ferrostatin-1 and Sepsis

Ferroptosis is a regulated form of cell death. At present, the role of ferroptosis in sepsis-induced acute kidney injury (SAKI) has not been studied. Melatonin (MEL) has been reported to be an effective ferroptosis inhibitor, but it is unclear whether Melatonin can regulate ferroptosis in SAKI and whether its downstream mechanism correlates with the Nrf2/HO-1 pathway.. The cecal ligation and puncture (CLP) method and LPS injection were used to induce SAKI in mouse model. Ferroptosis markers, including malondialdehyde (MDA) and glutathione peroxidase 4 (GPX4), were assessed. The ferroptosis inhibitor ferrostatin-1 (Fer-1) was used to explore the role of ferroptosis in SAKI. The GPX4 inhibitor RSL3, the HO-1 inhibitor zinc protoporphyrin(ZnPP), and the Nrf2 inhibitor ML385 were used to explore the specific mechanism of MEL in alleviation of SAKI.. The ferroptosis level was increased in the renal tissue of CLP- and LPS-induced septic mice. Both Fer-1 and MEL administration could suppress ferroptosis and attenuate kidney injury upon sepsis challenge. RSL3 partially blocked MEL's beneficial renal-protective effects. MEL up-regulated Nrf2 and HO-1 in CLP mice, and both ZnPP and ML385 blocked the MEL-mediated effects of ferroptosis inhibition and renal protection.. Ferroptosis aggravates SAKI. Melatonin treatment suppresses ferroptosis and alleviates kidney injury in the context of experimental sepsis by upregulating Nrf2/HO-1 pathway.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Ferroptosis; Lipopolysaccharides; Malondialdehyde; Melatonin; Mice; NF-E2-Related Factor 2; Phospholipid Hydroperoxide Glutathione Peroxidase; Sepsis; Signal Transduction

Cardiac dysfunction is a common complication of sepsis, and is attributed to severe inflammatory responses. Ferroptosis is reported to be involved in sepsis-induced cardiac inflammation. Therefore, we speculated that ferrostatin-1 (Fer-1), a ferroptosis inhibitor, improves cardiac dysfunction caused by sepsis. An intraperitoneal injection of lipopolysaccharide (LPS) was performed to induce a rat cardiac dysfunction model. Echocardiography, cardiac histopathology, biochemical and western blot results were analyzed. Twelve hours after the LPS injection, LPS-treated rats exhibited deteriorating cardiac systolic function, increased levels of cardiac injury markers and levels of ferroptosis markers prostaglandin endoperoxide synthase 2 (PTGS2). Additionally, LPS increased iron deposition in the myocardium, with downregulating ferroportin (FPN, SLC40A1) and transferrin receptor (TfR)expression, and upregulating ferritin light chain (FTL) and ferritin heavy chain (FTH1) expression. Meanwhile, LPS also increased lipid peroxidation in the rat heart by decreasing the expression of glutathione peroxidase 4 (GPX4). Moreover, the expression of inflammatory cytokines, such as tumor necrosis-alpha (TNF-α), interleukin-1 (IL-1β), and interleukin-6 (IL-6), and inflammatory cell infiltration were also increased following LPS challenge. Finally, the abovementioned adverse effects of LPS were relieved by Fer-1 except for TfR expression. Mechanistically, Fer-1 significantly reduced the levels of toll-like receptor 4 (TLR4), phospho-nuclear factor kappa B (NF-κB), and phospho-inhibitor of kappa Bα (IκBα) in LPS-treated rats. In summary, these findings imply that Fer-1 improved sepsis-induced cardiac dysfunction at least partially via the TLR4/NF-κB signaling pathway.

Topics: Animals; Cyclohexylamines; Electrocardiography; Heart; Inflammation; Lipopolysaccharides; Male; Myocardium; NF-kappa B; NF-KappaB Inhibitor alpha; Phenylenediamines; Rats, Wistar; Sepsis; Survival Analysis; Systole; Toll-Like Receptor 4