Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mecha...Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.展开更多
The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes und...The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes under both physiological and pathological conditions.These immune cells communicate with intrinsic and systemic factors and contribute to the structural and functional compartmentalization of the cerebellum.In this review,we discuss the roles of microglia in the cerebellar microenvironment,neuroinflammation,cerebellar adaptation,and neuronal activity,the associated molecular and cellular mechanisms,and potential therapeutic strategies targeting cerebellar microglia in the context of neuroinflammation.Future directions and unresolved questions in this field are further highlighted,particularly regarding therapeutic interventions targeting cerebellar microglia,functional mechanisms and activities of microglia in the cerebellar circuitry,neuronal connectivity,and neurofunctional outcomes of their activity.Cerebellar morphology and neuronal performance are influenced by both intrinsic and systemic factors that are actively monitored by microglia in both healthy and diseased states.Under pathological conditions,local subsets of microglia exhibit diverse responses to the altered microenvironment that contribute to the structural and functional compartmentalization of the cerebellum.Microglia in the cerebellum undergo early maturation during the embryonic stage and display specialized,highly immunogenic phenotypes.In summary,cerebellar microglia have the capacity to serve as regulatory tools that influence outcomes across a wide range of neurological and systemic conditions,including neurodevelopmental,neurodegenerative,metabolic,and stress-related disorders.展开更多
Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesi...Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesicles modulate target gene expression and impact disease-associated pathways.Chronic alcohol consumption leads to neuroinflammation,brain damage,and impaired cognition.Evidence indicates that females are more vulnerable to alcohol-induced damage than males.While mesenchymal stem cell-derived extracellular vesicles have been studied in various neuroinflammatory conditions,their potential to counteract alcohol-induced brain damage remains unclear.In this study,we investigated whether repeated intravenous administration of mesenchymal stem cell-derived extracellular vesicles could ameliorate neuroinflammation and behavioral impairment induced by chronic alcohol consumption in female mice.Mesenchymal stem cell-derived extracellular vesicles diminished the increased binding of a micro-positron emission tomography tracer(^(18)F-FDG)when analyzing whole-brain 3D images and brain coronal sections of ethanol-treated mice.Mesenchymal stem cell-derived extracellular vesicle administration protected against ethanol-induced proinflammatory gene upregulation,cognitive dysfunction,and the conditioned rewarding effects of cocaine.MiRNA sequencing data from mesenchymal stem cell-derived extracellular vesicles revealed the elevated expression of extracellular vesicle-derived miR-483-5p and miR-140-3p in the brains of ethanol-treated female mice following mesenchymal stem cell-derived extracellular vesicle administration.In addition,mesenchymal stem cell-derived extracellular vesicles modulated the expression of pro-inflammatory-related miRNA target genes(e.g.,Socs3,Tnf,Mtor,and Atf6)in the brains of ethanol-treated female mice.These results suggest that mesenchymal stem cell-derived extracellular vesicles could function as a neuroprotective therapy to ameliorate the neuroinflammation,cognitive dysfunction,and conditioned rewarding effects of cocaine associated with chronic alcohol consumption.展开更多
Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In th...Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In this study,we investigated the potential therapeutic effects of MCC950,a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor,on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats.Our results showed that chronic administration of MCC950(10 mg/kg)to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation,thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors,including interleukin-1βand-18.A decrease in astrocytic and microglial activation was also observed.We also found that MCC950 significantly inhibited autophagy.More importantly,behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function,which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain,such as blood‒brain barrier breakdown,white matter damage,and endothelial dysfunction.Thus,our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.展开更多
Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodul...Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodulation(PBM),as a non-invasive treatment,has been shown potential to alleviate inflammation of microglia or astrocytes.In this study,the spatiotemporal regulation and molecular mechanism of PBM on astrocytes were deeply explored by analyzing the effects and genomics at different time points.The results showed that PBM significantly attenuated the upregulation of inflammatory factors and mitochondrial dysfunction in astrocytes under LPS stimulation for 4 h and 24 h.RNA-seq analysis showed that the JAK-STAT pathway played an important role in the early stage of both LPS-induced astrocytic neuroin-flammation and PBM-alleviated astrocytic neuroinflammation.Under PBM treatment,Stat5a translocation to the nucleus and upregulated Socs3 expression were observed in LPS-treated astrocytes,which may inhibit the overactivation of the JAK-STAT inflammatory signaling pathway and thus alleviate astrocyte inflammation.Taken together,this study provides new insight into the molecular mechanism of the potential application of PBM in the treatment of neuroinflammation.展开更多
Microglia are the first immune cells that are activated in the brain following ischemic stroke.Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke.Caspase activation and recruitment ...Microglia are the first immune cells that are activated in the brain following ischemic stroke.Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke.Caspase activation and recruitment domain 19(CARD19)is involved in innate immune response and inflammatory response,which are also important functions of microglia.However,the role of CARD19 in microglial biology and ischemic stroke remains unknown.Here,we observed that CARD19 expression was significantly elevated in microglia in the penumbra after ischemic stroke via analyzing the spatial transcriptomic sequencing data of ischemic brain tissue,as well as in an in vitro model of microglial activation.Remarkably,conditional knockdown of Card19 in microglia promoted post-stroke neuroinflammation and worsened neurological outcomes in a mouse model of ischemic stroke.Mechanistically,we found that CARD19 localized to mitochondria and promoted the assembly of mitochondrial intermembrane bridge components,while CARD19 deficiency in microglia caused ultrastructural and functional damage to the mitochondrial cristae,leading to an exaggerated pro-inflammatory response.Thus,our findings suggest that preserving mitochondrial cristae,by targeting CARD19 could be a novel therapeutic strategy for ameliorating neuroinflammation post-stroke and decreasing the volume of the ischemic penumbra.展开更多
Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liv...Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liver disease.Central to this connection is the dysregulation of lipid metabolism,which extends beyond peripheral tissues to the brain,defective autolysosomal function,oxidative stress,inflammation,and insulin resistance.Lipids,which constitute over half of dry weight of the brain,play critical roles in ene rgy provisio n,structural integrity,and synaptic function.Dys regulation of lipid metabolism contributes to neuroinflammation,impaired neuronal function,and disrupted blood-brain barrier integrity.Palmitic acid,a saturated fatty acid abundant in high-fat diets,serves as a key model for studying lipid-induced toxicity(lipotoxicity)in the brain.Palmitic acid disrupts autophagy and lysosomal function,mitochondrial function,trigge ring oxidative stress,contributing to neuroinflammation and neurodegeneration.These effects are particularly pronounced in neurons,which are highly susceptible to lipid-induced toxicity due to their high metabolic demands.Glial cells,including astrocytes,microglia,and oligodendrocytes,also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation,further contributing to neuroinflammation and demyelination.Therapeutic strategies,such as supplementation with polyunsaturated fatty acids,AMP-activated protein kinase activation,and lysosome-ta rgeted interventions,show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis.This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types,including neurons,astrocytes,microglia,and oligodendrocytes.Additionally,it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions.Advances in multi-omics technologies and a deeper unde rstanding of intercellular crosstalk offer new avenues for develo ping targeted the rapies to resto re autolysosomal function,and attenuate neuroinflammation and neurodegeneration.展开更多
Previous studies have shown that endoplasmic reticulum stress induces neuronal apoptosis,necrosis,and pro-inflammatory microenvironment after spinal cord injury.The JNK pathway is activated by endoplasmic reticulum st...Previous studies have shown that endoplasmic reticulum stress induces neuronal apoptosis,necrosis,and pro-inflammatory microenvironment after spinal cord injury.The JNK pathway is activated by endoplasmic reticulum stress and reactive oxygen species.Our previous research demonstrated that cerebral dopamine neurotrophic factor has anti-inflammatory effects and promotes the repair of the damaged spinal cord after injury.However,the molecular mechanism remains unclear.In this study,we found that cerebral dopamine neurotrophic factor binds JNK1 and regulates JNK1/2-c-Jun-p53 signaling in lipopolysaccharide-induced microglia.Cerebral dopamine neurotrophic factor also alleviated neuroinflammation by reducing the secretion of pro-inflammatory cytokines.Overexpression of cerebral dopamine neurotrophic factor in a mouse model of spinal cord injury promoted nerve regeneration and motor function recovery.These findings indicate the possibility for cerebral dopamine neurotrophic factor treating spinal cord injury by targeting the JNK1/2-c-Jun-p53 pathway.展开更多
Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its prec...Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its precise mechanism in treating post-CHF cognitive dysfunction remains unclear.This study systematically investigates XJQ’s effects on post-CHF cognitive dysfunction and the underlying mechanisms.The components of XJQ were identified through liquid chromatography-mass spectrometry.CHF was induced in rats via ligation of the left anterior descending coronary artery,followed by six weeks of XJQ treatment.Cardiac function was evaluated through echocardiography and hemodynamic parameters,while cognitive function was assessed using Morris water maze(MWM)and open field tests(OFT).XJQ treatment enhanced both cardiac and cognitive functions in CHF rats.Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses,inflammation,and phosphodiesterase 4(PDE4)-dependent cyclic adenosine monophosphate(cAMP)signaling.XJQ inhibited microglial and astrocyte activation,decreased proinflammatory cytokines,and mitigated neuronal damage.Notably,XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP,protein kinase A(PKA),cAMP-response element binding protein(CREB),brain-derived neurotrophic factor(BDNF),PSD95,and synapsin I levels.Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin,kaempferol,isorhamnetin,and darutoside to PDE4.In conclusion,XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway.These findings provide valuable insight into the heart-brain axis.展开更多
The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol...The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol exposure trigge rs oxidative stress,glial activation,and sustained inflammation,ultimately contributing to cognitive decline and neuronal injury.展开更多
Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson'...Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).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
Neurodegenerative diseases affect millions of people worldwide,with Alzheimer’s disease(AD)being the leading cause of dementia.It is estimated that more than 50 million people live with this condition,which is expect...Neurodegenerative diseases affect millions of people worldwide,with Alzheimer’s disease(AD)being the leading cause of dementia.It is estimated that more than 50 million people live with this condition,which is expected to triple by 2050,driven mainly by the aging of the global population(GBD 2019 Dementia Forecasting Collaborators,2022).展开更多
Microglia-mediated neuroinflammation plays a crucial role in ischemic stroke;consequently,understanding its regulation could facilitate the development of therapies for ischemic stroke.Chemerin 15,a 15-amino acid pept...Microglia-mediated neuroinflammation plays a crucial role in ischemic stroke;consequently,understanding its regulation could facilitate the development of therapies for ischemic stroke.Chemerin 15,a 15-amino acid peptide derived from chemerin,exerts powerful anti-inflammatory effects through ChemR23,modulates macrophage polarization,and diminishes inflammatory cytokine expression in peripheral inflammation models.However,its effects on microglia and stroke remain unclear.In this study,we used an in vitro oxygen/glucose deprivation BV2 cell model and a mouse model of ischemia-reperfusion injury to investigate the role of chemerin 15 in stroke and the underlying mechanisms.We co-cultured BV2 microglial cells with HT-22 hippocampal neurons and observed that chemerin 15 reduced apoptosis in HT-22 cells.Furthermore,we found that chemerin 15 binds to the ChemR23 receptor on the cell surface,inducing its internalization.This process regulated the activity of adenosine 5ʹ-monophosphate-activated protein kinase and inhibited its downstream target nuclear factor kappa B.These effects could be reversed by treatment withα-NETA,a ChemR23 inhibitor.In mice with ischemia-reperfusion injury,chemerin 15 modulated microglial polarization,reduced infarct volume and neuronal apoptosis,and facilitated cognitive and neurological function recovery.Our findings suggest that chemerin 15 suppresses the microglia-mediated inflammatory response,decreases neuronal apoptosis,and enhances long-term neurological function recovery by inducing ChemR23 internalization and regulating the adenosine 5ʹ-monophosphate-activated protein kinase/nuclear factor kappa B signaling pathway.展开更多
Current treatments for neuropathic pain are suboptimal,necessitating the search for more effective therapeutics.Our previous study showed that inhibition of neuroinflammation in the spinal cord induced analgesic effec...Current treatments for neuropathic pain are suboptimal,necessitating the search for more effective therapeutics.Our previous study showed that inhibition of neuroinflammation in the spinal cord induced analgesic effects,and focal repetitive trans-spinal magnetic stimulation showed an anti-neuroinflammatory effect in spinal cord injury rat models.Here,we speculated that repetitive trans-spinal magnetic stimulation might induce an anti-inflammatory effect to alleviate neuropathic pain by upregulating calmodulin-dependent protein kinase kinase beta(CaMKKβ)/adenosine 5′-monophosphate-activated protein kinase(AMPK)/suppressor of cytokine signaling-3(SOCS3)signaling in microglia.Experiments have found that non-invasive focal repetitive trans-spinal magnetic stimulation effectively alleviates mechanical allodynia and spinal neuroinflammation in rats with neuropathic pain induced by chronic sciatic nerve ligation.Further research found that repetitive trans-spinal magnetic stimulation upregulated the expression of SOCS3 in spinal microglia,which subsequently inhibited the phosphorylation of p38 mitogen-activated protein kinase and signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 nuclear translocation in rats with neuropathic pain,thereby suppressing neuroinflammation.The upregulation of SOCS3 by repetitive trans-spinal magnetic stimulation may be achieved through the activation of the CaMKKβ/AMPK signaling pathway in microglia.The results suggested that focal repetitive trans-spinal magnetic stimulation inhibits spinal neuroinflammation and alleviates neuropathic pain by activating the CaMKKβ/AMPK/SOCS3 signaling pathway in spinal microglia.This mechanism provides an effective noninvasive treatment for neuropathic pain caused by peripheral nerve injury.展开更多
Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammati...Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammation plays a significant role in the progression of these diseases.However,there is limited research on therapeutic approaches to specifically target neuroinflammation.The role of T lymphocytes,which are crucial mediators of the adaptive immune response,in neurodegenerative diseases has been increasingly recognized.This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases.The pathogenesis of neurodegenerative diseases is complex,involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons,and T cells are a key component of these processes.One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells,including microglia,astrocytes,B cells,and natural killer cells.Different subsets of CD4~+T cells,such as Th1,Th2,Th17,and regulatory T cells,can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases.Additionally,CD8~+T cells,which can directly regulate immune responses and kill target cells,also play several important roles in neurodegenerative diseases.Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that,while some patients respond positively,others may not respond as well and may even experience adverse effects.Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system,which can lead to undesirable side effects.However,with new insights into the pathophysiology of neurodegenerative diseases,there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.展开更多
Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidati...Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.展开更多
Microglia,the resident monocyte of the central nervous system,play a crucial role in the response to spinal cord injury.However,the precise mechanism remains unclear.To investigate the molecular mechanisms by which mi...Microglia,the resident monocyte of the central nervous system,play a crucial role in the response to spinal cord injury.However,the precise mechanism remains unclear.To investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury,we performed single-cell RNA sequencing dataset analysis,focusing on changes in microglial subpopulations.We found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis,sphingomyelin metabolism,and neuroinflammation at high levels.Subsequently,we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord injury.Finally,we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron cells.Inhibiting ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced pyroptosis.Furthermore,ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling pathway.Inhibiting ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological function.Pla2g7 formed a“bridge”between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling pathway.Collectively,these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3,thereby exerting neuroprotective effects.展开更多
Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregati...Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregation,and alleviates scopolamine-induced cognitive impairment,similar to the phase Ⅲ clinical drug resveratrol.In this study,we established a mouse model of Alzheimer's disease via intracerebroventricular injection of fibrillar amyloid-β to investigate the effect of D30 on fibrillar amyloid-β-induced neuropathology.Our results showed that D30 alleviated fibrillar amyloid-β-induced cognitive impairment,promoted fibrillar amyloid-β clearance from the hippocampus and cortex,suppressed oxidative stress,and inhibited activation of microglia and astrocytes.D30 also reversed the fibrillar amyloid-β-induced loss of dendritic spines and synaptic protein expression.Notably,we demonstrated that exogenous fibrillar amyloid-βintroduced by intracerebroventricular injection greatly increased galectin-3 expression levels in the brain,and this increase was blocked by D30.Considering the role of D30 in clearing amyloid-β,inhibiting neuroinflammation,protecting synapses,and improving cognition,this study highlights the potential of galectin-3 as a promising treatment target for patients with Alzheimer's disease.展开更多
Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery...Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.展开更多
基金supported by the National Science Foundation of China,Nos.82325031(to FX),82030059(to YC),82102290(to YG),U23A20485(to YC)Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0505504(to FX),2023ZD0505500(to YC)the Key R&D Program of Shandong Province,No.2022ZLGX03(to YC).
文摘Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.
基金supported by grants from STI2030-Major Projects,No.2021ZD0204000(to YS)Key Strategic Science and Technology Cooperation Project of the Ministry of Science and Technology of China,No.SQ2023YFE0201430(to YS)+1 种基金the National Natural Science Foundation of China,Nos.31820103005(to YS),32200620(to LW)the Natural Science Foundation of Zhejiang Province of China,No.LZ24C090003(to YS)。
文摘The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes under both physiological and pathological conditions.These immune cells communicate with intrinsic and systemic factors and contribute to the structural and functional compartmentalization of the cerebellum.In this review,we discuss the roles of microglia in the cerebellar microenvironment,neuroinflammation,cerebellar adaptation,and neuronal activity,the associated molecular and cellular mechanisms,and potential therapeutic strategies targeting cerebellar microglia in the context of neuroinflammation.Future directions and unresolved questions in this field are further highlighted,particularly regarding therapeutic interventions targeting cerebellar microglia,functional mechanisms and activities of microglia in the cerebellar circuitry,neuronal connectivity,and neurofunctional outcomes of their activity.Cerebellar morphology and neuronal performance are influenced by both intrinsic and systemic factors that are actively monitored by microglia in both healthy and diseased states.Under pathological conditions,local subsets of microglia exhibit diverse responses to the altered microenvironment that contribute to the structural and functional compartmentalization of the cerebellum.Microglia in the cerebellum undergo early maturation during the embryonic stage and display specialized,highly immunogenic phenotypes.In summary,cerebellar microglia have the capacity to serve as regulatory tools that influence outcomes across a wide range of neurological and systemic conditions,including neurodevelopmental,neurodegenerative,metabolic,and stress-related disorders.
基金supported by the Spanish Ministry of Health‐Plan Nacional sobre Drogas(2023‐I024)the the Ministry of Science,Innovation and Universities/State ResearchAgency/10.13039/501100011033(PID2023-146865OB-I00)+2 种基金Generalitat Valenciana(CIAICO/2021/203)the Primary Addiction Care Research Network(RD21/0009/0005)FEDER Funds,GVA.
文摘Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesicles modulate target gene expression and impact disease-associated pathways.Chronic alcohol consumption leads to neuroinflammation,brain damage,and impaired cognition.Evidence indicates that females are more vulnerable to alcohol-induced damage than males.While mesenchymal stem cell-derived extracellular vesicles have been studied in various neuroinflammatory conditions,their potential to counteract alcohol-induced brain damage remains unclear.In this study,we investigated whether repeated intravenous administration of mesenchymal stem cell-derived extracellular vesicles could ameliorate neuroinflammation and behavioral impairment induced by chronic alcohol consumption in female mice.Mesenchymal stem cell-derived extracellular vesicles diminished the increased binding of a micro-positron emission tomography tracer(^(18)F-FDG)when analyzing whole-brain 3D images and brain coronal sections of ethanol-treated mice.Mesenchymal stem cell-derived extracellular vesicle administration protected against ethanol-induced proinflammatory gene upregulation,cognitive dysfunction,and the conditioned rewarding effects of cocaine.MiRNA sequencing data from mesenchymal stem cell-derived extracellular vesicles revealed the elevated expression of extracellular vesicle-derived miR-483-5p and miR-140-3p in the brains of ethanol-treated female mice following mesenchymal stem cell-derived extracellular vesicle administration.In addition,mesenchymal stem cell-derived extracellular vesicles modulated the expression of pro-inflammatory-related miRNA target genes(e.g.,Socs3,Tnf,Mtor,and Atf6)in the brains of ethanol-treated female mice.These results suggest that mesenchymal stem cell-derived extracellular vesicles could function as a neuroprotective therapy to ameliorate the neuroinflammation,cognitive dysfunction,and conditioned rewarding effects of cocaine associated with chronic alcohol consumption.
基金supported by the National Natural Science Foundation of China,No.82201626(to CC)the Natural Science Foundation of LiaoningProvince,No.2022-MS-442(to CC)the Dalian Municipal Medical Key Specialty Climbing Project,No.2024ZZ040(to MZ).
文摘Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In this study,we investigated the potential therapeutic effects of MCC950,a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor,on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats.Our results showed that chronic administration of MCC950(10 mg/kg)to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation,thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors,including interleukin-1βand-18.A decrease in astrocytic and microglial activation was also observed.We also found that MCC950 significantly inhibited autophagy.More importantly,behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function,which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain,such as blood‒brain barrier breakdown,white matter damage,and endothelial dysfunction.Thus,our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.
基金funded in part by the STI2030-Major Projects(2022ZD0212200)Hainan Province Key Area R&D Program(KJRC2023C30)+1 种基金Project of Collaborative Innovation Center of One Health(XTCX2022JKB02)Sanya Yazhou Bay Science and Technology City(SKJC-JYRC-2024-38).
文摘Neuroinflammation plays an important role in the occurrence and development of neurological diseases.In addition to microglia,the role of astrocytes in neuroinflammation has gradually attracted attention.Photobiomodulation(PBM),as a non-invasive treatment,has been shown potential to alleviate inflammation of microglia or astrocytes.In this study,the spatiotemporal regulation and molecular mechanism of PBM on astrocytes were deeply explored by analyzing the effects and genomics at different time points.The results showed that PBM significantly attenuated the upregulation of inflammatory factors and mitochondrial dysfunction in astrocytes under LPS stimulation for 4 h and 24 h.RNA-seq analysis showed that the JAK-STAT pathway played an important role in the early stage of both LPS-induced astrocytic neuroin-flammation and PBM-alleviated astrocytic neuroinflammation.Under PBM treatment,Stat5a translocation to the nucleus and upregulated Socs3 expression were observed in LPS-treated astrocytes,which may inhibit the overactivation of the JAK-STAT inflammatory signaling pathway and thus alleviate astrocyte inflammation.Taken together,this study provides new insight into the molecular mechanism of the potential application of PBM in the treatment of neuroinflammation.
基金National Natural Science Foundation of China,Nos.81920108017(to YX),82401546(to HL)Jiangsu Province Key Medical Discipline,No.ZDXK202216(to YX)the Key Research and Development Program of Jiangsu Province of China,No.BE2020620(to YX).
文摘Microglia are the first immune cells that are activated in the brain following ischemic stroke.Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke.Caspase activation and recruitment domain 19(CARD19)is involved in innate immune response and inflammatory response,which are also important functions of microglia.However,the role of CARD19 in microglial biology and ischemic stroke remains unknown.Here,we observed that CARD19 expression was significantly elevated in microglia in the penumbra after ischemic stroke via analyzing the spatial transcriptomic sequencing data of ischemic brain tissue,as well as in an in vitro model of microglial activation.Remarkably,conditional knockdown of Card19 in microglia promoted post-stroke neuroinflammation and worsened neurological outcomes in a mouse model of ischemic stroke.Mechanistically,we found that CARD19 localized to mitochondria and promoted the assembly of mitochondrial intermembrane bridge components,while CARD19 deficiency in microglia caused ultrastructural and functional damage to the mitochondrial cristae,leading to an exaggerated pro-inflammatory response.Thus,our findings suggest that preserving mitochondrial cristae,by targeting CARD19 could be a novel therapeutic strategy for ameliorating neuroinflammation post-stroke and decreasing the volume of the ischemic penumbra.
基金the Department of Biology at Syracuse University(to CHL)a start-up grant from the Department of Biomedical and Chemical Engineering at Syacuse University(to JZ)an NIH grant(R01DK141923)sub-contract to Co-Investigators JZ and CHL from the Principal Investigator Mark W.Grinstaff。
文摘Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liver disease.Central to this connection is the dysregulation of lipid metabolism,which extends beyond peripheral tissues to the brain,defective autolysosomal function,oxidative stress,inflammation,and insulin resistance.Lipids,which constitute over half of dry weight of the brain,play critical roles in ene rgy provisio n,structural integrity,and synaptic function.Dys regulation of lipid metabolism contributes to neuroinflammation,impaired neuronal function,and disrupted blood-brain barrier integrity.Palmitic acid,a saturated fatty acid abundant in high-fat diets,serves as a key model for studying lipid-induced toxicity(lipotoxicity)in the brain.Palmitic acid disrupts autophagy and lysosomal function,mitochondrial function,trigge ring oxidative stress,contributing to neuroinflammation and neurodegeneration.These effects are particularly pronounced in neurons,which are highly susceptible to lipid-induced toxicity due to their high metabolic demands.Glial cells,including astrocytes,microglia,and oligodendrocytes,also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation,further contributing to neuroinflammation and demyelination.Therapeutic strategies,such as supplementation with polyunsaturated fatty acids,AMP-activated protein kinase activation,and lysosome-ta rgeted interventions,show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis.This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types,including neurons,astrocytes,microglia,and oligodendrocytes.Additionally,it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions.Advances in multi-omics technologies and a deeper unde rstanding of intercellular crosstalk offer new avenues for develo ping targeted the rapies to resto re autolysosomal function,and attenuate neuroinflammation and neurodegeneration.
基金National Natural Science Foundation of China,No.81601067(to HZ)Shandong Natural Science Foundation of Shandong Province,Nos.ZR2021MH134(to HZ)and ZR2020MH080(to PD).
文摘Previous studies have shown that endoplasmic reticulum stress induces neuronal apoptosis,necrosis,and pro-inflammatory microenvironment after spinal cord injury.The JNK pathway is activated by endoplasmic reticulum stress and reactive oxygen species.Our previous research demonstrated that cerebral dopamine neurotrophic factor has anti-inflammatory effects and promotes the repair of the damaged spinal cord after injury.However,the molecular mechanism remains unclear.In this study,we found that cerebral dopamine neurotrophic factor binds JNK1 and regulates JNK1/2-c-Jun-p53 signaling in lipopolysaccharide-induced microglia.Cerebral dopamine neurotrophic factor also alleviated neuroinflammation by reducing the secretion of pro-inflammatory cytokines.Overexpression of cerebral dopamine neurotrophic factor in a mouse model of spinal cord injury promoted nerve regeneration and motor function recovery.These findings indicate the possibility for cerebral dopamine neurotrophic factor treating spinal cord injury by targeting the JNK1/2-c-Jun-p53 pathway.
基金supported by the National Natural Science Foundation of China(Nos.82430116 and 82574622)the Special Fund of Central Committee High Level Chinese Medicine Hospital(Nos.DZMG-LJRC-0014,DZMG-ZJXY-23013)+1 种基金Chinese Medicine Inheritance and Innovation“Thousand Million”Talents Project(Qihuang Project 2021)Qihuang Scholarsthe Medical and Health Industry Development Project of Tongzhou District(2023).
文摘Chronic heart failure(CHF)impairs cognitive function.Xijiaqi Formula(XJQ),a traditional Chinese medicine(TCM)used clinically to treat CHF,demonstrates potential for improving cognition in CHF patients.However,its precise mechanism in treating post-CHF cognitive dysfunction remains unclear.This study systematically investigates XJQ’s effects on post-CHF cognitive dysfunction and the underlying mechanisms.The components of XJQ were identified through liquid chromatography-mass spectrometry.CHF was induced in rats via ligation of the left anterior descending coronary artery,followed by six weeks of XJQ treatment.Cardiac function was evaluated through echocardiography and hemodynamic parameters,while cognitive function was assessed using Morris water maze(MWM)and open field tests(OFT).XJQ treatment enhanced both cardiac and cognitive functions in CHF rats.Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses,inflammation,and phosphodiesterase 4(PDE4)-dependent cyclic adenosine monophosphate(cAMP)signaling.XJQ inhibited microglial and astrocyte activation,decreased proinflammatory cytokines,and mitigated neuronal damage.Notably,XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP,protein kinase A(PKA),cAMP-response element binding protein(CREB),brain-derived neurotrophic factor(BDNF),PSD95,and synapsin I levels.Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin,kaempferol,isorhamnetin,and darutoside to PDE4.In conclusion,XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway.These findings provide valuable insight into the heart-brain axis.
基金UNMC to Dr.PPNational Institute on Alcohol Abuse and Alcoholism(AA031444,P50AA030407-5126,Pilot Core grant)to Dr.SS。
文摘The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol exposure trigge rs oxidative stress,glial activation,and sustained inflammation,ultimately contributing to cognitive decline and neuronal injury.
基金supported by grants from the Deutsche Forschungsgemeinschaft(HU 2614/1-1(Project No.462650276))the Fritz Thyssen Foundation(10.21.1.021MN)the Medical faculty of the University of Saarland(HOMFOR2016,HOMFORexzellent2017,HOMFOR2024 Anschubfinanzierung)to WH。
文摘Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).
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funded by the São Paulo Research Foundation (FAPESPgrant No. 2022/02327-6)supported by the FAPESP scholarship (2021/00270-4 and 2024/05491-7)
文摘Neurodegenerative diseases affect millions of people worldwide,with Alzheimer’s disease(AD)being the leading cause of dementia.It is estimated that more than 50 million people live with this condition,which is expected to triple by 2050,driven mainly by the aging of the global population(GBD 2019 Dementia Forecasting Collaborators,2022).
基金Gulin-Southwest Medical University Hospital Strategic Cooperation Project,No.2022 GLXNYDFY10(to JL)Suining First People’s Hospital-Southwest Medical University Cooperation Project,No.2021SNXNYD06(to JL)+2 种基金Postdoctoral Research Foundation of China,No.2021M692285(to LW)Key Research and Development Project of the Science and Technology Department of Sichuan Province,No.2022YFS0318(to LW)Post-Doctor Research Project of West China Hospital,Sichuan University,No.2021HXBH083(to LW).
文摘Microglia-mediated neuroinflammation plays a crucial role in ischemic stroke;consequently,understanding its regulation could facilitate the development of therapies for ischemic stroke.Chemerin 15,a 15-amino acid peptide derived from chemerin,exerts powerful anti-inflammatory effects through ChemR23,modulates macrophage polarization,and diminishes inflammatory cytokine expression in peripheral inflammation models.However,its effects on microglia and stroke remain unclear.In this study,we used an in vitro oxygen/glucose deprivation BV2 cell model and a mouse model of ischemia-reperfusion injury to investigate the role of chemerin 15 in stroke and the underlying mechanisms.We co-cultured BV2 microglial cells with HT-22 hippocampal neurons and observed that chemerin 15 reduced apoptosis in HT-22 cells.Furthermore,we found that chemerin 15 binds to the ChemR23 receptor on the cell surface,inducing its internalization.This process regulated the activity of adenosine 5ʹ-monophosphate-activated protein kinase and inhibited its downstream target nuclear factor kappa B.These effects could be reversed by treatment withα-NETA,a ChemR23 inhibitor.In mice with ischemia-reperfusion injury,chemerin 15 modulated microglial polarization,reduced infarct volume and neuronal apoptosis,and facilitated cognitive and neurological function recovery.Our findings suggest that chemerin 15 suppresses the microglia-mediated inflammatory response,decreases neuronal apoptosis,and enhances long-term neurological function recovery by inducing ChemR23 internalization and regulating the adenosine 5ʹ-monophosphate-activated protein kinase/nuclear factor kappa B signaling pathway.
基金National Natural Science Foundation of China,Nos.82302877(to QW),82172541(to TW)the Natural Science Foundation of Hunan Province,No.2023JJ30549(to QW)Clinical Medical Technology Innovation Guidance Project of Hunan Provincial Science and Technology Department,No.2021SK51815(to QW).
文摘Current treatments for neuropathic pain are suboptimal,necessitating the search for more effective therapeutics.Our previous study showed that inhibition of neuroinflammation in the spinal cord induced analgesic effects,and focal repetitive trans-spinal magnetic stimulation showed an anti-neuroinflammatory effect in spinal cord injury rat models.Here,we speculated that repetitive trans-spinal magnetic stimulation might induce an anti-inflammatory effect to alleviate neuropathic pain by upregulating calmodulin-dependent protein kinase kinase beta(CaMKKβ)/adenosine 5′-monophosphate-activated protein kinase(AMPK)/suppressor of cytokine signaling-3(SOCS3)signaling in microglia.Experiments have found that non-invasive focal repetitive trans-spinal magnetic stimulation effectively alleviates mechanical allodynia and spinal neuroinflammation in rats with neuropathic pain induced by chronic sciatic nerve ligation.Further research found that repetitive trans-spinal magnetic stimulation upregulated the expression of SOCS3 in spinal microglia,which subsequently inhibited the phosphorylation of p38 mitogen-activated protein kinase and signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 nuclear translocation in rats with neuropathic pain,thereby suppressing neuroinflammation.The upregulation of SOCS3 by repetitive trans-spinal magnetic stimulation may be achieved through the activation of the CaMKKβ/AMPK signaling pathway in microglia.The results suggested that focal repetitive trans-spinal magnetic stimulation inhibits spinal neuroinflammation and alleviates neuropathic pain by activating the CaMKKβ/AMPK/SOCS3 signaling pathway in spinal microglia.This mechanism provides an effective noninvasive treatment for neuropathic pain caused by peripheral nerve injury.
基金supported by Yunnan Provincial Science and Technology Department,Nos.202403AC100007(to NZ),202301AY070001-239(to JY)Yunnan Revitalization Talent Support Program,Nos.2019-069(to ZY)and 2019-300(to JY)+1 种基金the National Natural Science Foundation of China,Nos.32260196(to JY)a grant from Kunming Medical University,No.2024S085(to KL)。
文摘Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammation plays a significant role in the progression of these diseases.However,there is limited research on therapeutic approaches to specifically target neuroinflammation.The role of T lymphocytes,which are crucial mediators of the adaptive immune response,in neurodegenerative diseases has been increasingly recognized.This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases.The pathogenesis of neurodegenerative diseases is complex,involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons,and T cells are a key component of these processes.One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells,including microglia,astrocytes,B cells,and natural killer cells.Different subsets of CD4~+T cells,such as Th1,Th2,Th17,and regulatory T cells,can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases.Additionally,CD8~+T cells,which can directly regulate immune responses and kill target cells,also play several important roles in neurodegenerative diseases.Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that,while some patients respond positively,others may not respond as well and may even experience adverse effects.Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system,which can lead to undesirable side effects.However,with new insights into the pathophysiology of neurodegenerative diseases,there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.
基金supported by the National Natural Science Foundation of China,Nos.82271444(to JP),82271268(to BZ),and 82001346(to YL)the National Key Research and Development Program of China,No.2022YFE0210100(to BZ)。
文摘Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.
基金supported by grants from the National Key Research and Development Program of China,No.2017YFA0105400(to LR)the Key Research and Development Program of Guangdong Province,No.2019B020236002(to LR)the National Natural Science Foundation of China,Nos.81972111(to LZ),81772349(to BL).
文摘Microglia,the resident monocyte of the central nervous system,play a crucial role in the response to spinal cord injury.However,the precise mechanism remains unclear.To investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury,we performed single-cell RNA sequencing dataset analysis,focusing on changes in microglial subpopulations.We found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis,sphingomyelin metabolism,and neuroinflammation at high levels.Subsequently,we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord injury.Finally,we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron cells.Inhibiting ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced pyroptosis.Furthermore,ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling pathway.Inhibiting ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological function.Pla2g7 formed a“bridge”between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling pathway.Collectively,these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3,thereby exerting neuroprotective effects.
基金supported by the Research Foundation for Talented Scholars of Fujian Medical University,No.XRCZX2018014(to DZ)Startup Fund for Scientific Research,Fujian Medical University,No.2019QH1017(to CW)the Natural Science Foundation of Fujian Province,China,Nos.2021J01693(to DZ),2021J02032(to ZCY)。
文摘Previous studies have shown that the compound(E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one(D30),a pyromeconic acid derivative,possesses antioxidant and anti-inflammatory properties,inhibits amyloid-β aggregation,and alleviates scopolamine-induced cognitive impairment,similar to the phase Ⅲ clinical drug resveratrol.In this study,we established a mouse model of Alzheimer's disease via intracerebroventricular injection of fibrillar amyloid-β to investigate the effect of D30 on fibrillar amyloid-β-induced neuropathology.Our results showed that D30 alleviated fibrillar amyloid-β-induced cognitive impairment,promoted fibrillar amyloid-β clearance from the hippocampus and cortex,suppressed oxidative stress,and inhibited activation of microglia and astrocytes.D30 also reversed the fibrillar amyloid-β-induced loss of dendritic spines and synaptic protein expression.Notably,we demonstrated that exogenous fibrillar amyloid-βintroduced by intracerebroventricular injection greatly increased galectin-3 expression levels in the brain,and this increase was blocked by D30.Considering the role of D30 in clearing amyloid-β,inhibiting neuroinflammation,protecting synapses,and improving cognition,this study highlights the potential of galectin-3 as a promising treatment target for patients with Alzheimer's disease.
基金supported by the Department of Veterans Affairs(VA Merit Award BX004256)(to AMA)Emory Department of Neurosurgery Catalyst GrantEmory Medical Care Foundation Grant(to AMA and JG)。
文摘Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.
