Betulin exhibits anti-inflammatory activity in LPS-stimulated macrophages and endotoxin-shocked mice through an AMPK/AKT/Nrf2-dependent mechanism

Abstract

Continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer. Nuclear factor erythroid 2-related factor (Nrf2), a critical transcriptional activator for antioxidative responses, has envolved to be an attractive drug target for the treatment or prevention of human diseases. In the present study, we investigated the effects and mechanisms of betulin on Nrf2 activation and its involvement in the lipopolysaccharide (LPS)-triggered inflammatory system. In macrophages, betulin activated the Nrf2 signaling pathway and increased Nrf2-targeted antioxidant and detoxifying enzymes, including NADPH, quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), γ-glutamyl cysteine synthetase catalytic subunit (GCLC) and modifier subunit (GCLM) in a dose and time dependent manner. Importantly, we found betulin-induced activation of Nrf2 is AMPK/AKT/GSK3β dependent, as pharmacologically inactivating AMPK blocked the activating effect of betulin on AKT, GSK3β and Nrf2. Furthermore, betulin attenuated LPS-induced inflammatory mediators (iNOS and COX-2) and MAPK inflammatory signaling pathway. The effect of betulin on HO-1 and NQO1 upregulation, iNOS and COX-2 the downregulation, and survival time extension was largely weakened when Nrf2 was depleted in vitro and in vivo. Our results demonstrate that the AMPK/AKT/Nrf2 pathways are essential for the anti-inflammatory effects of betulin in LPS-stimulated macrophages and endotoxin-shocked mice.

Effect of metformin on ossification and inflammation of fibroblasts in ankylosing spondylitis: An in vitro study

“…Owing to il‐6 can inducing the ossification of fibroblasts from AS patient, metformin may also suppress ossification through anti‐inflammation effect. Moreover, Pi3k and Akt are both activated after metformin treatment, and the inflammation were suppressed may through the activation of Pi3k/Akt pathway . Therefore, metformin may a new way for AS treatment and anti‐inflammation effect of metformin through Pi3k/Akt and AMPK pathway may be one of the factor that metformin suppresses osteogenesis of fibroblasts.…”

Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway

“…To counteract oxidative stress, cells have developed adaptive, dynamic programs to maintain the cellular redox homeostasis and attenuate oxidative damage through a series of antioxidant molecules and detoxifying enzymes. The Nrf2 pathway, which plays an critical role in cellular redox homeostasis, is one of the main defense mechanisms against oxidative stress [26]. Pts, a natural activator of Nrf2, attenuates the intracellular ROS level, conferring neuroprotection depending on its antioxidative stress activity [27].…”

Mechanism of Oleogel‐S10: A triterpene preparation for the treatment of epidermolysis bullosa

“…The physiological process of wound healing has been described as a three-stage process of inflammation, tissue formation, and wound closure/remodeling (Valero, Javierre, Garcia-Aznar, Menzel, & Gomez-Benito, 2015). In various studies, dry extract from birch bark and its active marker substances have been shown to have activity in the first two stages of the wound healing process (Alakurtti, Makela, Koskimies, & Yli-Kauhaluoma, 2006;Bernard, Scior, Didier, Hibert, & Berthon, 2001;Ci et al, 2017;Doller et al, 2008;Ebeling et al, 2014;Galgon, Wohlrab, & Drager, 2005;Laszczyk, 2009;Lee, Nam, Kim, & Lee, 2006;Recio, Giner, Manez, & Rios, 1995;Saleem, Afaq, Adhami, & Mukhtar, 2004;Suksamrarn et al, 2006;Takada & Aggarwal, 2003;Tseng & Liu, 2004;Wardecki et al, 2016;Woelfle et al, 2010;Yadav, Prasad, Sung, Kannappan, & Aggarwal, 2010;Yogeeswari & Sriram, 2005;Yun et al, 2003). An overview of this activity is presented in Figure 1.…”

“…Anti-inflammatory activity of betulin, oleanolic acid, erythrodiol, betulinic acid, and lupeol has been shown in various experimental models (Bernard et al, 2001;Ci et al, 2017;Laszczyk, 2009;Saleem et al, 2004;Takada & Aggarwal, 2003;Tseng & Liu, 2004;Yadav et al, 2010;Yogeeswari & Sriram, 2005). Exact mechanisms of these activities are not yet completely understood, however, and further investigations are required to fully elucidate and delineate proinflammatory and anti-inflammatory effects of Oleogel-S10 and its various active marker substances.…”