Ferroptosis has been shown to mediate the development of fibrosis.Polyphyllin VII(PP7),a bioactive component of Paris polyphylla,exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosi...Ferroptosis has been shown to mediate the development of fibrosis.Polyphyllin VII(PP7),a bioactive component of Paris polyphylla,exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis.In this study,treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells(HSCs),which could be suppressed by a ferroptosis inhibitor.In addition,it promoted HSC ferroptosis by suppressing glutathione(GSH)peroxidase 4(GPX4)and enhanced the expression of CX3C chemokine ligand 1(CX3CL1).Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4.Notably,CX3CL1 directly interacted with GPX4,triggering HSC ferroptosis.The transcription factor hypermethylated in cancer 1(Hic1),which binds to the Cx3cl1 promoter,increased the expression of CX3CL1.Its absence resulted in downregulation of CX3CL1,suppressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation.HIC1 was found to directly interact with PP7 at the GLY164 site.Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes.HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo.These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.展开更多
Background:Radiotherapy,a primary approach in cancer treatment,damages normal cells while targeting cancer cells.Therefore,it is crucial to identify drugs with minimal side effects,high reliability,and radioprotective...Background:Radiotherapy,a primary approach in cancer treatment,damages normal cells while targeting cancer cells.Therefore,it is crucial to identify drugs with minimal side effects,high reliability,and radioprotective effects to develop novel radiotherapy strategies.Hemerocallis citrina extracts(HCE),which are derived from plants with medicinal and culinary applications,possess antioxidative and anticancer properties.Methods:In this study,we investigated the radioprotective effects of HCE on LO2 cells exposed to radiation to determine whether these effects were mediated through the nuclear factor erythroid 2–related factor 2-cystine–glutamate antiporter/glutathione peroxidase 4 pathway.Results:Cell proliferation experiments demonstrated the radioprotective effect of HCE on LO2 cells.Western blot analysis revealed that HCE regulated B-cell lymphoma protein 2-associated X,Cleaved-caspase 3,and B-cell lymphoma protein 2,thereby inhibiting radiation-induced apoptosis,which was consistent with the flow cytometry results.Conclusions:Moreover,the detection of ferroptosis-related markers indicated that HCE alleviated radiation-induced ferroptosis in LO2 cells through the nuclear factor erythroid 2–related factor 2-cystine–glutamate antiporter/glutathione peroxidase 4 pathway.These findings provide a theoretical basis for the radioprotective effects of HCE on LO2 cells and offer new insights into the development of radioprotective drugs.展开更多
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
As one of the key targets of tumor metabolic therapy,glucose dyshomeostasis by disrupting glucose metabolism possesses the potential to reverse therapeutic resistance of a variety of regulated cell deaths(RCDs),but th...As one of the key targets of tumor metabolic therapy,glucose dyshomeostasis by disrupting glucose metabolism possesses the potential to reverse therapeutic resistance of a variety of regulated cell deaths(RCDs),but the functional pathways are not fully revealed and employed.Herein,we demonstrate that the intervention on SLC7A11/GSH/GPX4 antioxidant axis by glucose dyshomeostasis can simultaneously promote disulfidptosis,cuproptosis and ferroptosis,which is verified by employing glucose oxidase(GOx)-modified copper-apigenin(CuAp)network nanoshuttles(CuAp@GOx NSs)in ovarian tumor therapy.Ap and GOx can jointly induce glucose dyshomeostasis respectively by inhibiting glucose transporter 1-mediated glucose uptake upstream,and consuming massive glucose downstream.As a result of glucose dyshomeostasis,the NADPH supplement is downregulated,which further disrupts SLC7A11/GSH/GPX4 antioxidant axis.This simultaneously boosts disulfidptosis by facilitating cystine accumulation,cuproptosis by attenuating GSH-mediated Cu+inactivation,and ferroptosis by downregulating GPX4 expression.Owing to the combination of disulfidptosis,cuproptosis and ferroptosis,CuAp@GOx NSs exhibit good efficacy in treating ovarian tumor model.This work proposes an alternative strategy for tumor therapy based on glucose dyshomeostasis,which mainly targets the RCDs relating to SLC7A11/GSH/GPX4 axis.展开更多
Tendinopathy is a common and complex musculoskeletal disorder,unfortunately current clinical strategies for tendinopathy have low therapeutic efficacy because of complicated pathogenesis.Oxidative stress is considered...Tendinopathy is a common and complex musculoskeletal disorder,unfortunately current clinical strategies for tendinopathy have low therapeutic efficacy because of complicated pathogenesis.Oxidative stress is considered as the major cause of tendinopathy as well as the important target,but still lacking ideal antioxidant solution.To this end,an efficient reactive oxygen species(ROS)biocatalyst,PtIrRuRhCu high-entropy alloy nanozyme(HEANZ),has been designed for treatment of tendinopathy.The non-ionic block copolymer(polyvinyl pyrrolidone)coated PtIrRuRhCu HEANZ with size of~4.0 nm exhibits good biocompatibility and multiple enzyme-like antioxidant activity(including peroxidase,catalase and superoxide dismutase(SOD)-like)to modulate ROS.The therapeutic efficacy of PtIrRuRhCu HEANZ in tendinopathy has been systematically demonstrated in vitro and in vivo.PtIrRuRhCu HEANZ can alleviate the t-Butyl hydroperoxide(TBHP)stimulated tendinopathy by clearing ROS,reducing inflammation and restoring mitochondrial autophagy.Using phosphoglycerate mutase family member 5(PGAM5)siRNA and FUN14 domain containing protein 1(FUNDC1)siRNA for intervention,we clearly revealed that PtIrRuRhCu HEANZ promots mitochondrial autophagy through upregulating the PGAM5/FUNDC1/glutathione peroxidase 4(GPX4)axis.This study provides a nanozyme strategy for the antioxidant treatment of tendinopathy and provides insights into the therapeutic mechanism.展开更多
Objective:To investigate potential mechanisms of anti-atherosclerosis by berberine(BBR)using ApoE-/-mice.Methods:Eight 8-week-old C57BL/6J mice were used as a blank control group(normal),and 568-week-old AopE-/-mice w...Objective:To investigate potential mechanisms of anti-atherosclerosis by berberine(BBR)using ApoE-/-mice.Methods:Eight 8-week-old C57BL/6J mice were used as a blank control group(normal),and 568-week-old AopE-/-mice were fed a high-fat diet for 12 weeks,according to a completely random method,and were divided into the model group,BBR low-dose group(50 mg/kg,BBRL),BBR medium-dose group(100 mg/kg,BBRM),BBR high-dose group(150 mg/kg,BBRH),BBR+nuclear factor erythroid 2-related factor 2(NRF2)inhibitor group(100 mg/kg BBR+30 mg/kg ML385,BBRM+ML385),NRF2 inhibitor group(30 mg/kg,ML385),and positive control group(2.5 mg/kg,atorvastatin),8 in each group.After 4 weeks of intragastric administration,samples were collected and serum,aorta,heart and liver tissues were isolated.Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde(MDA)and superoxide dismutase(SOD)in all experimental groups.The pathological changes of atherosclerosis(AS)were observed by aorta gross Oil Red O,aortic sinus hematoxylin-eosin(HE)and Masson staining.Liver lipopathy was observed in mice by HE staining.The morphology of mitochondria in aorta cells was observed under transmission electron microscope.Flow cytometry was used to detect reactive oxygen species(ROS)expression in aorta of mice in each group.The content of ferrous ion Fe^(2+)in serum of mice was detected by biochemical kit.The mRNA and protein relative expression levels of NRF2,glutathione peroxidase 4(GPX4)and recombinant solute carrier family 7 member 11(SLC7A11)were detected by quantitative real time polymerase chain reaction(RT-q PCR)and Western blot,respectively.Results:BBRM and BBRH groups delayed the progression of AS and reduced the plaque area(P<0.01).The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice,and the content of Fe^(2+)in BBR group was significantly lower than that in the model group(P<0.01).BBR decreased ROS and MDA levels in mouse aorta,increased SOD activity(P<0.01),significantly up-regulated NRF2/SLC7A11/GPX4 protein and mRNA expression levels(P<0.01),and inhibited lipid peroxidation.Compared with the model group,the body weight,blood lipid level and aortic plaque area of ML385 group increased(P<0.01);the morphology of mitochondria showed significant ferroptosis characteristics;the serum Fe^(2+),MDA and ROS levels increased(P<0.05 or P<0.01),and the activity of SOD decreased(P<0.01).Compared with BBRM group,the iron inhibition effect of BBRM+ML385 group was significantly weakened,and the plaque area significantly increased(P<0.01).Conclusion:Through NRF2/SLC7A11/GPX4 pathway,BBR can resist oxidative stress,inhibit ferroptosis,reduce plaque area,stabilize plaque,and exert anti-AS effects.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:81873576)Wenzhou Municipal Science and Technology Bureau,China(Grant No.:Y20220023).
文摘Ferroptosis has been shown to mediate the development of fibrosis.Polyphyllin VII(PP7),a bioactive component of Paris polyphylla,exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis.In this study,treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells(HSCs),which could be suppressed by a ferroptosis inhibitor.In addition,it promoted HSC ferroptosis by suppressing glutathione(GSH)peroxidase 4(GPX4)and enhanced the expression of CX3C chemokine ligand 1(CX3CL1).Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4.Notably,CX3CL1 directly interacted with GPX4,triggering HSC ferroptosis.The transcription factor hypermethylated in cancer 1(Hic1),which binds to the Cx3cl1 promoter,increased the expression of CX3CL1.Its absence resulted in downregulation of CX3CL1,suppressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation.HIC1 was found to directly interact with PP7 at the GLY164 site.Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes.HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo.These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.
基金supported by the Natural Science Foundation of Hunan Province(2021JJ30592)Health Commission Scientific Research Project of Hunan Province(D202309037942)+1 种基金Key Research Project of Education Department of Hunan Province(19A429)National Natural Science Foundation of China(81272994).
文摘Background:Radiotherapy,a primary approach in cancer treatment,damages normal cells while targeting cancer cells.Therefore,it is crucial to identify drugs with minimal side effects,high reliability,and radioprotective effects to develop novel radiotherapy strategies.Hemerocallis citrina extracts(HCE),which are derived from plants with medicinal and culinary applications,possess antioxidative and anticancer properties.Methods:In this study,we investigated the radioprotective effects of HCE on LO2 cells exposed to radiation to determine whether these effects were mediated through the nuclear factor erythroid 2–related factor 2-cystine–glutamate antiporter/glutathione peroxidase 4 pathway.Results:Cell proliferation experiments demonstrated the radioprotective effect of HCE on LO2 cells.Western blot analysis revealed that HCE regulated B-cell lymphoma protein 2-associated X,Cleaved-caspase 3,and B-cell lymphoma protein 2,thereby inhibiting radiation-induced apoptosis,which was consistent with the flow cytometry results.Conclusions:Moreover,the detection of ferroptosis-related markers indicated that HCE alleviated radiation-induced ferroptosis in LO2 cells through the nuclear factor erythroid 2–related factor 2-cystine–glutamate antiporter/glutathione peroxidase 4 pathway.These findings provide a theoretical basis for the radioprotective effects of HCE on LO2 cells and offer new insights into the development of radioprotective drugs.
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 National Natural Science Foundation of China(Grant Number 82373399,52303085)the Science and Tech-nology Development Program of Jilin Province(Grant Number 202302001)Special Project from MOST of China.Thanks to Min-gjie Chen(Shanghai NewCore Biotechnology Co.,Ltd.)for providing data analysis and visualization support.
文摘As one of the key targets of tumor metabolic therapy,glucose dyshomeostasis by disrupting glucose metabolism possesses the potential to reverse therapeutic resistance of a variety of regulated cell deaths(RCDs),but the functional pathways are not fully revealed and employed.Herein,we demonstrate that the intervention on SLC7A11/GSH/GPX4 antioxidant axis by glucose dyshomeostasis can simultaneously promote disulfidptosis,cuproptosis and ferroptosis,which is verified by employing glucose oxidase(GOx)-modified copper-apigenin(CuAp)network nanoshuttles(CuAp@GOx NSs)in ovarian tumor therapy.Ap and GOx can jointly induce glucose dyshomeostasis respectively by inhibiting glucose transporter 1-mediated glucose uptake upstream,and consuming massive glucose downstream.As a result of glucose dyshomeostasis,the NADPH supplement is downregulated,which further disrupts SLC7A11/GSH/GPX4 antioxidant axis.This simultaneously boosts disulfidptosis by facilitating cystine accumulation,cuproptosis by attenuating GSH-mediated Cu+inactivation,and ferroptosis by downregulating GPX4 expression.Owing to the combination of disulfidptosis,cuproptosis and ferroptosis,CuAp@GOx NSs exhibit good efficacy in treating ovarian tumor model.This work proposes an alternative strategy for tumor therapy based on glucose dyshomeostasis,which mainly targets the RCDs relating to SLC7A11/GSH/GPX4 axis.
基金supported by the National Major Research plan of NSFC(No.92368201)the National Key Research and Development Program of China(No.2021YFA1201404)+2 种基金Major Project of the National Natural Science Foundation of China(No.81991514)Jiangsu Province Medical Innovation Center of Orthopedic Surgery(No.CXZX202214)Jiangsu Provincial Key Medical Center Foundation,Jiangsu Provincial Medical Outstanding Talent Foundation,Jiangsu Provincial Medical Youth Talent Foundation and Jiangsu Provincial Key Medical Talent Foundation,and the Fundamental Research Funds for the Central Universities(Nos.14380493,and 14380494).
文摘Tendinopathy is a common and complex musculoskeletal disorder,unfortunately current clinical strategies for tendinopathy have low therapeutic efficacy because of complicated pathogenesis.Oxidative stress is considered as the major cause of tendinopathy as well as the important target,but still lacking ideal antioxidant solution.To this end,an efficient reactive oxygen species(ROS)biocatalyst,PtIrRuRhCu high-entropy alloy nanozyme(HEANZ),has been designed for treatment of tendinopathy.The non-ionic block copolymer(polyvinyl pyrrolidone)coated PtIrRuRhCu HEANZ with size of~4.0 nm exhibits good biocompatibility and multiple enzyme-like antioxidant activity(including peroxidase,catalase and superoxide dismutase(SOD)-like)to modulate ROS.The therapeutic efficacy of PtIrRuRhCu HEANZ in tendinopathy has been systematically demonstrated in vitro and in vivo.PtIrRuRhCu HEANZ can alleviate the t-Butyl hydroperoxide(TBHP)stimulated tendinopathy by clearing ROS,reducing inflammation and restoring mitochondrial autophagy.Using phosphoglycerate mutase family member 5(PGAM5)siRNA and FUN14 domain containing protein 1(FUNDC1)siRNA for intervention,we clearly revealed that PtIrRuRhCu HEANZ promots mitochondrial autophagy through upregulating the PGAM5/FUNDC1/glutathione peroxidase 4(GPX4)axis.This study provides a nanozyme strategy for the antioxidant treatment of tendinopathy and provides insights into the therapeutic mechanism.
基金Supported by the Henan Province Science and Technology Research Project(No.182102310093)。
文摘Objective:To investigate potential mechanisms of anti-atherosclerosis by berberine(BBR)using ApoE-/-mice.Methods:Eight 8-week-old C57BL/6J mice were used as a blank control group(normal),and 568-week-old AopE-/-mice were fed a high-fat diet for 12 weeks,according to a completely random method,and were divided into the model group,BBR low-dose group(50 mg/kg,BBRL),BBR medium-dose group(100 mg/kg,BBRM),BBR high-dose group(150 mg/kg,BBRH),BBR+nuclear factor erythroid 2-related factor 2(NRF2)inhibitor group(100 mg/kg BBR+30 mg/kg ML385,BBRM+ML385),NRF2 inhibitor group(30 mg/kg,ML385),and positive control group(2.5 mg/kg,atorvastatin),8 in each group.After 4 weeks of intragastric administration,samples were collected and serum,aorta,heart and liver tissues were isolated.Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde(MDA)and superoxide dismutase(SOD)in all experimental groups.The pathological changes of atherosclerosis(AS)were observed by aorta gross Oil Red O,aortic sinus hematoxylin-eosin(HE)and Masson staining.Liver lipopathy was observed in mice by HE staining.The morphology of mitochondria in aorta cells was observed under transmission electron microscope.Flow cytometry was used to detect reactive oxygen species(ROS)expression in aorta of mice in each group.The content of ferrous ion Fe^(2+)in serum of mice was detected by biochemical kit.The mRNA and protein relative expression levels of NRF2,glutathione peroxidase 4(GPX4)and recombinant solute carrier family 7 member 11(SLC7A11)were detected by quantitative real time polymerase chain reaction(RT-q PCR)and Western blot,respectively.Results:BBRM and BBRH groups delayed the progression of AS and reduced the plaque area(P<0.01).The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice,and the content of Fe^(2+)in BBR group was significantly lower than that in the model group(P<0.01).BBR decreased ROS and MDA levels in mouse aorta,increased SOD activity(P<0.01),significantly up-regulated NRF2/SLC7A11/GPX4 protein and mRNA expression levels(P<0.01),and inhibited lipid peroxidation.Compared with the model group,the body weight,blood lipid level and aortic plaque area of ML385 group increased(P<0.01);the morphology of mitochondria showed significant ferroptosis characteristics;the serum Fe^(2+),MDA and ROS levels increased(P<0.05 or P<0.01),and the activity of SOD decreased(P<0.01).Compared with BBRM group,the iron inhibition effect of BBRM+ML385 group was significantly weakened,and the plaque area significantly increased(P<0.01).Conclusion:Through NRF2/SLC7A11/GPX4 pathway,BBR can resist oxidative stress,inhibit ferroptosis,reduce plaque area,stabilize plaque,and exert anti-AS effects.
