Background Nrf2-Bach1 antioxidant signaling pathway is considered as one of the most important mechanisms of cellular resistance to oxidative injury. The effect of hyperoside (Hyp) on the expression and distribution of Bach1, the relationship of Hyp’s antioxidative effect and the influence of Bach1 remains unclear. Purpose The aim of this study was to investigate the role and mechanisms of Bach1 in the protective effect of Hyp on oxidative liver injury. Methods The protective effect of Hyp on oxidative stress injury was observed in vivo and in vitro. Next, the influence of Hyp on Bach1 expression and distribution, and competitive combination of Nrf2-Bach1 with ARE in H 2 O 2 -induced L02 cell was studied by Western blot, RT-PCR, immunofluorescence and CHIP assay. Finally, the expressions of Crm1, ERK and p38 and their roles on Hyp mediated nuclear export of Bach1 were investigated by Western blot. Results Hyp ameliorated the pathological damage, reduced the liver index, AST, ALT and MDA activities, and increased SOD and GSH levels in the CCl 4 -induced acute liver injury mouse model. Hyp attenuated H 2 O 2 -induced oxidative stress injury in L02 cells. Hyp promoted the early rapid redistribution of Bach1 from nucleus to cytoplasm. CHIP analyses demonstrated that Hyp enhanced the levels of Nrf2-ARE complex, and weakened the levels of Bach1-ARE complex within three hours. In addition, Hyp enhanced transport protein Crm1 expression and ERK1/2 activity. And LMB, a Crm1 inhibitor, attenuated the effect of Hyp on Bach1 nuclear export and anti-oxidation. U0126, an ERK1/2 inhibitor, reduced the effect of Hyp on Crm1 expression and the Bach1 redistribution. Conclusion The hepatoprotective mechanism of Hyp was related to improve Bach1 nuclear export depending on ERK1/2-Crm1 to upregulate the level of Nrf2 binding to ARE.
Hai-Wei Xu,Shilong Jia,Mengbo Liu,Xiaobo Li,Xia Meng,Xinxin Wu,Lu Yu,Menglin Wang,Cheng-Yun Jin
Chromosome region maintenance 1 (CRM1) is the sole nuclear exporter of several tumor suppressor , a growth regulatory protein as an attractive cancer drug target. In the present work, a novel CRM1 degrader was discovered from newly synthesized α , β-unsaturated-δ-lactone based on a natural product Goniothalamin. It induces apoptosis of both MGC803 and HGC27 cell lines via degrading CRM1. Selective inhibition was observed for the proliferation of gastric cancer cell lines MGC803, HGC27 comparing to Human Gastric Mucosal Epithelial Cell Line (GES1). For the first time, CRM1 inhibitor or degrader inducing apoptosis in gastric carcinoma was investigated.
Adhesive interface stiffness is capable of modulating cellular behavior and gene expression, yet the underlying mechanobiological mechanisms remain unclear. In this study, we investigated the effects of interface stiffness on gene expression pathways by hydrogels with divergent stiffness. Our results reveal that adhesive interface stiffness affects cytoplasmic mechanotranduction as well as nuclear mechanics, and ultimately regulating the subcellular localization of HDAC3. Further investigation unfolds that HDAC3 directly affects global acetylation levels within nucleus. And HDAC3-induced acetylation changes are regulated by myosin contraction, thereby portraying downstream gene expression. Additionally, our study indicates that the interface stiffness-mediated regulation of HDAC3 nuclear-cytoplasmic redistribution is dependent on CRM1, and inhibition of CRM1 impedes the nuclear export of HDAC3. In summary, our work provides an overview of how the subcellular localization of HDAC3 can be manipulated through the regulation of cell adhesion interface stiffness, thereby altering upstream RNA polymerase II activity and gene expression.
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