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Oxidative stress is detrimental to animals and can depress the growth performance and regulate the gene expression of animals. However, it remains unclear how oxidative stress regulates the expression of long noncoding RNAs (lncRNAs) and mRNAs. Therefore, the purpose of this article was to explore the profiles of lncRNAs and mRNAs in the liver of piglets under oxidative stress. Here, we constructed a piglet oxidative stress model induced by diquat and evaluated the effects of oxidative stress on the growth performance and antioxidant enzyme activity of piglets. We also used RNA-Seq to examine the global expression of lncRNAs and mRNAs in piglets under oxidative stress. The targets of lncRNAs and mRNAs were enriched in gene ontology (GO) terms and signaling pathways. The results show that the growth performance and activities of antioxidant enzymes were decreased in piglets under oxidative stress. Moreover, eight lncRNAs (6 upregulated and 2 downregulated) and 30 mRNAs (8 upregulated and 22 downregulated) were differentially expressed in the oxidative stress group of piglets compared to the negative control group. According to biological processes in enriched GO terms, the oxoacid metabolic process, intramolecular oxidoreductase activity, and oxidation-reduction process play important roles in oxidative stress. Pathway analysis showed that the signaling pathways involved in insulin and glucose metabolism had a close relationship with oxidative stress. Further in vitro experiments showed that the expression of the upregulated gene GNMT was significantly increased in primary porcine hepatocytes after diquat stimulation. In contrast, the level of the downregulated gene GCK was significantly decreased at 12 h in primary porcine hepatocytes after diquat stimulation. Our results expand our knowledge of the lncRNAs and mRNAs transcribed in the livers of piglets under oxidative stress and provide a basis for future research on the molecular mechanisms mediating oxidative stress and tissue damage.

Aristolochic acids (AAs) are naturally occurring nitro phenanthrene carboxylic acids primarily found in plants of the Aristolochiaceae family. Aristolochic acid D (AAD) is a major constituent in the roots and rhizomes of the Chinese herb Xixin (the roots and rhizomes of Asarum heterotropoides F. Schmidt), which is a key material for preparing a suite of marketed Chinese medicines. Structurally, AAD is nearly identical to the nephrotoxic aristolochic acid I (AAI), with an additional phenolic group at the C-6 site. Although the nephrotoxicity and metabolic pathways of AAI have been well-investigated, the metabolic pathway(s) of AAD in humans and the influence of AAD metabolism on its nephrotoxicity has not been investigated yet. To identify the major metabolites of AAD in human tissues and to characterize AAD O -glucuronidation kinetics in different enzyme sources, as well as to explore the influence of AAD O -glucuronidation on its nephrotoxicity. The O -glucuronide of AAD was biosynthesized and its chemical structure was fully characterized by both 1H-NMR and 13C-NMR. Reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses were conducted to assess the crucial enzymes involved in AAD O -glucuronidation in humans. Docking simulations were performed to mimic the catalytic conformations of AAD in human UDP-glucuronosyltransferases (UGTs), while the predicted binding energies and distances between the deprotonated C-6 phenolic group of AAD and the glucuronyl moiety of UDPGA in each tested human UGT isoenzyme were measured. The mitochondrial membrane potentials (MMP) and reactive oxygen species (ROS) levels in HK-2 cells treated with either AAI, or AAD, or AAD O -glucuronide were tested, to elucidate the impact of O -glucuronidation on the nephrotoxicity of AAD. AAD could be rapidly metabolized in human liver and intestinal microsomes (HLM and HIM, respectively) to form a mono-glucuronide, which was purified and fully characterized as AAD-6- O -β-D-glucuronide (AADG) by NMR. UGT1A1 was the predominant enzyme responsible for AAD-6- O -glucuronidation, while UGT1A9 contributed to a lesser extent. AAD-6- O -glucuronidation in HLM, HIM, UGT1A1 and UGT1A9 followed Michaelis-Menten kinetics, with the K m values of 4.27 μM, 9.05 μM, 3.87 μM, and 7.00 μM, respectively. Docking simulations suggested that AAD was accessible to the catalytic cavity of UGT1A1 or UGT1A9 and formed catalytic conformations. Further investigations showed that both AAI and AAD could trigger the elevated intracellular ROS levels and induce mitochondrial dysfunction and in HK-2 cells, but AADG was hardly to trigger ROS accumulation and mitochondrial dysfunction. Collectively, UGT1A-catalyzed AAD 6- O -glucuronidation represents a crucial detoxification pathway of this naturally occurring AAI analogs in humans, which is very different from that of AAI. Aristolochic acid D (AAD), an abundant naturally occurring aristolochic acid derivative isolated from the Chinese herb Xixin (the roots and rhizomes of Asarum heterotropoides F. Schmidt), can be rapidly converted into AAD-6- O -β-D-glucuronide (AADG) in human tissue preparations. UGT1A-catalyzed AAD 6- O -glucuronidation offers a crucial detoxification pathway of this aristolochic acid derivative in humans, which is very different from that of the nephrotoxin aristolochic acid I (AAI). [Display omitted] • AAD- O -glucuronidation was a major metabolic pathway of AAD in humans. • The glucuronide was biosynthesized and characterized as AAD-6- O -β-D-glucuronide. • UGT1A1 was the predominant enzyme responsible for AAD-6- O -glucuronidation. • AAD-6- O -glucuronidation offers a crucial detoxification pathway of AAD in humans. [ABSTRACT FROM AUTHOR]