Silibinin Attenuates Silica Dioxide Nanoparticles-Induced Inflammation by Suppressing TXNIP/MAPKs/AP-1 Signaling

Abstract

Silica dioxide nanoparticles (SiONPs) have been applied to several fields, such as drug delivery and gene therapy. However, SiONPs are a constituent of fine dust and can induce excessive inflammatory responses in the lungs via the airways. Silibinin, a major component of silymarin, has been known for its anti-oxidant and anti-inflammatory effects. In the present study, we explored the protective effects of silibinin against SiONPs-induced airway inflammation and explored its underlying mechanism of action, focusing on thioredoxin-interacting protein (TXNIP)/mitogen-activated protein kinases (MAPKs) in vitro and in vivo. In SiONPs-stimulated NCI-H292 airway epithelial cells, silibinin treatment effectively suppressed the elevation of the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β, which was accompanied by the reduction in the expression of TXNIP, MAPKs, and activator protein-1 (AP-1). In SiONPs-treated mice, silibinin administration inhibited the increase in inflammatory cell counts and proinflammatory mediators, and it alleviated airway inflammation by SiONPs exposure. In addition, silibinin administration effectively suppressed the elevation of TXNIP/MAPKs/AP-1 signaling by SiONPs exposure. Taken together, silibinin effectively inhibited SiONPs-induced inflammatory responses, and this effect was closely related to the inhibition of TXNIP/MAPK/AP-1 signaling. These results suggested that silibinin might be useful for reducing pulmonary inflammation induced by SiONPs.

Melatonin Alleviates Silica Nanoparticle-Induced Lung Inflammation via Thioredoxin-Interacting Protein Downregulation

“…Moreover, melatonin treatment alleviates the pulmonary inflammation associated with cigarette smoke-induced COPD by suppressing MAPK phosphorylation [21]. In this study, SiONPs induced the inhibition of several inflammatory mediators as previously reported [15,16]. However, treatment with melatonin reduced the inflammatory index, including those of inflammatory cells and cytokines, in both the SiONPs-exposed mice and SiONPs-stimulated cells.…”

Tumor-educated monocyte-dendritic progenitors promote a metastatic switch

“…S4F). Importantly, some of these genes (THBS1, MAPKAPK2, CD9, TXNIP) were strongly associated with IL-6 signaling (Lim et al, 2020;Lopez-Dee et al, 2011;Shi et al, 2017), indicating that IL-6 or its associated genes are associated with metastatic tumors, in alignment with our previous findings. Overall, these findings may explain the increased myeloid bias in met-high compared to met-low tumors.…”

IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells

“…Furthermore, to strengthen the involvement of IL-6 in met-high tumors, transcription signatures of CD45+ stroma cells obtained from the tumor microenvironment of B16 melanoma, assessed by NanoString approach, revealed seven upregulated genes, including THBS1, MAPKAPK2, CD9, TXNIP, CD24, ITGA5, and SYK (online supplemental figure S5D). Importantly, some of these genes (THBS1, MAPKAPK2, CD9, TXNIP) were strongly associated with IL-6 signaling, [29][30][31] indicating that IL-6 or its associated genes are coupled with metastatic tumors, in alignment with our previous findings. Overall, these findings may explain the increased myeloid bias in met-high compared with met-low tumors.…”