Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe n...Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.展开更多
We previously demonstrated that inhibiting neural stem cells necroptosis enhances functional recovery after spinal cord injury.While exosomes are recognized as playing a pivotal role in neural stem cells exocrine func...We previously demonstrated that inhibiting neural stem cells necroptosis enhances functional recovery after spinal cord injury.While exosomes are recognized as playing a pivotal role in neural stem cells exocrine function,their precise function in spinal cord injury remains unclear.To investigate the role of exosomes generated following neural stem cells necroptosis after spinal cord injury,we conducted singlecell RNA sequencing and validated that neural stem cells originate from ependymal cells and undergo necroptosis in response to spinal cord injury.Subsequently,we established an in vitro necroptosis model using neural stem cells isolated from embryonic mice aged 16-17 days and extracted exosomes.The results showed that necroptosis did not significantly impact the fundamental characteristics or number of exosomes.Transcriptome sequencing of exosomes in necroptosis group identified 108 differentially expressed messenger RNAs,104 long non-coding RNAs,720 circular RNAs,and 14 microRNAs compared with the control group.Construction of a competing endogenous RNA network identified the following hub genes:tuberous sclerosis 2(Tsc2),solute carrier family 16 member 3(Slc16a3),and forkhead box protein P1(Foxp1).Notably,a significant elevation in TSC2 expression was observed in spinal cord tissues following spinal cord injury.TSC2-positive cells were localized around SRY-box transcription factor 2-positive cells within the injury zone.Furthermore,in vitro analysis revealed increased TSC2 expression in exosomal receptor cells compared with other cells.Further assessment of cellular communication following spinal cord injury showed that Tsc2 was involved in ependymal cellular communication at 1 and 3 days post-injury through the epidermal growth factor and midkine signaling pathways.In addition,Slc16a3 participated in cellular communication in ependymal cells at 7 days post-injury via the vascular endothelial growth factor and macrophage migration inhibitory factor signaling pathways.Collectively,these findings confirm that exosomes derived from neural stem cells undergoing necroptosis play an important role in cellular communication after spinal cord injury and induce TSC2 upregulation in recipient cells.展开更多
Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that ...Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.展开更多
Active ingredients from highland barley have received considerable attention as natural products for developing treatments and dietary supplements against obesity.In practical application,the research of food combinat...Active ingredients from highland barley have received considerable attention as natural products for developing treatments and dietary supplements against obesity.In practical application,the research of food combinations is more significant than a specific food component.This study investigated the lipid-lowering effect of highland barley polyphenols via lipase assay in vitro and HepG2 cells induced by oleic acid(OA).Five indexes,triglyceride(TG),total cholesterol(T-CHO),low density lipoprotein-cholesterol(LDL-C),aspartate aminotransferase(AST),and alanine aminotransferase(ALT),were used to evaluate the lipidlowering effect of highland barley extract.We also preliminary studied the lipid-lowering mechanism by Realtime fluorescent quantitative polymerase chain reaction(q PCR).The results indicated that highland barley extract contains many components with lipid-lowering effects,such as hyperoside and scoparone.In vitro,the lipase assay showed an 18.4%lipase inhibition rate when the additive contents of highland barley extract were 100μg/m L.The intracellular lipid-lowering effect of highland barley extract was examined using 0.25 mmol/L OA-induced HepG2 cells.The results showed that intracellular TG,LDL-C,and T-CHO content decreased by 34.4%,51.2%,and 18.4%,respectively.ALT and AST decreased by 51.6%and 20.7%compared with the untreated hyperlipidemic HepG2 cells.q PCR results showed that highland barley polyphenols could up-regulation the expression of lipid metabolism-related genes such as PPARγand Fabp4.展开更多
The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the bloo...The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases.展开更多
Infection caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2)virus,responsible for the coronavirus disease 2019(COVID-19)pandemic,induces symptoms including increased inflammatory response,severe ...Infection caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2)virus,responsible for the coronavirus disease 2019(COVID-19)pandemic,induces symptoms including increased inflammatory response,severe acute respiratory syndrome(SARS),cognitive dysfunction like brain fog,and cardiovascular defects.Long-term effects of SARS-CoV2 COVID-19 syndrome referred to as post-COVID-19 syndrome on age-related progressive neurodegenerative disorders such as Alzheimer's disease remain understudied.Using the targeted misexpression of individual SARS-CoV2 proteins in the retinal neurons of the Drosophila melanogaster eye,we found that misexpression of nonstructural protein 3(Nsp3),a papain-like protease,ablates the eye and generates dark necrotic spots.Targeted misexpression of Nsp3 in the eye triggers reactive oxygen species production and leads to apoptosis as shown by cell death reporters,terminal deoxynucleotidyl transferase(TdT)dUTP Nick-end labeling(TUNEL)assay,and dihydroethidium staining.Furthermore,Nsp3 misexpression activates both apoptosis and autophagy mechanism(s)to regulate tissue homeostasis.Transient expression of SARS-CoV2 Nsp3 in murine neuroblastoma,Neuro-2a cells,significantly reduced the metabolic activity of these cells and triggers cell death.Misexpression of SARS-CoV2 Nsp3 in an Alzheimer's disease transgenic fly eye model(glass multiple repeats[GMR]>amyloidβ42)further enhances the neurodegenerative rough eye phenotype due to increased cell death.These findings suggest that SARS-CoV2 utilizes Nsp3 protein to potentiate cell death response in a neurodegenerative disease background that has high pre-existing levels of neuroinflammation and cell death.展开更多
Runx2 is a major regulator of osteoblast differentiation and function;however,the role of Runx2 in peripheral nerve repair is unclea r.Here,we analyzed Runx2expression following injury and found that it was specifical...Runx2 is a major regulator of osteoblast differentiation and function;however,the role of Runx2 in peripheral nerve repair is unclea r.Here,we analyzed Runx2expression following injury and found that it was specifically up-regulated in Schwann cells.Furthermore,using Schwann cell-specific Runx2 knocko ut mice,we studied peripheral nerve development and regeneration and found that multiple steps in the regeneration process following sciatic nerve injury were Runx2-dependent.Changes observed in Runx2 knoc kout mice include increased prolife ration of Schwann cells,impaired Schwann cell migration and axonal regrowth,reduced re-myelination of axo ns,and a block in macrophage clearance in the late stage of regeneration.Taken together,our findings indicate that Runx2 is a key regulator of Schwann cell plasticity,and therefore peripheral nerve repair.Thus,our study shows that Runx2 plays a major role in Schwann cell migration,re-myelination,and peripheral nerve functional recovery following injury.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82071307(to HL),82271362(to HL),82171294(to JW),82371303(to JW),and 82301460(to PX)the Natural Science Foundation of Jiangsu Province,No.BK20211552(to HL)+1 种基金Suzhou Medical Technology Innovation Project-Clinical Frontier,No.SKY2022002(to ZY)the Science and Education Foundation for Health of Suzhou for Youth,No.KJXW2023001(to XL)。
文摘Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.
基金supported by the National Natural Science Foundation of China,No.81801907(to NC)Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research,No.ZDSYS20230626091402006(to NC)+2 种基金Sanming Project of Medicine in Shenzhen,No.SZSM201911002(to SL)Foundation of Shenzhen Committee for Science and Technology Innovation,Nos.JCYJ20230807110310021(to NC),JCYJ20230807110259002(to JL)Science and Technology Program of Guangzhou,No.2024A04J4716(to TL)。
文摘We previously demonstrated that inhibiting neural stem cells necroptosis enhances functional recovery after spinal cord injury.While exosomes are recognized as playing a pivotal role in neural stem cells exocrine function,their precise function in spinal cord injury remains unclear.To investigate the role of exosomes generated following neural stem cells necroptosis after spinal cord injury,we conducted singlecell RNA sequencing and validated that neural stem cells originate from ependymal cells and undergo necroptosis in response to spinal cord injury.Subsequently,we established an in vitro necroptosis model using neural stem cells isolated from embryonic mice aged 16-17 days and extracted exosomes.The results showed that necroptosis did not significantly impact the fundamental characteristics or number of exosomes.Transcriptome sequencing of exosomes in necroptosis group identified 108 differentially expressed messenger RNAs,104 long non-coding RNAs,720 circular RNAs,and 14 microRNAs compared with the control group.Construction of a competing endogenous RNA network identified the following hub genes:tuberous sclerosis 2(Tsc2),solute carrier family 16 member 3(Slc16a3),and forkhead box protein P1(Foxp1).Notably,a significant elevation in TSC2 expression was observed in spinal cord tissues following spinal cord injury.TSC2-positive cells were localized around SRY-box transcription factor 2-positive cells within the injury zone.Furthermore,in vitro analysis revealed increased TSC2 expression in exosomal receptor cells compared with other cells.Further assessment of cellular communication following spinal cord injury showed that Tsc2 was involved in ependymal cellular communication at 1 and 3 days post-injury through the epidermal growth factor and midkine signaling pathways.In addition,Slc16a3 participated in cellular communication in ependymal cells at 7 days post-injury via the vascular endothelial growth factor and macrophage migration inhibitory factor signaling pathways.Collectively,these findings confirm that exosomes derived from neural stem cells undergoing necroptosis play an important role in cellular communication after spinal cord injury and induce TSC2 upregulation in recipient cells.
基金financially supported by the National Natural Science Foundation of China,Nos.82172104(to CX),81873767(to HZ)a grant from Jiangsu Provincial Research Hospital,Nos.YJXYY202204(to HZ),YJXYY202204-ZD04(to HZ)+5 种基金a grant from Jiangsu Provincial Key Medical CenterJiangsu Provincial Medical Innovation Center,No.CXZX202212Jiangsu Provincial Medical Key Discipline,No.ZDXK202240the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Technology Project of Nantong,No.MS22022008(to HZ)Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.SJCX21_1457(to WW)。
文摘Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.
基金financially supported by the National Key Research and Development Program of China(2021YFD2100904)the National Natural Science Foundation of China(31871729,32172147)+2 种基金the Modern Agriculture key Project of Jiangsu Province of China(BE2022317)the Modern Agricultural Industrial Technology System Construction Project of Jiangsu Province of China(JATS[2021]522)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)。
文摘Active ingredients from highland barley have received considerable attention as natural products for developing treatments and dietary supplements against obesity.In practical application,the research of food combinations is more significant than a specific food component.This study investigated the lipid-lowering effect of highland barley polyphenols via lipase assay in vitro and HepG2 cells induced by oleic acid(OA).Five indexes,triglyceride(TG),total cholesterol(T-CHO),low density lipoprotein-cholesterol(LDL-C),aspartate aminotransferase(AST),and alanine aminotransferase(ALT),were used to evaluate the lipidlowering effect of highland barley extract.We also preliminary studied the lipid-lowering mechanism by Realtime fluorescent quantitative polymerase chain reaction(q PCR).The results indicated that highland barley extract contains many components with lipid-lowering effects,such as hyperoside and scoparone.In vitro,the lipase assay showed an 18.4%lipase inhibition rate when the additive contents of highland barley extract were 100μg/m L.The intracellular lipid-lowering effect of highland barley extract was examined using 0.25 mmol/L OA-induced HepG2 cells.The results showed that intracellular TG,LDL-C,and T-CHO content decreased by 34.4%,51.2%,and 18.4%,respectively.ALT and AST decreased by 51.6%and 20.7%compared with the untreated hyperlipidemic HepG2 cells.q PCR results showed that highland barley polyphenols could up-regulation the expression of lipid metabolism-related genes such as PPARγand Fabp4.
基金supported by the National Natural Science Foundation of China,No.82104412(to TD)Shaanxi Provincial Key R&D Program,No.2023-YBSF-165(to TD)+1 种基金the Natural Science Foundation of Shaanxi Department of Science and Technology,No.2018JM7022(to FM)Shaanxi Provincial Key Industry Chain Project,No.2021ZDLSF04-11(to PW)。
文摘The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases.
基金supported by 1RO1EY032959-01 from NIHSchuellein Chair Endowment FundSTEM Catalyst Grant from the University of Dayton(all to AS)。
文摘Infection caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2)virus,responsible for the coronavirus disease 2019(COVID-19)pandemic,induces symptoms including increased inflammatory response,severe acute respiratory syndrome(SARS),cognitive dysfunction like brain fog,and cardiovascular defects.Long-term effects of SARS-CoV2 COVID-19 syndrome referred to as post-COVID-19 syndrome on age-related progressive neurodegenerative disorders such as Alzheimer's disease remain understudied.Using the targeted misexpression of individual SARS-CoV2 proteins in the retinal neurons of the Drosophila melanogaster eye,we found that misexpression of nonstructural protein 3(Nsp3),a papain-like protease,ablates the eye and generates dark necrotic spots.Targeted misexpression of Nsp3 in the eye triggers reactive oxygen species production and leads to apoptosis as shown by cell death reporters,terminal deoxynucleotidyl transferase(TdT)dUTP Nick-end labeling(TUNEL)assay,and dihydroethidium staining.Furthermore,Nsp3 misexpression activates both apoptosis and autophagy mechanism(s)to regulate tissue homeostasis.Transient expression of SARS-CoV2 Nsp3 in murine neuroblastoma,Neuro-2a cells,significantly reduced the metabolic activity of these cells and triggers cell death.Misexpression of SARS-CoV2 Nsp3 in an Alzheimer's disease transgenic fly eye model(glass multiple repeats[GMR]>amyloidβ42)further enhances the neurodegenerative rough eye phenotype due to increased cell death.These findings suggest that SARS-CoV2 utilizes Nsp3 protein to potentiate cell death response in a neurodegenerative disease background that has high pre-existing levels of neuroinflammation and cell death.
基金supported by the National Natural Science Foundation of China,No.82104795 (to RH)。
文摘Runx2 is a major regulator of osteoblast differentiation and function;however,the role of Runx2 in peripheral nerve repair is unclea r.Here,we analyzed Runx2expression following injury and found that it was specifically up-regulated in Schwann cells.Furthermore,using Schwann cell-specific Runx2 knocko ut mice,we studied peripheral nerve development and regeneration and found that multiple steps in the regeneration process following sciatic nerve injury were Runx2-dependent.Changes observed in Runx2 knoc kout mice include increased prolife ration of Schwann cells,impaired Schwann cell migration and axonal regrowth,reduced re-myelination of axo ns,and a block in macrophage clearance in the late stage of regeneration.Taken together,our findings indicate that Runx2 is a key regulator of Schwann cell plasticity,and therefore peripheral nerve repair.Thus,our study shows that Runx2 plays a major role in Schwann cell migration,re-myelination,and peripheral nerve functional recovery following injury.
