Objective This study investigated the effect of reducing soluble epoxide hydrolase(sEH,encoded by the Ephx2 gene)on the mediation of EETs metabolism during ferroptosis in emphysema in vivo.Methods Male C57BL/6J wild-t...Objective This study investigated the effect of reducing soluble epoxide hydrolase(sEH,encoded by the Ephx2 gene)on the mediation of EETs metabolism during ferroptosis in emphysema in vivo.Methods Male C57BL/6J wild-type(WT)and Ephx2^(-/-)mice received whole-body exposure to either cigarette smoke(CS)or air for 16 weeks.The alveolar structure,pulmonary function,lung tissue morphology,cell death,and ferroptosis levels were assessed following exposure.Results CS exposure caused emphysema,reduced pulmonary function,and induced ferroptosis in mice compared with exposure to air.In contrast,following CS exposure,Ephx2^(-/-)mice exhibited significantly lower levels of emphysema,impaired lung function,lung cell death,intracellular iron,lipid reactive oxygen species,cyclooxygenase-2,4-hydroxynonenal,and malondialdehyde levels than those of WT mice.However,Ephx2^(-/-)mice exhibited higher levels of glutathione and ferritin heavy chain 1 than those of WT mice.SLC7A11 expression was significantly reduced,whereas glutathione peroxidase 4 expression was markedly increased in Ephx2^(-/-)mice compared with WT mice.Statistically significant differences(P<0.05)were observed.Conclusion These results suggest that Ephx2 deficiency inhibits ferroptosis to alleviate CS-induced emphysema,primarily by mitigating its inhibitory effect on the cystine/glutathione/glutathione peroxidase 4 axis.Therefore,Ephx2 represents an effective therapeutic target in CS-induced chronic obstructive pulmonary disease(COPD).展开更多
Esculetin,a natural dihydroxy coumarin derived from the Chinese herbal medicine Cortex Fraxini,has demonstrated significant pharmacological activities,including anticancer properties.Ferroptosis,an iron-dependent form...Esculetin,a natural dihydroxy coumarin derived from the Chinese herbal medicine Cortex Fraxini,has demonstrated significant pharmacological activities,including anticancer properties.Ferroptosis,an iron-dependent form of regulated cell death,has garnered considerable attention due to its lethal effect on tumor cells.However,the exact role of ferroptosis in esculetin-mediated anti-hepatocellular carcinoma(HCC)effects remains poorly understood.This study investigated the impact of esculetin on HCC cells both in vitro and in vivo.The findings indicate that esculetin effectively inhibited the growth of HCC cells.Importantly,esculetin promoted the accumulation of intracellular Fe^(2+),leading to an increase in ROS production through the Fenton reaction.This event subsequently induced lipid peroxidation(LPO)and triggered ferroptosis within the HCC cells.The occurrence of ferroptosis was confirmed by the elevation of malondialdehyde(MDA)levels,the depletion of glutathione peroxidase(GSH-Px)activity,and the disruption of mitochondrial morphology.Notably,the inhibitor of ferroptosis,ferrostatin-1(Fer-1),attenuated the anti-tumor effect of esculetin in HCC cells.Furthermore,the findings revealed that esculetin inhibited the Nrf2-xCT/GPx4 axis signaling in HCC cells.Overexpression of Nrf2 upregulated the expression of downstream SLC7A11 and GPX4,consequently alleviating esculetin-induced ferroptosis.In conclusion,this study suggests that esculetin exerts an anti-HCC effect by inhibiting the activity of the Nrf2-xCT/GPx4 axis,thereby triggering ferroptosis in HCC cells.These findings may contribute to the potential clinical use of esculetin as a candidate for HCC treatment.展开更多
基金funded by the National Natural Science Foundation of China(82000042,81870029)Beijing Municipal Natural Science Foundation(7204247)+3 种基金Capital’s Funds for Health Improvement and Research(grant number:2024-2-1101)Start-up Project of Beijing Friendship Hospital,Capital Medical University(Beijing,China)(yyqdktzx2020-3)Key Clinical Specialty Construction Program of Beijing(2020-2022)Research Fund of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital(24QNPY034).
文摘Objective This study investigated the effect of reducing soluble epoxide hydrolase(sEH,encoded by the Ephx2 gene)on the mediation of EETs metabolism during ferroptosis in emphysema in vivo.Methods Male C57BL/6J wild-type(WT)and Ephx2^(-/-)mice received whole-body exposure to either cigarette smoke(CS)or air for 16 weeks.The alveolar structure,pulmonary function,lung tissue morphology,cell death,and ferroptosis levels were assessed following exposure.Results CS exposure caused emphysema,reduced pulmonary function,and induced ferroptosis in mice compared with exposure to air.In contrast,following CS exposure,Ephx2^(-/-)mice exhibited significantly lower levels of emphysema,impaired lung function,lung cell death,intracellular iron,lipid reactive oxygen species,cyclooxygenase-2,4-hydroxynonenal,and malondialdehyde levels than those of WT mice.However,Ephx2^(-/-)mice exhibited higher levels of glutathione and ferritin heavy chain 1 than those of WT mice.SLC7A11 expression was significantly reduced,whereas glutathione peroxidase 4 expression was markedly increased in Ephx2^(-/-)mice compared with WT mice.Statistically significant differences(P<0.05)were observed.Conclusion These results suggest that Ephx2 deficiency inhibits ferroptosis to alleviate CS-induced emphysema,primarily by mitigating its inhibitory effect on the cystine/glutathione/glutathione peroxidase 4 axis.Therefore,Ephx2 represents an effective therapeutic target in CS-induced chronic obstructive pulmonary disease(COPD).
基金supported by the Natural Science Foundations of Fujian Province(Nos.2021J05063 and 2023J01541)a startup grant for High-level Talents of Fujian Medical University(No.XRCZX2021014)。
文摘Esculetin,a natural dihydroxy coumarin derived from the Chinese herbal medicine Cortex Fraxini,has demonstrated significant pharmacological activities,including anticancer properties.Ferroptosis,an iron-dependent form of regulated cell death,has garnered considerable attention due to its lethal effect on tumor cells.However,the exact role of ferroptosis in esculetin-mediated anti-hepatocellular carcinoma(HCC)effects remains poorly understood.This study investigated the impact of esculetin on HCC cells both in vitro and in vivo.The findings indicate that esculetin effectively inhibited the growth of HCC cells.Importantly,esculetin promoted the accumulation of intracellular Fe^(2+),leading to an increase in ROS production through the Fenton reaction.This event subsequently induced lipid peroxidation(LPO)and triggered ferroptosis within the HCC cells.The occurrence of ferroptosis was confirmed by the elevation of malondialdehyde(MDA)levels,the depletion of glutathione peroxidase(GSH-Px)activity,and the disruption of mitochondrial morphology.Notably,the inhibitor of ferroptosis,ferrostatin-1(Fer-1),attenuated the anti-tumor effect of esculetin in HCC cells.Furthermore,the findings revealed that esculetin inhibited the Nrf2-xCT/GPx4 axis signaling in HCC cells.Overexpression of Nrf2 upregulated the expression of downstream SLC7A11 and GPX4,consequently alleviating esculetin-induced ferroptosis.In conclusion,this study suggests that esculetin exerts an anti-HCC effect by inhibiting the activity of the Nrf2-xCT/GPx4 axis,thereby triggering ferroptosis in HCC cells.These findings may contribute to the potential clinical use of esculetin as a candidate for HCC treatment.
