Objectives:To evaluate clinical features,treatment strategies,and outcomes of pleural empyema for children who were treated at referral pediatric hospitals in 8 provinces of Iran.Methods:In this retrospective,multicen...Objectives:To evaluate clinical features,treatment strategies,and outcomes of pleural empyema for children who were treated at referral pediatric hospitals in 8 provinces of Iran.Methods:In this retrospective,multicenter cross sectional study,we retrospectively retrieved patients'data from 8 teaching hospitals during 2010 and 2017.A questionnaire was applied and filled,and all data were statistically and descriptively analyzed.Results:In total,191 children(109 males and 82 females)were included.Their mean age was 4.95 years and ranged from 11 months to 16 years.The majority of cases(45.1%)were 1-4 years old.Fever(70.3%),cough(65.6%),tachypnea(53.1%),chest pain(14.6%),and abdominal pain(12%)were the most common manifestations at admission.The mean length of admission in hospital was 16.4 d.Consequently,27 patients(14.1%)were admitted into the pediatric intensive unit because of severe illness,and 15 patients(7.9%)died.Logistic regression analysis showed that younger age(less than 12 months)and presence of underlying diseases(such as cardiovascular disease,immune deficiencies,malignancies,and neuro-developmental delay)significantly increased the mortality rate of patients with pleural empyema(P=0.004 and P=0.001,respectively).Conclusions:Pleural empyema children of younger age and with underlying diseases are at higher risks of death.In addition,guidelines for treating pleural empyema should be developed.展开更多
Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury respons...Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury response,including inflammation and repair.Although colony-stimulating factor 1 receptor inhibitors such as PLX5622 enable the selective depletion of microglia,their therapeutic potential in neonatal germinal matrix hemorrhage remains underexplored.Here,we used a collagenase-induced germinal matrix hemorrhage model in postnatal day 5 mice,and intraperitoneally administered PLX562272 hours post-germinal matrix hemorrhage to achieve targeted,temporary microglial depletion during the peak injury response.We then assessed the effects of this delayed intervention on oligodendrocyte lineage cell maturation,white matter integrity,and neurobehavioral outcomes.Additionally,RNA sequencing data from a germinal matrix hemorrhage rat model were analyzed using weighted gene co-expression network analysis to identify the critical phases for interventions.RNA sequencing data revealed a critical period in which key synaptic functions declined while immune responses intensified post-germinal matrix hemorrhage,thus pinpointing the critical response phases for potential interventions.Delayed PLX5622 treatment effectively depleted activated microglia,protecting against white matter injury and enhancing oligodendrocyte lineage cell maturation and myelination in subcortical white matter regions.Moreover,magnetic resonance imaging analysis revealed reduced brain lesion volumes in treated mice.Behaviorally,PLX5622-treated mice exhibited significant improvements in motor coordination and reduced hyperactivity compared with vehicle-treated germinal matrix hemorrhage model mice.These findings suggest that,when timed to avoid interference with initial oligodendrocyte lineage cell proliferation,targeted microglial depletion with PLX5622 significantly mitigates white matter damage and improves neurobehavioral outcomes in neonatal germinal matrix hemorrhage.The present study highlights the therapeutic potential of selectively modulating microglial reactivity to support neurodevelopment in preterm infants with brain injury.展开更多
Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration...Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.展开更多
Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription...Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription,RNA splicing,and protein synthesis.Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers,rendering cyclins and CDKs attractive therapeutic targets.Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use,fueling the development of CDK-targeted therapies.With this enthusiasm for finding novel CDK-targeting anti-cancer agents,there have also been exciting advances in the field of targeted protein degradation through innovative strategies,such as using proteolysis-targeting chimera,heat shock protein 90(HSP90)-mediated targeting chimera,hydrophobic tag-based protein degradation,and molecular glue.With a focus on the translational potential of cyclin-and CDK-targeting strategies in cancer,this review presents the fundamental roles of cyclins and CDKs in cancer.Furthermore,it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs,detailing the underlying mechanisms of action for each approach.A comprehensive overview of the structure and activity of existing CDK degraders is also provided.By examining the structure‒activity relationships,target profiles,and biological effects of reported cyclin/CDK degraders,this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.展开更多
The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate th...The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate the intrinsic growth capacity in mature neurons. Among them, PI3 kinase/Akt pathway is important for controlling axon elongation. As a negative regulator of this pathway, the tumor suppressor phosphatase and tensin homolog （PTEN） appears critical to con- trol the regenerative ability of young and adult neurons. This review will focus on recent research progress in axon regeneration and neural repair by PTEN inhibition and therapeutic potential of blocking this phosphatase for neurological disorders. Inhibition of PTEN by deletion in con- ditional knockout mice, knockdown by short-hairpin RNA, or blockade by pharmacological approaches, including administration of selective PTEN antagonist peptides, stimulates various degrees of axon regrowth in juvenile or adult rodents with central nervous system injuries. Im- portantly, post-injury PTEN suppression could enhance axonal growth and functional recovery in adult central nervous system after injury.展开更多
Reactive astrogliosis occurs after central nervous system（CNS） injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na？ve astrocytes are converted into reactive...Reactive astrogliosis occurs after central nervous system（CNS） injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na？ve astrocytes are converted into reactive astrocytes and eventually into scar-forming astrocytes that block axon regeneration and neural repair. It has been known for decades that scarring development and its related extracellular matrix molecules interfere with regeneration of injured axons after CNS injury, but the cellular and molecular mechanisms for controlling astrocytic scar formation and maintenance are not well known. Recent use of various genetic tools has made tremendous progress in better understanding genesis of reactive astrogliosis. Especially, the latest experiments demonstrate environment-dependent plasticity of reactive astrogliosis because reactive astrocytes isolated from injured spinal cord form scarring astrocytes when transplanted into injured spinal cord, but revert in retrograde to naive astrocytes when transplanted into naive spinal cord. The interactions between upregulated type I collagen and its receptor integrin β1 and the N-cadherin-mediated cell adhesion appear to play major roles for local astrogliosis around the lesion. This review centers on the environment-dependent plasticity of reactive astrogliosis after spinal cord injury and its potential as a therapeutic target.展开更多
The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination.Recent studies have shed light on the molecular mechanisms underlying these white matter abnor...The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination.Recent studies have shed light on the molecular mechanisms underlying these white matter abnormalities.Rodent models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor cells.Ethanol exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological specimens.Several studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system,including multiple sclerosis and fetal alcohol syndrome.Acute ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues,while ethanol increased the expression of tumor necrosis factor α in mouse and human neurons.White matter lesions have been induced in the developing sheep brain by alcohol exposure in early gestation.Rat fetal alcohol syndrome models have shown reduced axon diameters,with thinner myelin sheaths,as well as reduced numbers of oligodendrocytes,which were also morphologically aberrant oligodendrocytes.Expressions of markers for mature myelination,including myelin basic protein,also were reduced.The accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal development.Future studies using fetal oligodendrocyte-and oligodendrocyte precursor cell-derived exosomes isolated from the mother's blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in adulthood.By combining various imaging modalities with molecular studies,it may be possible to determine which fetuses are at risk and to intervene therapeutically early in the pregnancy.展开更多
Spinal cord injury leads to persistent behavioral deficits because mammalian central nervous system axons fail to regenerate. A neuron's response to axon injury results from a complex interplay of neuron-intrinsic...Spinal cord injury leads to persistent behavioral deficits because mammalian central nervous system axons fail to regenerate. A neuron's response to axon injury results from a complex interplay of neuron-intrinsic and environmental factors. The contribution of axotomy to the death of neurons in spinal cord injury is controversial because very remote axotomy is unlikely to result in neuronal death, whereas death of neurons near an injury may reflect environmental factors such as ischemia and inflammation. In lampreys, axotomy due to spinal cord injury results in delayed apoptosis of spinal-projecting neurons in the brain, beyond the extent of these environmental factors. This retrograde apoptosis correlates with delayed resealing of the axon, and can be reversed by inducing rapid membrane resealing with polyethylene glycol. Studies in mammals also suggest that polyethylene glycol may be neuroprotective, although the mechanism(s) remain unclear. This review examines the early, mechanical, responses to axon injury in both mammals and lampreys, and the potential of polyethylene glycol to reduce injury-induced pathology. Identifying the mechanisms underlying a neuron's response to axotomy will potentially reveal new therapeutic targets to enhance regeneration and functional recovery in humans with spinal cord injury.展开更多
Paralysis following spinal cord injury （SCI） is due to failure of axonal regeneration. It is believed that the capacities of neurons to regrow their axons are due partly to their intrinsic characteristics, which in ...Paralysis following spinal cord injury （SCI） is due to failure of axonal regeneration. It is believed that the capacities of neurons to regrow their axons are due partly to their intrinsic characteristics, which in turn are greatly influenced by several types of inhibitory molecules that are present, or even increased in the extracellular environment of the injured spinal cord. Many of these inhibitory molecules have been studied extensively in recent years. It has been suggested that the small GTPase RhoA is an intracellular convergence point for signaling by these extracellular inhibitory molecules, but due to the complexity of the central nervous system （CNS） in mammals, and the limitation of pharmacological tools, the specific roles of RhoA are unclear. By exploiting the anatomical and technical advantages of the lamprey CNS, we recently demonstrated that RhoA knockdown promotes true axon regeneration through the lesion site after SCI. In addition, we found that RhoA knockdown protects the large, identified reticulospinal neurons from apoptosis after their axons were axotomized in spinal cord. Therefore, manipulation of the RhoA signaling pathway may be an important approach in the development of treatments that are both neuroprotective and axon regeneration-promoting, to enhance functional recovery after SCI.展开更多
Have you heard of NG2 cells or NG2 glia or polydendro- cytes~. These are new names for the precursor cells that used to be referred to as oligodendrocyte precursor cells （OPCs）, which become the oligodendrocytes tha...Have you heard of NG2 cells or NG2 glia or polydendro- cytes~. These are new names for the precursor cells that used to be referred to as oligodendrocyte precursor cells （OPCs）, which become the oligodendrocytes that myelinate central nervous system （CNS） axons. Evidence suggests, however, that they have other functions, besides differentiating into oligodendrocytes. Most notably, the OPCs/NG2 cells are uni- formly distributed in grey matter as well as in white matter, which matches poorly with the distribution of myelinating oligodendrocytes. Furthermore, not every NG2 cell is fated to become an oligodendrocyte. Hence the term OPC can be fairly applied only when discussing the role of these cells in the oligodendrocyte lineage.展开更多
Some neurons,especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system(CNS)regenerate after axotomy,while most mammalian CNS neurons fail to regenerate.There is a...Some neurons,especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system(CNS)regenerate after axotomy,while most mammalian CNS neurons fail to regenerate.There is an emerging consensus that neurons have different intrinsic regenerative capabilities,which theoretically could be manipulated therapeutically to improve regeneration.Population-based comparisons between"good regenerating"and"bad regenerating"neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret.At least in part,this reflects the great diversity of cells in the mammalian CNS.Using mammalian nervous system imposes several methodical limitations.First,the small sizes and large numbers of neurons in the CNS make it very difficult to distinguish regenerating neurons from non-regenerating ones.Second,the lack of identifiable neurons makes it impossible to correlate biochemical changes in a neuron with axonal damage of the same neuron,and therefore,to dissect the molecular mechanisms of regeneration on the level of single neurons.This review will survey the reported responses to axon injury and the determinants of axon regeneration,emphasizing non-mammalian model organisms,which are often under-utilized,but in which the data are especially easy to interpret.展开更多
Injury to central nervous system axons is a common early characteristic of neurodegenerative diseases. Depending on its location and the type of neuron, axon injury often leads to axon degeneration, retrograde neurona...Injury to central nervous system axons is a common early characteristic of neurodegenerative diseases. Depending on its location and the type of neuron, axon injury often leads to axon degeneration, retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. Although these sequential events are clearly connected, ample evidence indicates that neuronal soma and axon degenerations are active autonomous processes with distinct molecular mechanisms. By exploiting the anatomical and techni- cal advantages of the retinal ganglion cell （RGC）/optic nerve （ON） system, we demonstrated that inhibition of the PERK-eIF2a-CHOP pathway and activation of the X-box binding protein 1 pathway synergistically protect RGC soma and axon, and preserve visual function, in both acute ON traumatic injury and chronic glaucomatous neuropathy. The autonomous endoplasmic reticulum （ER） stress pathway in neurons has been implicated in several other neurodegenerative diseases. In addition to the emerging role of ER mor- phology in axon maintenance, we propose that ER stress is a common upstream signal for disturbances in axon integrity, and that it leads to a retrograde signal that can subsequently induce neuronal soma death. Therefore manipulation of the ER stress pathway may be a key step toward developing the effective neuro- protectants that are greatly needed in the clinic.展开更多
Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles o...Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7(which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2(which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation.Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.展开更多
Celiac Disease(CD)had been considered uncommon in Asia for a long time.However,several studies suggested that,in the Indian subcontinent and Middle East countries,CD is present and as prevalent as in Western countries...Celiac Disease(CD)had been considered uncommon in Asia for a long time.However,several studies suggested that,in the Indian subcontinent and Middle East countries,CD is present and as prevalent as in Western countries.Outside these Asian regions,the information about the epidemiology of CD is still lacking or largely incomplete for different and variable reasons.Here,we discuss the epidemiological aspects and the diagnostic barriers in several Asian regions including China,Japan,Southeast Asia and Russia/Central Asia.In some of those regions,especially Russia and Central Asia,the prevalence of CD is very likely to be underestimated.Several factors may,to a different extent,contribute to CD underdiagnosis(and,thus,underestimation of its epidemiological burden),including the poor disease awareness among physicians and/or patients,limited access to diagnostic resources,inappropriate use or interpretation of the serological tests,absence of standardized diagnostic and endoscopic protocols,and insufficient expertise in histopathological interpretation.展开更多
Mucopolysaccharidosis type II （MPS II） is a rare X-linked disorder caused by alterations in the iduronate-2-sulfatase （IDS） gene. In this study, IDS activity in peripheral mononuclear blood monocytes （PMBCs） was...Mucopolysaccharidosis type II （MPS II） is a rare X-linked disorder caused by alterations in the iduronate-2-sulfatase （IDS） gene. In this study, IDS activity in peripheral mononuclear blood monocytes （PMBCs） was measured with a fluorimetric enzyme assay. Urinary glycosaminoglycans （GAGs） were quantified using a colorimetric assay. All IDS exons and intronic flanks were bidirectionally sequenced. A total of 15 mutations （all exonic region） were found in 17 MPS II patients. In this cohort of MPS II patients, all alterations in the IDS gene were caused by point nucleotide substitutions or small deletions. Mutations p.Arg88His and p.Arg172＊ occurred twice. All mu- tations were inherited except for p.Gly489Alafs＊7, a germline mutation. We found four new mutations （p.Ser142Phe, p.Arg233Gly, p.Glu430＊, and p.Ile360Tyrfs＊31）. In Epstein-Barr virus （EBV）-immortalized PMBCs derived from the MPS II patients, no IDS protein was detected in case of the p.Ser142Phe and p.Ile360Tyrfs＊31 mutants. For p.Arg233Gly and p.Glu430＊, we observed a residual expression of IDS. The p.Arg233Gly and p.Glu430＊ mutants had a residuary enzymatic activity that was lowered by 14.3 and 76-fold, respectively, compared with healthy controls. This observation may help explain the mild disease phenotype in MPS II patients who had these two mutations whereas the p.Ser142Phe and p.Ile360Tyrfs＊31 mutations caused the severe disease manifestation.展开更多
Permanent loss of vital functions after central nervous system （CNS） injury, e.g., blindness in traumatic optic nerve （ON） injury or paralysis in spinal cord injury, occurs in part because axons in the adult mamma...Permanent loss of vital functions after central nervous system （CNS） injury, e.g., blindness in traumatic optic nerve （ON） injury or paralysis in spinal cord injury, occurs in part because axons in the adult mammalian CNS do not regenerate after injury. Growth failure is due to the diminished intrinsic regenerative capacity of mature neurons and the inhibitory environment of the adult CNS. Neutralizing extracellular inhibitory molecules genetically or pharmacologically yields only limited regeneration and functional recovery, highlighting the critical importance of neuron-intrinsic factors.展开更多
基金This study was supported by eight educational hospitals in eight provinces of Iran.
文摘Objectives:To evaluate clinical features,treatment strategies,and outcomes of pleural empyema for children who were treated at referral pediatric hospitals in 8 provinces of Iran.Methods:In this retrospective,multicenter cross sectional study,we retrospectively retrieved patients'data from 8 teaching hospitals during 2010 and 2017.A questionnaire was applied and filled,and all data were statistically and descriptively analyzed.Results:In total,191 children(109 males and 82 females)were included.Their mean age was 4.95 years and ranged from 11 months to 16 years.The majority of cases(45.1%)were 1-4 years old.Fever(70.3%),cough(65.6%),tachypnea(53.1%),chest pain(14.6%),and abdominal pain(12%)were the most common manifestations at admission.The mean length of admission in hospital was 16.4 d.Consequently,27 patients(14.1%)were admitted into the pediatric intensive unit because of severe illness,and 15 patients(7.9%)died.Logistic regression analysis showed that younger age(less than 12 months)and presence of underlying diseases(such as cardiovascular disease,immune deficiencies,malignancies,and neuro-developmental delay)significantly increased the mortality rate of patients with pleural empyema(P=0.004 and P=0.001,respectively).Conclusions:Pleural empyema children of younger age and with underlying diseases are at higher risks of death.In addition,guidelines for treating pleural empyema should be developed.
基金supported by the National Key Research and Development Program of China,No.2022YFC2704801(to CZhu)the National Natural Science Foundation of China,Nos.U21A20347(to CZhu),82203969(to YX),82371472(to XZ)+3 种基金Health Commission of Henan Province,Nos.SBGJ202303039(to XZ),SBGJ202301009(to CZhu),YQRC2024018(to XZ),YQRC2024019(to YX)Henan Science and Technology Department,Nos.242102311054(to XZ),241111521300(to CZhu),GZS2023003(to XW)Swedish Research Council,Nos.2022-01019(to CZhu),2021-01950(to XW)Swedish Governmental Grants to Scientists Working in Healthcare,Nos.ALFGBG-1005209(to CZhu),ALFBG-1005257(to XW),ALFGBG-965197(to CZhu).
文摘Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury response,including inflammation and repair.Although colony-stimulating factor 1 receptor inhibitors such as PLX5622 enable the selective depletion of microglia,their therapeutic potential in neonatal germinal matrix hemorrhage remains underexplored.Here,we used a collagenase-induced germinal matrix hemorrhage model in postnatal day 5 mice,and intraperitoneally administered PLX562272 hours post-germinal matrix hemorrhage to achieve targeted,temporary microglial depletion during the peak injury response.We then assessed the effects of this delayed intervention on oligodendrocyte lineage cell maturation,white matter integrity,and neurobehavioral outcomes.Additionally,RNA sequencing data from a germinal matrix hemorrhage rat model were analyzed using weighted gene co-expression network analysis to identify the critical phases for interventions.RNA sequencing data revealed a critical period in which key synaptic functions declined while immune responses intensified post-germinal matrix hemorrhage,thus pinpointing the critical response phases for potential interventions.Delayed PLX5622 treatment effectively depleted activated microglia,protecting against white matter injury and enhancing oligodendrocyte lineage cell maturation and myelination in subcortical white matter regions.Moreover,magnetic resonance imaging analysis revealed reduced brain lesion volumes in treated mice.Behaviorally,PLX5622-treated mice exhibited significant improvements in motor coordination and reduced hyperactivity compared with vehicle-treated germinal matrix hemorrhage model mice.These findings suggest that,when timed to avoid interference with initial oligodendrocyte lineage cell proliferation,targeted microglial depletion with PLX5622 significantly mitigates white matter damage and improves neurobehavioral outcomes in neonatal germinal matrix hemorrhage.The present study highlights the therapeutic potential of selectively modulating microglial reactivity to support neurodevelopment in preterm infants with brain injury.
基金supported in part by NIH R01 NS100531,R01 NS103481NIH R21NS130241(to LD)+3 种基金Merit Review Award I01 BX002356,I01 BX003705 from the U.S.Department of Veterans AffairsIndiana Spinal Cord and Brain Injury Research Foundation(No.19919)Mari Hulman George Endowment Funds(to XMX)Indiana Spinal Cord&Brain Injury Research Fund from ISDH(to NKL and LD)。
文摘Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.
基金supported by the Zhejiang Provincial Nat ural Science Foundation of China(Nos.LZ23C060002 and LZ24H160004)the National Natural Science Foundation of China(Nos.32270746,82203247,82203415,82272637,82204429,and 82073332)+2 种基金the National Key Research and Development Program of China(No.2022YFE0107800)the Medical Interdisciplinary Innovation Program 2024,Zhejiang University School of Medicine,and the Fundamental Research Funds for the Central Universities(No.K20220228)It is add-itionally supported by the National Institute of Health(No.R01-CA200992-03).
文摘Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription,RNA splicing,and protein synthesis.Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers,rendering cyclins and CDKs attractive therapeutic targets.Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use,fueling the development of CDK-targeted therapies.With this enthusiasm for finding novel CDK-targeting anti-cancer agents,there have also been exciting advances in the field of targeted protein degradation through innovative strategies,such as using proteolysis-targeting chimera,heat shock protein 90(HSP90)-mediated targeting chimera,hydrophobic tag-based protein degradation,and molecular glue.With a focus on the translational potential of cyclin-and CDK-targeting strategies in cancer,this review presents the fundamental roles of cyclins and CDKs in cancer.Furthermore,it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs,detailing the underlying mechanisms of action for each approach.A comprehensive overview of the structure and activity of existing CDK degraders is also provided.By examining the structure‒activity relationships,target profiles,and biological effects of reported cyclin/CDK degraders,this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
基金supported by research grants to SL from NIH(1R21NS066114,1R01NS079432 and 1R01EY024575)Christopher&Dana Reeve Foundation(LA1-1002-2)Shriners Research Foundation(86300)
文摘The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate the intrinsic growth capacity in mature neurons. Among them, PI3 kinase/Akt pathway is important for controlling axon elongation. As a negative regulator of this pathway, the tumor suppressor phosphatase and tensin homolog （PTEN） appears critical to con- trol the regenerative ability of young and adult neurons. This review will focus on recent research progress in axon regeneration and neural repair by PTEN inhibition and therapeutic potential of blocking this phosphatase for neurological disorders. Inhibition of PTEN by deletion in con- ditional knockout mice, knockdown by short-hairpin RNA, or blockade by pharmacological approaches, including administration of selective PTEN antagonist peptides, stimulates various degrees of axon regrowth in juvenile or adult rodents with central nervous system injuries. Im- portantly, post-injury PTEN suppression could enhance axonal growth and functional recovery in adult central nervous system after injury.
基金supported by research grants to SL from NIH(1R01NS079432 and 1R01EY024575)Shriners Research Foundation(SHC-86300-PHI,SHC-86200-PHI-16 and SHC-85100)
文摘Reactive astrogliosis occurs after central nervous system（CNS） injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na？ve astrocytes are converted into reactive astrocytes and eventually into scar-forming astrocytes that block axon regeneration and neural repair. It has been known for decades that scarring development and its related extracellular matrix molecules interfere with regeneration of injured axons after CNS injury, but the cellular and molecular mechanisms for controlling astrocytic scar formation and maintenance are not well known. Recent use of various genetic tools has made tremendous progress in better understanding genesis of reactive astrogliosis. Especially, the latest experiments demonstrate environment-dependent plasticity of reactive astrogliosis because reactive astrocytes isolated from injured spinal cord form scarring astrocytes when transplanted into injured spinal cord, but revert in retrograde to naive astrocytes when transplanted into naive spinal cord. The interactions between upregulated type I collagen and its receptor integrin β1 and the N-cadherin-mediated cell adhesion appear to play major roles for local astrogliosis around the lesion. This review centers on the environment-dependent plasticity of reactive astrogliosis after spinal cord injury and its potential as a therapeutic target.
基金supported by NIH grants R01NS97846,R01NS097846-02S1 and R01NS092876 awarded to MESShriners research grant SHC-85400 awarded to MESUSA Pennsylvania State Department grant Project 10:420491-04400-02 to ND。
文摘The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination.Recent studies have shed light on the molecular mechanisms underlying these white matter abnormalities.Rodent models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor cells.Ethanol exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological specimens.Several studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system,including multiple sclerosis and fetal alcohol syndrome.Acute ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues,while ethanol increased the expression of tumor necrosis factor α in mouse and human neurons.White matter lesions have been induced in the developing sheep brain by alcohol exposure in early gestation.Rat fetal alcohol syndrome models have shown reduced axon diameters,with thinner myelin sheaths,as well as reduced numbers of oligodendrocytes,which were also morphologically aberrant oligodendrocytes.Expressions of markers for mature myelination,including myelin basic protein,also were reduced.The accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal development.Future studies using fetal oligodendrocyte-and oligodendrocyte precursor cell-derived exosomes isolated from the mother's blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in adulthood.By combining various imaging modalities with molecular studies,it may be possible to determine which fetuses are at risk and to intervene therapeutically early in the pregnancy.
基金supported by grants R01-NS092876(NIH,to MES)SHC-85400(Shriners Research Foundation,to MES)SHC-85220(Shriners Research Foundation,to MES)
文摘Spinal cord injury leads to persistent behavioral deficits because mammalian central nervous system axons fail to regenerate. A neuron's response to axon injury results from a complex interplay of neuron-intrinsic and environmental factors. The contribution of axotomy to the death of neurons in spinal cord injury is controversial because very remote axotomy is unlikely to result in neuronal death, whereas death of neurons near an injury may reflect environmental factors such as ischemia and inflammation. In lampreys, axotomy due to spinal cord injury results in delayed apoptosis of spinal-projecting neurons in the brain, beyond the extent of these environmental factors. This retrograde apoptosis correlates with delayed resealing of the axon, and can be reversed by inducing rapid membrane resealing with polyethylene glycol. Studies in mammals also suggest that polyethylene glycol may be neuroprotective, although the mechanism(s) remain unclear. This review examines the early, mechanical, responses to axon injury in both mammals and lampreys, and the potential of polyethylene glycol to reduce injury-induced pathology. Identifying the mechanisms underlying a neuron's response to axotomy will potentially reveal new therapeutic targets to enhance regeneration and functional recovery in humans with spinal cord injury.
基金supported by R01-NS092876(NIH,MES,PI)SHC-85400(Shriners Research Foundation,MES,PI)+1 种基金SHC-85220(Shriners Research Foundation,MES,PI)SHC-84293(Shriners Research Foundation,JH,PI)
文摘Paralysis following spinal cord injury （SCI） is due to failure of axonal regeneration. It is believed that the capacities of neurons to regrow their axons are due partly to their intrinsic characteristics, which in turn are greatly influenced by several types of inhibitory molecules that are present, or even increased in the extracellular environment of the injured spinal cord. Many of these inhibitory molecules have been studied extensively in recent years. It has been suggested that the small GTPase RhoA is an intracellular convergence point for signaling by these extracellular inhibitory molecules, but due to the complexity of the central nervous system （CNS） in mammals, and the limitation of pharmacological tools, the specific roles of RhoA are unclear. By exploiting the anatomical and technical advantages of the lamprey CNS, we recently demonstrated that RhoA knockdown promotes true axon regeneration through the lesion site after SCI. In addition, we found that RhoA knockdown protects the large, identified reticulospinal neurons from apoptosis after their axons were axotomized in spinal cord. Therefore, manipulation of the RhoA signaling pathway may be an important approach in the development of treatments that are both neuroprotective and axon regeneration-promoting, to enhance functional recovery after SCI.
基金supported by NIH NS079631,Shriners Hospitals for Children and Craig H.Neilsen Foundation
文摘Have you heard of NG2 cells or NG2 glia or polydendro- cytes~. These are new names for the precursor cells that used to be referred to as oligodendrocyte precursor cells （OPCs）, which become the oligodendrocytes that myelinate central nervous system （CNS） axons. Evidence suggests, however, that they have other functions, besides differentiating into oligodendrocytes. Most notably, the OPCs/NG2 cells are uni- formly distributed in grey matter as well as in white matter, which matches poorly with the distribution of myelinating oligodendrocytes. Furthermore, not every NG2 cell is fated to become an oligodendrocyte. Hence the term OPC can be fairly applied only when discussing the role of these cells in the oligodendrocyte lineage.
基金supported by 85310-PHI Shriners Research Foundation(to MIS)NIH R01 NS092876(to MES)
文摘Some neurons,especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system(CNS)regenerate after axotomy,while most mammalian CNS neurons fail to regenerate.There is an emerging consensus that neurons have different intrinsic regenerative capabilities,which theoretically could be manipulated therapeutically to improve regeneration.Population-based comparisons between"good regenerating"and"bad regenerating"neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret.At least in part,this reflects the great diversity of cells in the mammalian CNS.Using mammalian nervous system imposes several methodical limitations.First,the small sizes and large numbers of neurons in the CNS make it very difficult to distinguish regenerating neurons from non-regenerating ones.Second,the lack of identifiable neurons makes it impossible to correlate biochemical changes in a neuron with axonal damage of the same neuron,and therefore,to dissect the molecular mechanisms of regeneration on the level of single neurons.This review will survey the reported responses to axon injury and the determinants of axon regeneration,emphasizing non-mammalian model organisms,which are often under-utilized,but in which the data are especially easy to interpret.
基金supported by grants from National Eye Institute(R01EY023295,R01EY024932)BrightF ocus Foundation(G2013046)National Multiple Sclerosis Society(RG 5021A1)to YH
文摘Injury to central nervous system axons is a common early characteristic of neurodegenerative diseases. Depending on its location and the type of neuron, axon injury often leads to axon degeneration, retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. Although these sequential events are clearly connected, ample evidence indicates that neuronal soma and axon degenerations are active autonomous processes with distinct molecular mechanisms. By exploiting the anatomical and techni- cal advantages of the retinal ganglion cell （RGC）/optic nerve （ON） system, we demonstrated that inhibition of the PERK-eIF2a-CHOP pathway and activation of the X-box binding protein 1 pathway synergistically protect RGC soma and axon, and preserve visual function, in both acute ON traumatic injury and chronic glaucomatous neuropathy. The autonomous endoplasmic reticulum （ER） stress pathway in neurons has been implicated in several other neurodegenerative diseases. In addition to the emerging role of ER mor- phology in axon maintenance, we propose that ER stress is a common upstream signal for disturbances in axon integrity, and that it leads to a retrograde signal that can subsequently induce neuronal soma death. Therefore manipulation of the ER stress pathway may be a key step toward developing the effective neuro- protectants that are greatly needed in the clinic.
基金supported by grants from the National Institute of Dental and Craniofacial Research, NIH (DE024759, DE026208, DE026509, and DE026767), to J.I.UTHealth School of Dentistry faculty funds to J.I.
文摘Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7(which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2(which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation.Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.
基金Nazarbayev University Faculty Development Competitive Research Grant 2020-2022,No.240919FD3912.
文摘Celiac Disease(CD)had been considered uncommon in Asia for a long time.However,several studies suggested that,in the Indian subcontinent and Middle East countries,CD is present and as prevalent as in Western countries.Outside these Asian regions,the information about the epidemiology of CD is still lacking or largely incomplete for different and variable reasons.Here,we discuss the epidemiological aspects and the diagnostic barriers in several Asian regions including China,Japan,Southeast Asia and Russia/Central Asia.In some of those regions,especially Russia and Central Asia,the prevalence of CD is very likely to be underestimated.Several factors may,to a different extent,contribute to CD underdiagnosis(and,thus,underestimation of its epidemiological burden),including the poor disease awareness among physicians and/or patients,limited access to diagnostic resources,inappropriate use or interpretation of the serological tests,absence of standardized diagnostic and endoscopic protocols,and insufficient expertise in histopathological interpretation.
文摘Mucopolysaccharidosis type II （MPS II） is a rare X-linked disorder caused by alterations in the iduronate-2-sulfatase （IDS） gene. In this study, IDS activity in peripheral mononuclear blood monocytes （PMBCs） was measured with a fluorimetric enzyme assay. Urinary glycosaminoglycans （GAGs） were quantified using a colorimetric assay. All IDS exons and intronic flanks were bidirectionally sequenced. A total of 15 mutations （all exonic region） were found in 17 MPS II patients. In this cohort of MPS II patients, all alterations in the IDS gene were caused by point nucleotide substitutions or small deletions. Mutations p.Arg88His and p.Arg172＊ occurred twice. All mu- tations were inherited except for p.Gly489Alafs＊7, a germline mutation. We found four new mutations （p.Ser142Phe, p.Arg233Gly, p.Glu430＊, and p.Ile360Tyrfs＊31）. In Epstein-Barr virus （EBV）-immortalized PMBCs derived from the MPS II patients, no IDS protein was detected in case of the p.Ser142Phe and p.Ile360Tyrfs＊31 mutants. For p.Arg233Gly and p.Glu430＊, we observed a residual expression of IDS. The p.Arg233Gly and p.Glu430＊ mutants had a residuary enzymatic activity that was lowered by 14.3 and 76-fold, respectively, compared with healthy controls. This observation may help explain the mild disease phenotype in MPS II patients who had these two mutations whereas the p.Ser142Phe and p.Ile360Tyrfs＊31 mutations caused the severe disease manifestation.
基金supported by grants from National Eye Institute,Bright Focus Foundation and Shriners Hospital for Children
文摘Permanent loss of vital functions after central nervous system （CNS） injury, e.g., blindness in traumatic optic nerve （ON） injury or paralysis in spinal cord injury, occurs in part because axons in the adult mammalian CNS do not regenerate after injury. Growth failure is due to the diminished intrinsic regenerative capacity of mature neurons and the inhibitory environment of the adult CNS. Neutralizing extracellular inhibitory molecules genetically or pharmacologically yields only limited regeneration and functional recovery, highlighting the critical importance of neuron-intrinsic factors.
