Carnosic acid prevents dextran sulfate sodium-induced acute colitis associated with the regulation of the Keap1/Nrf2 pathway

Abstract

Crohn’s disease and ulcerative colitis are inflammatory bowel diseases (IBDs) with high prevalence in humans. Carnosic acid (CA) has been reported to possess antioxidative properties; however, its role in IBDs has not been determined. In the present study, we found that CA significantly prevented the loss of body weight and shortening of colon length in acute colitis induced by dextran sodium sulfate (DSS). Pronounced infiltration of immune cells and a loss of crypt architecture and goblet cells were ameliorated by CA. CA significantly decreased the activity of MPO and infiltration of F4/80+ macrophages in the colon. DSS-induced pro-inflammatory cytokine mRNA and protein levels in the colon were also attenuated by CA. CA decreased the activation of p65 and c-Jun signalling. CA inhibited DSS-induced NLRP3 inflammasome activation by reducing caspase 1 activity. In addition, CA increased the level of Nrf2 and prevented the degradation of Nrf2 via ubiquitination by blocking the interaction between Cullin3 and Keap1, which resulted in the decrease of Nrf2 target genes. Finally, GSH levels and SOD activity were increased after CA treatment, while MDA and iNOS levels were significantly reduced. Taken together, our data showed that CA may be useful as a potential therapeutic candidate for IBDs.

Idebenone Protects against Acute Murine Colitis via Antioxidant and Anti-Inflammatory Mechanisms

“…The antioxidants SOD and NQO-1 directly eliminate free superoxide radicals to protect against lipid peroxidation [50,51]. Previous reports of acute gut inflammation in the DSS model observed a significant increase in lipid peroxidation and reduced levels of antioxidant enzymes (NQO-1 and SOD) [18,19,[52][53][54][55][56], which were replicated in the present study. We also observed a significant reduction in MDA levels after treatment with idebenone, which is consistent with a previous report where idebenone effectively suppressed lipid peroxidation in brain mitochondria [57].…”

“…Therefore, at present, it is not possible to align the multiple contradicting results of the reported clinical trials. On the other side, a plethora of literature supports the role of oxidative stress in UC and consequently justifies the use of antioxidants as a therapeutic strategy [15,27,52,54,60,[98][99][100][101][102]. Since UC is a multifactorial disease, pharmacological targeting of individual factors appears of limited use to provide effective and sustainable therapy outcomes.…”

Periplaneta americana Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Rats by Keap1/Nrf-2 Activation, Intestinal Barrier Function, and Gut Microbiota Regulation

“…It has been substantially demonstrated that nuclear factor (erythroid derived 2)-like 2 (Nrf2), a redox-sensitive transcription factor, as well as its tight interact with Kelch-like ECH-associated protein 1 (Keap1) could promote the antioxidant activity and provide therapeutic benefits in inflammation and associated disorders. Keap1/Nrf-2 signaling pathway plays a key role in the protection of intestinal cells against oxidative stress ( Yang N. et al, 2017 ). Therefore, the mRNA expressions of Keap1 ( Figure 6A ) and Nrf-2 ( Figure 6B ) were measured by real-time quantitative PCR.…”

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

“…The nuclear receptor PXR and the transcription factor Nrf2 play important roles in elevating MDR1 gene transcription and ultimately increasing P-gp function (Chen et al, 2012;Jeddi et al, 2018). Additionally, dysregulation of PXR/Nrf2 activity in the intestine is thought to contribute to colitis pathophysiology (Khor et al, 2006;Yang et al, 2017). In the present study of DSS-induced colitis rats, PXR and Nrf2 expression were decreased in the colon, in accordance with previous studies (Hu et al, 2014;Yang et al, 2017); however, in the berberine-treated group, only the decrease in Nrf2 expression was reversed by berberine, with no effect observed on PXR expression ( Fig.…”