Antagonism of RIP1 using necrostatin-1 (Nec-1) ameliorated damage and inflammation of HBV X protein (HBx) in human normal hepatocytes

Abstract

Hepatitis B virus X protein (HBx), encoded by the hepatitis B virus (HBV) genome, plays a pivotal in mediating pathogenicity in liver diseases. However, the underlying mechanisms are still needed to be elucidated. Receptor-interacting protein 1 (RIP1) has been identified as a serine/threonine kinase with various biological functions in cell fate, proliferation, and death. In the current study, we found that overexpression of HBx in LO 2 human normal hepatocytes increased the expression of RIP1. Importantly, our results indicate that blockage of RIP1 using its specific antagonist necrostatin-1 (Nec-1) ameliorated HBx-induced oxidative stress by mitigating the production of ROS and Nox-4 expression. Also, the presence of Nec-1 improved HBx-induced mitochondrial dysfunction by increasing MMP. Importantly, we found that Nec-1 could inhibit the production of pro-inflammatory cytokines IL-6, IL-8, and CXCL2 as well as the secretion of HMGB1. Mechanistically, we found that Nec-1 treatment suppressed the activation of the JNK/AP-1 and NF-jB signalling pathways. Our findings implicated a novel biological function of RIP1 in HBx-induced cytotoxicity and inflammation in human normal hepatocytes. Antagonism of RIP1 might be a potential therapeutic approach for the treatment of HBV-associated liver diseases. ARTICLE HISTORY

Crucial role of the terminal complement complex in chondrocyte death and hypertrophy after cartilage trauma

“…This corresponds to our recent study that zVAD leads to pro-inflammatory effects after cartilage trauma probably by enhancing necroptotic processes due to CASP8-inhibiton 18 . According to previous findings, Nec reduces chemokine and catabolic enzyme expression by suppression of the JNK/AP-1 and NF-kB signaling pathways 30,47 . Previously, we reported similar features for the antioxidant NAC after cartilage trauma 24 , which also attenuated most of the TCC-induced processes in the present study.…”

Nec-1 Attenuates Neurotoxicity Induced by Titanium Dioxide Nanomaterials on Sh-Sy5y Cells Through RIP1

“…5 The mRNA expression after SH-SY5Y cells transfected with si-RIP1. ( **** p < 0.0001) exposed cells to TNPs with or without Nec-1 (a potent necroptosis inhibitor) [17,18], and measured the cell viability, LDH leakage, and the levels of inflammatory cytokines. Our data suggest that Nec-1 co-treatment can mitigate inflammatory injury induced by TNPs.…”

Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review

“…HBx overexpression in healthy hepatocytes induces serine/threonine kinases, in particular, receptor-interacting protein (RIP-1), which inherently aids in the production of pro-inflammatory cytokines IL-6, IL-8 and CXCL2, in addition to secreting HMGB1, a cytokine mediator of inflammation [ 85 ]. Moreover, HBx has been mechanistically demonstrated to induce S100A9 DAMP protein, by prompting translocation of cytoplasmic NF-kB into the nucleus followed by binding to activate its transcription [ 86 ].…”