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An electrochemical thioetherification of NH-sulfoximines with disulfides is reported. The use of electrochemistry to promote these oxidative coupling reactions not only obviates the requirement for external oxidants, bases, and metal catalysts but also ensures high environmental friendliness and selectivity to afford N-sulfenyl-sulfoximines. Good functional group tolerance, and readily available substrates offer this strategy incomparable advantages in preparing a variety of valuable N-sulfenyl-sulfoximines. Meanwhile, this reaction features simple operation, mild reaction conditions, and convenience of amplification, and has great potential in the subsequent modifications of pharmaceutical N-(2-thiophenyl)benzamide derivatives. Furthermore, the cytotoxic effects of the expected products toward different tumor cells were investigated in vitro and compared with 5-fluorouracil (5-Fu), the most widely used chemotherapeutic drug against malignant tumors. [ABSTRACT FROM AUTHOR]

Hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) is a syndrome with high short‐term mortality. The mechanism of the transcription factor ETS2 in ACLF remains unclear. This study aimed to clarify the molecular basis of ETS2 in ACLF pathogenesis. Peripheral blood mononuclear cells from patients with HBV‐ACLF (n = 50) were subjected to RNA sequencing. Transcriptome analysis showed that ETS2 expression was significantly higher in ACLF patients than in patients with chronic liver diseases and healthy subjects (all p < 0.001). Area‐under‐ROC analysis of ETS2 demonstrated high values for the prediction of 28‐/90‐day mortality in ACLF patients (0.908/0.773). Significantly upregulated signatures of the innate immune response (monocytes/neutrophils/inflammation‐related pathways) were observed in ACLF patients with high ETS2 expression. Myeloid‐specific ETS2 deficiency in liver failure mice resulted in deterioration of biofunctions and increased expression of pro‐inflammatory cytokines (IL‐6/IL‐1β/TNF‐α). Knockout of ETS2 in macrophages confirmed the downregulation of IL‐6 and IL‐1β caused by both HMGB1 and lipopolysaccharide, and an NF‐κB inhibitor reversed the suppressive effect of ETS2. ETS2 is a potential prognostic biomarker of ACLF patients that alleviates liver failure by downregulating the HMGB1‐/lipopolysaccharide‐triggered inflammatory response and may serve as a therapeutic target for ACLF. [ABSTRACT FROM AUTHOR]

Rationale: Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) have a high short-term mortality rate. Semaphorin-6B (SEMA6B) plays a crucial role in the pathogenesis of HBV-ACLF, but its molecular basis remains unclear. This study aimed to elucidate the mechanisms of SEMA6B in HBV-ACLF progression. Methods: A total of 321 subjects with HBV-ACLF, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NC) from a prospective multicenter cohort were studied. 84 subjects (HBV-ACLF, n = 50; LC, n = 10; CHB, n = 10; NC, n = 14) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs) to clarify the mechanisms of SEMA6B in HBV-ACLF. These mechanisms were validated through in vitro studies with hepatocytes and macrophages, as well as in vivo using SEMA6B knockout mice and mice treated with synthetic SEMA6B siRNA. Results: Transcriptome analysis of PBMCs showed that SEMA6B was among the most differentially expressed genes when comparing patients with HBV-ACLF to those with LC, CHB, or NC. ROC analysis demonstrated the reliable diagnostic value of SEMA6B for HBV-ACLF in both the sequencing cohort and an external validation cohort (AUROC = 0.9788 and 0.9026, respectively). SEMA6B levels were significantly higher in the HBV-ACLF patients, especially in non-survivors, with high expression mainly observed in macrophages and hepatocytes in liver tissue. Genes significantly associated with highly expressed SEMA6B were enriched in inflammation and apoptosis pathways in HBV-ACLF non-survivors. Overexpression of SEMA6B in macrophages activated systemic inflammatory responses, while its overexpression in hepatocytes inhibited proliferation through G0/G1 cell cycle arrest and induced apoptosis. Knocking out SEMA6B rescued mice with liver failure by improving liver functions, reducing inflammatory responses, and decreasing hepatocyte apoptosis. Transcriptome analysis of liver tissue showed that SEMA6B knockout significantly ameliorated the liver failure signature, significantly downregulating inflammation-related pathways. Importantly, therapeutic delivery of synthetic SEMA6B siRNA also improved liver function, and reduced both inflammation and hepatocyte apoptosis in mice with liver failure. Conclusion: SEMA6B, a potential diagnostic biomarker for HBV-ACLF, exacerbates liver failure through macrophage-mediated systemic inflammation and hepatocyte apoptosis. These findings highlight SEMA6B as a promising early treatment target for HBV-ACLF patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)