Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-κB signaling pathways in murine splenocytes

Abstract

The adverse effects of ionizing radiation occur due to the generation of reactive oxygen species (ROS). The aim of this study was to identify the protective effects of naringin (NG), a citrus flavonoid, on ionizing radiation (IR)-induced differential stress response, with an exploration of the mechanisms involved in this process. Isolated murine splenocytes were incubated in the presence and in the absence of different concentrations of NG (50 and 100 μM) for 1 h prior to 6 Gy γ-irradiation, and the molecular mechanisms of action were determined through biochemical, immunoblot, flow cytometric, and immunofluorescence studies. Pretreatment with NG significantly prevented IR-induced intracellular ROS generation, thereby preventing the formation of cellular TBARS and the development of cellular nitrite. NG significantly reduced nuclear DNA damage with respect to the irradiated splenocytes, through the inhibition of DNA-PKcs and p-γH2AX. The reduced cell viability as a result of irradiation was recovered by NG through modulation of the redox-regulated cell signaling system. NG pretreatment resulted in significant inhibition of IR-induced G1/S phase cell cycle arrest through the modulation of p53-dependent p21/WAF1, cyclin E, and CDK2 activation. The results also demonstrated that NG blocked the IR-induced p38 function and reversed IR-mediated differential stress response through inhibition of the NF-κB pathway. Thus, the p38/NF-κB pathway participated in the IR-induced inflammatory development, leading to upregulation of CRP, MCP-1, and iNOS2 gene expression. However, NG pretreatment reversed the inflammatory development through downregulation of NF-κB, and regulated the expression of CRP, MCP-1, and iNOS2. The above results provide a theoretical basis for the preventive use of NG against radiation-induced multiple cellular anomalies.

Potential Protective Effects of Ursolic Acid against Gamma Irradiation-Induced Damage Are Mediated through the Modulation of Diverse Inflammatory Mediators

“…The phosphorylation and translocation of NF-κB were also increased after exposure to gamma radiation, which were blocked upon the treatment of UA. Our observations could be supported by a recent study from Manna et al (2015), who showed that naringin inhibited gamma radiation-caused inflammation and oxidative DNA damage by controlling p53 and NF-κB signaling pathways in murine splenocytes (Manna et al, 2015). In another report, Lee et al (2014) showed that UV light exposure produced a loss of proliferation and an activation of NF-κB in the skin melanoma cells, while pre-treatment with UA significantly reduced the amount of phosphorylated NF-κB at 24 h post-exposure (Lee et al, 2014).…”

“…The modulation of NF-κB contributes to the survival of the irradiated cells (Manna et al, 2015). Our results demonstrated that exposure to the gamma radiation dose- and time-dependently increased NF-κB DNA binding activities in HaCaT cells, and UA treatment significantly suppressed this increase.…”

“…It acts as a redox sensor and has been reported to participate in the activation of radiation-induced inflammatory cascade, DNA damage and NO production (Ibuki et al, 2003; Manna et al, 2015). The treatment of diverse pharmacological agents, such as Naringin (Manna et al, 2015), Corilagin (Dong et al, 2010), Brazilin (Kang et al, 2016), and Baicalein (Pfalzgraff et al, 2016), have been previously reported to significantly reverse the inflammatory responses and oxidative DNA damage through the modulation of NF-κB signaling pathways. Therefore, we hypothesized that UA, being a potent NF-κB blocker, may also display protective effects against injury induced by gamma radiation.…”

Naringin Protects Against Cartilage Destruction in Osteoarthritis Through Repression of NF-κB Signaling Pathway

“…Studies also found that naringin is protective against inflammatory reaction [6]. Recently, it was reported that naringin protects against joint destruction in inflammatory arthritis models [7].…”

Key mechanisms involved in ionizing radiation-induced systemic effects. A current review

“…The importance of NF-κB in mediating irradiation-induced inflammatory responses has been recently shown by Manna et al, who, by selectively inhibiting NF-κB activity, could successfully reverse IR-induced stress response and inflammation development by downregulating the expression of CRP (C reactive protein), MCP-1 (monocyte chemotactic protein) and iNOS2 (inducible nitric oxide synthase 2). 147 Radiation-induced cytokine gene upregulation is often a biphasic process. Several inflammation-related cytokine genes are characteristically immediate early response genes that are activated within minutes to hours after irradiation.…”