Acute myocardial infarction(AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percut...Acute myocardial infarction(AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty(PCA) treatment, which quick-ly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxi-cally, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species(ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury(MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies(mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack- of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weak-nesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention,and its continuity may also have some responsibility for the lack- of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine(a glutathione do展开更多
Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition repre...Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows:(1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group.(2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group.(3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury.(4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group.(5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2(ACSF2) and iron-responsive element-binding protein 2(IREB2) were up-regulated in the Deferoxamine group.(6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.展开更多
Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation.Currently,the therapeutic role of ferroptosis on cancer is gaining increasing interest.Baicalin an acti...Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation.Currently,the therapeutic role of ferroptosis on cancer is gaining increasing interest.Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types;however,the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown.In the study,we investigated the effect of baicalin on bladder cancer cells5637 and KU-19-19.As a result,we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells.Subsequently,we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo,accompanied by reactive oxygen species(ROS) accumulation and intracellular chelate iron enrichment.The ferroptosis inhibitor deferoxamine but not necrostatin-1,chloroquine(CQ),N-acetyl-L-cysteine,L-glutathione reduced,or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone(Z-VAD-FMK) rescued baicalin-induced cell death,indicating ferroptosis contributed to baicalin-induced cell death.Mechanistically,we show that ferritin heavy chain1(FTH1) was a key determinant for baicalin-induced ferroptosis.Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells.Taken together,our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis,which will hopefully provide a prospective compound for bladder cancer treatment.展开更多
The iron chelator deferoxamine has been shown to inhibit ferroptosis in spinal cord injury.However,it is unclear whether deferoxamine directly protects neurons from ferroptotic cell death.By comparing the survival rat...The iron chelator deferoxamine has been shown to inhibit ferroptosis in spinal cord injury.However,it is unclear whether deferoxamine directly protects neurons from ferroptotic cell death.By comparing the survival rate and morphology of primary neurons and SH-SY5Y cells exposed to erastin,it was found that these cell types respond differentially to the duration and concentration of erastin treatment.Therefore,we studied the mechanisms of ferroptosis using primary cortical neurons from E16 mouse embryos.After treatment with 50μM erastin for 48 hours,reactive oxygen species levels increased,and the expression of the cystine/glutamate antiporter system light chain and glutathione peroxidase 4 decreased.Pretreatment with deferoxamine for 12 hours inhibited these changes,reduced cell death,and ameliorated cellular morphology.Pretreatment with the apoptosis inhibitor Z-DEVD-FMK or the necroptosis inhibitor necrostain-1 for 12 hours did not protect against erastin-induced ferroptosis.Only deferoxamine protected the primary cortical neurons from ferroptosis induced by erastin,confirming the specificity of the in vitro ferroptosis model.This study was approved by the Animal Ethics Committee at the Institute of Radiation Medicine of the Chinese Academy of Medical Sciences,China(approval No.DWLL-20180913)on September 13,2018.展开更多
Previous studies found that iron accumulates in the substantia nigra of Parkinson＇s disease patients However, it is still unclear whether other brain regions have iron accumulation as well. In this experiment, rats w...Previous studies found that iron accumulates in the substantia nigra of Parkinson＇s disease patients However, it is still unclear whether other brain regions have iron accumulation as well. In this experiment, rats with rotenone-induced Parkinson＇s disease were treated by gastric perfusion of baicalin or intraperitoneal injection of deferoxamine. Immunohistochemical staining demonstrated that iron accumulated not only in the substantia nigra pars compacta, but also significantly in the striatum globus pallidus, the dentate gyrus granular layer of the hippocampus, the dentate-interpositus and the facial nucleus of the cerebellum. Both baicalin and deferoxamine, which are iron chelating agents, significantly inhibited iron deposition in these brain areas, and substantially reduced the loss of tyrosine hydroxylase-positive cells. These chelators also reduced iron content in the substantia nigra. In addition to the substantia nigra, iron deposition was observed in other brain regions as well. Both baicalin and deferoxamine significantly inhibited iron accumulation in different brain regions, and had a protective effect on dopaminergic neurons.展开更多
Previous studies have shown that baicalin prevented iron accumulation after substantia nigra injury, reduced divalent metal transporter 1 expression, and increased ferroportin 1 expression in the substantia nigra of r...Previous studies have shown that baicalin prevented iron accumulation after substantia nigra injury, reduced divalent metal transporter 1 expression, and increased ferroportin 1 expression in the substantia nigra of rotenone-induced Parkinson＇s disease rats. In the current study, we investigated the relationship between iron accumulation and transferrin expression in C6 cells, to explore the mechanisms of the inhibitory effect of baicalin on iron accumulation observed in Parkinson＇s disease rats. Iron content was detected using inductively coupled plasma-atomic emission spectroscopy. Results showed that iron content decreased 41% after blocking divalent metal transporter 1 and ferroportin 1 proteins. After treatment with ferric ammonium citrate of differing concentrations （10, 50, 100, 400 ktg/mL） in C6 glioma cells, cell survival rate and ferroportin 1 expression were negatively correlated with ferric ammonium citrate concentration, but divalent metal transporter 1 expression positively correlated with ferric ammonium citrate concentration. Baicalin or deferoxamine reduced divalent metal transporter 1 expression, but increased ferroportin 1 expression in the 100 μg/mL ferric ammonium citrate-loaded C6 cells. These results indicate that baicalin down-regulated iron concentration, which positively regulat- ed divalent metal transporter 1 expression and negatively regulated ferroportin 1 expression, and decreased iron accumulation in the substantia nigra.展开更多
目的研究甲磺酸去铁胺对老年脑出血患者血肿及其周围水肿以及功能预后的影响。方法将19例脑出血患者随机分为去铁胺组12例和对照组7例,分析2组患者的影像学资料及入院第15、30及90天的改良Rankin量表评分（mRS）,将2组资料进行比较。结...目的研究甲磺酸去铁胺对老年脑出血患者血肿及其周围水肿以及功能预后的影响。方法将19例脑出血患者随机分为去铁胺组12例和对照组7例,分析2组患者的影像学资料及入院第15、30及90天的改良Rankin量表评分（mRS）,将2组资料进行比较。结果与去铁胺组比较,对照组1~8d血肿相对吸收量显著增加,差异有统计学意义（0.15±0.18 vs 0.42±0.23,P=0.013）;对照组8~15d血肿相对吸收量显著增加,差异有统计学意义（0.48±0.22 vs 0.74±0.29,P=0.042）。去铁胺组与对照组患者入院第15、30和90天mRS≥3分比例比较,差异无统计学意义（66.7%vs 42.9%,58.3%vs 28.6%,33.3%vs 28.6%,P〉0.05）。结论甲磺酸去铁胺能够抑制老年脑出血患者血肿的吸收。展开更多
Iron is essential for all organisms including microbial,cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overloa...Iron is essential for all organisms including microbial,cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalass展开更多
文摘Acute myocardial infarction(AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty(PCA) treatment, which quick-ly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxi-cally, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species(ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury(MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies(mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack- of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weak-nesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention,and its continuity may also have some responsibility for the lack- of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine(a glutathione do
基金supported by the National Natural Science Foundation of China,No.81672171(to XY),81330042(to SQF),81620108018(to SQF),81772342the State Key Laboratory of Medicinal Chemical Biology(Nankai University),China,No.2017027
文摘Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows:(1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group.(2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group.(3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury.(4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group.(5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2(ACSF2) and iron-responsive element-binding protein 2(IREB2) were up-regulated in the Deferoxamine group.(6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.
基金supported by the grants National Natural Science Foundation of China (Nos. 81874380 and 82022075, to Xinbing Sui81730108 and 81973635, to Tian Xie)+4 种基金Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars (No. LR18H160001, to Xinbing Sui)Zhejiang Provincial Natural Science Foundation of China (Nos. LQ20H160013, Ting DuanLQ21H160038, to Jiao Feng)Zhejiang Province Science and Technology Project of TCM (Nos. 2019ZZ016, to Xinbing Sui2020ZQ046, to Ruonan Zhang, China)。
文摘Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation.Currently,the therapeutic role of ferroptosis on cancer is gaining increasing interest.Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types;however,the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown.In the study,we investigated the effect of baicalin on bladder cancer cells5637 and KU-19-19.As a result,we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells.Subsequently,we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo,accompanied by reactive oxygen species(ROS) accumulation and intracellular chelate iron enrichment.The ferroptosis inhibitor deferoxamine but not necrostatin-1,chloroquine(CQ),N-acetyl-L-cysteine,L-glutathione reduced,or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone(Z-VAD-FMK) rescued baicalin-induced cell death,indicating ferroptosis contributed to baicalin-induced cell death.Mechanistically,we show that ferritin heavy chain1(FTH1) was a key determinant for baicalin-induced ferroptosis.Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells.Taken together,our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis,which will hopefully provide a prospective compound for bladder cancer treatment.
基金supported by the National Natural Science Foundation of China,Nos.81672171(to XY),81620108018(to SQF),81772342(to GZN)the State Key Laboratory of Medicinal Chemical Biology of Nankai University of China,No.2017027(to XY)
文摘The iron chelator deferoxamine has been shown to inhibit ferroptosis in spinal cord injury.However,it is unclear whether deferoxamine directly protects neurons from ferroptotic cell death.By comparing the survival rate and morphology of primary neurons and SH-SY5Y cells exposed to erastin,it was found that these cell types respond differentially to the duration and concentration of erastin treatment.Therefore,we studied the mechanisms of ferroptosis using primary cortical neurons from E16 mouse embryos.After treatment with 50μM erastin for 48 hours,reactive oxygen species levels increased,and the expression of the cystine/glutamate antiporter system light chain and glutathione peroxidase 4 decreased.Pretreatment with deferoxamine for 12 hours inhibited these changes,reduced cell death,and ameliorated cellular morphology.Pretreatment with the apoptosis inhibitor Z-DEVD-FMK or the necroptosis inhibitor necrostain-1 for 12 hours did not protect against erastin-induced ferroptosis.Only deferoxamine protected the primary cortical neurons from ferroptosis induced by erastin,confirming the specificity of the in vitro ferroptosis model.This study was approved by the Animal Ethics Committee at the Institute of Radiation Medicine of the Chinese Academy of Medical Sciences,China(approval No.DWLL-20180913)on September 13,2018.
基金sponsored by the Scientific Research Common Program of Beijing Municipal Commission of Education,No.KM201110025010
文摘Previous studies found that iron accumulates in the substantia nigra of Parkinson＇s disease patients However, it is still unclear whether other brain regions have iron accumulation as well. In this experiment, rats with rotenone-induced Parkinson＇s disease were treated by gastric perfusion of baicalin or intraperitoneal injection of deferoxamine. Immunohistochemical staining demonstrated that iron accumulated not only in the substantia nigra pars compacta, but also significantly in the striatum globus pallidus, the dentate gyrus granular layer of the hippocampus, the dentate-interpositus and the facial nucleus of the cerebellum. Both baicalin and deferoxamine, which are iron chelating agents, significantly inhibited iron deposition in these brain areas, and substantially reduced the loss of tyrosine hydroxylase-positive cells. These chelators also reduced iron content in the substantia nigra. In addition to the substantia nigra, iron deposition was observed in other brain regions as well. Both baicalin and deferoxamine significantly inhibited iron accumulation in different brain regions, and had a protective effect on dopaminergic neurons.
基金supported by the Scientific Research Common Program of Beijing Municipal Commission of Education,No.KM20110025010
文摘Previous studies have shown that baicalin prevented iron accumulation after substantia nigra injury, reduced divalent metal transporter 1 expression, and increased ferroportin 1 expression in the substantia nigra of rotenone-induced Parkinson＇s disease rats. In the current study, we investigated the relationship between iron accumulation and transferrin expression in C6 cells, to explore the mechanisms of the inhibitory effect of baicalin on iron accumulation observed in Parkinson＇s disease rats. Iron content was detected using inductively coupled plasma-atomic emission spectroscopy. Results showed that iron content decreased 41% after blocking divalent metal transporter 1 and ferroportin 1 proteins. After treatment with ferric ammonium citrate of differing concentrations （10, 50, 100, 400 ktg/mL） in C6 glioma cells, cell survival rate and ferroportin 1 expression were negatively correlated with ferric ammonium citrate concentration, but divalent metal transporter 1 expression positively correlated with ferric ammonium citrate concentration. Baicalin or deferoxamine reduced divalent metal transporter 1 expression, but increased ferroportin 1 expression in the 100 μg/mL ferric ammonium citrate-loaded C6 cells. These results indicate that baicalin down-regulated iron concentration, which positively regulat- ed divalent metal transporter 1 expression and negatively regulated ferroportin 1 expression, and decreased iron accumulation in the substantia nigra.
文摘目的研究甲磺酸去铁胺对老年脑出血患者血肿及其周围水肿以及功能预后的影响。方法将19例脑出血患者随机分为去铁胺组12例和对照组7例,分析2组患者的影像学资料及入院第15、30及90天的改良Rankin量表评分（mRS）,将2组资料进行比较。结果与去铁胺组比较,对照组1~8d血肿相对吸收量显著增加,差异有统计学意义（0.15±0.18 vs 0.42±0.23,P=0.013）;对照组8~15d血肿相对吸收量显著增加,差异有统计学意义（0.48±0.22 vs 0.74±0.29,P=0.042）。去铁胺组与对照组患者入院第15、30和90天mRS≥3分比例比较,差异无统计学意义（66.7%vs 42.9%,58.3%vs 28.6%,33.3%vs 28.6%,P〉0.05）。结论甲磺酸去铁胺能够抑制老年脑出血患者血肿的吸收。
文摘Iron is essential for all organisms including microbial,cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalass
