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GB1a Ameliorates Ulcerative Colitis via Regulation of the NF-κB and Nrf2 Signaling Pathways in an Experimental Model.

ABSTRACT: Ulcerative colitis (UC) is an inflammatory bowel disease. The intake of African Garcinia Kola nuts has been reported as a therapy for diarrhea and dysentery in the African population. However, the mechanism of action through which Garcinia Kola nuts act to ameliorates UC remains unknown. GB1a is the main active component of Garcinia Kola nuts. In this study, we explored the therapeutic effects and underlying mechanism of GB1a on dextran sodium sulfate (DSS)-induced UC. Human Colonic Epithelial Cells (HCoEpic) were challenged with TNF-α to test the effects of GB1a in protecting against oxidative stress and inflammation in vitro. Our data showed that GB1a significantly attenuated DSS-induced colonic inflammatory injury manifested as reversed loss of body weight and disease activity index (DAI) scores in UC mice. We also showed that GB1a improved the permeability of the intestinal epithelium by modulating the expression of tight junction proteins (ZO-1, Occludin). Mechanistically, GB1a may activate the Nrf2 antioxidant signaling pathway and suppress the nuclear translocation of NF-κB in reduced oxidative stress and expression of inflammatory genes induced by TNF-α in HCoEpic cells. Our study suggests that GB1a alleviates inflammation, oxidative stress and the permeability of the colonic epithelial mucosa in UC mice via the repression of NF-κB and activation of Nrf2 signaling pathway.

SUBMITTER: Yu Y

PROVIDER: S-EPMC8452853 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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GB1a Ameliorates Ulcerative Colitis via Regulation of the NF-κB and Nrf2 Signaling Pathways in an Experimental Model.

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