Spinal cord injury is accompanied by a substantial loss of neurons.Cell replacement therapy improves motor and sensory dysfunction by replacing dead neurons,and endogenous neurogenesis is an important cell replacement...Spinal cord injury is accompanied by a substantial loss of neurons.Cell replacement therapy improves motor and sensory dysfunction by replacing dead neurons,and endogenous neurogenesis is an important cell replacement source.Stimulating endogenous neurogenesis is therefore a viable approach for treating spinal cord injury.Given that basic fibroblast growth factor is a potent inducer of neurogenesis,we developed a sustained-release system of basic fibroblast growth factor-chitosan to enhance tissue repair in spinal cord injury.In the present study,we isolated neural stem cells from the spinal cords of neonatal rats and used single-cell RNA sequencing to trace the complete process of neurogenesis under ex vivo culture conditions.Under the influence of basic fibroblast growth factor-chitosan,neural stem cells were able to transition from a quiescent state to an activated state and subsequently differentiate into neuronal precursor cells and immature neurons.Additionally,basic fibroblast growth factor-chitosan significantly enhanced neural stem cell proliferation in vitro and promoted neuronal generation.Subsequent in vivo experiments confirmed the therapeutic efficacy of basic fibroblast growth factor-chitosan in spinal cord injury,demonstrating enhanced neurogenesis and tissue repair.展开更多
As a promising candidate seed cell type in regenerative medicine,mesenchymal stem cells(MSCs)have attracted considerable attention.The unique capacity of MSCs to exert a regulatory effect on immunity in an autologous/...As a promising candidate seed cell type in regenerative medicine,mesenchymal stem cells(MSCs)have attracted considerable attention.The unique capacity of MSCs to exert a regulatory effect on immunity in an autologous/allergenic manner makes them an attractive therapeutic cell type for immune disorders.In this review,we discussed the current knowledge of and advances in MSCs,including its basic biological properties,i.e.,multilineage differentiation,secretome,and immunomodulation.Specifically,on the basis of our previous work,we proposed three new concepts of MSCs,i.e.,“subtotipotent stem cell”hypothesis,MSC system,and“Yin and Yang”balance of MSC regulation,which may bring new insights into our understanding of MSCs.Furthermore,we analyzed data from the Clinical Trials database(http://clinicaltrials.gov)on registered clinical trials using MSCs to treat a variety of immune diseases,such as graft-versus-host disease,systemic lupus erythematosus,and multiple sclerosis.In addition,we highlighted MSC clinical trials in China and discussed the challenges and future directions in the field of MSC clinical application.展开更多
The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate ne...The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.展开更多
Remembrance activities can support the Culture of Care(CoC)in Laboratory Animal Science(LAS)not only by promoting a culture of respect,gratitude and thankfulness for animal life but also by helping the emotional proce...Remembrance activities can support the Culture of Care(CoC)in Laboratory Animal Science(LAS)not only by promoting a culture of respect,gratitude and thankfulness for animal life but also by helping the emotional processing and healing of lab animal researchers and animal facility staff.Even though remembrance activities are practiced in many parts of the world,we did not come across any reported cases in Sri Lanka before 2022.Therefore,here,we report on the various remembrance activities and practices observed within our local scientific community.展开更多
This study explores whether the current external quality assessment(EQA)level and acceptable bias for basic semen analysis in China are clinically useful.We collected data of semen EQA from Andrology laboratories in t...This study explores whether the current external quality assessment(EQA)level and acceptable bias for basic semen analysis in China are clinically useful.We collected data of semen EQA from Andrology laboratories in the Hunan Province(China)in 2022 and searched for data in the published literature from January2000 to December 2023 in China.On the basis of these data,we analyzed the coefficients of variation and acceptable biases of different quality control materials for basic semen analysis through robust statistics.We compared these findings with quality specifications based on biological variation from optimal,desirable,and minimum levels of bias to seek a unified and more suitable semen EQAbias evaluation standard for China's national conditions.Different sources of semen quality control material exhibited considerable variation in acceptable biases among laboratories,ranging from 8.2%to 56.9%.A total of 50.0% of the laboratories met the minimum quality specifications for progressive motility(PR),whereas 100.0%and 75.0%of laboratories met only the minimum quality specifications for sperm concentration and total motility(nonprogressive[NP]+PR),respectively.The Z value for sperm concentration and PR+NP was equivalent to the desirable performance specification,whereas the Z value for PR was equivalent only to the minimum performance specification.This study highlights the feasibility of operating external quality assessment schemes for basic semen analysis using quality specifications based on biological variation.These specifications should be unified among external quality control(EQC)centers based on biological variation.展开更多
Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesi...Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesics,including opioids and nonsteroidal anti-inflammatory drugs,are often limited by their insufficient efficacy,tolerance,and risk of dependence.Traditional Chinese Medicine(TCM),characterized by its multi-component,multi-target,and systemic regulatory properties,has shown promising potential in cancer pain management.This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain(including nerve infiltration,dysregulation of inflammatory mediators and ion channels,central sensitization,neuro-immune crosstalk,metabolic reprogramming,and gut-brain axis impairment),as well as the analgesic effects of representative TCM agents in cancer pain management.For example,bioactive components such as tetrahydroberberine,levo-tetrahydropalmatine,and piperine exert analgesic effects,thereby improving the quality of life of patients by inhibiting inflammatory cascades,regulating neurotransmitter systems,and preserving neural integrity.Commonly used preclinical models,including bone cancer pain,pancreatic cancer pain,and chemotherapy-induced peripheral neuropathy models,are summarized for their utility in mechanistic studies and efficacy evaluations.This review also discusses the current limitations of clinical evidence,such as small sample sizes,short follow-up periods,and limited translation from animal models,alongside major challenges in standardization,mechanistic elucidation,and clinical trial design.Future directions should focus on precise pain phenotyping,integrated multi-target interventions,rigorous efficacy safety validation,and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.展开更多
Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)mode...Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)models were established by colorectal distention in newborn rats aged 8 to 14 days,and visceral hypersensitivity was assessed using electromyogram(EMG).Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats.The protein expressions of oxytocin receptor(OTR),γ-aminobutyric acid type B1 receptor(GABAB1),and transient receptor potential vanilloid 1(TRPV1)in the lumbosacral spinal cord regions were measured.IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression.Intrathecal oxytocin treatment not only normalized these molecular alterations(increasing GABAB1 while decreasing TRPV1)but also ameliorated visceral pain behaviors.Crucially,this therapeutic effect was fully reversed by GABAB1 inhibition,establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia.Collectively,these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.展开更多
Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles ...Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles in rapid,multiplexed shunting and regulation of sensory signals.This specialized geometry enables separation,filtering,and feedback regulation of neuronal signals,thereby coordinating peripheral and central responses at multiple levels.Recent advances,including spatial transcriptomics,single-cell sequencing,super-resolution microscopy,organoid models,and novel electrophysiological methods,have permitted more precise dissection of the T-junction's molecular composition,ion-channel distribution,and electrophysiological properties.Here,we review current knowledge of the T-junction's developmental regulation and multilayered molecular networks,and we detail its functional alterations in both physiological signaling and pathological pain states,with particular emphasis on ion-channel modulation,signal attenuation,and selective transmission mechanisms.Finally,we discuss contemporary pain-intervention approaches and prospects for precision-targeted therapies,aiming to provide a theoretical foundation for future studies in pain physiology and clinical translation.展开更多
Knee osteoarthritis(KOA)represents one of the most common causes of chronic pain.The high prevalence and disability rates of KOA impose a severe burden on both individuals and society.In contrast to cutaneous pain,KOA...Knee osteoarthritis(KOA)represents one of the most common causes of chronic pain.The high prevalence and disability rates of KOA impose a severe burden on both individuals and society.In contrast to cutaneous pain,KOA-induced joint pain is characterized as a deep tissue pain that potentially involves distinct subgroups of peripheral sensory neurons and central processing mechanisms.Furthermore,KOA pain is closely related to locomotion activity.Impaired sensorimotor integration and pain mutually reinforce each other in KOA,forming a vicious cycle that exacerbates disease progression.In this review,we highlight the key differences between KOA pain and cutaneous pain,and the latter has been extensively studied in the pain field.We hope to offer new insights into the central mechanisms and development of new treatment strategies for KOA based on the interactions between impaired sensorimotor integration and chronic joint pain.展开更多
Neutralizing antibodies are essential tools in antiviral therapy and epidemic preparedness,capable of directlyinhibiting viral entry and limiting disease progression.However,traditional antibody discovery strategies—...Neutralizing antibodies are essential tools in antiviral therapy and epidemic preparedness,capable of directlyinhibiting viral entry and limiting disease progression.However,traditional antibody discovery strategies—suchas animal immunization or B cell isolation from infected individuals—are often hindered by biosafety concerns,lengthy development timelines,and limited adaptability during outbreaks.In the present study,we aimed toestablish a robust and rapid in vitro platform for the efficient isolation of neutralizing antibodies targetingconserved viral epitopes.We developed an epitope-guided negative screening strategy that integrates phagedisplay technology with rational antigen mutagenesis to exclude antibodies against variable regions whileenriching for those that recognize functionally constrained epitopes.When applied to the receptor-binding domainof severe acute respiratory syndrome coronavirus 2,this method enabled the identification of six neutralizingantibodies(one IgG and five nanobodies)exhibiting broad-spectrum neutralizing activity across multiple viralvariants.Notably,antibodies recognizing distinct epitopes demonstrated significant synergistic neutralizationwhen used in combination(P<0.05).This screening approach facilitates the rapid discovery of potent andmutation-resistant antibodies and holds promise for application to other emerging pathogens.Our findingsunderscore the potential of epitope-guided,in vitro platforms in expediting therapeutic antibody developmentunder conditions of high biosafety requirements.展开更多
Neuropathic pain is a complex and debilitating condition caused by lesions or dysfunction within the somatosensory nervous system.Affecting an estimated 7%-10%of the global population,it presents with spontaneous pain...Neuropathic pain is a complex and debilitating condition caused by lesions or dysfunction within the somatosensory nervous system.Affecting an estimated 7%-10%of the global population,it presents with spontaneous pain,hyperalgesia,and allodynia,often accompanied by long-term emotional and cognitive consequences,such as depression and anxiety,which result in a reduced quality of life.Despite extensive research efforts,effective treatments remain limited.This limited efficacy likely stems,in part,from the heterogeneous nature of neuropathic pain,which varies widely across individuals in both clinical presentation and treatment responsiveness.展开更多
Two new linear furocoumarins were isolated from Notopterygium incisum using silica gel,gel Sephadex LH-20 column chromatography,and preparative high-performance liquid chromatography.The structures of the new compound...Two new linear furocoumarins were isolated from Notopterygium incisum using silica gel,gel Sephadex LH-20 column chromatography,and preparative high-performance liquid chromatography.The structures of the new compounds were elucidated through analysis of spectroscopic evidence,including data obtained from high-resolution electrospray ionization mass spectrometry(HRESIMS)and nuclear magnetic resonance(NMR).The absolute configurations of Notoprenylate L(1)and Nototerprinol K(2)were further confirmed using electronic circular dichroism(ECD)calculations.Compound 1 demonstrated the ability to inhibit the expression of nitric oxide(NO),a pro-inflammatory factor,in lipopolysaccharide-induced RAW264.7 macrophages at a concentration of 7.5μmol/L,indicating its potential for anti-inflammatory activity.展开更多
Severe fever with thrombocytopenia syndrome(SFTS),caused by Dabie bandavirus(DBV),triggers aberrant immune activation and cytokine storms,contributing to poor prognosis;however,its immune dysfunction mechanism remains...Severe fever with thrombocytopenia syndrome(SFTS),caused by Dabie bandavirus(DBV),triggers aberrant immune activation and cytokine storms,contributing to poor prognosis;however,its immune dysfunction mechanism remains unclear.Current management relies on symptomatic treatment and glucocorticoids,but no standardized treatment guidelines exist.This study investigated the mechanisms of abnormal lymphocyte function in acute-phase SFTS and the effects of glucocorticoid treatment on lymphoid cells using single-cell RNA sequencing(scRNA-seq)and bioinformatics analysis.We enrolled three healthy volunteers and 13 patients with acute SFTS and divided them into four groups.ScRNA-seq was performed on peripheral blood mononuclear cells from all 16 participants,capturing transcripts from the 3′ends of mRNA.Bioinformatics analyses were used to profile patient immunological signatures,characterize subpopulation compositions,infer developmental trajectories,and assess lymphoid cell interactions.We obtained 120886 lymphoid cells,which were clustered into 23 functionally heterogeneous subsets.Results showed that patients with severe SFTS exhibited stronger inflammatory and adaptive immune responses.Glucocorticoid treatment suppressed inflammation and the interferon response but also inhibited the production of virus-specific antibodies.These findings suggest that appropriate glucocorticoid administration may alleviate the hyperinflammatory state in severe SFTS during the acute phase,although it is not recommended as a conventional treatment because of its potential to suppress antiviral immunity.This study provides insights into SFTS immunopathology and informs the optimized clinical use of glucocorticoids.展开更多
The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitte...The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitter,plays a crucial role in coordinating synapse formation,neuronal proliferation,and migration during this time.展开更多
Objective:To investigate the potential of oral probiotics to improve sperm motility and decrease DNA fragmentation in men diagnosed with asthenozoospermia.Methods:Men diagnosed with asthenozoospermia,aged between 18 a...Objective:To investigate the potential of oral probiotics to improve sperm motility and decrease DNA fragmentation in men diagnosed with asthenozoospermia.Methods:Men diagnosed with asthenozoospermia,aged between 18 and 40 years,were randomly assigned to receive probiotic or placebo for 10 weeks.Sperm parameters(count,motility,and morphology)and seminal fluid biochemical markers were assessed using light microscopy and Diff-Quik staining.Intracellular reactive oxygen species levels were measured using the malondialdehyde(MDA)technique,while DNA fragmentation index(DFI)was evaluated through acidic aniline blue staining.Data from both groups were compared to determine the effects of probiotic supplementation.Results:Sixteen men were included.The probiotic group(n=8)showed a significant increase in total sperm motility(P<0.001)and progressive motility(P=0.003)compared to the placebo group(n=8).Additionally,sperm count in the probiotic group was significantly higher than in the placebo group,although other sperm parameters did not show significant changes.Notably,levels of MDA(P=0.027)and DFI(P=0.004)were significantly reduced in the probiotic group,indicating a decrease in oxidative stress and DNA damage.Conclusions:Probiotic supplementation effectively enhances sperm quality by mitigating oxidative stress and reducing DNA damage,thereby improving sperm motility in men with asthenozoospermia.Study registration:The trial was registered with the Iranian Registry of Clinical Trials(IRCT20220119053769N1).展开更多
As oncologic therapies continue to advance,the overall survival of cancer patients has markedly increased.Nevertheless,virtually every anticancer treatment modality is accompanied by some degree of cardiotoxicity.Epid...As oncologic therapies continue to advance,the overall survival of cancer patients has markedly increased.Nevertheless,virtually every anticancer treatment modality is accompanied by some degree of cardiotoxicity.Epidemiological data indicate that approximately 30%of cancer survivors ultimately die from cardiovascular disease.Among the cardiotoxic agents,the anthracycline doxorubicin(DOX)is the most widely used.It effectively suppresses a variety of malignant tumors——including breast cancer,lymphoma,and acute leukemia——but its cardiac toxicity limits further escalation of clinical dosing.Literature reports identify a cumulative dose of≥250 mg/m²as the threshold of high risk,with roughly 25%of patients receiving DOX developing varying degrees of myocardial injury;severe cases progress to heart failure.Even at cumulative doses below the traditional safety limit,some patients exhibit cardiac dysfunction after the first administration,suggesting that cardiotoxicity is not solely a linear function of dose.DOX related cardiotoxicity can be classified as acute(hours to days after administration),sub acute(weeks to months),and chronic/late onset(years later).Most patients initially exhibit only mild reductions in left ventricular ejection fraction(LVEF)or subtle abnormalities in global longitudinal strain(GLS),often without symptoms.Recently,cardiac biomarkers(cTn,NT proBNP)combined with high sensitivity echocardiography(speckle tracking)have been recommended for monitoring high risk individuals,enabling detection of subclinical injury before overt LVEF decline.Currently,several preventive and therapeutic approaches are used in clinical practice,which can be summarized into the following four points.(1)Dose limitation and administration strategies:fractionated low dose regimens,liposomal encapsulation,or continuous infusion lower peak plasma concentrations,thereby reducing cardiac exposure.(2)Pharmacologic prophylaxis:βblockers(e.g.,carvedilol)and ACE inhibitors/ARBs have shown protective effects on LVEF in some randomized trials,though results remain inconsistent and require larger confirmatory studies.(3)Metabolic targeted interventions:animal experiments indicate that activation of PPARαor supplementation with L carnitine restores fatty acid oxidation and improves ATP generation,suggesting metabolic modulators as promising cardioprotective candidates.(4)Lifestyle modifications:regular aerobic exercise up regulates mitochondrial biogenesis genes(PGC-1α)and reduces reactive oxygen species(ROS)production;small clinical studies have demonstrated a potential benefit in attenuating cTnT elevation.However,DOX-induced cardiotoxicity has not been effectively controlled,indicating that the core mechanism underlying DOX‑related cardiac toxicity remains unidentified.Cardiomyocytes are high energy demand cells,and metabolic dysregulation is considered a central component of DOX induced cardiotoxicity.DOX disrupts myocardial metabolic balance through several interrelated pathways.(1)Oxidative stress and mitochondrial damage:DOX generates abundant ROS within cells,leading to mitochondrial membrane potential loss,lipid peroxidation,and iron accumulation,which suppress electron transport chain activity and markedly reduce ATP synthesis efficiency.(2)Autophagy dysregulation:DOX interferes with autophagic flux,preventing the clearance of damaged mitochondria and further aggravating apoptosis and inflammatory responses.(3)Inflammation and cytokine release:oxidative stress activates NF‑κB,up-regulating pro inflammatory cytokines such as TNF‑αand IL-6,creating a chronic inflammatory microenvironment that weakens myocardial contractility.(4)Epigenetic modifications:studies have shown that DOX alters DNA methylation and histone acetylation patterns in cardiomyocytes,affecting the expression of key metabolic genes(e.g.,PGC-1α,CPT-1)and further inhibiting fatty acidβoxidation.These mechanisms collectively lead to suppressed fatty acid oxidation and compensatory up regulation of glycolysis,manifested by an elevated lactate/pyruvate ratio,accumulation of medium chain acyl carnitines,and a pronounced decline in ATP production.The resulting energy deficit precipitates left ventricular contractile dysfunction and,ultimately,heart failure.Despite extensive basic and clinical research on DOX cardiotoxicity,a unified risk assessment model and precise interventions targeting metabolic disturbances remain lacking.This review systematically summarizes recent progress on DOX induced cardiotoxicity and highlights that impairment of myocardial energy metabolism is a central mechanism of injury,thereby deepened our understanding of how impaired myocardial energy metabolism drives DOX induced injury,we can move toward safer chemotherapy protocols that achieve“cure cancer without harming the heart”.展开更多
Neuromorphic circuits based on superconducting tunnel junctions have attracted much attention due to their highspeed computing capabilities and low energy consumption.Josephson junction circuits can effectively mimic ...Neuromorphic circuits based on superconducting tunnel junctions have attracted much attention due to their highspeed computing capabilities and low energy consumption.Josephson junction circuits can effectively mimic biological neural dynamics.Leveraging these advantages,we construct a Josephson junction neuron-like model with a phasedependent dissipative current,referred to as a memristive current.The proposed memristive Josephson junction model exhibits complex dynamical behaviors.Furthermore,considering the effect of a fast-modulated synapse,we explore synchronization phenomena in coupled networks under varying coupling conductances and excitatory/inhibitory interactions.Finally,we extend the neuromorphic Josephson junction model—exhibiting complex dynamics—to the field of image encryption.These results not only enrich the understanding of the dynamical characteristics of memristive Josephson junctions but also provide a theoretical basis and technical support for the development of new neural networks and their applications in information security technology.展开更多
AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in vario...AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.展开更多
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271403(to XL),82272171(to ZY),31730030(to XL),81941011(to XL),31971279(to ZY)the Natural Science Foundation of Beijing,No.7222004(to HD).
文摘Spinal cord injury is accompanied by a substantial loss of neurons.Cell replacement therapy improves motor and sensory dysfunction by replacing dead neurons,and endogenous neurogenesis is an important cell replacement source.Stimulating endogenous neurogenesis is therefore a viable approach for treating spinal cord injury.Given that basic fibroblast growth factor is a potent inducer of neurogenesis,we developed a sustained-release system of basic fibroblast growth factor-chitosan to enhance tissue repair in spinal cord injury.In the present study,we isolated neural stem cells from the spinal cords of neonatal rats and used single-cell RNA sequencing to trace the complete process of neurogenesis under ex vivo culture conditions.Under the influence of basic fibroblast growth factor-chitosan,neural stem cells were able to transition from a quiescent state to an activated state and subsequently differentiate into neuronal precursor cells and immature neurons.Additionally,basic fibroblast growth factor-chitosan significantly enhanced neural stem cell proliferation in vitro and promoted neuronal generation.Subsequent in vivo experiments confirmed the therapeutic efficacy of basic fibroblast growth factor-chitosan in spinal cord injury,demonstrating enhanced neurogenesis and tissue repair.
基金the Key Program for Beijing Municipal Natural Science Foundation(No.7141006)National Collaborative Innovation Program(for Biotherapy)+2 种基金Beijing Science and Technology Project(No.Z151100001615-063)National Key Research and Development Program(Nos.2016YFA0101000 and 2016YFA0101003)PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(No.3332013141).
文摘As a promising candidate seed cell type in regenerative medicine,mesenchymal stem cells(MSCs)have attracted considerable attention.The unique capacity of MSCs to exert a regulatory effect on immunity in an autologous/allergenic manner makes them an attractive therapeutic cell type for immune disorders.In this review,we discussed the current knowledge of and advances in MSCs,including its basic biological properties,i.e.,multilineage differentiation,secretome,and immunomodulation.Specifically,on the basis of our previous work,we proposed three new concepts of MSCs,i.e.,“subtotipotent stem cell”hypothesis,MSC system,and“Yin and Yang”balance of MSC regulation,which may bring new insights into our understanding of MSCs.Furthermore,we analyzed data from the Clinical Trials database(http://clinicaltrials.gov)on registered clinical trials using MSCs to treat a variety of immune diseases,such as graft-versus-host disease,systemic lupus erythematosus,and multiple sclerosis.In addition,we highlighted MSC clinical trials in China and discussed the challenges and future directions in the field of MSC clinical application.
基金supported by the National Natural Science Foundation of China,Nos.82272171(to ZY),82271403(to XL),81941011(to XL),31971279(to ZY),31730030(to XL)the Natural Science Foundation of Beijing,No.7222004(to HD).
文摘The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.
文摘Remembrance activities can support the Culture of Care(CoC)in Laboratory Animal Science(LAS)not only by promoting a culture of respect,gratitude and thankfulness for animal life but also by helping the emotional processing and healing of lab animal researchers and animal facility staff.Even though remembrance activities are practiced in many parts of the world,we did not come across any reported cases in Sri Lanka before 2022.Therefore,here,we report on the various remembrance activities and practices observed within our local scientific community.
基金supported by the Hunan Province Municipal Natural Science Foundation(2022JJ30018)the Hunan Province Health Commission Science Foundation(B202301037899)to WNL。
文摘This study explores whether the current external quality assessment(EQA)level and acceptable bias for basic semen analysis in China are clinically useful.We collected data of semen EQA from Andrology laboratories in the Hunan Province(China)in 2022 and searched for data in the published literature from January2000 to December 2023 in China.On the basis of these data,we analyzed the coefficients of variation and acceptable biases of different quality control materials for basic semen analysis through robust statistics.We compared these findings with quality specifications based on biological variation from optimal,desirable,and minimum levels of bias to seek a unified and more suitable semen EQAbias evaluation standard for China's national conditions.Different sources of semen quality control material exhibited considerable variation in acceptable biases among laboratories,ranging from 8.2%to 56.9%.A total of 50.0% of the laboratories met the minimum quality specifications for progressive motility(PR),whereas 100.0%and 75.0%of laboratories met only the minimum quality specifications for sperm concentration and total motility(nonprogressive[NP]+PR),respectively.The Z value for sperm concentration and PR+NP was equivalent to the desirable performance specification,whereas the Z value for PR was equivalent only to the minimum performance specification.This study highlights the feasibility of operating external quality assessment schemes for basic semen analysis using quality specifications based on biological variation.These specifications should be unified among external quality control(EQC)centers based on biological variation.
基金supported by the National Natural Science Foundation of China(No.82360238,82071245)。
文摘Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesics,including opioids and nonsteroidal anti-inflammatory drugs,are often limited by their insufficient efficacy,tolerance,and risk of dependence.Traditional Chinese Medicine(TCM),characterized by its multi-component,multi-target,and systemic regulatory properties,has shown promising potential in cancer pain management.This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain(including nerve infiltration,dysregulation of inflammatory mediators and ion channels,central sensitization,neuro-immune crosstalk,metabolic reprogramming,and gut-brain axis impairment),as well as the analgesic effects of representative TCM agents in cancer pain management.For example,bioactive components such as tetrahydroberberine,levo-tetrahydropalmatine,and piperine exert analgesic effects,thereby improving the quality of life of patients by inhibiting inflammatory cascades,regulating neurotransmitter systems,and preserving neural integrity.Commonly used preclinical models,including bone cancer pain,pancreatic cancer pain,and chemotherapy-induced peripheral neuropathy models,are summarized for their utility in mechanistic studies and efficacy evaluations.This review also discusses the current limitations of clinical evidence,such as small sample sizes,short follow-up periods,and limited translation from animal models,alongside major challenges in standardization,mechanistic elucidation,and clinical trial design.Future directions should focus on precise pain phenotyping,integrated multi-target interventions,rigorous efficacy safety validation,and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.
基金supported by the National Natural Science Foundation of China(No.82471229)Science and Technology Collaborative Innovation Fund of Fujian Province(No.2021Y9172)the Natural Science Foundation of Fujian Province,China(No.2023J01169)。
文摘Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)models were established by colorectal distention in newborn rats aged 8 to 14 days,and visceral hypersensitivity was assessed using electromyogram(EMG).Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats.The protein expressions of oxytocin receptor(OTR),γ-aminobutyric acid type B1 receptor(GABAB1),and transient receptor potential vanilloid 1(TRPV1)in the lumbosacral spinal cord regions were measured.IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression.Intrathecal oxytocin treatment not only normalized these molecular alterations(increasing GABAB1 while decreasing TRPV1)but also ameliorated visceral pain behaviors.Crucially,this therapeutic effect was fully reversed by GABAB1 inhibition,establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia.Collectively,these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.
基金supported by grant from the National Key Technology Support Program of the Ministry of Science and Technology of China(No.2021ZD0203204)。
文摘Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles in rapid,multiplexed shunting and regulation of sensory signals.This specialized geometry enables separation,filtering,and feedback regulation of neuronal signals,thereby coordinating peripheral and central responses at multiple levels.Recent advances,including spatial transcriptomics,single-cell sequencing,super-resolution microscopy,organoid models,and novel electrophysiological methods,have permitted more precise dissection of the T-junction's molecular composition,ion-channel distribution,and electrophysiological properties.Here,we review current knowledge of the T-junction's developmental regulation and multilayered molecular networks,and we detail its functional alterations in both physiological signaling and pathological pain states,with particular emphasis on ion-channel modulation,signal attenuation,and selective transmission mechanisms.Finally,we discuss contemporary pain-intervention approaches and prospects for precision-targeted therapies,aiming to provide a theoretical foundation for future studies in pain physiology and clinical translation.
基金supported by the Natural Science Foundation of Beijing Municipality(No.F252065)the National Natural Science Foundation of China(No.32271190,32571323)the STI 2030 Major Project(No.2021ZD0203202)。
文摘Knee osteoarthritis(KOA)represents one of the most common causes of chronic pain.The high prevalence and disability rates of KOA impose a severe burden on both individuals and society.In contrast to cutaneous pain,KOA-induced joint pain is characterized as a deep tissue pain that potentially involves distinct subgroups of peripheral sensory neurons and central processing mechanisms.Furthermore,KOA pain is closely related to locomotion activity.Impaired sensorimotor integration and pain mutually reinforce each other in KOA,forming a vicious cycle that exacerbates disease progression.In this review,we highlight the key differences between KOA pain and cutaneous pain,and the latter has been extensively studied in the pain field.We hope to offer new insights into the central mechanisms and development of new treatment strategies for KOA based on the interactions between impaired sensorimotor integration and chronic joint pain.
基金supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.22KJB310001 to W.G.)the Special Project of the Jiangsu Provincial Department of Science and Technology(Grant No.BE2023603 to W.G.)the Nanjing Medical University Science and Technology Development Foundation(Grant No.NMUB20210006 to W.G.).
文摘Neutralizing antibodies are essential tools in antiviral therapy and epidemic preparedness,capable of directlyinhibiting viral entry and limiting disease progression.However,traditional antibody discovery strategies—suchas animal immunization or B cell isolation from infected individuals—are often hindered by biosafety concerns,lengthy development timelines,and limited adaptability during outbreaks.In the present study,we aimed toestablish a robust and rapid in vitro platform for the efficient isolation of neutralizing antibodies targetingconserved viral epitopes.We developed an epitope-guided negative screening strategy that integrates phagedisplay technology with rational antigen mutagenesis to exclude antibodies against variable regions whileenriching for those that recognize functionally constrained epitopes.When applied to the receptor-binding domainof severe acute respiratory syndrome coronavirus 2,this method enabled the identification of six neutralizingantibodies(one IgG and five nanobodies)exhibiting broad-spectrum neutralizing activity across multiple viralvariants.Notably,antibodies recognizing distinct epitopes demonstrated significant synergistic neutralizationwhen used in combination(P<0.05).This screening approach facilitates the rapid discovery of potent andmutation-resistant antibodies and holds promise for application to other emerging pathogens.Our findingsunderscore the potential of epitope-guided,in vitro platforms in expediting therapeutic antibody developmentunder conditions of high biosafety requirements.
基金Institute for Basic Science(IBS)Center for Cognition and Sociality(IBS-R001-D2 to BL).
文摘Neuropathic pain is a complex and debilitating condition caused by lesions or dysfunction within the somatosensory nervous system.Affecting an estimated 7%-10%of the global population,it presents with spontaneous pain,hyperalgesia,and allodynia,often accompanied by long-term emotional and cognitive consequences,such as depression and anxiety,which result in a reduced quality of life.Despite extensive research efforts,effective treatments remain limited.This limited efficacy likely stems,in part,from the heterogeneous nature of neuropathic pain,which varies widely across individuals in both clinical presentation and treatment responsiveness.
文摘Two new linear furocoumarins were isolated from Notopterygium incisum using silica gel,gel Sephadex LH-20 column chromatography,and preparative high-performance liquid chromatography.The structures of the new compounds were elucidated through analysis of spectroscopic evidence,including data obtained from high-resolution electrospray ionization mass spectrometry(HRESIMS)and nuclear magnetic resonance(NMR).The absolute configurations of Notoprenylate L(1)and Nototerprinol K(2)were further confirmed using electronic circular dichroism(ECD)calculations.Compound 1 demonstrated the ability to inhibit the expression of nitric oxide(NO),a pro-inflammatory factor,in lipopolysaccharide-induced RAW264.7 macrophages at a concentration of 7.5μmol/L,indicating its potential for anti-inflammatory activity.
基金supported by the National Natural Science Foundation of China(Grant No.81871242)the"YiQi"Fund Project(Grant Nos.2024YQZL01 and 2023YQFH05)the National Key Research and Development Program of China(Grant No.2022YFF0710100).
文摘Severe fever with thrombocytopenia syndrome(SFTS),caused by Dabie bandavirus(DBV),triggers aberrant immune activation and cytokine storms,contributing to poor prognosis;however,its immune dysfunction mechanism remains unclear.Current management relies on symptomatic treatment and glucocorticoids,but no standardized treatment guidelines exist.This study investigated the mechanisms of abnormal lymphocyte function in acute-phase SFTS and the effects of glucocorticoid treatment on lymphoid cells using single-cell RNA sequencing(scRNA-seq)and bioinformatics analysis.We enrolled three healthy volunteers and 13 patients with acute SFTS and divided them into four groups.ScRNA-seq was performed on peripheral blood mononuclear cells from all 16 participants,capturing transcripts from the 3′ends of mRNA.Bioinformatics analyses were used to profile patient immunological signatures,characterize subpopulation compositions,infer developmental trajectories,and assess lymphoid cell interactions.We obtained 120886 lymphoid cells,which were clustered into 23 functionally heterogeneous subsets.Results showed that patients with severe SFTS exhibited stronger inflammatory and adaptive immune responses.Glucocorticoid treatment suppressed inflammation and the interferon response but also inhibited the production of virus-specific antibodies.These findings suggest that appropriate glucocorticoid administration may alleviate the hyperinflammatory state in severe SFTS during the acute phase,although it is not recommended as a conventional treatment because of its potential to suppress antiviral immunity.This study provides insights into SFTS immunopathology and informs the optimized clinical use of glucocorticoids.
基金supported by the Center for Cognition and Sociality,Institute for Basic Science(IBS)(IBS-R001-D2)(to WK).
文摘The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitter,plays a crucial role in coordinating synapse formation,neuronal proliferation,and migration during this time.
基金supported by Kashan University of Medical Science,Kashan,Iran(Grant No.40001).
文摘Objective:To investigate the potential of oral probiotics to improve sperm motility and decrease DNA fragmentation in men diagnosed with asthenozoospermia.Methods:Men diagnosed with asthenozoospermia,aged between 18 and 40 years,were randomly assigned to receive probiotic or placebo for 10 weeks.Sperm parameters(count,motility,and morphology)and seminal fluid biochemical markers were assessed using light microscopy and Diff-Quik staining.Intracellular reactive oxygen species levels were measured using the malondialdehyde(MDA)technique,while DNA fragmentation index(DFI)was evaluated through acidic aniline blue staining.Data from both groups were compared to determine the effects of probiotic supplementation.Results:Sixteen men were included.The probiotic group(n=8)showed a significant increase in total sperm motility(P<0.001)and progressive motility(P=0.003)compared to the placebo group(n=8).Additionally,sperm count in the probiotic group was significantly higher than in the placebo group,although other sperm parameters did not show significant changes.Notably,levels of MDA(P=0.027)and DFI(P=0.004)were significantly reduced in the probiotic group,indicating a decrease in oxidative stress and DNA damage.Conclusions:Probiotic supplementation effectively enhances sperm quality by mitigating oxidative stress and reducing DNA damage,thereby improving sperm motility in men with asthenozoospermia.Study registration:The trial was registered with the Iranian Registry of Clinical Trials(IRCT20220119053769N1).
基金supported by grants from the Applied Basic Research Foundation of Yunnan Province(202301AT070095)the Candidate Talents Training Fund of Yunnan Province(H-2024069)。
文摘As oncologic therapies continue to advance,the overall survival of cancer patients has markedly increased.Nevertheless,virtually every anticancer treatment modality is accompanied by some degree of cardiotoxicity.Epidemiological data indicate that approximately 30%of cancer survivors ultimately die from cardiovascular disease.Among the cardiotoxic agents,the anthracycline doxorubicin(DOX)is the most widely used.It effectively suppresses a variety of malignant tumors——including breast cancer,lymphoma,and acute leukemia——but its cardiac toxicity limits further escalation of clinical dosing.Literature reports identify a cumulative dose of≥250 mg/m²as the threshold of high risk,with roughly 25%of patients receiving DOX developing varying degrees of myocardial injury;severe cases progress to heart failure.Even at cumulative doses below the traditional safety limit,some patients exhibit cardiac dysfunction after the first administration,suggesting that cardiotoxicity is not solely a linear function of dose.DOX related cardiotoxicity can be classified as acute(hours to days after administration),sub acute(weeks to months),and chronic/late onset(years later).Most patients initially exhibit only mild reductions in left ventricular ejection fraction(LVEF)or subtle abnormalities in global longitudinal strain(GLS),often without symptoms.Recently,cardiac biomarkers(cTn,NT proBNP)combined with high sensitivity echocardiography(speckle tracking)have been recommended for monitoring high risk individuals,enabling detection of subclinical injury before overt LVEF decline.Currently,several preventive and therapeutic approaches are used in clinical practice,which can be summarized into the following four points.(1)Dose limitation and administration strategies:fractionated low dose regimens,liposomal encapsulation,or continuous infusion lower peak plasma concentrations,thereby reducing cardiac exposure.(2)Pharmacologic prophylaxis:βblockers(e.g.,carvedilol)and ACE inhibitors/ARBs have shown protective effects on LVEF in some randomized trials,though results remain inconsistent and require larger confirmatory studies.(3)Metabolic targeted interventions:animal experiments indicate that activation of PPARαor supplementation with L carnitine restores fatty acid oxidation and improves ATP generation,suggesting metabolic modulators as promising cardioprotective candidates.(4)Lifestyle modifications:regular aerobic exercise up regulates mitochondrial biogenesis genes(PGC-1α)and reduces reactive oxygen species(ROS)production;small clinical studies have demonstrated a potential benefit in attenuating cTnT elevation.However,DOX-induced cardiotoxicity has not been effectively controlled,indicating that the core mechanism underlying DOX‑related cardiac toxicity remains unidentified.Cardiomyocytes are high energy demand cells,and metabolic dysregulation is considered a central component of DOX induced cardiotoxicity.DOX disrupts myocardial metabolic balance through several interrelated pathways.(1)Oxidative stress and mitochondrial damage:DOX generates abundant ROS within cells,leading to mitochondrial membrane potential loss,lipid peroxidation,and iron accumulation,which suppress electron transport chain activity and markedly reduce ATP synthesis efficiency.(2)Autophagy dysregulation:DOX interferes with autophagic flux,preventing the clearance of damaged mitochondria and further aggravating apoptosis and inflammatory responses.(3)Inflammation and cytokine release:oxidative stress activates NF‑κB,up-regulating pro inflammatory cytokines such as TNF‑αand IL-6,creating a chronic inflammatory microenvironment that weakens myocardial contractility.(4)Epigenetic modifications:studies have shown that DOX alters DNA methylation and histone acetylation patterns in cardiomyocytes,affecting the expression of key metabolic genes(e.g.,PGC-1α,CPT-1)and further inhibiting fatty acidβoxidation.These mechanisms collectively lead to suppressed fatty acid oxidation and compensatory up regulation of glycolysis,manifested by an elevated lactate/pyruvate ratio,accumulation of medium chain acyl carnitines,and a pronounced decline in ATP production.The resulting energy deficit precipitates left ventricular contractile dysfunction and,ultimately,heart failure.Despite extensive basic and clinical research on DOX cardiotoxicity,a unified risk assessment model and precise interventions targeting metabolic disturbances remain lacking.This review systematically summarizes recent progress on DOX induced cardiotoxicity and highlights that impairment of myocardial energy metabolism is a central mechanism of injury,thereby deepened our understanding of how impaired myocardial energy metabolism drives DOX induced injury,we can move toward safer chemotherapy protocols that achieve“cure cancer without harming the heart”.
基金supported by the National Natural Science Foundation of China(Grant No.12302070)the Natural Science Foundation of Ningxia(Grant No.2024AAC05002)+1 种基金the Youth Science and Technology Talent Cultivation Project of Ningxiathe Ningxia Science and Technology Leading Talent Training Program(Grant No.2022GKLRLX04)。
文摘Neuromorphic circuits based on superconducting tunnel junctions have attracted much attention due to their highspeed computing capabilities and low energy consumption.Josephson junction circuits can effectively mimic biological neural dynamics.Leveraging these advantages,we construct a Josephson junction neuron-like model with a phasedependent dissipative current,referred to as a memristive current.The proposed memristive Josephson junction model exhibits complex dynamical behaviors.Furthermore,considering the effect of a fast-modulated synapse,we explore synchronization phenomena in coupled networks under varying coupling conductances and excitatory/inhibitory interactions.Finally,we extend the neuromorphic Josephson junction model—exhibiting complex dynamics—to the field of image encryption.These results not only enrich the understanding of the dynamical characteristics of memristive Josephson junctions but also provide a theoretical basis and technical support for the development of new neural networks and their applications in information security technology.
基金supported by the National Natural Science Foundation of China,Nos.81870921(to YW),81974179(to ZZ),82271320(to ZZ),82071284(to YT)National Key R&D Program of China,No.2022YFA1603600(to ZZ),2019YFA0112000(to YT)+1 种基金Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY)Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY).
文摘AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
