TTB Protects Astrocytes Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury via Activation of Nrf2/HO-1 Signaling Pathway

Abstract

Neonatal hypoxic/ischemic encephalopathy (NHIE) is a severe condition that leads to death or neurological disability in newborns. The underlying pathological mechanisms are unclear, and developing the target neuroprotective strategies are urgent. 2,7,2′-trihydroxy-4,4′7′-trimethoxy-1,1′-biphenanthrene (TTB) is a natural product isolated from Cremastra appendiculata (D. Don) Makino and Liparis nervosa (Thunb.) Lindl. TTB has demonstrated potent cytotoxic activity against stomach (HGC-27) and colon (HT-29) cancer cell lines. However, none of the studies have addressed the effects of TTB in NHIE. In the present study, an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced astrocyte injury model was established to investigate the effect of TTB and its potential mechanisms. Our results showed that TTB alleviated the OGD/R-induced reactive oxygen species increase and the intracellular antioxidant capacity of superoxide dismutase activity decrease. Moreover, TTB potentially prolonged the activation state of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and maintained the protection against oxidative stress in OGD/R-induced astrocytes by inducing the nuclear translocation and up-regulation of Nrf2 along with the enhanced expression of the downstream target gene HO-1. Furthermore, TTB treatment diminished the accumulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression induced by OGD/R. We also found TTB-treated astrocytes reversed the inhibition of OGD/R on neurite growth of neurons by the astrocyte-neuron coculture system. In conclusion, TTB inhibited the OGD/R-induced astrocyte oxidative stress at least partially through the inhibition of HIF-1α and VEGF via the Nrf2/HO-1 signaling pathway.

TBHQ-Overview of Multiple Mechanisms against Oxidative Stress for Attenuating Methamphetamine-Induced Neurotoxicity

“…TBHQ increases the nuclear accumulation of Nrf2 and at the same time enhances the expression of antioxidative genes downstream of Nrf2 (including HO-1 and NQO1), moderately activates astrocytes, and reduces the production of inflammatory cytokines, thereby reducing apoptosis and neuronal death [ 89 ]. Under physiological conditions, Nrf2 binds to Keap1 to form the Nrf2 Keap1 complex [ 90 ]. Under oxidative stress, Nrf2 is released from Keap1's antioxidant response element; in this way, Nrf2 is activated.…”

“…Under oxidative stress, Nrf2 is released from Keap1's antioxidant response element; in this way, Nrf2 is activated. Meanwhile, Nrf2 achieves its accumulation in the nucleus by transferring from the cytoplasm to the nucleus, thereby playing a series of neuroprotective effects such as antioxidative stress [ 90 , 91 ]. HO-1 is induced after Nrf2 activation and is a target gene for antioxidative stress [ 92 , 93 ].…”

“…The HIF-1 α /VEGF pathway may be related to oxidative stress in astrocytes. The Nrf2/HO-1 signaling pathway may inhibit oxidative stress in astrocytes by regulating HIF-1 α and VEGF [ 90 ]. HO-1 is a phase II antioxidative enzyme, and its expression level can be regulated by TBHQ.…”

The first complete chloroplast genome of Liparis nervosa and its phylogenetic position within Orchidaceae

“…As an extensive used herb in Chinese traditional medicine, L. nervosa has been used for the treatment of hemostasis, carbuncle and furuncle. Until recently, most research on L. nervosa has focussed on phytochemical constituents (Liu et al 2016(Liu et al , 2019Chen et al 2018). Phenanthrenes have aroused extensive attention for its antitumor activity (Liu et al 2016).…”

“…Until recently, most research on L. nervosa has focussed on phytochemical constituents (Liu et al. 2016 , 2019 ; Chen et al. 2018 ).…”