Dataset Information

Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress.

ABSTRACT:

Background

The activation of NOD-like receptor protein 3 (NLRP3) inflammasome-dependent pyroptosis has been shown to play a vital role in the pathology of manganese (Mn)-induced neurotoxicity. Sodium para-aminosalicylic acid (PAS-Na) has a positive effect on the treatment of manganism. However, the mechanism is still unclear. We hypothesized that PAS-Na might act through NLRP3.

Methods

The microglial cell line BV2 and male Sprague-Dawley rats were used to investigate the impacts of PAS-Na on Mn-induced NLRP3 inflammasome-dependent pyroptosis. The related protein of the NF-κB pathway and NLRP3-inflammasome-dependent pyroptosis was detected by western blot. The reactive oxygen species and mitochondrial membrane potential were detected by immunofluorescence staining and flow cytometry. The activation of microglia and the gasdermin D (GSDMD) were detected by immunofluorescence staining.

Results

Our results showed that Mn treatment induced oxidative stress and activated the NF-κB pathway by increasing the phosphorylation of p65 and IkB-α in BV2 cells and in the basal ganglia of rats. PAS-Na could alleviate Mn-induced oxidative stress damage by inhibiting ROS generation, increasing mitochondrial membrane potential and ATP levels, thereby reducing the phosphorylation of p65 and IkB-α. Besides, Mn treatment could activate the NLRP3 pathway and promote the secretion of IL-18 and IL-1β, mediating pyroptosis in BV2 cells and in the basal ganglia and hippocampus of rats. But an inhibitor of NF-κb (JSH-23) treatment could significantly reduce LDH release, the expression of NLRP3 and Cleaved CASP1 protein and IL-1β and IL-18 mRNA level in BV2 cells. Interestingly, the effect of PAS-Na treatment in Mn-treated BV2 cells is similar to those of JSH-23. Besides, immunofluorescence results showed that PAS-Na reduced the increase number of activated microglia, which stained positively for GSDMD.

Conclusion

PAS-Na antagonized Mn-induced NLRP3 inflammasome dependent pyroptosis through inhibiting NF-κB pathway activation and oxidative stress.

SUBMITTER: Peng D

PROVIDER: S-EPMC7670624 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress.

Peng Dongjie D Li Junyan J Deng Yue Y Zhu Xiaojuan X Zhao Lin L Zhang Yuwen Y Li Zhaocong Z Ou Shiyan S Li Shaojun S Jiang Yueming Y

Journal of neuroinflammation 20201117 1

<h4>Background</h4>The activation of NOD-like receptor protein 3 (NLRP3) inflammasome-dependent pyroptosis has been shown to play a vital role in the pathology of manganese (Mn)-induced neurotoxicity. Sodium para-aminosalicylic acid (PAS-Na) has a positive effect on the treatment of manganism. However, the mechanism is still unclear. We hypothesized that PAS-Na might act through NLRP3.<h4>Methods</h4>The microglial cell line BV2 and male Sprague-Dawley rats were used to investigate the impacts o ...[more]

PMID: 33203418

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Project description:IntroductionYunvjian (YNJ) decoction, a classic traditional Chinese medicine prescription for inflammatory diseases, has demonstrated good therapeutic effects in the clinical treatment of pneumonia. The aim of this study was to clarify the effective ingredients and mechanism of action of YNJ on lipopolysaccharide (LPS)-induced acute lung injury (ALI).MethodsThe effects of YNJ were evaluated in a mouse model of LPS-induced ALI and in LPS-treated MLE-12 murine lung epithelial cells and RAW264.7 macrophages in vitro. The mechanism of action of YNJ on these model systems was studied using RNA sequencing, immunohistochemical analysis, immunoblotting, immunofluorescence, ELISA, and polymerase chain reaction assays. Ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was applied to identify the absorbed components of YNJ.ResultsYNJ attenuated pulmonary damage in LPS-treated mice, as evidenced by reduced protein content in bronchoalveolar lavage fluid, decreased lung wet/dry weight ratio, and improved respiratory function. Analysis of pneumonia-related lung injury samples from patients in the Gene Expression Omnibus dataset GSE40012 indicated that NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis was a primary mechanism in ALI. YNJ reduced the phosphorylation of nuclear factor-kappa B (NF-κB) and decreased the expression levels of lung NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1, and interleukin-1β levels (IL-1β) in vivo. Administration of YNJ-containing mouse serum increased cell viability and decreased malondialdehyde and reactive oxidative species contents in LPS-stimulated MLE-12 cells. YNJ-containing serum also decreased the secretion of tumor necrosis factor-α, IL-6, and IL-1β in LPS-stimulated RAW264.7 macrophages, and promoted macrophage polarization toward an M2 phenotype. A total of 23 absorbed components were identified in YNJ-containing serum. Among those, network analysis and in vitro experiments indicated that diosgenin, timosaponin BII, and mangiferin are anti-inflammatory active substances.ConclusionYNJ attenuates LPS-induced ALI in mice by inhibiting pyroptosis of lung epithelial cells and macrophages via suppression of the NF-κB/NLRP3 pathway. Our findings provide novel insights into the therapeutic effects of YNJ on ALI.

Dataset Information

Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress.

Background

Methods

Results

Conclusion

Publications

Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress.

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