Ce rebral palsy is a diagnostic term utilized to describe a group of permanent disorders affecting movement and posture.Patients with cerebral palsy are often only capable of limited activity,resulting from non-progre...Ce rebral palsy is a diagnostic term utilized to describe a group of permanent disorders affecting movement and posture.Patients with cerebral palsy are often only capable of limited activity,resulting from non-progressive disturbances in the fetal or neonatal brain.These disturbances severely impact the child’s daily life and impose a substantial economic burden on the family.Although cerebral palsy encompasses various brain injuries leading to similar clinical outcomes,the unde rstanding of its etiological pathways remains incomplete owing to its complexity and heterogeneity.This review aims to summarize the current knowledge on the genetic factors influencing cerebral palsy development.It is now widely acknowledged that genetic mutations and alterations play a pivotal role in cerebral palsy development,which can be further influenced by environmental fa ctors.Des pite continuous research endeavors,the underlying fa ctors contributing to cerebral palsy remain are still elusive.However,significant progress has been made in genetic research that has markedly enhanced our comprehension of the genetic factors underlying cerebral palsy development.Moreove r,these genetic factors have been categorized based on the identified gene mutations in patients through clinical genotyping,including thrombosis,angiogenesis,mitochondrial and oxidative phosphorylation function,neuronal migration,and cellular autophagy.Furthermore,exploring targeted genotypes holds potential for precision treatment.In conclusion,advancements in genetic research have substantially improved our understanding of the genetic causes underlying cerebral palsy.These breakthroughs have the potential to pave the way for new treatments and therapies,consequently shaping the future of cerebral palsy research and its clinical management.The investigation of cerebral palsy genetics holds the potential to significantly advance treatments and management strategies.By elucidating the underlying cellular mechanisms,we can develop to rgeted interventions to optimize outcomes.A continued collaboration between researchers and clinicians is imperative to comprehensively unravel the intricate genetic etiology of cerebral palsy.展开更多
See related article,pp 357-363Extensive neuronal cell death occurs during nervous system development to remove surplus,unwanted,and damaged cells.This is a highly regulated physiological process that plays a pivotal r...See related article,pp 357-363Extensive neuronal cell death occurs during nervous system development to remove surplus,unwanted,and damaged cells.This is a highly regulated physiological process that plays a pivotal role in nervous system homeostasis and normal development.In some brain regions,more than half of the neurons are removed during normal development without interfering with the remaining cells.This gene-regulated neuronal cell deletion process is called programmed cell death(Fricker et al.,2018).展开更多
Perinatal complications,such as asphyxia,can cause brain injuries that are often associated with subsequent neurological deficits,such as cerebral palsy or mental retardation.The mechanisms of perinatal brain injury a...Perinatal complications,such as asphyxia,can cause brain injuries that are often associated with subsequent neurological deficits,such as cerebral palsy or mental retardation.The mechanisms of perinatal brain injury are not fully understood,but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion.Among these proteins,apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia,but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury.In this review,we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy,specifically on the importance of apoptosis-inducing factor.The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality,especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress,acting as a free radical scavenger.We also discuss all the different apoptosis-inducing factor isoforms discovered,focusing especially on apoptosis-inducing factor 2,which is only expressed in the brain and the functions of which are starting now to be clarified.Finally,we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions(prosurvival and pro-apoptotic)and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.展开更多
BACKGROUND:The mobilization of endogenous stem cells is an effective way to promote repair following ischemic brain damage.Buyang Huanwu decoction(BHD) can effectively improve cerebral blood flow and protect against c...BACKGROUND:The mobilization of endogenous stem cells is an effective way to promote repair following ischemic brain damage.Buyang Huanwu decoction(BHD) can effectively improve cerebral blood flow and protect against cerebral ischemia/reperfusion damage. OBJECTIVE:To study the effects of BHD on cell proliferation and differentiation in the hippocampal dentate gyrus of rats following cerebral infarction,to investigate the protective effects of BHD against cerebral infarction,and to analyze the dose-effect relationship. DESIGN,TIME AND SETTING:This randomized,controlled,animal study was performed at the Laboratory of Department of Physiology,Henan College of Traditional Chinese Medicine,China from June 2007 to February 2008. MATERIALS:A total of 36 male,Sprague Dawley rats,aged 20-21 months,were equally and randomly assigned to the following groups:sham operation,model control,and nimodipine,as well as high-dose,moderate-dose,and low-dose BHD.BHD was composed of milkvetch root,Chinese angelica,red peony root,earthworm,peach seed,safflower,and Szechwan Iovage rhizome,which were provided by the Outpatient Department,Henan College of Traditional Chinese Medicine, China. METHODS:The Chinese medicinal ingredients described above were decocted.The external carotid artery was ligated in rats from the sham operation group.Rat models of focal cerebral infarction were established by middle cerebral artery occlusion in the model control and nimodipine groups,as well as the high-dose,moderate-dose,and low-dose BHD groups.The drugs were administered by gavage 5 days,as well as 2 hours,prior to model induction.Rats in the nimodipine group were daily administered a 6 mg/kg nimodipine suspension by gavage.Rats in the high-dose, moderate-dose,and low-dose BHD groups were administered daily 26,13,and 6.5 g/kg BHD, respectively.Rats in the sham operation and model control groups were treated with an equal volume of saline. MAIN OUTCOME MEASURES:The effects of BHD on neurological dysfunction score,brain water content,cell proliferation and differentiation in the hippocampal dentate gyrus,and pathological changes in the ischemic brain hemisphere were measured in cerebral infarction rats. RESULTS:Compared with the sham operation group,the neurological dysfunction score,brain water content,number of BrdU-positive cells,BrdU/NeuN-positive cells,and BrdU/GFAP-positive cells in the hippocampal dentate gyrus significantly increased in the model control group(P<0.01). Compared with the model control group,neurological dysfunction score and brain water content were significantly decreased(P<0.01 or 0.05),as were the number of BrdU-positive and BrdU/NeuN-positive cells(P<0.01 or 0.05).The number of BrdU/GFAP-positive cells was significantly reduced(P<0.05) in the nimodipine group,high-dose,moderate-dose,and low-dose BHD groups.Compared with the nimodipine group,the neurological dysfunction score was significantly reduced in the moderate-dose BHD group(P<0.05).However,the number of BrdU-positive cells was significantly increased in the rat hippocampal dentate gyrus in the high-dose and moderate-close BHD groups(P<0.01 or 0.05).The following was determined by microscopy: slightly disarranged neural cells,mild vascular dilatation,inflammatory cell infiltration,and light tissue edema were observed in the nimodipine group;inflammatory cell infiltration was reduced in the low-dose BHD group;cerebral edema and inflammatory cell infiltration were significantly reduced in the high-dose and in the moderate-dose BHD group.Electron microscopy revealed lipofuscin, slightly swollen mitochondria,and normal rough endoplasmic reticulum in the high-dose and moderate-dose BHD groups.Improvement was best in the moderate-dose BHD group. CONCLUSION:Cerebral ischemia activated proliferation of neural stem cells in the rat hippocampal dentate gyrus.The actions of BHD against cerebral ischemia/reperfusion damage correlated with proliferation and differentiation of neural stem cells in the hippocampal dentate gyrus.A moderate-dose of BHD resulted in the most effective outcome.展开更多
Cerebral palsy (CP) is a nonprogressive dyskinesia syndrome caused by early brain injury,with an incidence of approximately2.0—3.5/1000 live births worldwide (Li et al.,2021;Moreno-DeLuca et al.,2021).Currently,there...Cerebral palsy (CP) is a nonprogressive dyskinesia syndrome caused by early brain injury,with an incidence of approximately2.0—3.5/1000 live births worldwide (Li et al.,2021;Moreno-DeLuca et al.,2021).Currently,there are more than 300,000 children aged 0—6 years diagnosed with CP in China (Liu et al.,1999;Yang et al.,2021),thus making it one of the most common debilitating diseases affecting children.展开更多
基金supported by the National Natural Science Foundation of China,No.U21A20347(to CZ)the National Key Research and Development Program of China,No.2022YFC2704801(to CZ)+1 种基金the Henan Key Laboratory of Population Defects Prevention,No.ZD202103(to YX)the Department of Science and Technology of Henan Province of China,No.212102310221(to YX)。
文摘Ce rebral palsy is a diagnostic term utilized to describe a group of permanent disorders affecting movement and posture.Patients with cerebral palsy are often only capable of limited activity,resulting from non-progressive disturbances in the fetal or neonatal brain.These disturbances severely impact the child’s daily life and impose a substantial economic burden on the family.Although cerebral palsy encompasses various brain injuries leading to similar clinical outcomes,the unde rstanding of its etiological pathways remains incomplete owing to its complexity and heterogeneity.This review aims to summarize the current knowledge on the genetic factors influencing cerebral palsy development.It is now widely acknowledged that genetic mutations and alterations play a pivotal role in cerebral palsy development,which can be further influenced by environmental fa ctors.Des pite continuous research endeavors,the underlying fa ctors contributing to cerebral palsy remain are still elusive.However,significant progress has been made in genetic research that has markedly enhanced our comprehension of the genetic factors underlying cerebral palsy development.Moreove r,these genetic factors have been categorized based on the identified gene mutations in patients through clinical genotyping,including thrombosis,angiogenesis,mitochondrial and oxidative phosphorylation function,neuronal migration,and cellular autophagy.Furthermore,exploring targeted genotypes holds potential for precision treatment.In conclusion,advancements in genetic research have substantially improved our understanding of the genetic causes underlying cerebral palsy.These breakthroughs have the potential to pave the way for new treatments and therapies,consequently shaping the future of cerebral palsy research and its clinical management.The investigation of cerebral palsy genetics holds the potential to significantly advance treatments and management strategies.By elucidating the underlying cellular mechanisms,we can develop to rgeted interventions to optimize outcomes.A continued collaboration between researchers and clinicians is imperative to comprehensively unravel the intricate genetic etiology of cerebral palsy.
基金supported by the National Nature Science Foundation of China(81901335 to YS,U21A20347 to CZ)China Postdoctoral Science Foundation(2020M672288 to YS)Henan Postdoctoral Research Grant(201902007 to YS)。
文摘See related article,pp 357-363Extensive neuronal cell death occurs during nervous system development to remove surplus,unwanted,and damaged cells.This is a highly regulated physiological process that plays a pivotal role in nervous system homeostasis and normal development.In some brain regions,more than half of the neurons are removed during normal development without interfering with the remaining cells.This gene-regulated neuronal cell deletion process is called programmed cell death(Fricker et al.,2018).
基金the Swedish Research Council(2018-02667)the National Natural Science Foundation of China(31761133015,U1704281,81901335)+3 种基金the Swedish Childhood Cancer Foundation(PR2018-0082)Swedish Governmental Grants to Scientists Working in Health Care(ALFGBG-717791)the Swedish Brain Foundation(FO2018-0034)the Chinese Scholarship Council to TL(201707040025)and to YX(201507040082)。
文摘Perinatal complications,such as asphyxia,can cause brain injuries that are often associated with subsequent neurological deficits,such as cerebral palsy or mental retardation.The mechanisms of perinatal brain injury are not fully understood,but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion.Among these proteins,apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia,but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury.In this review,we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy,specifically on the importance of apoptosis-inducing factor.The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality,especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress,acting as a free radical scavenger.We also discuss all the different apoptosis-inducing factor isoforms discovered,focusing especially on apoptosis-inducing factor 2,which is only expressed in the brain and the functions of which are starting now to be clarified.Finally,we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions(prosurvival and pro-apoptotic)and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.
文摘BACKGROUND:The mobilization of endogenous stem cells is an effective way to promote repair following ischemic brain damage.Buyang Huanwu decoction(BHD) can effectively improve cerebral blood flow and protect against cerebral ischemia/reperfusion damage. OBJECTIVE:To study the effects of BHD on cell proliferation and differentiation in the hippocampal dentate gyrus of rats following cerebral infarction,to investigate the protective effects of BHD against cerebral infarction,and to analyze the dose-effect relationship. DESIGN,TIME AND SETTING:This randomized,controlled,animal study was performed at the Laboratory of Department of Physiology,Henan College of Traditional Chinese Medicine,China from June 2007 to February 2008. MATERIALS:A total of 36 male,Sprague Dawley rats,aged 20-21 months,were equally and randomly assigned to the following groups:sham operation,model control,and nimodipine,as well as high-dose,moderate-dose,and low-dose BHD.BHD was composed of milkvetch root,Chinese angelica,red peony root,earthworm,peach seed,safflower,and Szechwan Iovage rhizome,which were provided by the Outpatient Department,Henan College of Traditional Chinese Medicine, China. METHODS:The Chinese medicinal ingredients described above were decocted.The external carotid artery was ligated in rats from the sham operation group.Rat models of focal cerebral infarction were established by middle cerebral artery occlusion in the model control and nimodipine groups,as well as the high-dose,moderate-dose,and low-dose BHD groups.The drugs were administered by gavage 5 days,as well as 2 hours,prior to model induction.Rats in the nimodipine group were daily administered a 6 mg/kg nimodipine suspension by gavage.Rats in the high-dose, moderate-dose,and low-dose BHD groups were administered daily 26,13,and 6.5 g/kg BHD, respectively.Rats in the sham operation and model control groups were treated with an equal volume of saline. MAIN OUTCOME MEASURES:The effects of BHD on neurological dysfunction score,brain water content,cell proliferation and differentiation in the hippocampal dentate gyrus,and pathological changes in the ischemic brain hemisphere were measured in cerebral infarction rats. RESULTS:Compared with the sham operation group,the neurological dysfunction score,brain water content,number of BrdU-positive cells,BrdU/NeuN-positive cells,and BrdU/GFAP-positive cells in the hippocampal dentate gyrus significantly increased in the model control group(P<0.01). Compared with the model control group,neurological dysfunction score and brain water content were significantly decreased(P<0.01 or 0.05),as were the number of BrdU-positive and BrdU/NeuN-positive cells(P<0.01 or 0.05).The number of BrdU/GFAP-positive cells was significantly reduced(P<0.05) in the nimodipine group,high-dose,moderate-dose,and low-dose BHD groups.Compared with the nimodipine group,the neurological dysfunction score was significantly reduced in the moderate-dose BHD group(P<0.05).However,the number of BrdU-positive cells was significantly increased in the rat hippocampal dentate gyrus in the high-dose and moderate-close BHD groups(P<0.01 or 0.05).The following was determined by microscopy: slightly disarranged neural cells,mild vascular dilatation,inflammatory cell infiltration,and light tissue edema were observed in the nimodipine group;inflammatory cell infiltration was reduced in the low-dose BHD group;cerebral edema and inflammatory cell infiltration were significantly reduced in the high-dose and in the moderate-dose BHD group.Electron microscopy revealed lipofuscin, slightly swollen mitochondria,and normal rough endoplasmic reticulum in the high-dose and moderate-dose BHD groups.Improvement was best in the moderate-dose BHD group. CONCLUSION:Cerebral ischemia activated proliferation of neural stem cells in the rat hippocampal dentate gyrus.The actions of BHD against cerebral ischemia/reperfusion damage correlated with proliferation and differentiation of neural stem cells in the hippocampal dentate gyrus.A moderate-dose of BHD resulted in the most effective outcome.
基金supported by the Shanghai Municipal Commission of Science and Technology Research Project(19JC1411000)the National Key Research and Development Plan for Stem Cell and Transformation Research(2017YFA0104202)+8 种基金the National Natural Science Foundation of China(U1604165,U1704281,81771418,31972880)the collaborative innovation center project construction for Shanghai women and children’s health(15GWZK0401)the Department of Science and Technology,Henan Province,China(171100310200)Health Department of Henan Province(SB201901055)the Swedish Research Council(2018-02667)Swedish Governmental grants to scientists working in health care(ALFGBG-717791)VINNMER-Marie Curie(VINNOVA,201504780)the Henan Medical Science and Technique Foundation(212102310221)the National Health Commission Key Laboratory of Birth Defects Prevention and Henan Key Laboratory of Population Defects Prevention(2021—03)。
文摘Cerebral palsy (CP) is a nonprogressive dyskinesia syndrome caused by early brain injury,with an incidence of approximately2.0—3.5/1000 live births worldwide (Li et al.,2021;Moreno-DeLuca et al.,2021).Currently,there are more than 300,000 children aged 0—6 years diagnosed with CP in China (Liu et al.,1999;Yang et al.,2021),thus making it one of the most common debilitating diseases affecting children.
