Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis.

BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.

Optimization for the production of a polyketone 3S,4S-DMD from Panus lecomtei (Agaricomycetes) by submerged fermentation.

3,4-Dihydroxy-2,2-dimethyl-chroman derivatives have diverse physiological properties. A polyketone (3S,4S)-3,4-Dihydroxy-6-methoxy-2,2-dimethylchromom (3S,4S-DMD) with antibacterial activity was isolated from the solid culture of rare edible fungus Panus lecomtei. However, the yield of 3S,4S-DMD in solid culture of P. lecomtei is very low and the production period are too long. In this work, efficient accumulation of 3S,4S-DMD in P. lecomtei by submerged fermentation is studied. The key fermentation factors of P. lecomtei for 3S,4S-DMD production were optimised by single-factor experiment successively, and then a Box-Behnken design (BBD) experiment was carried out to further enhance 3S,4S-DMD production. A maximum 3S,4S-DMD yield of 196.3 mg/L was obtained at 25.78 g/L glucose, 1.67 g/L MgSO4 · 7H2O, 40°C and 197 r/min, respectively, which increased by 1.3-fold in comparison with that in the non-optimised fermentation conditions. Furthermore, an enhanced yield of 3S,4S-DMD (261.6 mg/L) was obtained in 5-L agitated fermenter. The 3S,4S-DMD productivity in flask and fermenter reached to 7.26 and 8.07 mg/g per day, respectively, which considerably increased by over 121-fold in comparison with that in the solid fermentation (0.06 mg/g per day). This study presents a potential method for the production of 3S,4S-DMD by submerged fermentation.

Dual antioxidant activity and the related mechanisms of a novel pentapeptide GLP4 from the fermented mycelia of Ganoderma lingzhi.

Oxidative stress causes chronic inflammation, and mediates various diseases. The discovery of antioxidants from natural sources is important to research. Here we identified a novel antioxidant peptide (GLP4) from Ganoderma lingzhi mycelium and investigated its antioxidant type and potential protective mechanisms. Through free radical scavenging assay, active site shielding validation, superoxide dismutase (SOD) activity assay, and lipid peroxidation assay, we demonstrated that GLP4 was a novel protective agent with both direct and indirect antioxidant activities. GLP4 could directly enter human umbilical vein endothelial cells (HUVECs) as an exogenous substance. Meanwhile, GLP4 promoted the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and activated the Nrf2/antioxidant response element (ARE) signaling pathway, exhibiting antioxidant and anti-apoptotic cytoprotective effects on hydrogen peroxide (H2O2)-induced HUVECs. Pull-down experiments of GLP4 target proteins, bioinformatics analysis and molecular docking further revealed that GLP4 mediated Nrf2 activation through binding to phosphoglycerate mutase 5 (PGAM5). The results suggested that GLP4 is a novel peptide with dual antioxidant activity and has promising potential as a protective agent in preventing oxidative stress-related diseases.

New meroterpenoid compounds from the culture of mushroom Panus lecomtei.

Two new meroterpenoid compounds (1 and 2) together with five known meroterpenoid derivatives (3-7) were isolated from solid culture of mushroom Panus lecomtei. The structures of new compounds were confirmed by the analysis of NMR and HR-ESI-MS spectroscopic data. The biosynthetic pathway of 1-7 was postulated. All isolated compounds were evaluated for antibacterial activities against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa and Bacillus Calmette-Guérin. Compound 3 exhibited weak antibacterial activity against Bacillus Calmette-Guérin with the inhibition rate of 83.6% at 100 µmol·L-1. Other compounds showed no antibacterial activities against all tested pathogens at 100 µmol·L-1.