HX‐1171, a Novel Nrf2 Activator, Induces NQO1 and HMOX1 Expression

Abstract

HX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a novel synthesized vitamin E derivative, which reportedly has positive effects on various diseases and conditions, such as liver fibrosis, hepatic cirrhosis, and cancer. In this study, we analyzed the transcriptional activity induced by HX-1171. Results from reverse transcription polymerase chain reaction and promoter assays reveal that HX-1171 increased the expression of NQO1 and HMOX1, encoding antioxidant-related enzymes, in A549 human lung epithelial cells. The activity of nuclear factor-E2-related factor (Nrf2), a key transcriptional factor for antioxidative enzymes, was examined in HX-1171-treated cells. Confocal microscopy and Western blotting showed that HX-1171 effectively induced the nuclear translocation and transcriptional activity of Nrf2. We conclude that HX-1171, a novel Nrf2 activator, may be a promising therapeutic agent for oxidative stress-induced diseases. J. Cell. Biochem. 118: 3372-3380, 2017. © 2017 Wiley Periodicals, Inc.

Discovery of Novel Small-Molecule Inducers of Heme Oxygenase-1 That Protect Human iPSC-Derived Cardiomyocytes from Oxidative Stress

“…The observed increase in HMOX1 expression induced by CP-312 was greater and more rapid compared with CDDO-Me or CoPP, which induce HMOX1 by activating Nrf2 pathway via inhibition of keap1 interaction with Nrf2. In addition to HMOX1, NQO1 is a prototypical target gene of Nrf2 (Kumar et al, 2011;Kim et al, 2017). Differences in the dynamics of the HMOX1 response and the lack of NQO1 upregulation in hiPSC-CMs treated with CP-312 lead us to speculate that CP-312 may be regulating HMOX1 expression in a Nrf2independent manner.…”

HX-1171 attenuates pancreatic β-cell apoptosis and hyperglycemia-mediated oxidative stress via Nrf2 activation in streptozotocin-induced diabetic model

“…In a previous study, we discovered a new Nrf2 activator, HX-1171. HX-1171 showed superiority in increasing the expression of Nrf2 target genes compared to tBHQ, another Nrf2 activator, and a remarkable effect in promoting nuclear translocation of Nrf2 [ 29 ]. Thus, we investigated the efficacy of HX-1171 in an STZ-induced diabetic model to confirm whether HX-1171 could be effective for diabetic conditions like other Nrf2 activators.…”

“…In addition, genetic Nrf2 induction significantly reduced beta cell damage in the reactive oxygen species (ROS)-mediated mouse model of diabetes, whereas genetic Nrf2 deficiency resulting from conditional-Nrf2 knockout markedly aggravated beta cell damage [ 28 ]. Therefore, we investigated the antidiabetic effect of HX-1171, a newly discovered Nrf2 activator [ 29 ], in the INS-1 pancreatic beta cell line and the STZ-induced diabetic mouse model.…”

“…HX-1171 is a non-cytotoxic compound that enhances the expression of antioxidant enzymes very effectively by promoting nuclear translocation of Nrf2 [ 29 ]. In the pancreatic beta cell line, INS-1, HX-1171 diminished rate of cell apoptosis and generation of intracellular ROS induced by STZ treatment.…”

BTT‐105 ameliorates hepatic fibrosis in non‐alcoholic fatty liver animal model

“…BTT‐105 (1‐O‐hexyl‐2,3,5‐trimethylhydroquinone), a hydroquinone derivative, is a potent anti‐oxidant and anti‐fibrotic small molecule 2–6 . BTT‐105 showed that increased anti‐oxidant defense genes through increasing the nuclear erythroid 2‐related factor 2 (Nrf2) 7 . BTT‐105 finished Phase I study, and showed well tolerability and safety in normal healthy subjects up to 2000 mg/day 8…”