The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release.

Background: Sepsis is a common severe complication in major burn victims and is characterized by a dysregulated systemic response to inflammation. YTH domain family 2 (YTHDF2), a well-studied N6-methyladenosine (m6A) reader that specifically recognizes and binds to m6A-modified transcripts to mediate their degradation, is connected to pathogenic and physiological processes in eukaryotes, but its effect on sepsis is still unknown. We aimed to discover the effects and mechanisms of YTHDF2 in sepsis. Methods: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot analyses were used to measure the expression of YTHDF2, the interleukin 6 receptor (IL-6R), high-mobility group box-1 (HMGB1), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1) under different in vitro conditions. Enzyme-linked immunosorbent assays were utilized to evaluate the expression of HMGB1, IL-6, IL-1ß and tumor necrosis factor-α. To confirm that YTHDF2 specifically targets IL-6R mRNA, RNA immunoprecipitation and dual-luciferase reporter assays were performed. Finally, we utilized a mouse model of lipopolysaccharide (LPS)-induced sepsis to verify the effects of YTHDF2 in vivo. Results: According to our findings, YTHDF2 was expressed at a low level in peripheral blood mononuclear cells from septic mice and patients as well as in LPS-induced RAW264.7 cells. Overexpression of YTHDF2 alleviated the inflammatory response by inhibiting HMGB1 release and JAK2/STAT1 signalling in LPS-stimulated cells. Mechanistically, YTHDF2 suppressed JAK2/STAT1 signalling by directly recognizing the m6A-modified site in IL-6R and decreasing the stability of IL-6R mRNA, thereby inhibiting HMGB1 release. In vivo experiments showed that YTHDF2 played a protective role in septic mice by suppressing the IL-6R/JAK2/STAT1/HMGB1 axis. Conclusions: In summary, these findings demonstrate that YTHDF2 plays an essential role as an inhibitor of inflammation to reduce the release of HMGB1 by inhibiting the IL-6R/JAK2/STAT1 pathway, indicating that YTHDF2 is a novel target for therapeutic interventions in sepsis.

LncRNA GAS5 suppresses inflammatory responses by inhibiting HMGB1 release via miR-155-5p/SIRT1 axis in sepsis.

Sepsis comprises a lethal immunologic response due to infection. Increasingly, evidence has demonstrated the important role of long non-coding RNA growth arrest-specific transcript 5 (GAS5) in the regulation of sepsis. Nevertheless, the mechanisms by which GAS5 participates in the progression of sepsis remain unclear. Our study demonstrated the role and underlying mechanism of GAS5 in regulating lipopolysaccharide (LPS)-induced inflammation. In this study, GAS5 expression was found to be markedly decreased in serum samples of sepsis patients and a sepsis mouse model, and was negatively related with HMGB1 expression. GAS5 overexpression inhibited cell inflammatory responses by decreasing HMGB1 release. Furthermore, GAS5 inhibited LPS-mediated hyperacetylation and the release of HMGB1 by increasing the expression of sirtuin1 (SIRT1). Additionally, upregulated GAS5 attenuated inflammatory responses in vitro and vivo, and the knockdown of a miR-155-5p mimic and SIRT1 rescued the effects of GAS5 upregulation. Mechanistically, GAS5 sponged miR-155-5p to upregulate SIRT1, thereby inhibiting HMGB1 acetylation and release. In conclusion, our findings indicate that GAS5 suppresses inflammatory responses by modulating the miR-155-5p/SIRT1/HMGB1 axis in sepsis, providing a novel therapeutic target for inflammation in sepsis.

Cost analysis of severe burn victims in Southwest China: A 7-year retrospective study.

Background: Severe burn injury can be a life-threatening experience and can also lead to financial issues for suffers. The purpose of the current study was to analyze the direct hospitalization costs of severe burn inpatients in Southwest China. Methods: Data related to all inpatients admitted with severe burns [total body surface area (TBSA) ≥30%] pooled from 2015 to 2021 were reviewed retrospectively at the Institute of Burn Research of Army Medical University. Demographic parameters, medical economics, and clinical data were obtained from medical records. Results: A total of 668 cases were identified. The average age was 37.49 ± 21.00 years, and 72.3% were men. The average TBSA was 51.35 ± 19.49%. The median length of stay of inpatients in the burn intensive care unit was 14 [interquartile range (IQR): 5.0-34.8] days, and the median length of stay (LOS) was 41 (IQR: 22.0-73.8) days. The mortality rate was 1.6%. The median total cost was 212,755.45 CNY (IQR: 83,908.80-551,621.57 CNY) per patient varying from 3,521.30 to 4,822,357.19 CNY. The direct cost of scald burns was dramatically lower compared with that of other types of burns, with 11,213.43 to 2,819,019.14 CNY. Medical consumables presented the largest portion of total costs, with a median cost of 65,942.64 CNY (IQR: 18,771.86-171,197.97 CNY). The crucial risk factors for medical cost in our study were TBSA, surgical frequency, LOS, depth of burn, and outcome. Conclusion: We conclude that an effective burn prevention program, shorter hospital stays, and facilitating the healing of wounds should be focused on with tailored precautionary protocols to reduce the medical costs of inpatients with severe burns.