Abstract
Apoptosis of intestinal epithelial cells following oxidative stress is a major cause of mucosal barrier dysfunction and is associated with the pathogenesis of various gastrointestinal diseases. Although L-tryptophan (Trp) is known to improve intestinal integrity and function, a beneficial effect of N-acetyl serotonin (NAS), a metabolite of Trp, on the apoptosis of enterocytes and the underlying mechanisms remain largely unknown. In the present study, we showed that porcine enterocytes treated with 4-hydroxy-2-nonenal (4-HNE), a metabolite of lipid peroxidation, led to upregulation of apoptotic proteins, including Bax and cleaved caspase-3, and reduction of tight junction proteins. These effects of 4-HNE were significantly abrogated by NAS. In addition, NAS reduced ROS accumulation while increasing the intracellular concentration of glutathione (GSH), and the abundance of the Nrf2 protein in the nucleus and its downstream target proteins. Importantly, these protective effects of NAS were abrogated by Atra, an inhibitor of Nrf2, indicating a dependence on Nrf2 signaling. Taken together, we demonstrated that NAS attenuated oxidative stress-induced cellular injury in porcine enterocytes by regulating Nrf2 signaling. These findings provide new insights into a functional role of NAS in maintaining intestinal homeostasis.
Highlights
The intestinal monolayer epithelium serves as the major site for the digestion and absorption of nutrients, electrolytes, and water from the intestinal lumen, while preventing the permeation of toxins, allergens, and pathogens from the gut lumen into mucosal tissue [1]
Western blot analysis showed that 4-HNE treatment led to enhancement of the protein level of cleaved caspase-3, a characteristic of apoptosis, which was abrogated by 100 μM of N-acetyl serotonin (NAS) (Figure 1B and 1C)
These results suggested that NAS administration attenuated the 4-HNE-induced apoptosis of IPEC-1 cells
Summary
The intestinal monolayer epithelium serves as the major site for the digestion and absorption of nutrients, electrolytes, and water from the intestinal lumen, while preventing the permeation of toxins, allergens, and pathogens from the gut lumen into mucosal tissue [1]. A state of imbalance between the generation of ROS and antioxidant defenses [3,4], has been reported to induce cell apoptosis in both in vitro and in vivo experiments, and contributes to impaired intestinal mucosal barrier function [5,6]. Accumulating evidence shows that oxidative damage in the small intestinal epithelium is a major cause. 4-Hydroxy-2-nonenal (4-HNE), a metabolite of lipid peroxidation in response to intracellular damage, is associated with oxidative stress in various cells and tissues [9]. A recent study has shown that the nuclear translocation of nuclear factor erythroid
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