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Updated: Jun 13, 2025
Analyzing Oxidative Stress in Murine Intestinal Organoids using Reactive Oxygen Species-Sensitive Fluorogenic Probe
Published on: September 17, 2021
The PI3K/Akt-Nrf2 Signaling Pathway and Mitophagy Synergistically Mediate Hydroxytyrosol to Alleviate Intestinal
Xiaobin Wen1, Shanlong Tang1, Fan Wan1
1State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
Abstract:
Oxidative stress is a major pathogenic factor in many intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). The Nrf2 signaling pathway and mitophagy can reduce reactive oxygen species (ROS) and alleviate oxidative stress, but their relationship is unclear. Hydroxytyrosol (HT), a polyphenolic compound abundant in olive oil, has strong antioxidant activity and may help treat these diseases. We used pigs as a model to investigate HT's effect on intestinal oxidative damage and its mechanisms. Diquat (DQ) induced oxidative stress and impaired intestinal barrier function, which HT mitigated. Mechanistic studies in IPEC-J2 cells showed that HT protected against oxidative damage by activating the PI3K/Akt-Nrf2 signaling pathway and promoting mitophagy. Our study highlighted the synergistic relationship between Nrf2 and mitophagy in mediating HT's antioxidant effects. Inhibition studies confirmed that disrupting either pathway compromised HT's protective effects. Maintaining redox balance through Nrf2 and mitophagy is important for eliminating excess ROS. Nrf2 increases antioxidant enzymes to clear existing ROS, while mitophagy removes damaged mitochondria and reduces ROS generation. This study demonstrates that these pathways collaboratively modulate the antioxidant effects of HT, with neither being dispensable. Targeting Nrf2 and mitophagy could be a promising strategy for treating oxidative stress-related intestinal diseases, with HT as a potential treatment.
Insights
Hydroxytyrosol (HT) protects the intestine from oxidative stress by activating the Nrf2 pathway and promoting mitophagy. These mechanisms work together to reduce reactive oxygen species (ROS) and are crucial for HT
Area of Science:
- Gastroenterology
- Cell Biology
- Nutritional Science
Background:
- Oxidative stress is a key factor in intestinal diseases like IBD and CRC.
- The Nrf2 pathway and mitophagy reduce reactive oxygen species (ROS), but their interplay is not fully understood.
- Hydroxytyrosol (HT), from olive oil, possesses antioxidant properties with potential therapeutic applications.
Purpose of the Study:
- To investigate the effects of HT on intestinal oxidative damage in a pig model.
- To elucidate the underlying mechanisms of HT's protective actions, focusing on the Nrf2 pathway and mitophagy.
- To explore the synergistic relationship between Nrf2 and mitophagy in HT's antioxidant effects.
Main Methods:
- Induction of oxidative stress using Diquat (DQ) in a pig model and IPEC-J2 cells.
- Administration of Hydroxytyrosol (HT) to assess its protective effects against DQ-induced damage.
- Mechanistic studies involving the PI3K/Akt-Nrf2 signaling pathway and mitophagy assessment.
- Inhibition studies to confirm the roles of Nrf2 and mitophagy in HT's efficacy.
Main Results:
- HT treatment mitigated Diquat-induced oxidative stress and improved intestinal barrier function.
- HT activated the PI3K/Akt-Nrf2 signaling pathway and promoted mitophagy in intestinal cells.
- Disrupting either the Nrf2 pathway or mitophagy abolished HT's protective effects, indicating a synergistic relationship.
- Both Nrf2-mediated antioxidant enzyme induction and mitophagy-driven ROS reduction are essential for HT's action.
Conclusions:
- HT exerts protective effects against intestinal oxidative stress through a synergistic action of the Nrf2 pathway and mitophagy.
- Maintaining intestinal redox balance via Nrf2 and mitophagy is critical for mitigating oxidative damage.
- Targeting both Nrf2 and mitophagy pathways, potentially with HT, offers a promising therapeutic strategy for oxidative stress-related intestinal diseases.
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