Background Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) induces uncontrolled and self-amplified pulmonary inflammation, and has high morbidity and mortality rates in critically ill patients. In recent years, many bioactive ingredients extracted from herbs have been reported to effectively ameliorate ALI/ARDS via different mechanisms. Ferroptosis, categorized as regulated necrosis, is more immunogenic than apoptosis and contributes to the progression of ALI. In this study, we examined the impact of panaxydol (PX), isolated from the roots of Panax ginseng, on lipopolysaccharide (LPS)-induced ALI in mice. Methods In vivo, the role of PX on LPS-induced ALI in mice was tested by determination of LPS-induced pulmonary inflammation, pulmonary edema and ferroptosis. In vitro, BEAS-2B cells were used to investigate the molecular mechanisms by which PX functions via determination of inflammation, ferroptosis and their relationship. Results Administration of PX protected mice against LPS-induced ALI, including significantly ameliorated lung pathological changes, and decreased the extent of lung edema, inflammation, and ferroptosis. In vitro, PX inhibited LPS-induced ferroptosis and inflammation in bronchial epithelial cell line BEAS-2B cells. The relationship between ferroptosis and inflammation was investigated. The results showed that ferroptosis mediated inflammation in LPS-treated BEAS-2B cells, and PX might ameliorate LPS-induced inflammation via inhibiting ferroptosis. Meanwhile, PX could upregulate Keap1-Nrf2/HO-1 pathway, and selective inhibition of Keap1-Nrf2/HO-1 pathway significantly abolished the anti-ferroptotic and anti-inflammatory functions of PX in LPS-treated cells. Conclusion PX attenuates ferroptosis against LPS-induced ALI via Keap1-Nrf2/HO-1 pathway, and is a promising novel therapeutic candidate for ALI.

Background: Myocardial injury induced by refeeding syndrome (RFS) is one of the important causes of deterioration in critically ill patients. Sirtuin-3 (SIRT3) has been shown to regulate mitochondrial autophagy in myocardial ischemia/reperfusion injury; however, the role of mitochondrial autophagy on RFS-related myocardial injury in patients in critical condition has not been reported on.Methods: Thirty Sprague-Dawley (SD) rats were divided into 3 groups (n=10 each group): the control group; the standard calorie refeeding (SCR) group; and the low calorie refeeding (LCR) group. The rats were weighed every third or four days from day 1 to day 14. On day 14, all rats were anesthetized and received an echocardiography test. Blood and bronchoalveolar lavage fluid (BALF) were collected and tested for arterial oxygen pressure (PaO 2 ), phosphorus (P), and calcium (Ca), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin 1 (cTnI), myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6. The histopathological change of hearts and lungs were evaluated, and lung injury score was calculated. Mitochondrial autophagy related proteins (including Beclin1, LC3, mitofusin-2, Mfn2, PINK1, Parkin, and SIRT3) were analyzed using a Western blot. To evaluate the effect of SIRT3, 20 rats were divided into 2 groups (n=10 each group): The adeno-associated virus 9 (AAV9-Nc) group; and the AAV9-SIRT3 overexpression (AAV9-SIRT3) group. The protocols for rats were the same as the SCR group since day 22 after injection of AAV9. The protein expressions of PINK1, Parkin, and SIRT3 were compared between the AAV9-Nc group and AAV9-SIRT3 group.Results: SCR caused significant decline in cardiac contractility and increased inflammatory cell infiltration in myocardial tissue. Meanwhile, Beclin1, LC3, PINK1, Parkin, and SIRT3 levels decreased, while Mfn2 showed no significant change. Furthermore, significant positive correlations were also found between SIRT3 and P, PINK1, and Parkin, and significant negative correlations were found between SIRT3 and CK-MB, LDH, and cTnI. Overexpression of SIRT3 activated the PINK1/Parkin mediated mitochondrial autophagy.Conclusions: SIRT3 has an essential role in RFS-related myocardial injury during LPS induced chronic sepsis in rats, probably via regulating mitochondrial autophagy.