GL-V9, a new synthetic flavonoid derivative, ameliorates DSS-induced colitis against oxidative stress by up-regulating Trx-1 expression via activation of AMPK/FOXO3a pathway

Abstract

GL-V9, a new synthesized flavonoid derivative, has been reported to possess anticancer properties in our previous studies. Uncontrolled overproduction of reactive oxygen species (ROS) has been implicated in oxidative damage of inflammatory bowel disease (IBD). In this study, we aimed to investigate the protective effect of GL-V9 against dextran sulfate sodium (DSS)-induced colitis. GL-V9 attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. GL-V9 also inhibited inflammatory cells infiltration and decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities. Moreover, GL-V9 inhibited ROS and malondialdehyde (MDA) generation, but enhanced superoxide dismutase (SOD), glutathione (GSH) and total antioxidant capacity. GL-V9 reduced pro-inflammatory cytokines production in serum and colon as well. Mechanically, GL-V9 could increase Trx-1 via activation of AMPK/FOXO3a to suppress DSS-induced colonic oxidative stress. Furthermore, GL-V9 decreased pro-inflammatory cytokines and ROS production and increased the antioxidant defenses in the mouse macrophage cells RAW264.7 by promoting Trx-1 expression. In conclusion, our study demonstrated that GL-V9 attenuated DSS-induced colitis against oxidative stress by up-regulating Trx-1 via activation of AMPK/FOXO3a pathway, suggesting that GL-V9 might be a potential effective drug for colitis.

Casticin suppresses the carcinogenesis of small cell lung cancer H446 cells through activation of AMPK/FoxO3a signaling

“…Given that casticin suppresses cell growth in ovarian cancer (SKOV3) cells through FOXO3a activation (13), we aimed to ascertain whether casticin inhibits in vitro carcinogenesis and CSC characteristics in SCLC LCSLCs by activating FOXO3a, a transcription factor inactivated by AMPK (14)(15)(16)24). We first found that casticin significantly increased the phosphorylation levels of AMPK and ACC, in a concentration-dependent manner.…”

“…Furthermore, Sato et al proposed that metformin efficaciously eliminates glioma stem cell-like cells by activating FOXO3 via AMPK (8). Moreover, Zhao et al provided evidence that GL-V9, a new synthetic flavonoid derivative, improved the state of animals with DSS-induced colitis from oxidative stress by upregulating Trx-1 via activation of the AMPK/FOXO3a pathway (15). However, whether the anticancer effects of casticin involve AMPK/FoxO3a signaling remains undefined.…”

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

“…Studies revealed that FOXO3α form a complex with PGC‐1α to transactivate their downstream targets, which are mostly antioxidants, such as catalase, MnSOD, peroxiredoxin 3 (PRDX3), peroxiredoxin 5, thioredoxin 2, thioredoxin reductase 2, and uncoupling protein 2 (Nemoto, Fergusson, & Finkel, ). Its involvement in UC has been well analyzed in several studies (Min et al, ; Zhao et al, ).…”

Forkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss

“…As an example, FoxO proteins are considered as therapeutic targets for cancer (23, 82–84), diabetes mellitus (30, 85, 86), and pathways involving oxidative stress (82, 87, 88). Interestingly, FoxO transcription factors also play a significant role in inflammation.…”