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Published on: January 5, 2017
Β-Resorcylaldehyde attenuates DSS-induced colitis by inhibiting inflammation and oxidative stress through the
Lei Xiang1, Xue Yang2, Qingzhou Li1
1School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Background:
Ulcerative colitis (UC), a bowel condition marked by heightened oxidative stress, ongoing inflammation, and intestinal barrier dysfunction, has limited therapeutic options that are both effective and safe.
Aim:
This study evaluated the therapeutic impacts and mechanisms of β-Resorcylaldehyde (BRAL), the natural phenolic aldehyde derived from Morus alba wood, on dextran sulfate sodium (DSS)-induced UC.
Methods:
A murine DSS-induced UC model was employed to assess the therapeutic effects of BRAL by assessing disease activity, histopathology, oxidative stress, cytokine expression, and intestinal barrier integrity in vivo. To investigate the underlying molecular mechanisms, RNA sequencing, quantitative PCR, and Western blot experiments were conducted. For in vitro validation, RAW264.7 macrophages and THP-1 cells stimulated with lipopolysaccharide and intestinal epithelial cells injured by tert-butyl hydroperoxide were utilized. The assessment of target engagement was carried out using the cellular thermal shift assay, molecular docking, and molecular dynamics simulation.
Results:
BRAL markedly alleviated the symptoms of DSS-induced UC, reduced oxidative stress and inflammatory reactions, along with restored tight junction protein expression. Transcriptomic and biochemical analyses indicated that BRAL suppressed pro-inflammatory cytokine production while enhancing antioxidant defenses. Mechanistically, BRAL directly bound to Keap1, thereby promoting Nrf2 nuclear translocation and Nrf2/HO-1 pathway activation. Notably, pharmacological inhibition of Nrf2 with the well-known inhibitor ML385 abolished the protective effects of BRAL.
Conclusion:
BRAL improves DSS-induced UC through targeting Keap1 to activate Nrf2 signaling, thereby restoring redox homeostasis, suppressing inflammation, and preserving epithelial barrier integrity. These findings suggest that BRAL is a promising natural candidate for treating UC.
Insights
β-Resorcylaldehyde (BRAL) effectively treats ulcerative colitis (UC) by activating the Nrf2 pathway, reducing inflammation, and restoring gut barrier function. This natural compound shows promise as a safe and effective therapeutic option for UC patients.
Area of Science:
- Pharmacology
- Gastroenterology
- Natural Product Chemistry
Background:
- Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by oxidative stress and compromised intestinal barrier function.
- Current UC treatments have limitations in efficacy and safety, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the therapeutic potential of β-Resorcylaldehyde (BRAL), a natural phenolic aldehyde from Morus alba, in a dextran sulfate sodium (DSS)-induced mouse model of UC.
- To elucidate the underlying molecular mechanisms of BRAL's action in UC.
Main Methods:
- Established a murine DSS-induced UC model to evaluate BRAL's effects on disease activity, histopathology, oxidative stress, and intestinal barrier integrity.
- Employed RNA sequencing, qPCR, and Western blot for mechanistic studies, alongside in vitro assays using cell lines.
- Utilized cellular thermal shift assay, molecular docking, and molecular dynamics simulations to assess target engagement.
Main Results:
- BRAL significantly ameliorated UC symptoms, reduced oxidative stress and inflammation, and restored tight junction protein expression.
- BRAL suppressed pro-inflammatory cytokines and enhanced antioxidant defenses by directly binding Keap1, activating the Nrf2/HO-1 pathway.
- Pharmacological inhibition of Nrf2 negated BRAL's protective effects, confirming the Nrf2 pathway's critical role.
Conclusions:
- BRAL demonstrates therapeutic efficacy in DSS-induced UC by targeting Keap1 to activate Nrf2 signaling.
- This activation restores redox balance, reduces inflammation, and preserves epithelial barrier integrity.
- BRAL represents a promising natural therapeutic candidate for ulcerative colitis.
