Coagulation factor Ⅷ and antithrombin Ⅲ activity were detected in 15 health donors. It was found that antithrombin Ⅲ activity decreased obviously 12 h after blood drawing. It lost 56 % of the activity at the 3rd ...Coagulation factor Ⅷ and antithrombin Ⅲ activity were detected in 15 health donors. It was found that antithrombin Ⅲ activity decreased obviously 12 h after blood drawing. It lost 56 % of the activity at the 3rd day, and 70 % of the activity at the 7th day. FⅧ:c showed no obvious change after 24 h, until the 3rd day. It lost 40 %-60 % of the activity after 36 h and was reduced to the 30 % of the original activity at the 5th day. Our results suggested that at the 3rd day coagulation factor Ⅷ of bank stored blood can be used to replenish antithrombin Ⅲ, while bank stored blood in one day can be used to replenish FⅧ.展开更多
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 y...Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently regeneration.However,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive.In this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.展开更多
Brain-derived neurotrophic factor is a crucial neurotrophic factor that plays a significant role in brain health. Although the vast majority of meta-analyses have confirmed that exercise interventions can increase bra...Brain-derived neurotrophic factor is a crucial neurotrophic factor that plays a significant role in brain health. Although the vast majority of meta-analyses have confirmed that exercise interventions can increase brain-derived neurotrophic factor levels in children and adolescents, the effects of specific types of exercise on brain-derived neurotrophic factor levels are still controversial. To address this issue, we used meta-analytic methods to quantitatively evaluate, analyze, and integrate relevant studies. Our goals were to formulate general conclusions regarding the use of exercise interventions, explore the physiological mechanisms by which exercise improves brain health and cognitive ability in children and adolescents, and provide a reliable foundation for follow-up research. We used the Pub Med, Web of Science, Science Direct, Springer, Wiley Online Library, Weipu, Wanfang, and China National Knowledge Infrastructure databases to search for randomized controlled trials examining the influences of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents. The extracted data were analyzed using Review Manager 5.3. According to the inclusion criteria, we assessed randomized controlled trials in which the samples were mainly children and adolescents, and the outcome indicators were measured before and after the intervention. We excluded animal experiments, studies that lacked a control group, and those that did not report quantitative results. The mean difference(MD;before versus after intervention) was used to evaluate the effect of exercise on brain-derived neurotrophic factor levels in children and adolescents. Overall, 531 participants(60 children and 471 adolescents, 10.9–16.1 years) were included from 13 randomized controlled trials. Heterogeneity was evaluated using the Q statistic and I^(2) test provided by Review Manager software. The meta-analysis showed that there was no heterogeneity among the studies(P = 0.67, I^(2) = 0.00%). The combined effect of the interventions was significant(MD = 2.88, 95% CI: 1.53–4.22, P < 0.0001), indicating that the brain-derived neurotrophic factor levels of the children and adolescents in the exercise group were significantly higher than those in the control group. In conclusion, different types of exercise interventions significantly increased brain-derived neurotrophic factor levels in children and adolescents. However, because of the small sample size of this meta-analysis, more high-quality research is needed to verify our conclusions. This metaanalysis was registered at PROSPERO(registration ID: CRD42023439408).展开更多
After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact...After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.展开更多
Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecu...Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.展开更多
During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their el...During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.展开更多
Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report...Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.展开更多
Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progre...Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progression and survival. MFG-E8 contains a signal sequence for secretion, two epidermal growth factor(EGF)-like domains at the NH2 terminus and two discoidin domains with blood-clotting factor V/factor Ⅷ(C1 and C2) at the COOH terminus. The second EGF domain contains an arginine-glycine-aspartic(RGD) integrin-binding motif that engages α_vβ_5 integrins to facilitate cell adhesion and induce integrinmediated signal transduction. Integrin α_vβ_3 associates with VEGF receptor 2, engagement of integrins can promote angiogenesis, which plays key roles in growth, proliferation, and survival of cancer cells. VEGF stimulates the expression of α_vβ_3 and α_vβ_5 integrins on angiogenic vasculature, thereby potentiating effects of VEGF receptor engagement. Mice expressing a mutant form of α_vβ_3 integrin are unable to undergo tyrosine phosphorylation, confirming the important role that this integrin plays in pathological angiogenesis and providing important mechanistic insights. The C-terminus discoidin-like domains promote binding to membrane phospholipids, functioning close to VEGF like angiogenesis. MFG-E8 is an opsonin for apoptotic cells, and it acts as a bridging protein between apoptotic cells and phagocytes. It also influences cell immunities by altering CD4^+ and/or CD8^+ cells. Antibody or small peptide works with MFG-E8 at different functional sites or interacts with EGF-like domains and/or discoidin-like domains may play an important role in anti-angiogenesis or immune restoration. Altering the structures and/or functions of MFG-E8 and/or its domains is promising for development of novel anti-cancer strategies.展开更多
Hemophilia A is caused by a genetic mutation in coagulation factor VIII （FVIII） gene and gene therapy is considered to be a promising strategy for its treatment. We recently demonstrated that co-delivery of two vect...Hemophilia A is caused by a genetic mutation in coagulation factor VIII （FVIII） gene and gene therapy is considered to be a promising strategy for its treatment. We recently demonstrated that co-delivery of two vectors expressing M662C mutated heavy and D1828C mutated light chain genes of B-domain-deleted coagulation factor VIII （BDD-FVIII） leads to inter-chain disulfide cross-linking and improved heavy chain secretion in vitro. In this study, co-injection of both M662C and D1828C mutated BDD-FVIII gene expression vectors into mice resulted in increased heavy chain secretion and coagulation activity in plasma in vivo. Approximately （239＋_56） ng mL-1 above endogenous levels of transgenic FVIII heavy chain was found in mouse plasma using a chain-specific ELISA. For FVIII coagulation activity, approximately （1.09＋_0.25） IU mL-1 above en- dogenous levels were detected in co-injected transgenic mouse plasma using a chromogenic assay. These data demonstrate that inter-chain disulfide bonds likely increase heavy chain secretion and coagulation activity in the plasma of transgenic mice with an improved efficacy of a dual-vector delivery of BDD-FVIII gene. These findings support our ongoing efforts to develop a gene therapy for hemophilia A treatment using dual-AAV vectors.展开更多
BACKGROUND Intensive care unit-acquired weakness(ICU-AW)is a common complication that significantly impacts the patient's recovery process,even leading to adverse outcomes.Currently,there is a lack of effective pr...BACKGROUND Intensive care unit-acquired weakness(ICU-AW)is a common complication that significantly impacts the patient's recovery process,even leading to adverse outcomes.Currently,there is a lack of effective preventive measures.AIM To identify significant risk factors for ICU-AW through iterative machine learning techniques and offer recommendations for its prevention and treatment.METHODS Patients were categorized into ICU-AW and non-ICU-AW groups on the 14th day post-ICU admission.Relevant data from the initial 14 d of ICU stay,such as age,comorbidities,sedative dosage,vasopressor dosage,duration of mechanical ventilation,length of ICU stay,and rehabilitation therapy,were gathered.The relationships between these variables and ICU-AW were examined.Utilizing iterative machine learning techniques,a multilayer perceptron neural network model was developed,and its predictive performance for ICU-AW was assessed using the receiver operating characteristic curve.RESULTS Within the ICU-AW group,age,duration of mechanical ventilation,lorazepam dosage,adrenaline dosage,and length of ICU stay were significantly higher than in the non-ICU-AW group.Additionally,sepsis,multiple organ dysfunction syndrome,hypoalbuminemia,acute heart failure,respiratory failure,acute kidney injury,anemia,stress-related gastrointestinal bleeding,shock,hypertension,coronary artery disease,malignant tumors,and rehabilitation therapy ratios were significantly higher in the ICU-AW group,demonstrating statistical significance.The most influential factors contributing to ICU-AW were identified as the length of ICU stay(100.0%)and the duration of mechanical ventilation(54.9%).The neural network model predicted ICU-AW with an area under the curve of 0.941,sensitivity of 92.2%,and specificity of 82.7%.CONCLUSION The main factors influencing ICU-AW are the length of ICU stay and the duration of mechanical ventilation.A primary preventive strategy,when feasible,involves minimizing both ICU stay and mechanical ventilation duration.展开更多
Objective Hemophilia A,an X-linked bleeding disorder,affecting 1 in 5 000 males is caused by heterogeneous mutations in factor Ⅷ gene.Inversion mutation in intron 22 of F8C gene remains its leading cause.The aim of t...Objective Hemophilia A,an X-linked bleeding disorder,affecting 1 in 5 000 males is caused by heterogeneous mutations in factor Ⅷ gene.Inversion mutation in intron 22 of F8C gene remains its leading cause.The aim of this study was to evaluate the frequency and distribution of the intron 22-inversion mutation in the patients and in the family members in the region.Methods 29 hemophilia A patients from Jammu and Kashmir(20 severe,8 moderate and 1 mild) were analyzed for intron 22-inversion mutation.Results 11(38%) were positive for the distal type of inversion mutation.The mutation was found in 9/20(45%) patients with severe factor Ⅷ deficiency and 2/8(25%) with moderate severity hemophilia A,whereas the patient with mild hemophilia A was found to be negative for inversion mutation.Evaluation of twenty-six female relatives from 11 families of inversion mutation positive patients identified one mother and one sister from one family to be the carrier,suggesting its origin in the mother. Conclusion The present study confirms the intron-22 inversion mutation in F8C gene as the major cause of hemophilia A in the population from Jammu and Kashmir with a higher frequency of inversion mutation in sporadic cases compared to the familial cases.展开更多
Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,an...Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.展开更多
AIM:To explore the effects of hepatocyte growth factor(HGF)on retinal pigment epithelium(RPE)cell behaviors.METHODS:The human adult retinal pigment epithelial cell line-19(ARPE-19)were treated by HGF or mesenchymalepi...AIM:To explore the effects of hepatocyte growth factor(HGF)on retinal pigment epithelium(RPE)cell behaviors.METHODS:The human adult retinal pigment epithelial cell line-19(ARPE-19)were treated by HGF or mesenchymalepithelial transition factor(MET)inhibitor SU11274 in vitro.Cell viability was detected by a Cell Counting Kit-8 assay.Cell proliferation and motility was detected by a bromodeoxyuridine incorporation assay and a wound healing assay,respectively.The expression levels of MET,phosphorylated MET,protein kinase B(AKT),and phosphorylated AKT proteins were determined by Western blot assay.The MET and phosphorylated MET proteins were also determined by immunofluorescence assay.RESULTS:HGF increased ARPE-19 cells’viability,proliferation and migration,and induced an increase of phosphorylated MET and phosphorylated AKT proteins.SU11274 significantly reduced cell viability,proliferation,and migration and decreased the expression of MET and AKT proteins.SU11274 suppressed HGF-induced increase of viability,proliferation,and migration in ARPE-19 cells.Additionally,SU11274 also blocked HGF-induced phosphorylation of MET and AKT proteins.CONCLUSION:HGF enhances cellular viability,proliferation,and migration in RPE cells through the MET/AKT signaling pathway,whereas this enhancement is suppressed by the MET inhibitor SU11274.HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival.展开更多
文摘Coagulation factor Ⅷ and antithrombin Ⅲ activity were detected in 15 health donors. It was found that antithrombin Ⅲ activity decreased obviously 12 h after blood drawing. It lost 56 % of the activity at the 3rd day, and 70 % of the activity at the 7th day. FⅧ:c showed no obvious change after 24 h, until the 3rd day. It lost 40 %-60 % of the activity after 36 h and was reduced to the 30 % of the original activity at the 5th day. Our results suggested that at the 3rd day coagulation factor Ⅷ of bank stored blood can be used to replenish antithrombin Ⅲ, while bank stored blood in one day can be used to replenish FⅧ.
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
基金supported by National Health and Medical Research Council GNT1105374,GNT1137645,GNT2000766 and veski Innovation Fellowship(VIF23)to RP.
文摘Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently regeneration.However,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive.In this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.
基金supported by the STI 2030-Major Projects,No. 2021ZD0200500 (to XS)。
文摘Brain-derived neurotrophic factor is a crucial neurotrophic factor that plays a significant role in brain health. Although the vast majority of meta-analyses have confirmed that exercise interventions can increase brain-derived neurotrophic factor levels in children and adolescents, the effects of specific types of exercise on brain-derived neurotrophic factor levels are still controversial. To address this issue, we used meta-analytic methods to quantitatively evaluate, analyze, and integrate relevant studies. Our goals were to formulate general conclusions regarding the use of exercise interventions, explore the physiological mechanisms by which exercise improves brain health and cognitive ability in children and adolescents, and provide a reliable foundation for follow-up research. We used the Pub Med, Web of Science, Science Direct, Springer, Wiley Online Library, Weipu, Wanfang, and China National Knowledge Infrastructure databases to search for randomized controlled trials examining the influences of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents. The extracted data were analyzed using Review Manager 5.3. According to the inclusion criteria, we assessed randomized controlled trials in which the samples were mainly children and adolescents, and the outcome indicators were measured before and after the intervention. We excluded animal experiments, studies that lacked a control group, and those that did not report quantitative results. The mean difference(MD;before versus after intervention) was used to evaluate the effect of exercise on brain-derived neurotrophic factor levels in children and adolescents. Overall, 531 participants(60 children and 471 adolescents, 10.9–16.1 years) were included from 13 randomized controlled trials. Heterogeneity was evaluated using the Q statistic and I^(2) test provided by Review Manager software. The meta-analysis showed that there was no heterogeneity among the studies(P = 0.67, I^(2) = 0.00%). The combined effect of the interventions was significant(MD = 2.88, 95% CI: 1.53–4.22, P < 0.0001), indicating that the brain-derived neurotrophic factor levels of the children and adolescents in the exercise group were significantly higher than those in the control group. In conclusion, different types of exercise interventions significantly increased brain-derived neurotrophic factor levels in children and adolescents. However, because of the small sample size of this meta-analysis, more high-quality research is needed to verify our conclusions. This metaanalysis was registered at PROSPERO(registration ID: CRD42023439408).
基金supported by European Regional Development Funds RE0022527 ZEBRATOX(EU-Région Réunion-French State national counterpart,to Nicolas Diotel and Jean-Loup Bascands).
文摘After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.
基金supported by the Start-up Fund for new faculty from the Hong Kong Polytechnic University(PolyU)(A0043215)(to SA)the General Research Fund and Research Impact Fund from the Hong Kong Research Grants Council(15106018,R5032-18)(to DYT)+1 种基金the Research Center for SHARP Vision in PolyU(P0045843)(to SA)the InnoHK scheme from the Hong Kong Special Administrative Region Government(to DYT).
文摘Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.
基金supported by Catalan Government,Nos.2014SGR344(to JT),2017SGR704(to JT),2021SGR01214(to MAL)MCIN/AEI/10.13039/501100011033/by“ERDF A way of making Europe,”Nos.SAF2015-67143(to JT),PID2019-106332GB-I00(to JT and MAL)and PID2022-141252NB-I00(to MAL).
文摘During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.
基金supported by the National Natural Science Foundation of China,Nos.82171429,81771384a grant from Wuxi Municipal Health Commission,No.1286010241190480(all to YS)。
文摘Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.
基金Supported by a grant from Medical Technology Research Center for Health Development of China National Health and Family Planning Commission(No.W2012FZ007)
文摘Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progression and survival. MFG-E8 contains a signal sequence for secretion, two epidermal growth factor(EGF)-like domains at the NH2 terminus and two discoidin domains with blood-clotting factor V/factor Ⅷ(C1 and C2) at the COOH terminus. The second EGF domain contains an arginine-glycine-aspartic(RGD) integrin-binding motif that engages α_vβ_5 integrins to facilitate cell adhesion and induce integrinmediated signal transduction. Integrin α_vβ_3 associates with VEGF receptor 2, engagement of integrins can promote angiogenesis, which plays key roles in growth, proliferation, and survival of cancer cells. VEGF stimulates the expression of α_vβ_3 and α_vβ_5 integrins on angiogenic vasculature, thereby potentiating effects of VEGF receptor engagement. Mice expressing a mutant form of α_vβ_3 integrin are unable to undergo tyrosine phosphorylation, confirming the important role that this integrin plays in pathological angiogenesis and providing important mechanistic insights. The C-terminus discoidin-like domains promote binding to membrane phospholipids, functioning close to VEGF like angiogenesis. MFG-E8 is an opsonin for apoptotic cells, and it acts as a bridging protein between apoptotic cells and phagocytes. It also influences cell immunities by altering CD4^+ and/or CD8^+ cells. Antibody or small peptide works with MFG-E8 at different functional sites or interacts with EGF-like domains and/or discoidin-like domains may play an important role in anti-angiogenesis or immune restoration. Altering the structures and/or functions of MFG-E8 and/or its domains is promising for development of novel anti-cancer strategies.
基金supported by the Natural Science Foundation of Shandong Province,China(Grant No.ZR2010CM061)the Scientific Research Foundation from Ministry of Education for Returned Overseas Chinese Scholars(Grant No.20071108)
文摘Hemophilia A is caused by a genetic mutation in coagulation factor VIII （FVIII） gene and gene therapy is considered to be a promising strategy for its treatment. We recently demonstrated that co-delivery of two vectors expressing M662C mutated heavy and D1828C mutated light chain genes of B-domain-deleted coagulation factor VIII （BDD-FVIII） leads to inter-chain disulfide cross-linking and improved heavy chain secretion in vitro. In this study, co-injection of both M662C and D1828C mutated BDD-FVIII gene expression vectors into mice resulted in increased heavy chain secretion and coagulation activity in plasma in vivo. Approximately （239＋_56） ng mL-1 above endogenous levels of transgenic FVIII heavy chain was found in mouse plasma using a chain-specific ELISA. For FVIII coagulation activity, approximately （1.09＋_0.25） IU mL-1 above en- dogenous levels were detected in co-injected transgenic mouse plasma using a chromogenic assay. These data demonstrate that inter-chain disulfide bonds likely increase heavy chain secretion and coagulation activity in the plasma of transgenic mice with an improved efficacy of a dual-vector delivery of BDD-FVIII gene. These findings support our ongoing efforts to develop a gene therapy for hemophilia A treatment using dual-AAV vectors.
基金Supported by Science and Technology Support Program of Qiandongnan Prefecture,No.Qiandongnan Sci-Tech Support[2021]12Guizhou Province High-Level Innovative Talent Training Program,No.Qiannan Thousand Talents[2022]201701.
文摘BACKGROUND Intensive care unit-acquired weakness(ICU-AW)is a common complication that significantly impacts the patient's recovery process,even leading to adverse outcomes.Currently,there is a lack of effective preventive measures.AIM To identify significant risk factors for ICU-AW through iterative machine learning techniques and offer recommendations for its prevention and treatment.METHODS Patients were categorized into ICU-AW and non-ICU-AW groups on the 14th day post-ICU admission.Relevant data from the initial 14 d of ICU stay,such as age,comorbidities,sedative dosage,vasopressor dosage,duration of mechanical ventilation,length of ICU stay,and rehabilitation therapy,were gathered.The relationships between these variables and ICU-AW were examined.Utilizing iterative machine learning techniques,a multilayer perceptron neural network model was developed,and its predictive performance for ICU-AW was assessed using the receiver operating characteristic curve.RESULTS Within the ICU-AW group,age,duration of mechanical ventilation,lorazepam dosage,adrenaline dosage,and length of ICU stay were significantly higher than in the non-ICU-AW group.Additionally,sepsis,multiple organ dysfunction syndrome,hypoalbuminemia,acute heart failure,respiratory failure,acute kidney injury,anemia,stress-related gastrointestinal bleeding,shock,hypertension,coronary artery disease,malignant tumors,and rehabilitation therapy ratios were significantly higher in the ICU-AW group,demonstrating statistical significance.The most influential factors contributing to ICU-AW were identified as the length of ICU stay(100.0%)and the duration of mechanical ventilation(54.9%).The neural network model predicted ICU-AW with an area under the curve of 0.941,sensitivity of 92.2%,and specificity of 82.7%.CONCLUSION The main factors influencing ICU-AW are the length of ICU stay and the duration of mechanical ventilation.A primary preventive strategy,when feasible,involves minimizing both ICU stay and mechanical ventilation duration.
文摘Objective Hemophilia A,an X-linked bleeding disorder,affecting 1 in 5 000 males is caused by heterogeneous mutations in factor Ⅷ gene.Inversion mutation in intron 22 of F8C gene remains its leading cause.The aim of this study was to evaluate the frequency and distribution of the intron 22-inversion mutation in the patients and in the family members in the region.Methods 29 hemophilia A patients from Jammu and Kashmir(20 severe,8 moderate and 1 mild) were analyzed for intron 22-inversion mutation.Results 11(38%) were positive for the distal type of inversion mutation.The mutation was found in 9/20(45%) patients with severe factor Ⅷ deficiency and 2/8(25%) with moderate severity hemophilia A,whereas the patient with mild hemophilia A was found to be negative for inversion mutation.Evaluation of twenty-six female relatives from 11 families of inversion mutation positive patients identified one mother and one sister from one family to be the carrier,suggesting its origin in the mother. Conclusion The present study confirms the intron-22 inversion mutation in F8C gene as the major cause of hemophilia A in the population from Jammu and Kashmir with a higher frequency of inversion mutation in sporadic cases compared to the familial cases.
文摘Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.
基金the Natural Science Foundation of Shaanxi Province(No.2022JM-521)the Science and Technology Plan Project of Xi’an(No.21YXYJ0031).
文摘AIM:To explore the effects of hepatocyte growth factor(HGF)on retinal pigment epithelium(RPE)cell behaviors.METHODS:The human adult retinal pigment epithelial cell line-19(ARPE-19)were treated by HGF or mesenchymalepithelial transition factor(MET)inhibitor SU11274 in vitro.Cell viability was detected by a Cell Counting Kit-8 assay.Cell proliferation and motility was detected by a bromodeoxyuridine incorporation assay and a wound healing assay,respectively.The expression levels of MET,phosphorylated MET,protein kinase B(AKT),and phosphorylated AKT proteins were determined by Western blot assay.The MET and phosphorylated MET proteins were also determined by immunofluorescence assay.RESULTS:HGF increased ARPE-19 cells’viability,proliferation and migration,and induced an increase of phosphorylated MET and phosphorylated AKT proteins.SU11274 significantly reduced cell viability,proliferation,and migration and decreased the expression of MET and AKT proteins.SU11274 suppressed HGF-induced increase of viability,proliferation,and migration in ARPE-19 cells.Additionally,SU11274 also blocked HGF-induced phosphorylation of MET and AKT proteins.CONCLUSION:HGF enhances cellular viability,proliferation,and migration in RPE cells through the MET/AKT signaling pathway,whereas this enhancement is suppressed by the MET inhibitor SU11274.HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival.
