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Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and
Jie Han1, Qian Zhao, Christine Basmadjian
1*Department of Internal Medicine, Division of Gastroenterology, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas; and †Therapeutic Innovation Laboratory, CNRS/Université de Strasbourg, Illkirch, France.
Background:
Flavaglines are a family of natural compounds shown to have anti-inflammatory and cytoprotective effects in neurons and cardiomyocytes. Flavaglines target prohibitins as ligands, which are scaffold proteins that regulate mitochondrial function, cell survival, and transcription. This study tested the therapeutic potential of flavaglines to promote intestinal epithelial cell homeostasis and to protect against a model of experimental colitis in which inflammation is driven by epithelial ulceration.
Methods:
Survival and homeostasis of Caco2-BBE and IEC-6 intestinal epithelial cell lines were measured during treatment with the flavaglines FL3 or FL37 alone and in combination with the proinflammatory cytokines tumor necrosis factor (TNF) α and interferon γ. Wild-type mice were intraperitoneally injected with 0.1 mg/kg FL3 or vehicle once daily for 4 days during dextran sodium sulfate-induced colitis to test the in vivo anti-inflammatory effect of FL3.
Results:
FL3 and FL37 increased basal Caco2-BBE and IEC-6 cell viability, decreased apoptosis, and decreased epithelial monolayer permeability. FL3 and FL37 inhibited TNFα- and interferon γ-induced nuclear factor kappa B and Cox2 expression, apoptosis, and increased permeability in Caco2-BBE cells. FL3 and FL37 protected against TNFα-induced mitochondrial superoxide generation by preserving respiratory chain complex I activity and prohibitin expression. p38-MAPK activation was essential for the protective effect of FL3 and FL37 on barrier permeability and mitochondrial-derived reactive oxygen species production during TNFα treatment. Mice administered FL3 during dextran sodium sulfate colitis exhibited increased colonic prohibitin expression and p38-MAPK activation, preserved barrier function, and less inflammation.
Conclusions:
These results suggest that flavaglines exhibit therapeutic potential against colitis and preserve intestinal epithelial cell survival, mitochondrial function, and barrier integrity.
Insights
Flavaglines protect intestinal cells and improve gut barrier function in colitis models. These natural compounds enhance cell survival and mitochondrial health, offering therapeutic potential for inflammatory bowel diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Flavaglines are natural compounds with known anti-inflammatory and cytoprotective properties.
- They target prohibitins, proteins crucial for mitochondrial function and cell survival.
- This study investigates flavaglines' potential in maintaining intestinal epithelial cell homeostasis and protecting against experimental colitis.
Purpose of the Study:
- To evaluate the therapeutic potential of flavaglines in promoting intestinal epithelial cell homeostasis.
- To assess the protective effects of flavaglines against experimental colitis models.
- To understand the molecular mechanisms underlying flavagline-mediated protection.
Main Methods:
- Assessed intestinal epithelial cell line (Caco2-BBE, IEC-6) viability, apoptosis, and permeability under flavagline treatment with or without pro-inflammatory cytokines (TNFα, interferon γ).
- Investigated the role of nuclear factor kappa B, Cox2, mitochondrial superoxide generation, and p38-MAPK activation.
- Tested the in vivo anti-inflammatory effect of flavagline FL3 in a dextran sodium sulfate-induced colitis mouse model.
Main Results:
- Flavaglines FL3 and FL37 enhanced cell viability, reduced apoptosis, and decreased permeability in intestinal epithelial cells.
- They inhibited pro-inflammatory cytokine-induced NF-κB and Cox2 expression, apoptosis, and barrier dysfunction.
- FL3 and FL37 protected against mitochondrial damage by preserving Complex I activity and prohibitin expression, with p38-MAPK activation being essential.
- In vivo, FL3 treatment in mice with colitis preserved barrier function and reduced inflammation, with increased prohibitin and p38-MAPK activation.
Conclusions:
- Flavaglines demonstrate therapeutic potential for colitis.
- They preserve intestinal epithelial cell survival, mitochondrial function, and barrier integrity.
- Targeting prohibitins and p38-MAPK pathways may be key mechanisms for flavagline efficacy.
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