Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis.
Ischemia-reperfusion (I/R) is a pathological process that occurs in numerous organs throughout the human body and is frequently associated with severe cellular damage and death. Puerarin is an isoflavone compound extracted from the root of Pueraria lobata and has pharmacological effects such as dilating cerebral vessels and anti-free radical generation in cerebral ischemic tissues. With the deepening of experimental research and clinical research on puerarin, it has been found that puerarin has a protective effect on ischemia-reperfusion injury (IRI) of the heart, brain, spinal cord, lung, intestine and other organs. In summary, puerarin has a vast range of pharmacological effects and significant protective effects, and it also has obvious advantages in the clinical protection of patients with organ IRI. With the deepening of experimental pharmacological research and clinical research, it is expected to be an effective drug for IRI treatment. In this review, we summarize the current knowledge of the protective effect of puerarin on I/R organ injury and its possible underlying molecular mechanisms.
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