Inflammatory response and oxidative stress attenuated by sulfiredoxin‑1 in neuron‑like cells depends on nuclear factor erythroid‑2‑related factor 2

Abstract

Sulfiredoxin-1 (SRX1) is a conserved endogenous antioxidative protein, which is involved in the response to cellular damage caused by oxidative stress. Oxidative stress and inflammation are the primary pathological changes in spinal cord injuries (SCI). The aim of present study was to explore the roles of SRX1 in SCI. Using reverse transcription-quantitative PCR and western blotting, the present study discovered that the expression levels of SRX1 were downregulated in the spinal cord tissues of SCI model rats. Massive irregular cavities and decreased Nissl bodies were observed in the model group compared with the sham group. Thus, to determine the underlying mechanisms, neuron-like PC12 cells were cultured in vitro. Western blotting analysis indicated that SRX1 expression levels were downregulated following the exposure of cells to lipopolysaccharide (LPS). Following the transfection with the SRX1 overexpression plasmid and stimulation with LPS, the results of the Cell Counting Kit-8 assay indicated that the cell viability was increased compared with LPS stimulation alone. Furthermore, the expression levels of proinflammatory cytokines secreted by LPS-treated PC12 cells were downregulated following SRX1 overexpression. Increased malondialdehyde content, decreased superoxide dismutase activity and reactive oxygen species production were also identified in PC12 cells treated with LPS using commercial detection kits, whereas the overexpression of SRX1 partially reversed the effects caused by LPS stimulation. The aforementioned results were further verified by determining the expression levels of antioxidative proteins using western blotting analysis. In addition, nuclear factor erythroid-2-related factor 2 (NRF2), a transcription factor known to regulate SRX1, was indicated to participate in the protective effect of SRX1 against oxidative stress. Inhibition of NRF2 further downregulated the expression levels of SRX1, NAD(P)H dehydrogenase quinone 1 and heme oxygenase-1 in the presence of LPS, while activation of NRF2 reversed the effects of LPS on the expression levels of these proteins. In conclusion, the results of the present study indicated that the anti-inflammatory and antioxidative effects of SRX1 may depend on NRF2, providing evidence that SRX1 may serve as a novel molecular target to exert a neuroprotective effect in SCI.

Zerumbone reduces TLR2 stimulation-induced M1 macrophage polarization pattern via upregulation of Nrf-2 expression in murine macrophages

“…Hyperuricemia is considered the primary pathogenic factor in the etiopathogenesis of gout arthritis, where the precipitation of MSU crystals in the lower limbs joints and cartilage causes synovitis and cartilage degeneration through stimulation of the innate immune receptor ( Braga et al, 2017 , Chen-Xu et al, 2019 ). Uric acid acts as a danger signal, resulting in a low grade of inflammation in gout and other metabolic disorders ( Wu et al, 2020 , Kushiyama et al, 2012 ). In response to innate immune danger e.g., uric acid in the joint microenvironment, synovial macrophages can be activated by urate crystals to enhance the secretion of IL-1β, recruit inflammatory monocytes, and shift the macrophages population into a pro-inflammatory phenotype which in turn drives the acute inflammatory response ( Liu et al, 2022 , Zhao et al, 2022 ).…”

“…Nuclear factor erythroid 2-related factor (Nrf2) contributes significantly to cellular defense against oxidative insult via binding to the antioxidant response element (ARE). This binding enhances the expression of genes coding for antioxidant proteins, including HMOX1 and srxn1 ( He et al, 2020 ; Loboda et al, 2016 , Wu et al, 2020 ). Previous findings demonstrated that Zer inhibited reactive oxygen species (ROS) generation via upregulation of Nrf2 expression ( Wu et al, 2020 , Yang et al, 2018 ; Leung et al, 2017 ; Yang et al, 2018 ).…”

“…This binding enhances the expression of genes coding for antioxidant proteins, including HMOX1 and srxn1 ( He et al, 2020 ; Loboda et al, 2016 , Wu et al, 2020 ). Previous findings demonstrated that Zer inhibited reactive oxygen species (ROS) generation via upregulation of Nrf2 expression ( Wu et al, 2020 , Yang et al, 2018 ; Leung et al, 2017 ; Yang et al, 2018 ). Interestingly, our finding showed that Zer significantly alleviated the negative effects of sUA and Pam3CSK4 on Nrf2 expression in M2 BMDMs.…”

Hyperoxidation of Peroxiredoxins and Effects on Physiology of Drosophila

“…In contrast, overexpression of Srx prevents many oxidative damages and apoptosis by modulating the activity of the stress response, inflammatory and apoptotic pathways [ 33 ]. In this way, Srx may confer a neuroprotective function [ 42 , 43 , 44 ] or rescue cardio tissues from injury [ 45 ] or play a role in kidney protection [ 46 ]. Srx is also essential for normal responses to receptor stimulation in endocrine system signaling [ 47 ].…”