Inhibition of fucosylation by 2-fluorofucose attenuated acetaminophen-induced liver injury via its anti-inflammation and anti-oxidative stress effects

Abstract

Fucosylation is a common glycan terminal modification, which has been reported to be inhibited by 2-fluorofucose (2FF) both in vivo and in vitro. The present study aimed to investigate the effect of 2FF on acetaminophen (APAP)-induced acute liver injury, and further clarified the possible mechanisms. In the present study, inhibition of fucosylation by 2FF relieved APAP-induced acute liver injury in vivo. Pretreatment with 2FF remarkably suppressed APAP-induced oxidative stress and mitochondria damage. 2FF markedly enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and simultaneously promoted the expression of downstream proteins including HO-1 and NQO1. Furthermore, pretreatment with 2FF significantly suppressed the expression of inflammation-associated proteins, such as COX2 and iNOS. The data from lectin blot assay revealed that the alteration of α1,6-fucosylation was involved in APAP-induced acute liver injury. The second part of this study further confirmed that the enhancements to antioxidant capacity of 2FF pretreatment and α1,6-fucose deficiency were related to Nrf2/keap1 and NF-κB signaling pathways in HepG2 cells. Taken together, the current study suggested that 2FF might have a potential therapeutic effect for APAP-induced acute liver injury.

Aberrant fucosylation sustains the NOTCH and EGFR/NF-κB pathways and has a prognostic value in human intrahepatic cholangiocarcinoma

“…Both molecular cascades have been previously shown to be modulated by fucosylation in other tumor types 10,11,21 and might be the critical oncogenic drivers targeted by fucosylation inhibitors in this deadly tumor. Moreover, 6AF decreased inducible nitric oxide synthase (iNOS) and NRF2 levels in HUCCT1 and KKU-M213 cell lines (Supplementary Figure 10A, http://links.lww.com/HEP/D423) following previous evidence on the antiinflammatory effects of fucosylation inhibition 25 . Also, 6AF administration reduced CD44 and CXCR4 stem cell markers in the same cell lines and CXCR4 in the CAM (Supplementary Figure 10B,C, http://links.lww.com/HEP/D423), suggesting a pro-stemness action of fucosylation in iCCA.…”

“…Moreover, 6AF decreased inducible nitric oxide synthase (iNOS) and NRF2 levels in HUCCT1 and KKU-M213 cell lines (Supplementary Figure 10A, http://links.lww.com/HEP/ D423) following previous evidence on the antiinflammatory effects of fucosylation inhibition. [25] Also, 6AF administration reduced CD44 and CXCR4 stem cell markers in the same cell lines and CXCR4 in the CAM (Supplementary Figure 10B,C, http://links.lww.com/ HEP/D423), suggesting a pro-stemness action of fucosylation in iCCA. On the other hand, various oncogenic pathways, including the AKT/mTOR, Ras/ MAPK, Hippo, etc., remained unaffected by 6AF administration in the same cells (Supplementary Figure 11, http://links.lww.com/HEP/D423).…”