked increase in their expression levels.

Conclusion: This research highlights the harmful impact of Nickel, a heavy metal, on lung health, while simultaneously examining the beneficial properties of probiotics, particularly their antioxidant and anti-inflammatory effects. Given the significant risk associated with heavy metal exposure, the incorporation of probiotics emerges as a promising strategy to mitigate oxidative stress and prevent a range of pulmonary disorders, including those linked to inflammation.

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.