Upregulated dual oxidase 1-induced oxidative stress and caspase-1-dependent pyroptosis reflect the etiologies of heart failure.

BACKGROUND: Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in oxidative stress. This study was designed to evaluate the potential role of DUOX1 in heart failure. MATERIALS AND METHODS: AC16 cells were treated with 2 µmol/L of doxorubicin (DOX) for 12, 24, and 48 h to construct a heart failure model. DUOX1 overexpression and silencing in AC16 cell were established. DUOX1 expression was detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Pyroptosis and reactive oxygen species (ROS) production were measured by flow cytometry. RESULTS: Increased DUOX1 expression levels were observed after DOX treatment for 24 h in AC16 cells. DUOX1 silencing inhibited DOX-induced pyroptosis and ROS production. The release of IL-1ß, IL-18, and lactate dehydrogenase (LDH), and expression levels of pyroptosis-related proteins were also decreased. DUOX1 overexpression increased pyroptosis, ROS production, IL-1ß, IL-18, and LDH release, and pyroptosis-related protein expression. N-acetyl-cysteine (NAC) significantly reversed DUOX1-induced pyroptosis, ROS, and related factors. CONCLUSION: These results suggest that DUOX1-derived genotoxicity could promote heart failure development. In the process, oxidative stress and pyroptosis may be involved in the regulation of DUOX1 in heart failure.

[Effects of transcription factor T-bet, GATA-3, FoxP3 and CD4(+)CD25(+)regulatory T cells in pathogenesis of child Hench-Schonlein purpura].

The aim of this study was to investigate the effects of transcription factors T-bet, GATA-3 in the pathogenesis of Hench-Schonlein purpura (HSP) in children, the relationship between CD4(+)CD25(+)regulatory T cells, transcription factor FoxP3 and the development of child HSP, and the molecular mechanisms of Th1/Th2 imbalance of child HSP at acute phase, so as to may provide a new approach and strategy for the treatment of HSP at the molecular levels. The expression of T-bet, GATA-3 and FoxP3 mRNA were detected by real time PCR using SYBR Green I in 46 patients with HSP at acute phase and 30 healthy children as controls. The expression of T lymphocyte subsets CD4(+)CD25(+) in peripheral blood mononuclear cells was detected by flow cytometry. The results showed that the relative level of GATA-3 mRNA in peripheral blood mononuclear cells of patients with HSP was significantly higher than those of the control group (964.30 ± 655.18 vs 78.09 ± 57.20, P < 0.01). The relative level of T-bet mRNA in peripheral blood mononuclear cells of patients with HSP was lower than those of the control group (53.98 ± 35.79 vs 181.56 ± 96.90, P < 0.01). The expression level of FoxP3 mRNA with HSP was lower than that of the control group (32.17 ± 23.04 vs 147.91 ± 99.15, P < 0.01). The result of CD4(+)CD25(+) Treg with HSP was lower than those of the control group [(5.34 ± 2.51)% vs (7.85 ± 1.97)%, P < 0.01)]. It is concluded that Th1/Th2 imbalance exists in acute phase of child HSP, especially predominant activation of Th2, which correlates with the abnormal expression of transcription factor T-bet and GATA-3 mRNA. At acute phase of child HSP, the expression of CD4(+)CD25(+)Treg and its special transcription factor FoxP3 mRNA are down-regulated. Treg cells decreases, which indicates that insufficient immunosuppressive effects resulting from the reduction of Treg cells may be one of the important reason in the immune imbalance of HSP acute phase. This study provides experimental evidence for illustrating the pathogenesis of HSP from the molecular mechanism of Treg cells and its regulation, and also provides a new thinking and new strategies for the treatment of HSP at molecular levels.