Dehydrocostus lactone (DHL), a natural sesquiterpene lactone isolated from the traditional Chinese herbs Saussurea lappa and Inula helenium L., has important anti-inflammatory properties used for treating colitis, fibrosis, and Gram-negative bacteria-induced acute lung injury (ALI). However, the effects of DHL on Gram-positive bacteria-induced macrophage activation and ALI remains unclear. In this study, we found that DHL inhibited the phosphorylation of p38 MAPK, the degradation of IκBα, and the activation and nuclear translocation of NF-κB p65, but enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Nrf2 and HO-1 in lipoteichoic acid (LTA)-stimulated RAW264.7 cells and primary bone-marrow-derived macrophages (BMDMs). Given the critical role of the p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways in the balance of M1/M2 macrophage polarization and inflammation, we speculated that DHL would also have an effect on macrophage polarization. Further studies verified that DHL promoted M2 macrophage polarization and reduced M1 polarization, then resulted in a decreased inflammatory response. An in vivo study also revealed that DHL exhibited anti-inflammatory effects and ameliorated methicillin-resistant Staphylococcus aureus (MRSA)-induced ALI. In addition, DHL treatment significantly inhibited the p38 MAPK/NF-κB pathway and activated AMPK/Nrf2 signaling, leading to accelerated switching of macrophages from M1 to M2 in the MRSA-induced murine ALI model. Collectively, these data demonstrated that DHL can promote macrophage polarization to an anti-inflammatory M2 phenotype via interfering in p38 MAPK/NF-κB signaling, as well as activating the AMPK/Nrf2 pathway in vitro and in vivo. Our results suggested that DHL might be a novel candidate for treating inflammatory diseases caused by Gram-positive bacteria.

Radiation pneumonitis (RP) is a prevalent and fatal complication of thoracic radiotherapy due to the lack of effective treatment options. RP primarily arises from mitochondrial injury in lung epithelial cells. The mitochondrial-derived peptide MOTS-c has demonstrated protective effects against various diseases by mitigating mitochondrial injury. C57BL/6 mice were exposed to 20 Gy of lung irradiation (IR) and received daily intraperitoneal injections of MOTS-c for 2 weeks. MOTS-c significantly ameliorated lung tissue damage, inflammation, and oxidative stress caused by radiation. Meanwhile, MOTS-c reversed the apoptosis and mitochondrial damage of alveolar epithelial cells in RP mice. Furthermore, MOTS-c significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells and primary mouse lung epithelial cells. Mechanistically, MOTS-c increased the nuclear factor erythroid 2-related factor (Nrf2) level and promoted its nuclear translocation. Notably, Nrf2 deficiency abolished the protective function of MOTS-c in mice with RP. In conclusion, MOTS-c alleviates RP by protecting mitochondrial function through an Nrf2-dependent mechanism, indicating that MOTS-c may be a novel potential protective agent against RP.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disease with a limited therapeutic strategy. Mitochondrial oxidative stress in macrophages is directly linked to IPF. Elamipretide(SS-31) is a mitochondrion-targeted peptide that has been shown to be safe and beneficial for multiple diseases. However, whether SS-31 alleviates IPF is unclear. In the present study, we used a bleomycin (BLM)-induced mouse model followed by SS-31 injection every other day to investigate its role in IPF and explore the possible mechanism. Our results showed that SS-31 treatment significantly suppressed BLM-induced pulmonary fibrosis and inflammation, with improved histological change, and decreased extracellular matrix deposition and inflammatory cytokines release. Impressively, the expression percentage of IL-1β and IL-18 was downregulated to lower than half with SS-31 treatment. Mechanistically, SS-31 inhibited IL-33- or lipopolysaccharide(LPS)/IL-4-induced production of IL-1β and IL-18 in macrophages by suppressing NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome activation. Nuclear factor erythroid 2-related factor 2(Nrf2) was dramatically upregulated along with improved mitochondrial function after SS-31 treatment in activated macrophages and BLM-induced mice. Conversely, there was no significant change after SS-31 treatment in Nrf2−/− mice and macrophages. These findings indicated that SS-31 protected against pulmonary fibrosis and inflammation by inhibiting the Nrf2-mediated NLRP3 inflammasome in macrophages. Our data provide initial evidence for the therapeutic efficacy of SS-31 in IPF.

Staphylococcus aureus (SA) is a major cause of sepsis, leading to acute lung injury (ALI) characterized by inflammation and oxidative stress. However, the role of the Nrf2/PHB2 pathway in SA‐induced ALI (SA‐ALI) remains unclear. In this study, serum samples were collected from SA‐sepsis patients, and a SA‐ALI mouse model was established by grouping WT and Nrf2^−/− mice after 6 h of intraperitoneal injection. A cell model simulating SA‐ALI was developed using lipoteichoic acid (LTA) treatment. The results showed reduced serum Nrf2 levels in SA‐sepsis patients, negatively correlated with the severity of ALI. In SA‐ALI mice, downregulation of Nrf2 impaired mitochondrial function and exacerbated inflammation‐induced ALI. Moreover, PHB2 translocation from mitochondria to the cytoplasm was observed in SA‐ALI. The p‐Nrf2/total‐Nrf2 ratio increased in A549 cells with LTA concentration and treatment duration. Nrf2 overexpression in LTA‐treated A549 cells elevated PHB2 content on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division. Bioinformatic analysis and dual‐luciferase reporter assay confirmed direct binding of Nrf2 to the PHB2 promoter, resulting in increased PHB2 expression. In conclusion, Nrf2 plays a role in alleviating SA‐ALI by directly regulating PHB2 transcription and maintaining mitochondrial function in lung cells.

Naringenin is a natural flavanone with potent pharmacological properties. It has demonstrated therapeutic potential in treating various diseases and organ injuries, including radiation-induced lung injury (RILI). Ferroptosis is a newly type of cell death, and naringenin has been shown to attenuates ferroptosis. To evaluate the inhibitory effect and molecular mechanism of naringenin on ferroptosis during RILI process. Firstly, BEAS-2B and HUVECs cells were pre-incubated with naringenin for 1 h prior to 8 Gy of X-ray irradiation to evaluate oxidative stress, inflammation, and the mRNA levels of ferroptosis-related genes. Next, target genes of naringenin, RILI, and ferroptosis were identified using the TCMSP, SwissTargetPrediction, and GeneCards databases. The target network was constructed with Cytoscape and STRING. Finally, the core target genes were identified through in vitro experiments by qRT-PCR, western blot and immunofluorescence staining. Naringenin effectively reduced radiation-induced increasement of oxidative stress, inflammation, and ferroptosis markers in both cell lines. Network pharmacology identified 14 target genes, with prostaglandin endoperoxide synthase (PTGS2) and Valosin-containing protein (VCP) mRNA levels being prominent, which were crucial for ferroptosis regulation. Molecular docking revealed strong binding interactions between naringenin and the two target proteins. Subsequently, experimental validation confirmed that naringenin reduced the elevated levels of PTGS2 and VCP induced by radiation. Naringenin alleviates radiation-induced lung damage by inhibiting ferroptosis, with PTGS2 and VCP emerging as potential therapeutic targets.