Yi-Qi-Jian-Pi formula inhibits hepatocyte pyroptosis through the IDH2-driven tricarboxylic acid cycle to reduce liver injury in acute-on-chronic liver failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Yi-Qi-Jian-Pi formula (YQJPF) is a commonly used traditional Chinese medicine (TCM) compound used to treat acute-on-chronic liver failure (ACLF) in China, but its specific mechanism of action has not been fully clarified. AIM OF THE STUDY: The aim of this study was to determine the effect of YQJPF on liver injury and hepatocyte pyroptosis in rats and further explore its molecular mechanism of action. MATERIALS AND METHODS: This study established carbon tetrachloride (CCl4)-, lipopolysaccharide (LPS)- and D-galactose (D-Gal)-induced in vivo models of ACLF in rats and in vitro LPS-induced hepatocyte injury models. Animal experiments were divided into the following groups: control, ACLF model, groups with different doses of YQJPF (5.4, 10.8, and 21.6 g/kg), and western medicine (methylprednisolone). There were 7 rats in the control group and 11 in the other groups. Serological, immunohistochemical, and pathological analyses were used to observe the effect of YQJPF on the liver of ACLF rats. The protective effect of YQJPF on hepatocytes was further verified by RT-qPCR, western blotting, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and other methods. RESULTS: YQJPF significantly improved liver injury in vivo and in vitro, which depended on the regulation of hepatocyte NLRP3/GSDMD-induced pyroptosis. In addition, we found that mitochondrial membrane potential and ATP production decreased after LPS treatment of hepatocytes, which suggested that YQJPF may improve mitochondrial energy metabolism disorders in hepatocytes. We administered a hepatocyte mitochondrial uncoupling agent, FCCP, to determine whether mitochondrial metabolic disorders affected cell pyroptosis. The results showed that the expression of IL-18, IL-1ß, and NLRP3 proteins increased significantly, indicating that the effect of this drug on hepatocyte pyroptosis may be related to mitochondrial metabolism disorders. We found that YQJPF significantly restored the tricarboxylic acid (TCA) cycle rate-limiting enzyme activity and affected the content of TCA metabolites. Furthermore, we revealed that the IDH2 gene, which plays a unique role in ACLF, is a key factor in the regulation of the mitochondrial TCA cycle and can be upregulated under the action of YQJPF. CONCLUSIONS: YQJPF can inhibit classical pyroptosis in hepatocytes by regulating TCA cycle metabolism, thus alleviating liver injury, and IDH2 may be a potential upstream regulatory target of YQJPF.

Peripheral T lymphocytes predict the severity and prognosis in patients with HBV-related acute-on-chronic liver failure.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening syndrome with high mortality. Biomarkers are urgently needed to predict the prognosis of HBV-ACLF. Recent evidence suggests a key role for immune system in the pathology of HBV-ACLF. Here, we analyzed the correlation between peripheral blood T lymphocytes and the severity and prognosis in HBV-ACLF patients. METHOD: Sixty-six patients with HBV-ACLF received conventional medical treatments for 4 weeks. Twenty-five healthy subjects and 20 HBV patients were enrolled for comparison. We determined white blood cell count, lymphocytes, CD3+, CD4+ and CD8+ T cells, and CD4+CD25+ Treg cells in the blood of all subjects. Their associations with laboratory parameters before or after treatments were statistically analyzed. RESULT: The results showed that compare normal subjects and chronic hepatitis B patients, HBV-ACLF patients had significantly increased white blood count, CD4+ T cells and decreased lymphocytes, CD3+ T cells, and Treg cells. Correlation analysis showed that white blood cell, lymphocytes, and peripheral T lymphocytes were correlated with prothrombin activity (PTA) and model for end-stage liver disease (MELD) scores. After treatment, white blood cell, lymphocytes, and peripheral T lymphocytes were also correlated with PTA and MELD scores. Additionally, total bilirubin (TBIL), alanine aminotransferase (ALT), international standard ratio (INR), MELD, and white blood cell count were potential prognostic criteria for HBV-ACLF patients. CONCLUSION: HBV-ACLF patients had depletion and dysfunction of immune system. Changes of peripheral T lymphocytes were closely related to the pathogenesis and prognosis of disease. Our results may contribute to predict the severity of HBV-ACLF, and provide a prognosis response to improve the treatment of HBV-ACLF.

A special symptom of olfactory dysfunction in coronavirus disease 2019: report of three cases.

Three patients of coronavirus disease (COVID-19) showed the symptoms of olfactory dysfunction. Clinical characteristics and treatment were retrospective analyzed. Olfactory disorders are uncommon symptoms of COVID-19 in China. Early diagnosis and intervention are keys to the recovery of olfactory disorders. Particular attention should be devoted to olfactory dysfunction.