Triptriolide Alleviates Lipopolysaccharide-Induced Liver Injury by Nrf2 and NF-κB Signaling Pathways

Abstract

Nrf2 (Nuclear Factor Erythroid 2 Related Factor 2) transcription factor not only regulates oxidative stress response, but also represses inflammation by regulating cytokines production and cross-talking with NF-κB signaling pathways. Nrf2 plays an essential role in liver injury induced by oxidative stress and inflammation. Triptriolide (T11) is a minor component of Tripterygium wilfordii Hook F. (TwHF), which can be obtained by hydrolysis reaction of triptolide (T9). The major purpose of this study is to clarify the regulating effects of T11 on oxidative stress and inflammation in vivo and in vitro. LPS-stimulated RAW 264.7 cells were used to verify the regulating effects of T11 on oxidative stress (ROS and Nrf2 signaling pathway) and inflammatory cytokines production (TNF-α, IL-6 and IL-1β). The antioxidant responsive element (ARE) luciferase assay was employed to evaluate Nrf2 activation effect of T11 in HEK-293T cells. Lipopolysaccharides (LPS) induced acute liver injury (ALI) in BALB/c mice were used to study the protective effects (ALT, AST, MDA, SOD, histopathology and neutrophils/macrophages filtration) and the underlying protection mechanisms of ALI amelioration (Nrf2 and NF-κB signaling pathway) of T11. Firstly, the results showed that T11 can not only effectively decrease the productions of inflammatory cytokines (TNF-α, IL-6 and IL-1β), ROS and NO in LPS-stimulated RAW 264.7 cells, but also further significantly increase the activity of Nrf2 in HEK-293T cells. Secondly, the results suggested that T11 could dramatically decrease the oxidative stress responses (SOD and MDA) and inflammation (histopathology, neutrophils/macrophages filtration, TNF-α, IL-6 and IL-1β production) in LPS-induced ALI in BALB/c mice. Finally, the results implied that T11 could dramatically increase Nrf2 protein expression and decrease p-TAK1, p-IκBα and NF-κB protein expression both in vivo and in vitro. In conclusion, our findings indicated that T11 could alleviate LPS induced oxidative stress and inflammation by regulating Nrf2 and NF-κB signaling pathways in vitro and in vivo, which offers a novel insights for the application of TwHF in clinical.

Triptolide Inhibits Preformed Fibril-Induced Microglial Activation by Targeting the MicroRNA155-5p/SHIP1 Pathway

“…T10 is an active component extracted from the Chinese medical plant, Tripterygium wilfordii Hook F, which displays strong anti-inflammatory and immunosuppressive activities. According to previous studies, T10 has been proved to be a negative regulator of the NF- κ B pathway in diverse cell models [25, 26]. Consistent with previous studies, T10 exerted a repressive effect on the phosphorylation of NF- κ B in the PFF-induced inflammatory model, as well as on the expression of p-IKK α / β , which is associated with phosphorylation of I κ B, an inhibitor of NF- κ B.…”

Colquhounia Root Tablet Protects Rat Pulmonary Microvascular Endothelial Cells against TNF‐α‐Induced Injury by Upregulating the Expression of Tight Junction Proteins Claudin‐5 and ZO‐1

“…Dex regulates the expression of anti-inflammatory genes by binding to the glucocorticoid receptor (GR) [40]. In contrast, CRT does not exert the anti-inflammatory effect via the pituitary-adrenal system [41], but instead reduces oxidative stress and inflammation by regulating NF- κ B signaling pathway [42]. The NF- κ B pathway directly regulates tight junctions, and its activation increases paracellular permeability and impairs barrier function [43, 44].…”

Gut Microbiota, a Potential New Target for Chinese Herbal Medicines in Treating Diabetes Mellitus

“…[30], and several herbal polysaccharides [31, 32, 34–36] also have antioxidant activities. In the diabetic state, enterogenous endotoxin not only is a source of inflammation but may lead to oxidative stress in some organs, such as pancreas [60] and liver [61]. Through regulating the gut microbiota and repairing the intestinal mucosal barrier, herbal medicines can reduce endotoxin damage and avoid a series of problems caused by it.…”