Crm1-Dependent Nuclear Export of Bach1 is Involved in the Protective Effect of Hyperoside on Oxidative Damage in Hepatocytes and CCl4-induced Acute Liver Injury

Abstract

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.

Functional transcriptomic landscape informs novel therapeutic strategies in multiple myeloma

“…The TFs BACH1 and RELA (an NF-κB subunit) were enriched in PI resistance, and RELA regulation of cIAP2 gene could be a key mediator of PI-resistance in MM 51,52 . BACH1, also enriched in SELI resistance, is exported from the nucleus by XPO1 (the target of SELI) and recruits PRC2 to promote H3K27me3 modi cations 53,54 , in accord with the association of H3K27me3 with SELI resistance (Fig. 3e).…”

“…4c), an observation we have con rmed by scATAC-seq in primary MM samples 43 . Finally, SELI inhibits XPO1 activity, which directs nuclear export of multiple TFs, including BACH1, which recruits PRC2 and promotes H3K27me3 modi cations 53,54 . Collectively, these ndings support a model whereby DARA-refractory MM cells epigenetically suppress immunogenic genes through H3K27me3, which in turn makes them more vulnerable to disruption of nuclear export machinery that is needed to maintain suppression.…”

Hyperoside as a Potential Natural Product Targeting Oxidative Stress in Liver Diseases

“…When rodents or liver cells are exposed to toxic chemicals, such as carbon tetrachloride (CCl 4 ), hydrogen peroxide (H 2 O 2 ), tert-butyl hydroperoxide (t-BHP), alcohol, and D-galactosamine ( d -GalN), significant alterations in their liver function are observed, with substantial evidence that elevated serum liver enzymes correlate with the severity of liver injury. These high levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are mostly accompanied by histological deterioration of the liver tissue [ 34 , 35 , 36 , 37 , 38 , 39 ].…”

“…As depicted in Figure 2 , Hyp serves as an effective hepatoprotective agent by reducing hepatocellular damage due to oxidative stress induced by chemicals [ 34 , 35 , 36 , 37 , 40 , 41 , 42 , 43 ]. Similar antioxidative properties of Hyp were shown in H 2 O 2 -induced intracellular oxidative stress in HepG2 cell [ 44 ].…”

Nrf2 in Cancer, Detoxifying Enzymes and Cell Death Programs

“…This affects its DNA binding capability, leading to promoter derepression [58]. Bach1 is then exported from the nucleus by Crm1 [59] where its degradation is mediated by Fbxo22 and Skp1-Cul1 [60].…”