Isofraxidin attenuates dextran sulfate sodium-induced ulcerative colitis through inhibiting pyroptosis by upregulating Nrf2 and reducing reactive oxidative species.

BACKGROUND: Ulcerative colitis (UC), a non-specific gastrointestinal disease, is commonly managed with aminosalicylic acids and immunosuppressive agents to control inflammation and relieve symptoms, despite frequent relapses. Isofraxidin is a coumarin compound extracted from traditional Chinese medicine, exhibiting anti-inflammatory and antioxidant properties; however, its alleviating effect on UC remains unclear. Therefore, we investigated the mechanism of isofraxidin in lipopolysaccharide (LPS)-induced cell inflammation in human intestinal epithelial cell (HIEC) and human colorectal adenocarcinoma cells (Caco-2), as well as in dextran sulfate sodium (DSS)-induced UC in mice. METHODS: We established colitis models in HIEC and Caco-2 cells and mice with LPS and DSS, respectively. Additionally, NLRP3 knockout mice and HIEC cells transfected with NLRP3 silencing gene and ML385 illustrated the role of isofraxidin in pyroptosis and oxidative stress. Data from cells and mice analyses were subjected to one-way analysis of variance or a paired t-test. RESULTS: Isofraxidin significantly alleviated LPS-induced cell inflammation and reduced lactic dehydrogenase release. Isofraxidin also reversed DSS- or LPS-induced pyroptosis in vivo and in vitro, increasing the expression of pyroptosis-related proteins. Moreover, isofraxidin alleviated oxidative stress induced by DSS or LPS, reducing reactive oxidative species (ROS), upregulation nuclear factor erythroid 2-related factor 2 (Nrf2), and promoting its entry into the nucleus. Mechanistically, ML385 reversed the inhibitory effect of isofraxidin on ROS and increased pyroptosis. CONCLUSION: Isofraxidin can inhibit pyroptosis through upregulating Nrf2, promoting its entry into the nucleus, and reducing ROS, thereby alleviating DSS-induced UC. Our results suggest isofraxidin as a promising therapeutic strategy for UC treatment.

[Chronic myeloid leukemia onset with marked thrombocythemia].

This study was aimed to investigate the clinical, pathological and biological features of a special case of chronic myeloid leukemia (CML) with marked thrombocythemic onset. The morphological changes of cells were analyzed by using bone marrow smear and biopsy; Ph chromosome, a specific marker of CML, was assayed by conventional chromosomal analysis and fluorescence in situ hybridization, bcr/abl fusion gene was detected by reverse transcription-polymerase chain reaction. The results indicated that CML mimicked essential thrombocythemia (ET) at presentation was relatively rare and might be misdiagnosed as ET, bone marrow smear and biopsy revealed, marked thrombocytosis and moderate leukocytosis; RT-PCR, FISH and conventional chromosomal analysis demonstrated the existence of Ph chromosome and bcr/abl fusion gene. This special CML could progress into accelerated phase or blast crisis. The megakaryocytes in Ph+ ET were smaller than normal ones and had typically hypolobulated round nuclei. Patients diagnosed as Ph+ ET might progress into CML and showed a high tendency to myelofibrosis and blastic transformation. It is concluded that the value of routine cytogenetical and molecular biological analysis in diagnosis for potential CML cases, which mimicked ET as in this presentation, is very distinctive, and the importance is magnified by the recent availability of imatinib, a specific inhibitor of the bcr/abl tyrosine kinase produced by the Philadelphia chromosome. Every case of "ET" should be tested for the Philadelphia chromosome and bcr/abl transcript.