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Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Aim: To study the inducing effect of bicyclol on heat shock protein 27 (HSP27) and its role on anti-apoptosis in HepG2 cells intoxicated with D-galactosamine (D-GaIN)., Methods: HepG2 cells were treated with various concentrations of bicyclol and then subjected to D-GaIN intoxication. Apoptosis was assayed by hoechst 33258 staining and flow cytometry analysis. HSP27, cytochrome c, apoptosis inducing factor (AIF) and c-Jun N-terminal kinase (JNK) were assayed by Western blot. Heat shock factor 1 (HSF1) was determined by electrophoretic mobility shift assay and the interactions of HSP27 with cytochrome c and AIF were detected by co-immunoprecipitation., Results: The results showed that bicyclol induced HSP27 protein and mRNA expression in HepG2 cells in both time- and dose-dependent manners (the maximal response: 1.23 fold increase at 100 micromol/L). Bicyclol treatment stimulated HSF1 activation and increased the HSF1-HSE binding activity (the maximal response: 2.1 fold increase at 100 micromol/L). This inducing effect of bicyclol on HSP27 and HSF1 was markedly blocked by quercetin. Pretreatment of the cells with bicyclol markedly attenuated D-GaIN-induced apoptosis and the release of cytochrome c and AIF from mitochondria. The induced HSP27 by bicyclol suppressed the activity of caspase-3 and the phosphorylation of JNK caused by D-GaIN in HepG2 cells. All the above effect of bicyclol against D-GaIN-induced hepatocytes apoptosis were significantly reversed by quercetin., Conclusion: HSP27 is involved in the anti-hepatocytes apoptosis of bicyclol, and this effect of bicyclol-induced HSP27 is mainly through inhibition of mitochondria and JNK apoptotic pathways.