Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction

Abstract

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.

Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation

“…Deletion of PHB damages mitochondrial morphology and reduces membrane potential and complex I activity [ 17 18 ]. The anti-inflammatory effect of PHB was demonstrated in intestinal epithelial cells [ 19 ], and it was also suggested that PHB functioned as a transcription factor [ 20 ] and mitochondrial chaperone [ 21 ]. Moreover, it has been reported that a specific deficiency of PHB in β-cells induced mitochondrial dysfunction and β-cell loss, and finally caused the failure of glucose homeostasis [ 22 ].…”

Mitochondria and redox balance in coeliac disease: A case‐control study

“…These organelles, being origin and target of the major cell amount of ROS, play a pivotal role in tissue oxidative stress . Perturbed mitochondrial function has been demonstrated in the setting of intestinal inflammation during intestinal bowel disease (IBD) and in mice undergoing experimental colitis . Bacterial toxins‐treated epithelial monolayers and patients with gut inflammation showed structurally abnormal mitochondria.…”

Effect of TrkB-PLC/IP3 pathway on intestinal inflammatory factors and enterocyte apoptosis in mice with colitis

“…Enterocyte cell cycle distribution and apoptosis were detected by flow cytometry [29][30][31][32] Moreover, both increased expressions and decreased expressions in K252a group were significantly more than those in model group. High enterocyte apoptotic rate which might be affected through…”