Abstract
Apoptosis plays a crucial role in maintaining the structural and functional integrity of the intestinal epithelial barrier. Autophagy mediates injury to and repair of the intestinal epithelial barrier through multiple pathways in pathophysiological conditions. Our earlier study has found that cucurbitacin E (CuE) regulates the proliferation, migration, and permeability of human intestinal epithelial cells (IECs); however, its effects and mechanisms on apoptosis and autophagy are still unclear. This study reported CuE induced apoptosis and promoted autophagy of IECs in a concentration-dependent manner. The results showed that CuE could inhibit the expression of apoptosis-related protein Bcl-2 and drove activation of caspase-3 and cleavage of its substrate poly (ADP-ribose) polymerase. CuE also facilitated the expression of endoplasmic reticulum stress-related proteins, CHOP and Grp78, and autophagy-related proteins, Beclin1 and LC3, while inhibiting the phosphorylation of AKT and mammalian target of rapamycin (mTOR). An autophagy inhibitor, 3-methyladenine, reduced CuE-induced apoptosis. These results suggest that CuE may induce apoptosis and autophagy in IECs via the PI3K/AKT/mTOR signaling pathway and that autophagy following endoplasmic reticulum stress participates in the pro-apoptotic process induced by CuE.
Highlights
The structural and functional integrity of the intestinal epithelial barrier depends on the presence of healthy epithelial cells and normally functioning paracellular pathways
It has been shown that apoptosis plays a crucial role in intestinal epithelial barrier function, and disorders of apoptosis regulation may lead to the development of inflammatory bowel disease and intestinal tumors (Watson, 2004; Pedersen et al, 2014)
Caco-2 cell line is the most widely used in the intestinal research in recent years, which has appropriate similarity with healthy intestinal epithelium in morphology and biochemical properties
Summary
The structural and functional integrity of the intestinal epithelial barrier depends on the presence of healthy epithelial cells and normally functioning paracellular pathways. If the physiological proliferation or apoptosis of human intestinal epithelial cells (IECs) changes, inflammatory cytokines can impair intestinal epithelial barrier function via the transepithelial pathway, leading to the occurrence of bacterial translocation, chronic intestinal infection, and even tumors (Peterson and Artis, 2014; Okumura and Takeda, 2017). It has been shown that autophagy mediates the repair of intestinal epithelial barrier injury via multiple pathways, for instance, by regulating intestinal epithelial tight junctions, participating in pathogen clearance, controlling inflammatory signal expression and immune. The medicinal value of cucurbitacin, an effective ingredient in plants of the family Cucurbitaceae, has received increasing attention. The effects of CuE on apoptosis and autophagy in IECs are still unclear and deserve further investigation
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