Abstract
Eucommia ulmoides flavones (EUF) have been demonstrated to alleviate oxidative stress and intestinal damage in piglets, but their effect target is still poorly understood. NF-E2-related factor 2 (Nrf2) pathway plays a very important role in the defense mechanism. This study was designed to investigate the regulation of EUF on the Nrf2 pathway and inhibition of Nrf2 on oxidative stress in the intestine of piglets. An in vivo study was conducted in weaned piglets treated with basal diet, basal diet+diquat, and 100 mg/kg EUF diet+diquat for 14 d to determine Nrf2 and Keap1 protein expressions, as well as downstream antioxidant gene mRNA expression. An in vitro study was performed in a porcine jejunal epithelial cell line to investigate the effect of inhibiting Nrf2 on cell growth and intracellular oxidative stress parameters. The results showed that the supplementation of EUF decreased the oxidized glutathione (GSSG) concentration and the ratio of GSSG to glutathione (GSH) but increased the protein expressions of nuclear Nrf2 and Kelch-like ECH-associated protein 1 (Keap1) as well as mRNA expression of heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1), and glutamate cysteine ligase catalytic subunit (GCLC) in the small intestinal mucosa of diquat-challenged piglets. When Nrf2 was inhibited by using ML385, cell viability, cellular antioxidant activities, expressions of nuclear Nrf2 and Keap1 protein, and downstream antioxidant enzyme (HO-1, NQO-1, and GCLC) mRNA were decreased in paraquat-treated enterocytes. These results showed that the Nrf2 signaling pathway played an important role in EUF-regulating oxidative stress in the intestine of piglets.
Highlights
The intestinal tract of piglets is not fully developed and highly susceptible to stress due to its special vascular anatomical structure and convective oxygen exchange mechanism [1]
Targeting NF-E2-related factor 2 (Nrf2)-antioxidative stress signaling is an ideal strategy to prevent or treat oxidative stress-related diseases [12, 13, 19]. It has been proved by a large number of studies that some plant extracts could be potential inducers of the Kelchlike ECH-associated protein 1 (Keap1)-Nrf2 pathway [20,21,22,23,24,25]
Eucommia ulmoides flavones (EUF) has shown antioxidative activity and antiinflammatory effects in piglets in the previous study; the present study is, focusing on its regulatory mechanisms involved in the Keap1-Nrf2 pathway
Summary
The intestinal tract of piglets is not fully developed and highly susceptible to stress due to its special vascular anatomical structure and convective oxygen exchange mechanism [1]. Stress can induce the production of a large number of toxic reactive oxygen species (ROS) metabolites in the enterocytes and affect the stability of DNA and RNA as well as the activities of enzymes, resulting in intestinal mucosal damage [3]. Yin et al found that early weaning at the age of 14 d damaged the oxidation balance of piglets, and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in plasma were significantly reduced, especially at 3 days after weaning [4]. Wang et al found that 21-day-old weaning could reduce glutathione (GSH) content by 25% and increase the ratio of oxidized glutathione (GSSG) to GSH by 59% in the jejunum of piglets [5].
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