We have previously shown the success of polyethylene glycol fusion repair of segmental-loss peripheral nerve injuries in rats using freshly harvested,viable peripheral nerve allografts that can conduct action potentia...We have previously shown the success of polyethylene glycol fusion repair of segmental-loss peripheral nerve injuries in rats using freshly harvested,viable peripheral nerve allografts that can conduct action potentials.Because clinical application of polyethylene glycol fusion with viable peripheral nerve allografts demands pre-transplant donor tissue storage,we developed a protocol for ex vivo storage of rat sciatic nerves as viable peripheral nerve allografts,preserving many axons for up to 5 days.The current study evaluated the in vivo use of these stored viable peripheral nerve allografts.We hypothesized that stored viable peripheral nerve allografts with viable axons would enable successful in vivo repair of segmental-loss peripheral nerve injuries via polyethylene glycol-fusion.Polyethylene glycol-fused viable peripheral nerve allografts were classified as successful if they produced significantly improved locomotor recovery,as evaluated by the sciatic functional index,within 8 weeks post-repair.Many Sprague-Dawley and Lewis rats with successfully polyethylene glycol-fused viable peripheral nerve allografts had significantly improved sciatic functional index scores beginning at 5 weeks post-operatively.There was no significant difference in the efficiency and extent of successful polyethylene glycol fusion between stored and freshly harvested viable peripheral nerve allografts.In contrast,rats with non-fused negative control viable peripheral nerve allografts showed no recovery by 8 weeks post-operatively.Additional confirmatory outcome measures included in vivo compound action potentials and assessments of axon morphometry.These results suggest that viable peripheral nerve allografts can be stored and later used for successful polyethylene glycol fusion repair of segmental-loss peripheral nerve injuries.展开更多
The gut microbiota:The human body is colonized by a diverse and complex microbial community–including bacteria,viruses,archaea,and unicellular eukaryotes–that plays a central role in human wellbeing.Indeed,microbiot...The gut microbiota:The human body is colonized by a diverse and complex microbial community–including bacteria,viruses,archaea,and unicellular eukaryotes–that plays a central role in human wellbeing.Indeed,microbiota is crucial for several functions,including host metabolism,physiology,maintenance of the intestinal epithelial integrity,nutrition,and immune function,earning it the designation of a“vital organ”(Guinane and Cotter,2013).展开更多
Peripheral sensory neurons perceive external signals and convey signals to the central nervous system(CNS).Information transmission occurs via often extremely long axons and timely reactions of the animal require a fa...Peripheral sensory neurons perceive external signals and convey signals to the central nervous system(CNS).Information transmission occurs via often extremely long axons and timely reactions of the animal require a fast conductance velocity.This not only depends on axonal diameter and insulation by glial processes,but it requires the structural integrity of the axon.展开更多
The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral bloo...The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain.The discovery that all tissues,including the brain,release extracellular vesicles(Raposo and Stoorvogel,2013)and cell free DNAs(Chan et al.,2013)into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system(CNS)and has given rise to the term“liquid biopsy.”The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative.The ability to predict episodic events such as mania,depression,and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes.Additionally,biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects.展开更多
Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages.Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and m...Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages.Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and myelin during Wallerian degeneration,which is a prerequisite for nerve regeneration,we hypothesized that microRNA-301a regulates Wallerian degeneration and nerve regeneration via impacts on Schwann cell migration and phagocytosis.Herein,we found low expression of microRNA-301a in intact sciatic nerves,with no impact of the microRNA-301a knockout on nerve structure and function.By contrast,we found significant upregulation of microRNA-301a in injured sciatic nerves.We established a sciatic nerve crush model in microRNA-301a knockout mice,which exhibited attenua9ted morphological and functional regeneration following sciatic nerve crush injury.The microRNA-301a knockout also led to significantly inhibited Wallerian degeneration in an in vivo sciatic nerve-transection model and in an in vitro nerve explant block model.Schwann cells with the microRNA-301a knockout showed inhibition of phagocytosis and migration,which was reversible under transfection with microRNA-301a mimics.Rescue experiments involving transfection of microRNA-301a-knockout Schwann cells with microRNA-301a mimics or treatment with the C-X-C motif receptor 4 inhibitor WZ811 indicated the mechanistic involvement of the Yin Yang 1/C-X-C motif receptor 4 pathway in the role of microRNA-301a.Combined with our previous findings in macrophages,we conclude that microRNA-301a plays a key role in peripheral nerve injury and repair by regulating the migratory and phagocytic capabilities of Schwann cells and macrophages via the Yin Yang 1/C-X-C motif receptor 4 pathway.展开更多
AIM:To evaluate the clinical features,diagnosis,treatment,and outcome of peripheral exudative hemorrhagic chorioretinopathy(PEHCR),a variant of polypoidal choroidal vasculopathy(PCV),in a case series of Chinese patien...AIM:To evaluate the clinical features,diagnosis,treatment,and outcome of peripheral exudative hemorrhagic chorioretinopathy(PEHCR),a variant of polypoidal choroidal vasculopathy(PCV),in a case series of Chinese patients.METHODS:This study was retrospectively conducted from September 2018 to March 2025.Clinical examinations included color fundus photography,B-scan ultrasonography,fluorescein angiography(FA),indocyanine green angiography(ICGA),swept-source optical coherence tomography(SS-OCT),and optical coherence tomography angiography(OCTA),and two active or inactive subgroups and misdiagnosed cases were analyzed.RESULTS:Totally 19 patients(21 eyes)with a mean age of 54.3±9.4(range,36–68)y were included,with a majority of women(n=13,68.4%).The mean follow-up period was 13±1.4(range:1–57)mo.Decreased visual acuity was the most frequent initial manifestation(17 eyes,84.2%),and lesions were mainly distributed in the inferotemporal or temporal quadrant(14 eyes,66.7%),with choroidal polyps and branching neovascular networks revealed by OCTA and ICGA.Nine patients had been previously misdiagnosed with choroidal melanoma,and 6 of them had massive vitreous hemorrhage(VH).PEHCR manifested along a spectrum ranging from active or inactive subretinal hemorrhagic forms to chronic fibrotic or atrophic forms.One patient experienced natural regression.Ten eyes received a mean of 4.7±1.1(range:3–7)intravitreal anti-vascular endothelial growth factor(VEGF)injections,two eyes underwent vitrectomy,and six eyes were treated with vitrectomy combined with anti-VEGF therapy.Best-corrected visual acuity(logMAR)in treated eyes(18 eyes)improved to 0.31±0.25 from the baseline of 1.50±0.75(P<0.001).CONCLUSION:PEHCR is a variant of PCV.Chinese patients with PEHCR have a relatively younger age of onset.Anti-VEGF injections and/or vitrectomy are treatment options for lesion regression or dense VH to gain better visual outcomes.展开更多
Traditional nerve repair methods,such as autologous nerve grafting and allogeneic nerve grafting,face issues such as donor shortage,functional loss,and immune rejection.Decellularized extracellular matrix-based grafts...Traditional nerve repair methods,such as autologous nerve grafting and allogeneic nerve grafting,face issues such as donor shortage,functional loss,and immune rejection.Decellularized extracellular matrix-based grafts have emerged as highly promising alternatives,capable of uniquely recreating the natural neural mic roenvironment,promoting host cell remodeling,and ultimately enhancing functional neural regeneration.This review comprehensively analyzes the key mechanisms of peripheral nerve injury and regeneration,focusing on contemporary therapeutic strategies for key aspects such as axonal apoptosis inhibition,enhanced intrinsic regenerative capacity,construction of regenerative microenvironment,and prevention of target organ atrophy.Findings from this review has shown that decellularized extra cellular matrix grafts can promote the migration,prolife ration,and differentiation of nerve cells by providing physical suppo rt,chemical signals,and mechanical stability.Decellularized extracellular matrix grafts are mainly used as ne rve conduits,scaffolds,hydrogels,and3D printing inks.Decellularized extra cellular matrix grafts have demonstrated significant advantages in promoting nerve regeneration by regulating the prolife ration and differentiation of Schwann cells,improving the neural microenvironment,reducing inflammato ry responses,and promoting angiogenesis.Additionally,decellularized extracellular matrix grafts can se rve as drug carrie rs,enabling the controlled release of growth factors,which further enhances nerve regeneration.However,these grafts also have some limitations,including the presence of immunogenic residues,inadequate mechanical prope rties,inter-batch variability,and uncontrollable degradation rates.Future research should focus on optimizing the decellularization process,enhancing the mechanical prope rties of decellularized extracellular matrix grafts,reducing immunogenicity,improving biocompatibility and safety,and developing new composite mate rials.Furthermore,exploring their application potential in complex nerve injuries,such as diabetic neuropathy,is crucial to meet the needs of peripheral nerve regeneration and repair.展开更多
Peripheral nerve injury is a complex condition presenting significant clinical treatment challenges due to the limited regenerative capacity of peripheral nerves.Nerve conduits have been seen as a promising strategy t...Peripheral nerve injury is a complex condition presenting significant clinical treatment challenges due to the limited regenerative capacity of peripheral nerves.Nerve conduits have been seen as a promising strategy to overcome the shortage of other treatment options(e.g.,nerve graft).However,nerve regeneration occurs within a complex environment,and elaborate modulation is needed to meet repair requirements.The aim of this study was to investigate and explore a multifunctional nerve conduit with reactive oxygen species clearing,immune modulation to reshape the regenerative environment,and topographic cues and electrical signals to guide nerve growth.We developed an electroactive nerve guidance conduit composed of polylactic-glycolic acid and carbon nanotubes with an oriented structure using electrospinning and modified it with mussel-inspired polydopamine combining neurotrophin-3.The resulting nerve scaffold exhibited favorable orientation,electrical conductivity,and mechanical properties.Continuous release of neurotrophin-3 from the nerve conduit supported nerve regeneration throughout the repair process.In vitro assessments confirmed the cytocompatibility,reactive oxygen species scavenging,and immune regulation capabilities of the nerve scaffolds.In a rat sciatic nerve defect model,the nerve scaffolds effectively prevented muscle atrophy and promoted nerve regeneration and functional recovery over a 12-week period.These findings suggest that polydopamine-modified,electroactive,oriented nerve guidance conduits with multiple bioactive functions hold great promise for the repair of peripheral nerve injuries.展开更多
Peripheral nerve injury causes severe neuroinflammation and has become a global medical challenge.Previous research has demonstrated that porcine decellularized nerve matrix hydrogel exhibits excellent biological prop...Peripheral nerve injury causes severe neuroinflammation and has become a global medical challenge.Previous research has demonstrated that porcine decellularized nerve matrix hydrogel exhibits excellent biological properties and tissue specificity,highlighting its potential as a biomedical material for the repair of severe peripheral nerve injury;however,its role in modulating neuroinflammation post-peripheral nerve injury remains unknown.Here,we aimed to characterize the anti-inflammatory properties of porcine decellularized nerve matrix hydrogel and their underlying molecular mechanisms.Using peripheral nerve injury model rats treated with porcine decellularized nerve matrix hydrogel,we evaluated structural and functional recovery,macrophage phenotype alteration,specific cytokine expression,and changes in related signaling molecules in vivo.Similar parameters were evaluated in vitro using monocyte/macrophage cell lines stimulated with lipopolysaccharide and cultured on porcine decellularized nerve matrix hydrogel-coated plates in complete medium.These comprehensive analyses revealed that porcine decellularized nerve matrix hydrogel attenuated the activation of excessive inflammation at the early stage of peripheral nerve injury and increased the proportion of the M2 subtype in monocytes/macrophages.Additionally,porcine decellularized nerve matrix hydrogel negatively regulated the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB axis both in vivo and in vitro.Our findings suggest that the efficacious anti-inflammatory properties of porcine decellularized nerve matrix hydrogel induce M2 macrophage polarization via suppression of the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB pathway,providing new insights into the therapeutic mechanism of porcine decellularized nerve matrix hydrogel in peripheral nerve injury.展开更多
Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells en...Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.展开更多
Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain ...Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain undefined.This study aims to identify ubiquitin-specific proteases(USPs)that deubiquitinate MafB and enhance its stability.Methods We constructed a MafB-conjugated luciferase and overexpressed 40 individual USPs,measuring changes in luciferase activity.The identified USP was overexpressed in human CD14^(+) peripheral blood mononuclear cells(PBMCs)to evaluate its effect.Osteoclast differentiation was assessed through osteoclast marker Integrin alpha-V(CD51)staining and Western blot analysis.Co-immunoprecipitation(co-IP)was performed to assess the interplay.The influence on MafB ubiquitination and degradation was evaluated via immunoprecipitation and Western blot.Finally,MafB was knocked down in the USP-overexpressing PBMCs to analyze its effect on osteoclast differentiation.Results Overexpression of ubiquitin-specific protease 29(USP29)significantly increased MafB expression by approximately 75%(p<0.0001).Elevated USP29 levels strongly inhibited osteoclastic differentiation in CD14^(+) PBMCs(p<0.0001).USP29 was found to interact with MafB,markedly reducing its ubiquitination and subsequent degradation in PBMCs(p<0.001).Knocking down MafB in USP29-overexpressing PBMCs alleviated the inhibitory effect of USP29 on osteoclastogenesis.Conclusion USP29 acts as a potent stabilizer of MafB,inhibiting osteoclastogenesis in human CD14^(+) PBMCs,at least in part,by enhancing MafB stability.These findings expand our understanding of USP29’s role and the post-translational regulation of MafB.Furthermore,USP29 serves as a vital factor that controls osteoclast differentiation,and its regulatory function is at least partially mediated by deubiquitinating and stabilizing MafB.展开更多
Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the mole...Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.展开更多
Oxaliplatin(OXA) is a widely used chemotherapeutic agent whose clinical utility is limited by OXA-induced peripheral neuropathy(OIPN). Sarco/endoplasmic reticulum Ca^(2+)-ATPase(SERCA) transports Ca^(2+) from the cyto...Oxaliplatin(OXA) is a widely used chemotherapeutic agent whose clinical utility is limited by OXA-induced peripheral neuropathy(OIPN). Sarco/endoplasmic reticulum Ca^(2+)-ATPase(SERCA) transports Ca^(2+) from the cytoplasm into the endoplasmic reticulum(ER), thereby maintaining intracellular Ca^(2+) homeostasis. Schefflera kwangsiensis Merr. ex H.L. Li(SKM) is traditionally used to treat neuropathic pain conditions such as trigeminal neuralgia and sciatica, and its active component Schekwanglupaside C has been identified as a potent SERCA activator. In this study, an OIPN mouse model was established by intraperitoneal administration of OXA(4 mg·kg^(-1)) on days 1, 2, 8, 9, 15, and 16. SERCA2b mRNA and protein expression in dorsal root ganglia(DRG) were evaluated by quantitative polymerase chain reaction(qPCR) and immunofluorescence. Mechanical allodynia was assessed using the Von Frey test.DRG neuronal excitability was examined by whole-cell current-clamp recordings, whereas oxidative stress and neuronal apoptosis/necrosis were assessed using the reactive oxygen species(ROS)-sensitive probe 2',7'-dichlorofluorescin diacetate(H2 DCFDA) and fluorescein isothiocyanate(FITC)/propidium iodide(PI) dual staining. This study identifies SERCA2b as a novel therapeutic target for OIPN. We observed that SERCA2b mRNA and protein levels were significantly downregulated during OIPN progression. Treatment with the SERCA agonist CDN1163(CDN), the ethyl acetate extract of SKM(SKM.Ext), or duloxetine(DLX) attenuated neuronal pathology, restored DRG neuron soma diameter, and reduced the expression of proinflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor α(TNF-α). Pre-incubation of DRG neurons with CDN1163 or SKM.Ext for 1 h significantly attenuated OXA-induced hyperexcitability and reduced the abnormal increase in voltage-gated sodium channel(VGSC) current density. Inhibition of oxidative stress with N-acetyl-L-cysteine(NAC) significantly restored SERCA expression in OIPN, indicating that oxidative stress downregulates SERCA2b in DRG. Collectively, these findings demonstrate that activation of SERCA2b by CDN1163 or Schefflera kwangsiensis extract enhances SERCA2b expression, reduces DRG neuronal sensitization, and alleviates OIPN. This work supports SERCA2b as a novel therapeutic target for OXA-induced neuropathy and expands the potential clinical analgesic indications of Schefflera kwangsiensis.展开更多
Background:Inflammation,caused by prolonged hyperglycemia,plays a substantially more important part in the progression of diabetic peripheral neuropathy(DPN).Notably,the MAPK pathway that mediates the Nuclear Factor-k...Background:Inflammation,caused by prolonged hyperglycemia,plays a substantially more important part in the progression of diabetic peripheral neuropathy(DPN).Notably,the MAPK pathway that mediates the Nuclear Factor-kappa B(NF-κB)pathway contributes to inflammation-induced peripheral nerve damage,affecting cell survival.Juan Bi Tong Luo(JBTL),a traditional Chinese medicine(TCM),has demonstrated favorable results in alleviating pain and numbness in patients with DPN;however,whether JBTL exerts its effect through the MAPK mediating NF-κB pathway remains unclear.Methods:This study investigated whether JBTL modulates apoptosis in DPN models and Schwann cells cultured in 100 mM of glucose by MAPK/NF-κB.Results:The JBTL altered inflammation,reduced peripheral nerve tissue damage,and improved cell survival rates by down-regulating MAPK/NF-κB.Conclusion:Our findings demonstrate that the effect of JBTL on DPN is likely mediated by suppressing inflammation induced by the MAPK/NF-κB pathway,thus providing evidence for the clinical efficacy of JBTL in treating DPN.展开更多
Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulat...Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.展开更多
“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health pro...“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health problem.Although severed peripheral nerves have been effectively joined and various therapies have been offered,recovery of sensory or motor functions remains limited,and efficacious therapies for complete repair of a nerve injury remain elusive.The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function.Mesenchymal stem cells,as large living cells responsive to the environment,secrete various factors and exosomes.The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins,microRNA,and messenger RNA derived from parent mesenchymal stem cells.Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function,offering solutions to changes associated with cell-based therapies.Despite ongoing investigations,mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage.A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation.This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury,exploring the underlying mechanisms.Subsequently,it provides an overview of the current status of mesenchymal stem cell and exosomebased therapies in clinical trials,followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes.Finally,the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes,offering potential solutions and guiding future directions.展开更多
Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes...Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.展开更多
Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition.Diabetic peripheral neuropathy,a common complication of dia...Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition.Diabetic peripheral neuropathy,a common complication of diabetes,is characterized by nerve damage due to high blood sugar levels that lead to symptoms,such as pain,tingling,and numbness,primarily in the hands and feet.The aim of this systematic review was to evaluate the efficacy of neuromodulatory techniques as potential therapeutic interventions for patients with diabetic peripheral neuropathy,while also examining recent developments in this domain.The investigation encompassed an array of neuromodulation methods,including frequency rhythmic electrical modulated systems,dorsal root ganglion stimulation,and spinal cord stimulation.This systematic review suggests that neuromodulatory techniques may be useful in the treatment of diabetic peripheral neuropathy.Understanding the advantages of these treatments will enable physicians and other healthcare providers to offer additional options for patients with symptoms refractory to standard pharmacologic treatments.Through these efforts,we may improve quality of life and increase functional capacity in patients suffering from complications related to diabetic neuropathy.展开更多
Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve rep...Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication.Nevertheless,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear.To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation.The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells.We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells.Subsequently,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded miR-21-5p.Finally,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously restored.These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p.miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome.This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves,and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.展开更多
Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzhei...Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.展开更多
基金National Institutes of Health(NIH)R01-NS128086 grant(to GDB and JSB)Lone Star Paralysis Foundation(to GDB).
文摘We have previously shown the success of polyethylene glycol fusion repair of segmental-loss peripheral nerve injuries in rats using freshly harvested,viable peripheral nerve allografts that can conduct action potentials.Because clinical application of polyethylene glycol fusion with viable peripheral nerve allografts demands pre-transplant donor tissue storage,we developed a protocol for ex vivo storage of rat sciatic nerves as viable peripheral nerve allografts,preserving many axons for up to 5 days.The current study evaluated the in vivo use of these stored viable peripheral nerve allografts.We hypothesized that stored viable peripheral nerve allografts with viable axons would enable successful in vivo repair of segmental-loss peripheral nerve injuries via polyethylene glycol-fusion.Polyethylene glycol-fused viable peripheral nerve allografts were classified as successful if they produced significantly improved locomotor recovery,as evaluated by the sciatic functional index,within 8 weeks post-repair.Many Sprague-Dawley and Lewis rats with successfully polyethylene glycol-fused viable peripheral nerve allografts had significantly improved sciatic functional index scores beginning at 5 weeks post-operatively.There was no significant difference in the efficiency and extent of successful polyethylene glycol fusion between stored and freshly harvested viable peripheral nerve allografts.In contrast,rats with non-fused negative control viable peripheral nerve allografts showed no recovery by 8 weeks post-operatively.Additional confirmatory outcome measures included in vivo compound action potentials and assessments of axon morphometry.These results suggest that viable peripheral nerve allografts can be stored and later used for successful polyethylene glycol fusion repair of segmental-loss peripheral nerve injuries.
基金supported by the European Union-Next Generation EU,Mission 4 Component 1,Project Title:“Gut and Neuro Muscular system:investigating the impact of microbiota on nerve regeneration and muscle reinnervation after peripheral nerve injury”,CUP D53D23007770006,MUR:20227YB93W,to GR。
文摘The gut microbiota:The human body is colonized by a diverse and complex microbial community–including bacteria,viruses,archaea,and unicellular eukaryotes–that plays a central role in human wellbeing.Indeed,microbiota is crucial for several functions,including host metabolism,physiology,maintenance of the intestinal epithelial integrity,nutrition,and immune function,earning it the designation of a“vital organ”(Guinane and Cotter,2013).
基金funded by a grant of the Deutsche Forschungsgemeinschaft(DFG)(SFB 1348,B5)to CK.
文摘Peripheral sensory neurons perceive external signals and convey signals to the central nervous system(CNS).Information transmission occurs via often extremely long axons and timely reactions of the animal require a fast conductance velocity.This not only depends on axonal diameter and insulation by glial processes,but it requires the structural integrity of the axon.
基金supported by Department of Defense grant HT9425-24-1-0030 a grant from the Stanley Medical Research Institute(to SS).
文摘The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain.The discovery that all tissues,including the brain,release extracellular vesicles(Raposo and Stoorvogel,2013)and cell free DNAs(Chan et al.,2013)into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system(CNS)and has given rise to the term“liquid biopsy.”The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative.The ability to predict episodic events such as mania,depression,and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes.Additionally,biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects.
基金supported by the National Natural Science Foundation of China,No.82071386(to JG).
文摘Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages.Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and myelin during Wallerian degeneration,which is a prerequisite for nerve regeneration,we hypothesized that microRNA-301a regulates Wallerian degeneration and nerve regeneration via impacts on Schwann cell migration and phagocytosis.Herein,we found low expression of microRNA-301a in intact sciatic nerves,with no impact of the microRNA-301a knockout on nerve structure and function.By contrast,we found significant upregulation of microRNA-301a in injured sciatic nerves.We established a sciatic nerve crush model in microRNA-301a knockout mice,which exhibited attenua9ted morphological and functional regeneration following sciatic nerve crush injury.The microRNA-301a knockout also led to significantly inhibited Wallerian degeneration in an in vivo sciatic nerve-transection model and in an in vitro nerve explant block model.Schwann cells with the microRNA-301a knockout showed inhibition of phagocytosis and migration,which was reversible under transfection with microRNA-301a mimics.Rescue experiments involving transfection of microRNA-301a-knockout Schwann cells with microRNA-301a mimics or treatment with the C-X-C motif receptor 4 inhibitor WZ811 indicated the mechanistic involvement of the Yin Yang 1/C-X-C motif receptor 4 pathway in the role of microRNA-301a.Combined with our previous findings in macrophages,we conclude that microRNA-301a plays a key role in peripheral nerve injury and repair by regulating the migratory and phagocytic capabilities of Schwann cells and macrophages via the Yin Yang 1/C-X-C motif receptor 4 pathway.
基金Supported by the National Natural Science Foundation of China(No.82220108017,No.82141128)The Capital Health Research and Development of Special(No.2024-1-2052)+1 种基金Science&Technology Project of Beijing Municipal Science&Technology Commission(No.Z201100005520045)Sanming Project of Medicine in Shenzhen(No.SZSM202311018)。
文摘AIM:To evaluate the clinical features,diagnosis,treatment,and outcome of peripheral exudative hemorrhagic chorioretinopathy(PEHCR),a variant of polypoidal choroidal vasculopathy(PCV),in a case series of Chinese patients.METHODS:This study was retrospectively conducted from September 2018 to March 2025.Clinical examinations included color fundus photography,B-scan ultrasonography,fluorescein angiography(FA),indocyanine green angiography(ICGA),swept-source optical coherence tomography(SS-OCT),and optical coherence tomography angiography(OCTA),and two active or inactive subgroups and misdiagnosed cases were analyzed.RESULTS:Totally 19 patients(21 eyes)with a mean age of 54.3±9.4(range,36–68)y were included,with a majority of women(n=13,68.4%).The mean follow-up period was 13±1.4(range:1–57)mo.Decreased visual acuity was the most frequent initial manifestation(17 eyes,84.2%),and lesions were mainly distributed in the inferotemporal or temporal quadrant(14 eyes,66.7%),with choroidal polyps and branching neovascular networks revealed by OCTA and ICGA.Nine patients had been previously misdiagnosed with choroidal melanoma,and 6 of them had massive vitreous hemorrhage(VH).PEHCR manifested along a spectrum ranging from active or inactive subretinal hemorrhagic forms to chronic fibrotic or atrophic forms.One patient experienced natural regression.Ten eyes received a mean of 4.7±1.1(range:3–7)intravitreal anti-vascular endothelial growth factor(VEGF)injections,two eyes underwent vitrectomy,and six eyes were treated with vitrectomy combined with anti-VEGF therapy.Best-corrected visual acuity(logMAR)in treated eyes(18 eyes)improved to 0.31±0.25 from the baseline of 1.50±0.75(P<0.001).CONCLUSION:PEHCR is a variant of PCV.Chinese patients with PEHCR have a relatively younger age of onset.Anti-VEGF injections and/or vitrectomy are treatment options for lesion regression or dense VH to gain better visual outcomes.
基金National Natural Science Foundation of China,No.32130060,No.81901256Jiangsu College Students Innovation and En trepreneurship Training Program,No.202310304120Y,No.202313993004Y2024 Medical Research Project by the Jiangsu Commission of Health,No.M2024009。
文摘Traditional nerve repair methods,such as autologous nerve grafting and allogeneic nerve grafting,face issues such as donor shortage,functional loss,and immune rejection.Decellularized extracellular matrix-based grafts have emerged as highly promising alternatives,capable of uniquely recreating the natural neural mic roenvironment,promoting host cell remodeling,and ultimately enhancing functional neural regeneration.This review comprehensively analyzes the key mechanisms of peripheral nerve injury and regeneration,focusing on contemporary therapeutic strategies for key aspects such as axonal apoptosis inhibition,enhanced intrinsic regenerative capacity,construction of regenerative microenvironment,and prevention of target organ atrophy.Findings from this review has shown that decellularized extra cellular matrix grafts can promote the migration,prolife ration,and differentiation of nerve cells by providing physical suppo rt,chemical signals,and mechanical stability.Decellularized extracellular matrix grafts are mainly used as ne rve conduits,scaffolds,hydrogels,and3D printing inks.Decellularized extra cellular matrix grafts have demonstrated significant advantages in promoting nerve regeneration by regulating the prolife ration and differentiation of Schwann cells,improving the neural microenvironment,reducing inflammato ry responses,and promoting angiogenesis.Additionally,decellularized extracellular matrix grafts can se rve as drug carrie rs,enabling the controlled release of growth factors,which further enhances nerve regeneration.However,these grafts also have some limitations,including the presence of immunogenic residues,inadequate mechanical prope rties,inter-batch variability,and uncontrollable degradation rates.Future research should focus on optimizing the decellularization process,enhancing the mechanical prope rties of decellularized extracellular matrix grafts,reducing immunogenicity,improving biocompatibility and safety,and developing new composite mate rials.Furthermore,exploring their application potential in complex nerve injuries,such as diabetic neuropathy,is crucial to meet the needs of peripheral nerve regeneration and repair.
基金supported by the National Key R&D Program of China,No.2022YFC3006200(to YW)the Natural Science Foundation of Beijing,No.7232190(to YW)+1 种基金Zhejiang Province Medical and Health Technology Plan Project,Nos.2022020506(to XW),2024KY1612(to JX),2024KY1615(to MY)Ningbo Clinical Research Center for Orthopedics and Sports Rehabilitation,No.2024L004(to XW).
文摘Peripheral nerve injury is a complex condition presenting significant clinical treatment challenges due to the limited regenerative capacity of peripheral nerves.Nerve conduits have been seen as a promising strategy to overcome the shortage of other treatment options(e.g.,nerve graft).However,nerve regeneration occurs within a complex environment,and elaborate modulation is needed to meet repair requirements.The aim of this study was to investigate and explore a multifunctional nerve conduit with reactive oxygen species clearing,immune modulation to reshape the regenerative environment,and topographic cues and electrical signals to guide nerve growth.We developed an electroactive nerve guidance conduit composed of polylactic-glycolic acid and carbon nanotubes with an oriented structure using electrospinning and modified it with mussel-inspired polydopamine combining neurotrophin-3.The resulting nerve scaffold exhibited favorable orientation,electrical conductivity,and mechanical properties.Continuous release of neurotrophin-3 from the nerve conduit supported nerve regeneration throughout the repair process.In vitro assessments confirmed the cytocompatibility,reactive oxygen species scavenging,and immune regulation capabilities of the nerve scaffolds.In a rat sciatic nerve defect model,the nerve scaffolds effectively prevented muscle atrophy and promoted nerve regeneration and functional recovery over a 12-week period.These findings suggest that polydopamine-modified,electroactive,oriented nerve guidance conduits with multiple bioactive functions hold great promise for the repair of peripheral nerve injuries.
基金supported by the Shenzhen Hong Kong Joint Funding Project,No.SGDX20230116093645007(to LY)the Shenzhen Science and Technology Innovation Committee International Cooperation Project,No.GJHZ20200731095608025(to LY)+7 种基金Shenzhen Development and Reform Commission’s Intelligent Diagnosis,Treatment and Prevention of Adolescent Spinal Health Public Service Platform,No.S2002Q84500835(to LY)Shenzhen Medical Research Fund,No.B2303005(to LY)Team-based Medical Science Research Program,No.2024YZZ02(to LY)Zhejiang Provincial Natural Science Foundation of China,No.LWQ20H170001(to RL)Basic Research Project of Shenzhen Science and Technology from Shenzhen Science and Technology Innovation Commission,No.JCYJ20210324103010029(to BY)Shenzhen Second People’s Hospital Clinical Research Fund of Guangdong Province High-level Hospital Construction Project,Nos.2023yjlcyj029(to BY),2023yjlcyj021(to LL)Guangdong Basic and Applied Basic Research Foundation,No.2022A1515110679(to LL)China Postdoctoral Science Foundation,No.2022M722203(to GL).
文摘Peripheral nerve injury causes severe neuroinflammation and has become a global medical challenge.Previous research has demonstrated that porcine decellularized nerve matrix hydrogel exhibits excellent biological properties and tissue specificity,highlighting its potential as a biomedical material for the repair of severe peripheral nerve injury;however,its role in modulating neuroinflammation post-peripheral nerve injury remains unknown.Here,we aimed to characterize the anti-inflammatory properties of porcine decellularized nerve matrix hydrogel and their underlying molecular mechanisms.Using peripheral nerve injury model rats treated with porcine decellularized nerve matrix hydrogel,we evaluated structural and functional recovery,macrophage phenotype alteration,specific cytokine expression,and changes in related signaling molecules in vivo.Similar parameters were evaluated in vitro using monocyte/macrophage cell lines stimulated with lipopolysaccharide and cultured on porcine decellularized nerve matrix hydrogel-coated plates in complete medium.These comprehensive analyses revealed that porcine decellularized nerve matrix hydrogel attenuated the activation of excessive inflammation at the early stage of peripheral nerve injury and increased the proportion of the M2 subtype in monocytes/macrophages.Additionally,porcine decellularized nerve matrix hydrogel negatively regulated the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB axis both in vivo and in vitro.Our findings suggest that the efficacious anti-inflammatory properties of porcine decellularized nerve matrix hydrogel induce M2 macrophage polarization via suppression of the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB pathway,providing new insights into the therapeutic mechanism of porcine decellularized nerve matrix hydrogel in peripheral nerve injury.
基金supported by the National Natural Science Foundation of China,No.32171356(to YW)Self-Support Research Projects of Shihezi University,No.ZZZC2021105(to WJ)+1 种基金Capital Medical University Natural Science Cultivation Fund,No.PYZ23044(to FQM)Beijing Municipal Natural Science Foundation,No.7244410(to JHD)。
文摘Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.
文摘Objectives Dysregulated osteoclast function contributes to skeletal diseases.However,the specific ubiquitination regulators of the osteoclastogenesis repressor MafB,particularly at the post-translational level,remain undefined.This study aims to identify ubiquitin-specific proteases(USPs)that deubiquitinate MafB and enhance its stability.Methods We constructed a MafB-conjugated luciferase and overexpressed 40 individual USPs,measuring changes in luciferase activity.The identified USP was overexpressed in human CD14^(+) peripheral blood mononuclear cells(PBMCs)to evaluate its effect.Osteoclast differentiation was assessed through osteoclast marker Integrin alpha-V(CD51)staining and Western blot analysis.Co-immunoprecipitation(co-IP)was performed to assess the interplay.The influence on MafB ubiquitination and degradation was evaluated via immunoprecipitation and Western blot.Finally,MafB was knocked down in the USP-overexpressing PBMCs to analyze its effect on osteoclast differentiation.Results Overexpression of ubiquitin-specific protease 29(USP29)significantly increased MafB expression by approximately 75%(p<0.0001).Elevated USP29 levels strongly inhibited osteoclastic differentiation in CD14^(+) PBMCs(p<0.0001).USP29 was found to interact with MafB,markedly reducing its ubiquitination and subsequent degradation in PBMCs(p<0.001).Knocking down MafB in USP29-overexpressing PBMCs alleviated the inhibitory effect of USP29 on osteoclastogenesis.Conclusion USP29 acts as a potent stabilizer of MafB,inhibiting osteoclastogenesis in human CD14^(+) PBMCs,at least in part,by enhancing MafB stability.These findings expand our understanding of USP29’s role and the post-translational regulation of MafB.Furthermore,USP29 serves as a vital factor that controls osteoclast differentiation,and its regulatory function is at least partially mediated by deubiquitinating and stabilizing MafB.
基金Natural Science Foundation of Beijing,No.7244428(to WZ)Peking University Medicine Sailing Program for Young Scholars’Scientific and Technological Innovation,No.BMU2023YFJHPY034(to WZ)+1 种基金the National Natural Science Foundation of China,Nos.81873784(to DF),82071426(to DF)Clinical Cohort Construction Program of Peking University Third Hospital,Nos.BYSYDL2019002(to DF)and BYSYZD2021004(to DF).
文摘Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.
基金supported by the Natural Science Foundation of Jiangsu Province of China (No. BK20221054)the National Natural Science Foundation of China (Nos. 82204653, 82373929, and82100585)+3 种基金the Major Program of Jiangsu Provincial Administration for Market Regulation (No. KJ2024014)“Double First-Class” University Project (No. CPU2022QZ30)the Open Fund Project of State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture (No.SKL2024Z0104)Xizang Autonomous Region Science and Technology Plan Project Key Project (No. XZ202301ZY0014G)。
文摘Oxaliplatin(OXA) is a widely used chemotherapeutic agent whose clinical utility is limited by OXA-induced peripheral neuropathy(OIPN). Sarco/endoplasmic reticulum Ca^(2+)-ATPase(SERCA) transports Ca^(2+) from the cytoplasm into the endoplasmic reticulum(ER), thereby maintaining intracellular Ca^(2+) homeostasis. Schefflera kwangsiensis Merr. ex H.L. Li(SKM) is traditionally used to treat neuropathic pain conditions such as trigeminal neuralgia and sciatica, and its active component Schekwanglupaside C has been identified as a potent SERCA activator. In this study, an OIPN mouse model was established by intraperitoneal administration of OXA(4 mg·kg^(-1)) on days 1, 2, 8, 9, 15, and 16. SERCA2b mRNA and protein expression in dorsal root ganglia(DRG) were evaluated by quantitative polymerase chain reaction(qPCR) and immunofluorescence. Mechanical allodynia was assessed using the Von Frey test.DRG neuronal excitability was examined by whole-cell current-clamp recordings, whereas oxidative stress and neuronal apoptosis/necrosis were assessed using the reactive oxygen species(ROS)-sensitive probe 2',7'-dichlorofluorescin diacetate(H2 DCFDA) and fluorescein isothiocyanate(FITC)/propidium iodide(PI) dual staining. This study identifies SERCA2b as a novel therapeutic target for OIPN. We observed that SERCA2b mRNA and protein levels were significantly downregulated during OIPN progression. Treatment with the SERCA agonist CDN1163(CDN), the ethyl acetate extract of SKM(SKM.Ext), or duloxetine(DLX) attenuated neuronal pathology, restored DRG neuron soma diameter, and reduced the expression of proinflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor α(TNF-α). Pre-incubation of DRG neurons with CDN1163 or SKM.Ext for 1 h significantly attenuated OXA-induced hyperexcitability and reduced the abnormal increase in voltage-gated sodium channel(VGSC) current density. Inhibition of oxidative stress with N-acetyl-L-cysteine(NAC) significantly restored SERCA expression in OIPN, indicating that oxidative stress downregulates SERCA2b in DRG. Collectively, these findings demonstrate that activation of SERCA2b by CDN1163 or Schefflera kwangsiensis extract enhances SERCA2b expression, reduces DRG neuronal sensitization, and alleviates OIPN. This work supports SERCA2b as a novel therapeutic target for OXA-induced neuropathy and expands the potential clinical analgesic indications of Schefflera kwangsiensis.
基金funded by grants from the Suzhou Gusu Health Talents Project(grant No.GSWS2024050 to Liu W)Natural Science Foundation Project of Nanjing University of Chinese Medicine(grant No.XZR2021043 to Liu W and grant No.XZR2023021 to Huang F)+1 种基金Suzhou Science Education Health Youth Project(grant No.KJXW2021046 to Liu W)Suzhou Major Disease Multi-center Clinical Research Project(grant No.DZXYJ202410 to Huang F).
文摘Background:Inflammation,caused by prolonged hyperglycemia,plays a substantially more important part in the progression of diabetic peripheral neuropathy(DPN).Notably,the MAPK pathway that mediates the Nuclear Factor-kappa B(NF-κB)pathway contributes to inflammation-induced peripheral nerve damage,affecting cell survival.Juan Bi Tong Luo(JBTL),a traditional Chinese medicine(TCM),has demonstrated favorable results in alleviating pain and numbness in patients with DPN;however,whether JBTL exerts its effect through the MAPK mediating NF-κB pathway remains unclear.Methods:This study investigated whether JBTL modulates apoptosis in DPN models and Schwann cells cultured in 100 mM of glucose by MAPK/NF-κB.Results:The JBTL altered inflammation,reduced peripheral nerve tissue damage,and improved cell survival rates by down-regulating MAPK/NF-κB.Conclusion:Our findings demonstrate that the effect of JBTL on DPN is likely mediated by suppressing inflammation induced by the MAPK/NF-κB pathway,thus providing evidence for the clinical efficacy of JBTL in treating DPN.
基金supported by the National Natural Science Foundation of China,Nos.82271411(to RG),51803072(to WLiu)grants from the Department of Finance of Jilin Province,Nos.2022SCZ25(to RG),2022SCZ10(to WLiu),2021SCZ07(to RG)+2 种基金Jilin Provincial Science and Technology Program,No.YDZJ202201ZYTS038(to WLiu)The Youth Support Programmed Project of China-Japan Union Hospital of Jilin University,No.2022qnpy11(to WLuo)The Project of China-Japan Union Hospital of Jilin University,No.XHQMX20233(to RG)。
文摘Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.
基金supported by the Key Research and Development Project of Hubei Province of China,2022BCA028(to HC)。
文摘“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health problem.Although severed peripheral nerves have been effectively joined and various therapies have been offered,recovery of sensory or motor functions remains limited,and efficacious therapies for complete repair of a nerve injury remain elusive.The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function.Mesenchymal stem cells,as large living cells responsive to the environment,secrete various factors and exosomes.The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins,microRNA,and messenger RNA derived from parent mesenchymal stem cells.Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function,offering solutions to changes associated with cell-based therapies.Despite ongoing investigations,mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage.A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation.This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury,exploring the underlying mechanisms.Subsequently,it provides an overview of the current status of mesenchymal stem cell and exosomebased therapies in clinical trials,followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes.Finally,the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes,offering potential solutions and guiding future directions.
基金supported by grants from the Natural Science Foundation of Tianjin(General Program),Nos.23JCYBJC01390(to RL),22JCYBJC00220(to XC),and 22JCYBJC00210(to QL).
文摘Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.
文摘Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition.Diabetic peripheral neuropathy,a common complication of diabetes,is characterized by nerve damage due to high blood sugar levels that lead to symptoms,such as pain,tingling,and numbness,primarily in the hands and feet.The aim of this systematic review was to evaluate the efficacy of neuromodulatory techniques as potential therapeutic interventions for patients with diabetic peripheral neuropathy,while also examining recent developments in this domain.The investigation encompassed an array of neuromodulation methods,including frequency rhythmic electrical modulated systems,dorsal root ganglion stimulation,and spinal cord stimulation.This systematic review suggests that neuromodulatory techniques may be useful in the treatment of diabetic peripheral neuropathy.Understanding the advantages of these treatments will enable physicians and other healthcare providers to offer additional options for patients with symptoms refractory to standard pharmacologic treatments.Through these efforts,we may improve quality of life and increase functional capacity in patients suffering from complications related to diabetic neuropathy.
基金supported by the National Natural Science Foundation of China,No.31870977(to HYS)the National Key Technologies Research and Development Program of China,No.2017YFA0104700(to FD)+2 种基金2022 Jiangsu Funding Program for Excellent Postdoctoral Talent(to MC)Priority Academic Program Development of Jiangsu Higher Education Institutions[PAPD]the Major Project of Basic Science(Natural Science)Research in Higher Education Institutions of Jiangsu Province,No.22KJA180001(to QRH)。
文摘Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication.Nevertheless,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear.To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation.The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells.We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells.Subsequently,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded miR-21-5p.Finally,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously restored.These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p.miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome.This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves,and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.
基金financially supported by the National Natural Science Foundation of China,No.823 74552 (to WP)the Science and Technology Innovation Program of Hunan Province,No.2022RC1220 (to WP)+1 种基金the Natural Science Foundation of Hunan Province of China,Nos.2020JJ4803 (to WP),2022JJ40723 (to MY)the Scientific Research Launch Project for New Employees of the Second Xiangya Hospital of Central South University (to MY)
文摘Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.
