Metabolic Profiling for Unveiling Mechanisms of Kushenol F against Imiquimod-Induced Psoriasis with UHPLC/MS Analysis.

Psoriasis is a common chronic immune-mediated inflammatory skin disorder. Sophora flavescens Alt. (S. flavescens) has been widely acknowledged in the prevention and treatment of psoriasis. Kushenol F (KSCF) is a natural isopentenyl flavonoid extracted from the root of S. flavescens. We aimed to investigate the effect and mechanism of KSCF on imiquimod (IMQ)-induced psoriasis-like skin lesions in mice. A mouse model of psoriasis was induced with 5% IMQ for 5 days, and the mice were given KSCF dermally for 5 days. Changes in skin morphology, the psoriasis area, the severity index (PASI), and inflammatory factors of psoriasis-like skin lesions were evaluated. Metabolites in the psoriasis-like skin lesions were analyzed with ultra-high-performance liquid chromatography/mass spectrometry followed by a multivariate statistical analysis to identify the differential metabolites and metabolic pathway. The results of the present study confirmed that KSCF significantly reduced PASI scores, epidermal thickening, and epidermal cell proliferation and differentiation. KSCF also reduced the levels of interleukin (IL)-1ß, IL-6, IL-8, IL-17A, IL-22, IL-23, and tumor necrosis factor (TNF)-α in the injured skin tissues while increasing IL-10 content. KSCF significantly regulated metabolites in the skin samples, and a total of 161 significant metabolites were identified. These differential metabolites involved sphingolipid and linoleic acid metabolism and steroid hormone biosynthesis. Collectively, KSCF inhibited the inflammatory response to prevent IMQ-induced psoriasis-like skin lesions in mice by call-backing the levels of 161 endogenous metabolites and affecting their related metabolic pathways. KSCF has the potential to be developed as a topical drug for treating psoriasis symptoms.

Association between the anion gap and mortality in critically ill patients with influenza: A cohort study.

Introduction: Influenza is an important global health concern, particularly in critically ill patients. The anion gap, a marker of metabolic acidosis, is associated with mortality in various critical illnesses. However, its association with mortality in critically ill patients with influenza remains unclear. This study investigated the association between the anion gap on admission and 28-day mortality in critically ill patients with influenza. Methods: A retrospective cohort study was conducted using data from MIMIC-IV database. Patients admitted to the intensive care unit (ICU) with influenza were included. The anion gap was measured within the first 24 h of ICU admission. The primary outcome was the 28-day mortality. The secondary outcomes were 60-day mortality and in-hospital mortality. Multivariable Cox regression was used to assess the association between the anion gap and mortality. Results: A total of 276 critically ill patients with influenza were included in the study. The mean age was 65 years, and 60 % were male. The overall 28-day mortality was 15.5 %. A greater anion gap on admission was associated with significantly increased 28-day mortality in the unadjusted analysis (hazard ratio [HR], 1.11; 95 % confidence interval [CI], 1.03-1.2; p < 0.001). The association remained significant after adjusting for age, sex, race, and illness severity (adjusted HR, 1.09; 95 % CI, 1.02-1.17; p = 0.017). Subgroup analysis showed consistent results across the different groups. Conclusion: A greater anion gap on admission was independently associated with increased 28-day mortality in critically ill patients with influenza. These findings suggest that the anion gap can be used as a prognostic marker in patients with influenza, aiding in risk stratification and guiding clinical management.

Cannabidiol mitigates radiation-induced intestine ferroptosis via facilitating the heterodimerization of RUNX3 with CBFß thereby promoting transactivation of GPX4.

Radiation enteritis remains a major challenge for radiotherapy against abdominal and pelvic malignancies. Nevertheless, there is no approved effective therapy to alleviate irradiation (IR)-induced gastrointestinal (GI) toxicity. In the current study, Cannabidiol (CBD) was found to mitigate intestinal injury by GPX4-mediated ferroptosis resistance upon IR exposure. RNA-sequencing was employed to investigate the underlying mechanism involved in the radio-protective effect of CBD, wherein runt-related transcription factor 3 (RUNX3) and its target genes were changed significantly. Further experiment showed that the transactivation of GPX4 triggered by the direct binding of RUNX3 to its promoter region, or by stimulating the transcriptional activity of NF-κB via RUNX3-mediated LILRB3 upregulation was critical for the anti-ferroptotic effect of CBD upon IR injury. Specially, CBD was demonstrated to be a molecular glue skeleton facilitating the heterodimerization of RUNX3 with its transcriptional chaperone core-biding factor ß (CBFß) thereby promoting their nuclear localization and the subsequent transactivation of GPX4 and LILRB3. In short, our study provides an alternative strategy to counteract IR-induced enteritis during the radiotherapy on abdominal/pelvic neoplasms.