Nur77 attenuates inflammatory responses and oxidative stress by inhibiting phosphorylated IκB-α in Parkinson’s disease cell model

Abstract

Neuroinflammation and oxidative stress play key roles in the pathological development of Parkinson's disease (PD). Nerve growth factor-induced gene B (Nur77) is closely related to dopamine neurotransmission, and its pathogenesis is unclear. This study aims to investigate the role and mechanism of Nur77 in a cell model of Parkinson's disease. Silencing Nur77 with siRNA can aggravate intracellular LDH release, increase the expression of pro-inflammatory genes (such as tumor necrosis factor α, nuclear factor κB (p65), monocyte chemotactic protein 1, interleukin-6), and decrease cell survival, decrease expression of nuclear factor E2-related factor(Nrf2), heme oxygenase 1, NADPH quinineoxidoreductase-1. Cytosporone B (Nur77 agonist) has the opposite effect to Nur77 silencing. PDTC (NF-κB inhibitor / antioxidant) can also inhibit pro-inflammatory genes to a similar degree as Cytosporone B. Phosphorylated IκB-α can be inhibited by Cytosporone B, while silencing Nur77 can increase the protein expression level of phosphorylated IκB-α. After silencing IκB-α, both Cytosporone B and siNur77 did not affect pro-inflammatory genes and antioxidant stress. These findings reveal the first evidence that Nur77 exerts anti-inflammatory and antioxidant stress effects by inhibiting IκB-α phosphorylation expression in a Parkinson cell model. Nur77 may be a potential therapeutic target for Parkinson's disease.

Kurarinone alleviated Parkinson's disease via stabilization of epoxyeicosatrienoic acids in animal model

“…The inflammatory mediators IL-6, TNF-α, and ICAM-1 cause neuroinflammation and dopaminergic neuronal loss in PD, and are all regulated by a “master switch” for inflammatory gene expression—NF-κB ( 39 ). In the in vitro and in vivo PD models, expression levels of IL-6, TNF-α, p-p65, and MCP-1 were increased ( 40 , 41 ), changes that are found in PD brains as well ( 42 – 45 ). Previous studies showed that kurarinone, a lavandulyl flavanone from S. flavescens ( 21 ), inhibits iNOS-dependent nitric oxide release, reactive oxygen species generation, and expression of inflammatory cytokines (e.g., TNF-α, IL-1β, and iNOS) in lipopolysaccharide-induced RAW264.7 macrophages ( 24 ), which reveals that kurarinone might possess anti-inflammatory potential in PD.…”

The nuclear receptor NR4A1 restrains neutrophil granulocyte mediated brain damage in cerebral ischemia

“…Although NR4A1 is a so-called orphan receptor for which no natural ligands have yet been identified, synthetic ligands are available and have recently been successfully used in attenuating pro-inflammatory mediators (Cho et al 2007, Zhang et al 2008). Cytosporone-B mediated NR4A1-acitivation has further been shown to ameliorate osteoarthritis by reducing chondrocyte-mediated inflammation (Xiong et al, 2020), to attenuate inflammatory responses in a Parkinson’s disease model (Yan et al, 2020) or even in an experimental model of influenza virus infection via modulation of alveolar macrophages (Egarnes et al, 2017). Indeed, application of Cytosporone-B results in reduced infarcts and improved functional outcome and thus represents a promising future candidate for stroke treatment.…”

Nur77 Prevents Osteoporosis by Inhibiting the NF‐κB Signalling Pathway and Osteoclast Differentiation

“…10 In addition, in Nur77 knockout mice, the serum levels of LPS, TNFα and IL-1β were previously shown to be increased significantly. 31 This result mainly showed that the level of inflammation was increased in Nur77 knockout mice. To further clarify whether the increased number of osteoclasts in Nur77 knockout mice was associated with more inflammation, we next measured the levels of inflammation in mouse femurs.…”