Pseudotargeted metabolomics revealed the adaptive mechanism of Draba oreades Schrenk at high altitude

Strong ultraviolet radiation and low temperature environment on Gangshika Mountain, located in the eastern part of the Qilian Mountains in Qinghai Province, can force plants to produce some special secondary metabolites for resisting severe environmental stress. However, the adaptive mechanism of Draba oreades Schrenk at high altitude are still unclear. In the current study, Draba oreades Schrenk from the Gangshika Mountain at altitudes of 3800 m, 4000 m and 4200 m were collected for comprehensive metabolic evaluation using pseudotargeted metabolomics method. Through KEGG pathway enrichment analysis, we found that phenylpropanoid biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism related to the biosynthesis of flavonoids were up-regulated in the high-altitude group, which may enhance the environmental adaptability to strong ultraviolet intensity and low temperature stress in high altitude areas. By TopFc20 distribution diagram, the content of flavonoids gradually increased with the elevation of altitude, mainly including apigenin, luteolin, quercetin, hesperidin, kaempferol and their derivatives. Based on the random forest model, 10 important metabolites were identified as potential biomarkers. L-phenylalanine, L-histidine, naringenin-7-O-Rutinoside-4’-O-glucoside and apigenin related to the flavonoids biosynthesis and plant disease resistance were increased with the elevation of altitude. This study provided important insights for the adaptive mechanism of Draba oreades Schrenk at high altitude by pseudotargeted metabolomics

Human Ribonuclease A Superfamily Members, Eosinophil-Derived Neurotoxin and Pancreatic Ribonuclease, Induce Dendritic Cell Maturation and Activation

A number of mammalian antimicrobial proteins produced by neutrophils and cells of epithelial origin have chemotactic and activating effects on host cells, including cells of the immune system. Eosinophil granules contain an antimicrobial protein known as eosinophil-derived neurotoxin (EDN), which belongs to the RNase A superfamily. EDN has antiviral and chemotactic activities in vitro. In this study, we show that EDN, and to a lesser extent human pancreatic RNase (hPR), another RNase A superfamily member, activates human dendritic cells (DCs), leading to the production of a variety of inflammatory cytokines, chemokines, growth factors, and soluble receptors. Human angiogenin, a RNase evolutionarily more distant to EDN and hPR, did not display such activating effects. Additionally, EDN and hPR also induced phenotypic and functional maturation DCs. These RNases were as efficacious as TNF-α, but induced a different set of cytokine mediators. Furthermore, EDN production by human macrophages could be induced by proinflammatory stimuli. The results reveal the DC-activating activity of EDN and hPR and suggest that they are likely participants of inflammatory and immune responses. A number of endogenous mediators in addition to EDN have been reported to have both chemotactic and activating effects on APCs, and can thus amplify innate and Ag-specific immune responses to danger signals. We therefore propose these mediators be considered as endogenous multifunctional immune alarmins

Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis

Abstract Sodium aescinate (SA), a natural plant extract with various bioactivities, is widely used to treat oedema and inflammation in clinics. However, adverse events, including liver injury, kidney injury, and phlebitis, have been reported in patients with SA in recent years. In this study, we used BALB/c mice and L02 cells to evaluate the role of ferroptosis in SA-induced liver injury. SA significantly increased AST, ALT, MDA and Fe2+, decreased GSH levels, and induced pathological changes in the liver in vivo. SA also reduced the viability of L02 cells and induced LDH release, intracellular cysteine reduction, GSH depletion, iron accumulation, ROS production, and lipid peroxidation, indicating that SA causes ferroptosis. In addition, SA inhibited transcriptional activity of activating transcription factor 4 (ATF4) and subsequently reduced the expression of the downstream genes xCT (solute carrier family 7a member 11, SLC7A11) and Cystathionine gamma-lyase (CTH) which play vital roles in GSH biosynthesis. Interestingly, the cytotoxic effects of SA were effectively attenuated by ATF4 overexpression, while they were significantly aggravated by ATF4 silencing. These results revealed that SA triggers hepatocyte ferroptosis by inhibiting the activity of ATF4, which causes an oxidative imbalance