α-Ketoglutarate plays an inflammatory inhibitory role by regulating scavenger receptor class a expression through N6-methyladenine methylation during sepsis.

Sepsis arises from an uncontrolled inflammatory response triggered by infection or stress, accompanied by alteration in cellular energy metabolism, and a strong correlation exists between these factors. Alpha-ketoglutarate (α-KG), an intermediate product of the TCA cycle, has the potential to modulate the inflammatory response and is considered a crucial link between energy metabolism and inflammation. The scavenger receptor (SR-A5), a significant pattern recognition receptor, assumes a vital function in anti-inflammatory reactions. In the current investigation, we have successfully illustrated the ability of α-KG to mitigate inflammatory factors in the serum of septic mice and ameliorate tissue damage. Additionally, α-KG has been shown to modulate metabolic reprogramming and macrophage polarization. Moreover, our findings indicate that the regulatory influence of α-KG on sepsis is mediated through SR-A5. We also elucidated the mechanism by which α-KG regulates SR-A5 expression and found that α-KG reduced the N6-methyladenosine level of macrophages by up-regulating the m6A demethylase ALKBH5. α-KG plays a crucial role in inhibiting inflammation by regulating SR-A5 expression through m6A demethylation during sepsis. The outcomes of this research provide valuable insights into the relationship between energy metabolism and inflammation regulation, as well as the underlying molecular regulatory mechanism.

Praeruptorin A inhibits the activation of NF-κB pathway and the expressions of inflammatory factors in poly (I:C)-induced RAW264.7 cells.

Praeruptorin A (PA), a natural coumarin compound, has significant anti-inflammatory effects. In this study, we evaluate the anti-inflammatory effect of PA on RAW 264.7 mouse macrophages induced by Polyinosinic acid-polycytidylic acid (poly (I:C)). RAW 264.7 mouse macrophages induced by poly (I:C) were treated with or without PA, the viability of which was determined to screen working solution of PA. RNA-sequencing was applied to analyze the differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were carried out. The expressions of interleukin (IL)-1ß, heme oxygenase 1 (HMOX1), prostaglandin-endoperoxide synthase 2 (PTGS2), ATP binding cassette subfamily A member 1 (Abca1) and NF-κB-related proteins were measured by enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. As a result, PA at 1, 2, 3, 4 and 5 µM slightly affected cell viability, while PA at 6 and 7 µM significantly inhibited cell viability. GO and KEGG analysis results revealed that DEGs were mainly enriched in the pathways related to inflammatory signaling. Through further analysis, we obtained five possible targets of PA, and verified that PA inhibited the expressions of IL-1ß, HMOX1, PTGS2 and Abca1 as well as the activation of NF-κB pathway in poly (I:C)-induced RAW264.7 cells. To summarize, PA may inhibit expressions of the inflammation-related genes in poly (I:C)-induced RAW264.7 cells, which demonstrates its potential as a drug against virus related diseases.