Vein graft(VG)failure(VGF)is associated with VG intimal hyperplasia,which is characterized by abnormal accumulation of vascular smooth muscle cells(VSMCs).Most neointimal VSMCs are derived from pre-existing VSMCs via ...Vein graft(VG)failure(VGF)is associated with VG intimal hyperplasia,which is characterized by abnormal accumulation of vascular smooth muscle cells(VSMCs).Most neointimal VSMCs are derived from pre-existing VSMCs via a process of VSMC phenotypic transition,also known as dedifferentiation.There is increasing evidence to suggest that ginger or its bioactive ingredients may block VSMC dedifferentiation,exerting vasoprotective functions;however,the precise mechanisms have not been fully characterized.Therefore,we investigated the effect of ginger on VSMC phenotypic transition in VG remodeling after transplantation.Ginger significantly inhibited neointimal hyperplasia and promoted lumen(L)opening in a 3-month VG,which was primarily achieved by reducing ferroptotic stress.Ferroptotic stress is a pro-ferroptotic state.Contractile VSMCs did not die but instead gained a proliferative capacity and switched to the secretory type,forming neointima(NI)after vein transplantation.Ginger and its two main vasoprotective ingredients(6-gingerol and 6-shogaol)inhibit VSMC dedifferentiation by reducing ferroptotic stress.Network pharmacology analysis revealed that 6-gingerol inhibits ferroptotic stress by targeting P53,while 6-shogaol inhibits ferroptotic stress by targeting 5-lipoxygenase(Alox5),both promoting ferroptosis.Furthermore,both ingredients co-target peroxisome proliferator-activated receptor gamma(PPARγ),decreasing PPARγ-mediated nicotinamide adenine dinucleotide phosphate(NADPH)oxidase 1(Nox1)expression.Nox1 promotes intracellular reactive oxygen species(ROS)production and directly induces VSMC dedifferentiation.In addition,Nox1 is a ferroptosis-promoting gene that encourages ferroptotic stress production,indirectly leading to VSMC dedifferentiation.Ginger,a natural multi-targeted ferroptotic stress inhibitor,finely and effectively prevents VSMC phenotypic transition and protects against venous injury remodeling.展开更多
Ferroptosis has emerged as a crucial regulated cell death involved in a variety of physiological processes or pathological diseases,such as tumor suppression.Though initially being found from anticancer drug screening...Ferroptosis has emerged as a crucial regulated cell death involved in a variety of physiological processes or pathological diseases,such as tumor suppression.Though initially being found from anticancer drug screening and considered not essential as apoptosis for growth and development,numerous studies have demonstrated that ferroptosis is tightly regulated by key genetic pathways and/or genes,including several tumor suppressors and oncogenes.In this review,we introduce the basic concepts of ferroptosis,characterized by the features of non-apoptotic,iron-dependent,and overwhelmed accumulation of lipid peroxides,and the underlying regulated circuits are considered to be pro-ferroptotic pathways.Then,we discuss several established lipid peroxidation defending systems within cells,including SLC7A11/GPX4,FSP1/CoQ,GCH1/BH4,and mitochondria DHODH/CoQ,all of which serve as anti-ferroptotic pathways to prevent ferroptosis.Moreover,we provide a comprehensive summary of the genetic regulation of ferroptosis via targeting the above-mentioned pro-ferroptotic or anti-ferroptotic pathways.The regulation of proand anti-ferroptotic pathways gives rise to more specific responses to the tumor cells in a contextdependent manner,highlighting the unceasing study and deeper understanding of mechanistic regulation of ferroptosis for the purpose of applying ferroptosis induction in cancer therapy.展开更多
Metal wear particles generated by the movement of joint prostheses inevitably lead to aseptic osteolytic damage and ultimately prosthesis loosening,which are aggravated by various types of regulated cell death of bone...Metal wear particles generated by the movement of joint prostheses inevitably lead to aseptic osteolytic damage and ultimately prosthesis loosening,which are aggravated by various types of regulated cell death of bone.Nevertheless,the exact cellular nature and regulatory network underlying osteoferroptosis are poorly understood.Here,we report that titanium particles(TP)induced severe peri-implant osteolysis and ferroptotic changes with concomitant transcriptional repression of a key anti-ferroptosis factor,GPX4,in a mouse model of calvarial osteolysis.GPX4 repression was accompanied by an increase in DNA methyltransferases(DNMTs)1/3a/3b and hypermethylation of the Gpx4 promoter,which were partly mediated by the transcriptional regulator/co-repressor KLF5 and NCoR.Conversely,treatment with SGI-1027,a DNMT-specific inhibitor,resulted in marked reversal of Gpx4 promoter hypermethylation and GPX4 repression,as well as improvement in ferroptotic osteolysis to a similar extent as with a ferroptosis inhibitor,liproxstatin-1.This suggests that epigenetic GPX4 repression and ferroptosis caused by the increase of DNMT1/3a/3b have a causal influence on TP-induced osteolysis.In cultured primary osteoblasts and osteoclasts,GPX4 repression and ferroptotic changes were observed primarily in osteoblasts that were alleviated by SGI-1027 in a GPX4 inactivation-sensitive manner.Furthermore,we developed a mouse strain with Gpx4 haplodeficiency in osteoblasts(Gpx4^(0b+/-))thatexhibited worsened ferroptotic osteolysis in control and TP-treated calvaria and largely abolished the anti-ferroptosis and osteoprotective effects of SGl-1027.Taken together,our results demonstrate that DNMT1/3a/3b elevation,resulting GPX4 repression,and osteoblastic ferroptosis form a critical epigenetic pathway that significantly contributes to TP-induced osteolysis,and that targeting DNMT aberration and the associated osteoferroptosis could be a potential strategy to prevent or slow down prosthesis-related osteolytic complications.展开更多
基金supported by grants from the Natural Science Foundation of Shandong Province,China(Grant Nos.:ZR2019ZD28 and ZR2022QH008)the National Natural Science Foundation of China(Grant Nos.:82270301 and 82200465)+1 种基金China Postdoctoral Science Foundation(Grant No.:2023M731842)Shandong Postdoctoral Science Foundation,China(Grant No.:SDCX-ZG-202203013).
文摘Vein graft(VG)failure(VGF)is associated with VG intimal hyperplasia,which is characterized by abnormal accumulation of vascular smooth muscle cells(VSMCs).Most neointimal VSMCs are derived from pre-existing VSMCs via a process of VSMC phenotypic transition,also known as dedifferentiation.There is increasing evidence to suggest that ginger or its bioactive ingredients may block VSMC dedifferentiation,exerting vasoprotective functions;however,the precise mechanisms have not been fully characterized.Therefore,we investigated the effect of ginger on VSMC phenotypic transition in VG remodeling after transplantation.Ginger significantly inhibited neointimal hyperplasia and promoted lumen(L)opening in a 3-month VG,which was primarily achieved by reducing ferroptotic stress.Ferroptotic stress is a pro-ferroptotic state.Contractile VSMCs did not die but instead gained a proliferative capacity and switched to the secretory type,forming neointima(NI)after vein transplantation.Ginger and its two main vasoprotective ingredients(6-gingerol and 6-shogaol)inhibit VSMC dedifferentiation by reducing ferroptotic stress.Network pharmacology analysis revealed that 6-gingerol inhibits ferroptotic stress by targeting P53,while 6-shogaol inhibits ferroptotic stress by targeting 5-lipoxygenase(Alox5),both promoting ferroptosis.Furthermore,both ingredients co-target peroxisome proliferator-activated receptor gamma(PPARγ),decreasing PPARγ-mediated nicotinamide adenine dinucleotide phosphate(NADPH)oxidase 1(Nox1)expression.Nox1 promotes intracellular reactive oxygen species(ROS)production and directly induces VSMC dedifferentiation.In addition,Nox1 is a ferroptosis-promoting gene that encourages ferroptotic stress production,indirectly leading to VSMC dedifferentiation.Ginger,a natural multi-targeted ferroptotic stress inhibitor,finely and effectively prevents VSMC phenotypic transition and protects against venous injury remodeling.
基金the funding support from National Natural Science Foundation of China(82103272 to Y.Zhang)Xi’an Jiaotong University(xtr042021011 to Y.Zhang)+1 种基金Department of Science and Technology of Shaanxi Province(2022KW-48 to J Chen)supported by Top Young Talents Programme at Xi’an Jiaotong University。
文摘Ferroptosis has emerged as a crucial regulated cell death involved in a variety of physiological processes or pathological diseases,such as tumor suppression.Though initially being found from anticancer drug screening and considered not essential as apoptosis for growth and development,numerous studies have demonstrated that ferroptosis is tightly regulated by key genetic pathways and/or genes,including several tumor suppressors and oncogenes.In this review,we introduce the basic concepts of ferroptosis,characterized by the features of non-apoptotic,iron-dependent,and overwhelmed accumulation of lipid peroxides,and the underlying regulated circuits are considered to be pro-ferroptotic pathways.Then,we discuss several established lipid peroxidation defending systems within cells,including SLC7A11/GPX4,FSP1/CoQ,GCH1/BH4,and mitochondria DHODH/CoQ,all of which serve as anti-ferroptotic pathways to prevent ferroptosis.Moreover,we provide a comprehensive summary of the genetic regulation of ferroptosis via targeting the above-mentioned pro-ferroptotic or anti-ferroptotic pathways.The regulation of proand anti-ferroptotic pathways gives rise to more specific responses to the tumor cells in a contextdependent manner,highlighting the unceasing study and deeper understanding of mechanistic regulation of ferroptosis for the purpose of applying ferroptosis induction in cancer therapy.
基金supported by the National Major Research Plan of National Natural and Science Foundation of China(NSFC)(92368201)National Key Research and Development Project(2021YFA1201404)+4 种基金Major Project of NSFC(81991514)NSFC General Program(81970577)Jiangsu Provincial Key Medical Center Foundation,Jiangsu Province Medical Innovation Center of Orthopedic Surgery(CXZX-202214)Jiangsu Provincial Medical Youth Talent Foundation,Jiangsu Provincial Medical Outstanding Talent Foundation,Jiangsu Provincial Key Medical Talent Foundationthe Fundamental Research Funds for the Central Universities(14380493 and 14380494)。
文摘Metal wear particles generated by the movement of joint prostheses inevitably lead to aseptic osteolytic damage and ultimately prosthesis loosening,which are aggravated by various types of regulated cell death of bone.Nevertheless,the exact cellular nature and regulatory network underlying osteoferroptosis are poorly understood.Here,we report that titanium particles(TP)induced severe peri-implant osteolysis and ferroptotic changes with concomitant transcriptional repression of a key anti-ferroptosis factor,GPX4,in a mouse model of calvarial osteolysis.GPX4 repression was accompanied by an increase in DNA methyltransferases(DNMTs)1/3a/3b and hypermethylation of the Gpx4 promoter,which were partly mediated by the transcriptional regulator/co-repressor KLF5 and NCoR.Conversely,treatment with SGI-1027,a DNMT-specific inhibitor,resulted in marked reversal of Gpx4 promoter hypermethylation and GPX4 repression,as well as improvement in ferroptotic osteolysis to a similar extent as with a ferroptosis inhibitor,liproxstatin-1.This suggests that epigenetic GPX4 repression and ferroptosis caused by the increase of DNMT1/3a/3b have a causal influence on TP-induced osteolysis.In cultured primary osteoblasts and osteoclasts,GPX4 repression and ferroptotic changes were observed primarily in osteoblasts that were alleviated by SGI-1027 in a GPX4 inactivation-sensitive manner.Furthermore,we developed a mouse strain with Gpx4 haplodeficiency in osteoblasts(Gpx4^(0b+/-))thatexhibited worsened ferroptotic osteolysis in control and TP-treated calvaria and largely abolished the anti-ferroptosis and osteoprotective effects of SGl-1027.Taken together,our results demonstrate that DNMT1/3a/3b elevation,resulting GPX4 repression,and osteoblastic ferroptosis form a critical epigenetic pathway that significantly contributes to TP-induced osteolysis,and that targeting DNMT aberration and the associated osteoferroptosis could be a potential strategy to prevent or slow down prosthesis-related osteolytic complications.
