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
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 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
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
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
Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report...Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.展开更多
Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s di...Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease(PD)in zebrafish.Methods:In the current study,zebrafish were treated with CBL at doses of 1.25,2.5,and 5 mL/kg body weight for 7 consecutive days.MPTP(20 mg/kg body weight)was administered on alternative days-1st,3rd,5th,and 7th.On day 7,zebrafish were sacrificed,and their brains were isolated for biochemical,neurochemical,histopathological,IHC,and neurotransmitter analysis.Results:The treatment with CBL significantly increased total distance traveled and the number of entries in the top zone,which was impaired by MPTP.CBL treatment significantly restored the level of glutathione,superoxide dismutase,and catalase while reducing malondialdehyde level.It also reduced the level of pro-inflammatory mediators interleukin-1β,interleukin-6,and tumor necrosis factor-αin the MPTP-induced PD in the zebrafish model.In histopathological evaluation,pyknotic cells and signs of inflammation were significantly reduced in CBL-treated groups.A significant dose-dependent reduction in glutamate,along with elevations in dopamine,gamma-aminobutyric acid,serotonin,and noradrenaline,was observed in zebrafish treated with CBL.An immunohistochemistry analysis demonstrated that Akt was phosphorylated promptly by CBL,which was downregulated in MPTP-induced PD in zebrafish.Conclusions:These findings suggest that CBL exerts a neuroprotective effect through activation of Akt and may hold therapeutic potential for the treatment of this devastating neurological condition.展开更多
Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative...Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative stress,and causes pro-inflammatory cytokine release,creating a neurotoxic environment.In this context,we explore the intricate connection between hypertension,neuroinflammation,and neurodegeneration,as well as how hypertension interacts with other metabolic disorders,such as obesity and diabetes,to further worsen neuroinflammation.Additionally,we discuss the role of the reninangiotensin-aldosterone system,the impact of the microbiome,and the potential contribution of chronic infections in exacerbating neuroinflammation.It is essential to emphasize the potential of nanotechnology to transform therapeutic approaches.Nanoparticle-based drug delivery systems can enhance the bioavailability and selectivity of antihypertensive drugs,antioxidants,and neuroprotective compounds,enabling targeted delivery across the BBB.By combining effective blood pressure management with nanotechnology-enabled therapies that modulate inflammation,oxidative stress,and protein aggregation,we can explore new avenues for preventing and treating hypertension and metabolic disorder-associated neurodegenerative conditions.Ultimately,hypertension significantly contributes to neuroinflammation and neurodegeneration by promoting neuronal cell death,primarily through impaired cerebral blood flow and disruption of the BBB.The interaction of hypertension with metabolic disorders exacerbates these effects.However,advancements in our understanding and new technologies reveal promising nanopharmacological approaches for targeted drug delivery to the brain,thereby improving treatment outcomes,enhancing adherence,and reducing side effects.展开更多
Background:Maternal viral infection during pregnancy can lead to maternal immune activation(MIA),increasing the risk of neurodevelopmental disorders in offspring.Amantadine(AMA)exhibits antiviral activity and is widel...Background:Maternal viral infection during pregnancy can lead to maternal immune activation(MIA),increasing the risk of neurodevelopmental disorders in offspring.Amantadine(AMA)exhibits antiviral activity and is widely employed in the management of neurologic conditions.Nevertheless,the efficacy of AMA in treating MIA is currently not established.Methods:MIA was induced by polyinosinic acid-polycytidylic acid(poly(I:C));AMA was administered from embryonic(E)day 11.5 for 3 days.BV-2 cells were stimulated using poly(I:C)and treated with AMA.Behavior was assessed via open field test,elevated plus maze test,three-chamber sociability test,and marble burying test.Neuronal morphology was vizualized using Nissl stain;apoptosis via TUNEL(terminal deoxynucleotidyl transferase dUTP nick-end labeling)stain;protein expression(Iba1,NeuN,CD68,TNF-α[tumor necrosis factor-alpha],IL-1β[interleukin-1β])using immunofluorescence(IF);interleukin-6(IL-6)levels using enzyme-linked immunosorbent assay;reactive oxygen species using staining;Iba1,NeuN,Bcl-2,Bax,and cleaved caspase 3 using Western blot;and gene expression changes using RNA-seq.Results:AMA treatment reduced the levels of IL-6 in maternal blood,improved autism-like behaviors in MIA offspring,and effectively prevented neuronal damage and neuroinflammation.In vitro cellular studies have demonstrated that AMA effectively downregulates the expression levels of pro-inflammatory cytokines,including IL-6,TNF-α,and IL-1β.RNA-seq analysis indicated that AMA mitigates abnormal activation of microglia by modulating inflammatory pathways associated with IL-6.Conclusion:AMA can prevent the development of neuropsychiatric disorders in MIA offspring.This effect may be related to its ability to attenuate neuronal damage,reduce neuronal apoptosis,and inhibit neuroinflammation,indicating that the antiviral drug AMA may be a potential treatment for MIA.展开更多
Stroke results from a sudden interruption of blood supply to the brain,causing ischemia,hypoxia,and subsequent brain tissue damage.It is the second leading cause of death worldwide and a major contributor to disabilit...Stroke results from a sudden interruption of blood supply to the brain,causing ischemia,hypoxia,and subsequent brain tissue damage.It is the second leading cause of death worldwide and a major contributor to disability.Despite significant advancements in cerebral ischemia-reperfusion strategies,patients remain vulnerable to ischemia/reperfusion injury,with neuroinflammation playing a central role.Evidence suggests that neuroinflammatory responses persist throughout the entire course of ischemic stroke.This review explores the diverse immune cell types and mechanisms involved in neuroinflammation,highlighting their neurotoxic and neuroprotective effects.Additionally,it examines various therapeutic approaches targeting neuroinflammation,offering a comprehensive reference for related research efforts.展开更多
Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in re...Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in reduced ATP synthesis,elevated reactive oxygen species(ROS)formation,and mitochondrial malfunction,which instigates oxidative stress and cellular damage,critical elements in neurodegenerative disorders like Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and Alzheimer’s disease(AD).In addition to causing direct neuronal injury,rotenone significantly contributes to the activation of glial cells,specifically microglia and astrocytes.Activated microglia assumes a proinflammatory(M1)phenotype,distinguished by the secretion of inflammatory cytokines including tumor necrosis factor alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),with the generation of nitric oxide and ROS,which exacerbate the neuronal injury.Astrocytes can intensify neuroinflammation by secreting proinflammatory molecules and impairing their neuroprotective roles.Our hypothesis is that rotenone is posited to elicit a neuroinflammatory response via mitochondrial malfunction,ROS generation,and the activation of proinflammatory pathways in microglia and astrocytes.This mechanism leads to accelerated neuronal impair-ment,promoting neurodegeneration.Comprehending the inflammatory pathways activated by rotenone is crucial for pinpointing therapeutic targets to regulate glial responses and mitigate the advancement of neurodegenerative disorders linked to mitochondrial malfunction and chronic inflammation.This review examines the function of glial cells and critical inflammatory pathways,namely Nuclear factor kappaβ(NF-κB),Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin(PI3K/AKT/mTOR),and Wnt/β-catenin signaling pathway in Parkinson’s disease,Alzheimer’s disease,and ALS,emphasizing illness-specific responses and the translational constraints of rotenone-based models.The objective is to consolidate existing understanding regarding the role of rotenone-induced mitochondrial failure in promoting glial activation and neuroinflammation,highlighting the necessity for additional research into these pathways.Despite the prevalent application of rotenone in experimental models,its specific effects on glial-mediated inflammation are inadequately comprehended,necessitating further investigation to guide the formulation of targeted therapeutic strategies.展开更多
Objective:To elucidate the specific mechanisms by which electroacupuncture(EA)alleviates anxiety and fear behaviors associated with posttraumatic stress disorder(PTSD),focusing on the role of lipocalin-2(Lcn2).Methods...Objective:To elucidate the specific mechanisms by which electroacupuncture(EA)alleviates anxiety and fear behaviors associated with posttraumatic stress disorder(PTSD),focusing on the role of lipocalin-2(Lcn2).Methods:The PTSD mouse model was subjected to single prolonged stress and shock(SPS&S),and the animals received 15 min sessions of EA at Shenmen acupoint(HT7).Behavioral tests were used to investigate the effects of EA at HT7 on anxiety and fear.Western blotting and enzyme-linked immunosorbent assay were used to quantify Lcn2 and inflammatory cytokine levels in the prefrontal cortex(PFC).Additionally,the activity of PFC neurons was evaluated by immunofluorescence and in vivo electrophysiology.Results:Mice subjected to SPS&S presented increased anxiety-and fear-like behaviors.Lcn2 expression in the PFC was significantly upregulated following SPS&S,leading to increased expression of the proinflammatory cytokines tumor necrosis factor-a and interleukin-6 and suppression of PFC neuronal activity.However,EA at HT7 inhibited Lcn2 release,reducing neuroinflammation and hypoexcitability in the PFC.Lcn2 overexpression mitigated the effects of EA at HT7,resulting in anxiety-and fear-like behaviors.Conclusion:EA at HT7 can ameliorate PTSD-associated anxiety and fear,and its mechanism of action appears to involve the inhibition of Lcn2-mediated neural activity and inflammation in the PFC.展开更多
Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondr...Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondrial respiratory complexes and metabolites,in controlling myeloid immune responses,is well-documented but not fully understood in diseases of the central nervous system (CNS).The groundbreaking study by Prof.Peruzzotti-Jametti et al.[1],entitled"Mitochondrial complexⅠactivity in microglia sustains neuroinflammation"published in Nature,delves into the intricate dynamics between mitochondrial function within microglia and the perpetuation of chronic neuroinflammation,specifically in MS.The core point of their investigation is the hypothesis that mitochondrial complexⅠ(CI) activity,through a mechanism known as reverse electron transport (RET),generates reactive oxygen species (ROS) in microglia,thereby sustaining inflammatory response in the CNS.This increases ROS production from the mitochondria,which is thought to be a crucial factor in the maintenance of a pro-inflammatory state in the microglia,contributing to the pathology of MS and similar neuroinflammatory diseases.展开更多
BACKGROUND Human mesenchymal stromal cells(MSCs)possess regenerative potential due to pluripotency and paracrine functions.However,their stemness and immunomod-ulatory capabilities are sub-optimal in conventional two-...BACKGROUND Human mesenchymal stromal cells(MSCs)possess regenerative potential due to pluripotency and paracrine functions.However,their stemness and immunomod-ulatory capabilities are sub-optimal in conventional two-dimensional(2D)culture.AIM To enhance the efficiency and therapeutic efficacy of MSCs,an in vivo-like 3D culture condition was applied.METHODS MSCs were cultured on polystyrene(2D)or in a gellan gum-based 3D system.In vitro,prostaglandin-endoperoxide synthase 2,indoleamine-2,3-dioxygenase,heme oxygenase 1,and prostaglandin E synthase gene expression was quantified by quantitative real-time polymerase chain reaction.MSCs were incubated with lipopolysaccharide(LPS)-treated mouse splenocytes,and prostaglandin E2 and tumor necrosis factor-alpha levels were measured by enzyme linked immuno-sorbent assay.In vivo,LPS was injected into the lateral ventricle of mouse brain,and MSCs were administered intravenously the next day.Animals were sacrificed and analyzed on days 2 and 6.RESULTS Gellan gum polymer-based 3D culture significantly increased expression of octamer-binding transcription factor 4 and Nanog homeobox stemness markers in human MSCs compared to 2D culture.This 3D environment also heightened expression of cyclooxygenase-2 and heme-oxygenase 1,enzymes known for immunomodulatory functions,including production of prostaglandins and heme degradation,respectively.MSCs in 3D culture secreted more prostaglandin E2 and effectively suppressed tumor necrosis factor-alpha release from LPS-stimulated splenocytes and surpassed the efficiency of MSCs cultured in 2D.In a murine neuroinflammation model,intravenous injection of 3D-cultured MSCs significantly reduced ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein expression,mitigating chronic inflammation more effectively than 2D-cultured MSCs.CONCLUSION The microenvironment established in 3D culture serves as an in vivo mimetic,enhancing the immunomodulatory function of MSCs.This suggests that engineered MSCs hold significant promise a potent tool for cell therapy.展开更多
BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,...BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,over 30%of patients suffer from drug-resistant epilepsy,which can lead to severe cognitive impairments and adverse psychosocial outcomes.AIM To explore the role of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy,providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each,and the TLE model group was established by injecting kainic acid.BMSCs were isolated from the mice,and exosomes were purified using ultracentrifugation.Exosomal miR-203 was identified and characterized using highthroughput sequencing and quantitative reverse-transcription polymerase chain reaction.The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice.In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons,resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway,ultimately leading to enhanced secretion of pro-inflammatory cytokines.CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy.The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway,thus providing a potential avenue for the development of cell-free therapeutics.展开更多
Microglia,the resident immune cells in the central nervous system(CNS),rapidly transition from a resting to an active state in the acute phase of ischemic brain injury.This active state mediates a pro-inflammatory res...Microglia,the resident immune cells in the central nervous system(CNS),rapidly transition from a resting to an active state in the acute phase of ischemic brain injury.This active state mediates a pro-inflammatory response that can exacerbate the injury.Targeting the pro-inflammatory response of microglia in the semi-dark band during this acute phase may effectively reduce brain injury.Shionone(SH),an active ingredient extracted from the dried roots and rhizomes of the genus Aster(Asteraceae),has been reported to regulate the inflammatory response of macrophages in sepsis-induced acute lung injury.However,its function in post-stroke neuroinflammation,particularly microglia-mediated neuroinflammation,remains uninvestigated.This study found that SH significantly inhibited lipopolysaccharide(LPS)-induced elevation of inflammatory cytokines,including interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and inducible nitric oxide synthase(iNOS),in microglia in vitro.Furthermore,the results demonstrated that SH alleviated infarct volume and improved behavioral performance in middle cerebral artery occlusion(MCAO)mice,which may be attributed to the inhibition of the microglial inflammatory response induced by SH treatment.Mechanistically,SH potently inhibited the phosphorylation of serine-threonine protein kinase B(AKT),mammalian target of rapamycin(mTOR),and signal transducer and activator of transcription 3(STAT3).These findings suggest that SH may be a potential therapeutic agent for relieving ischemic stroke(IS)by alleviating microglia-associated neuroinflammation.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 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 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.
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 National Natural Science Foundation of China,Nos.82171429,81771384a grant from Wuxi Municipal Health Commission,No.1286010241190480(all to YS)。
文摘Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.
基金funded by ICMR,New Delhi(Grant No.45/29/2022-PHA/BMS).
文摘Objective:To investigate the effect of cerebrolysin(CBL)on motor impairment,neuroinflammation,oxidative stress,and neurotransmitter profile in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease(PD)in zebrafish.Methods:In the current study,zebrafish were treated with CBL at doses of 1.25,2.5,and 5 mL/kg body weight for 7 consecutive days.MPTP(20 mg/kg body weight)was administered on alternative days-1st,3rd,5th,and 7th.On day 7,zebrafish were sacrificed,and their brains were isolated for biochemical,neurochemical,histopathological,IHC,and neurotransmitter analysis.Results:The treatment with CBL significantly increased total distance traveled and the number of entries in the top zone,which was impaired by MPTP.CBL treatment significantly restored the level of glutathione,superoxide dismutase,and catalase while reducing malondialdehyde level.It also reduced the level of pro-inflammatory mediators interleukin-1β,interleukin-6,and tumor necrosis factor-αin the MPTP-induced PD in the zebrafish model.In histopathological evaluation,pyknotic cells and signs of inflammation were significantly reduced in CBL-treated groups.A significant dose-dependent reduction in glutamate,along with elevations in dopamine,gamma-aminobutyric acid,serotonin,and noradrenaline,was observed in zebrafish treated with CBL.An immunohistochemistry analysis demonstrated that Akt was phosphorylated promptly by CBL,which was downregulated in MPTP-induced PD in zebrafish.Conclusions:These findings suggest that CBL exerts a neuroprotective effect through activation of Akt and may hold therapeutic potential for the treatment of this devastating neurological condition.
基金Supported by Agencia Nacional de Promoción de la Investigación,el Desarrollo Tecnológico y la Innovación,No.PICT 2020 Serie A 4000.
文摘Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative stress,and causes pro-inflammatory cytokine release,creating a neurotoxic environment.In this context,we explore the intricate connection between hypertension,neuroinflammation,and neurodegeneration,as well as how hypertension interacts with other metabolic disorders,such as obesity and diabetes,to further worsen neuroinflammation.Additionally,we discuss the role of the reninangiotensin-aldosterone system,the impact of the microbiome,and the potential contribution of chronic infections in exacerbating neuroinflammation.It is essential to emphasize the potential of nanotechnology to transform therapeutic approaches.Nanoparticle-based drug delivery systems can enhance the bioavailability and selectivity of antihypertensive drugs,antioxidants,and neuroprotective compounds,enabling targeted delivery across the BBB.By combining effective blood pressure management with nanotechnology-enabled therapies that modulate inflammation,oxidative stress,and protein aggregation,we can explore new avenues for preventing and treating hypertension and metabolic disorder-associated neurodegenerative conditions.Ultimately,hypertension significantly contributes to neuroinflammation and neurodegeneration by promoting neuronal cell death,primarily through impaired cerebral blood flow and disruption of the BBB.The interaction of hypertension with metabolic disorders exacerbates these effects.However,advancements in our understanding and new technologies reveal promising nanopharmacological approaches for targeted drug delivery to the brain,thereby improving treatment outcomes,enhancing adherence,and reducing side effects.
基金Collaborative Innovation Project of Zigong Medical Big Data and Artificial Intelligence Research Institute,Grant/Award Number:2023-YGY-1-02 and 2024-YGY-02-04National Natural Science Foundation of China,Grant/Award Number:31900950+4 种基金Project Supported by the Natural Science Basic Research Plan in Shaanxi Province of China,Grant/Award Number:2024JCYBMS-706National Key Research and Development Program of China,Grant/Award Number:2022YFC2009900Zigong Science and Technology Program,Grant/Award Number:2023YKY11Scientific Research Project of Zigong Health Commission,Grant/Award Number:22yb001 and 24zd008Key Science and Technology Plan Projects in Zigong,Grant/Award Number:2022ZCNKY07,2023-NKY-01-02,2023-NKY-02-13 and 2023-NKY-02-14。
文摘Background:Maternal viral infection during pregnancy can lead to maternal immune activation(MIA),increasing the risk of neurodevelopmental disorders in offspring.Amantadine(AMA)exhibits antiviral activity and is widely employed in the management of neurologic conditions.Nevertheless,the efficacy of AMA in treating MIA is currently not established.Methods:MIA was induced by polyinosinic acid-polycytidylic acid(poly(I:C));AMA was administered from embryonic(E)day 11.5 for 3 days.BV-2 cells were stimulated using poly(I:C)and treated with AMA.Behavior was assessed via open field test,elevated plus maze test,three-chamber sociability test,and marble burying test.Neuronal morphology was vizualized using Nissl stain;apoptosis via TUNEL(terminal deoxynucleotidyl transferase dUTP nick-end labeling)stain;protein expression(Iba1,NeuN,CD68,TNF-α[tumor necrosis factor-alpha],IL-1β[interleukin-1β])using immunofluorescence(IF);interleukin-6(IL-6)levels using enzyme-linked immunosorbent assay;reactive oxygen species using staining;Iba1,NeuN,Bcl-2,Bax,and cleaved caspase 3 using Western blot;and gene expression changes using RNA-seq.Results:AMA treatment reduced the levels of IL-6 in maternal blood,improved autism-like behaviors in MIA offspring,and effectively prevented neuronal damage and neuroinflammation.In vitro cellular studies have demonstrated that AMA effectively downregulates the expression levels of pro-inflammatory cytokines,including IL-6,TNF-α,and IL-1β.RNA-seq analysis indicated that AMA mitigates abnormal activation of microglia by modulating inflammatory pathways associated with IL-6.Conclusion:AMA can prevent the development of neuropsychiatric disorders in MIA offspring.This effect may be related to its ability to attenuate neuronal damage,reduce neuronal apoptosis,and inhibit neuroinflammation,indicating that the antiviral drug AMA may be a potential treatment for MIA.
基金supported by the National Science Foundation of Foundation of Hebei Province China(H2024110042).
文摘Stroke results from a sudden interruption of blood supply to the brain,causing ischemia,hypoxia,and subsequent brain tissue damage.It is the second leading cause of death worldwide and a major contributor to disability.Despite significant advancements in cerebral ischemia-reperfusion strategies,patients remain vulnerable to ischemia/reperfusion injury,with neuroinflammation playing a central role.Evidence suggests that neuroinflammatory responses persist throughout the entire course of ischemic stroke.This review explores the diverse immune cell types and mechanisms involved in neuroinflammation,highlighting their neurotoxic and neuroprotective effects.Additionally,it examines various therapeutic approaches targeting neuroinflammation,offering a comprehensive reference for related research efforts.
文摘Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain.This inhibition results in reduced ATP synthesis,elevated reactive oxygen species(ROS)formation,and mitochondrial malfunction,which instigates oxidative stress and cellular damage,critical elements in neurodegenerative disorders like Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and Alzheimer’s disease(AD).In addition to causing direct neuronal injury,rotenone significantly contributes to the activation of glial cells,specifically microglia and astrocytes.Activated microglia assumes a proinflammatory(M1)phenotype,distinguished by the secretion of inflammatory cytokines including tumor necrosis factor alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),with the generation of nitric oxide and ROS,which exacerbate the neuronal injury.Astrocytes can intensify neuroinflammation by secreting proinflammatory molecules and impairing their neuroprotective roles.Our hypothesis is that rotenone is posited to elicit a neuroinflammatory response via mitochondrial malfunction,ROS generation,and the activation of proinflammatory pathways in microglia and astrocytes.This mechanism leads to accelerated neuronal impair-ment,promoting neurodegeneration.Comprehending the inflammatory pathways activated by rotenone is crucial for pinpointing therapeutic targets to regulate glial responses and mitigate the advancement of neurodegenerative disorders linked to mitochondrial malfunction and chronic inflammation.This review examines the function of glial cells and critical inflammatory pathways,namely Nuclear factor kappaβ(NF-κB),Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin(PI3K/AKT/mTOR),and Wnt/β-catenin signaling pathway in Parkinson’s disease,Alzheimer’s disease,and ALS,emphasizing illness-specific responses and the translational constraints of rotenone-based models.The objective is to consolidate existing understanding regarding the role of rotenone-induced mitochondrial failure in promoting glial activation and neuroinflammation,highlighting the necessity for additional research into these pathways.Despite the prevalent application of rotenone in experimental models,its specific effects on glial-mediated inflammation are inadequately comprehended,necessitating further investigation to guide the formulation of targeted therapeutic strategies.
基金supported by the Anhui Provincial Department of Education Outstanding Young Teachers Cultivation Key Project(No.YQZD2023046)the Anhui University of Traditional Chinese Medicine School Talent Support Program Project(Nos.DT2400000222 and DT2100000545)。
文摘Objective:To elucidate the specific mechanisms by which electroacupuncture(EA)alleviates anxiety and fear behaviors associated with posttraumatic stress disorder(PTSD),focusing on the role of lipocalin-2(Lcn2).Methods:The PTSD mouse model was subjected to single prolonged stress and shock(SPS&S),and the animals received 15 min sessions of EA at Shenmen acupoint(HT7).Behavioral tests were used to investigate the effects of EA at HT7 on anxiety and fear.Western blotting and enzyme-linked immunosorbent assay were used to quantify Lcn2 and inflammatory cytokine levels in the prefrontal cortex(PFC).Additionally,the activity of PFC neurons was evaluated by immunofluorescence and in vivo electrophysiology.Results:Mice subjected to SPS&S presented increased anxiety-and fear-like behaviors.Lcn2 expression in the PFC was significantly upregulated following SPS&S,leading to increased expression of the proinflammatory cytokines tumor necrosis factor-a and interleukin-6 and suppression of PFC neuronal activity.However,EA at HT7 inhibited Lcn2 release,reducing neuroinflammation and hypoexcitability in the PFC.Lcn2 overexpression mitigated the effects of EA at HT7,resulting in anxiety-and fear-like behaviors.Conclusion:EA at HT7 can ameliorate PTSD-associated anxiety and fear,and its mechanism of action appears to involve the inhibition of Lcn2-mediated neural activity and inflammation in the PFC.
基金supported by the Taishan Scholars Program of Shandong Province(tsqn202312344).
文摘Multiple sclerosis (MS) is characterized by chronic,slowly expanding lesions with the accumulation of myeloid cells,which lead to brain atrophy and progressive disability.The role of mitochondria,especially mitochondrial respiratory complexes and metabolites,in controlling myeloid immune responses,is well-documented but not fully understood in diseases of the central nervous system (CNS).The groundbreaking study by Prof.Peruzzotti-Jametti et al.[1],entitled"Mitochondrial complexⅠactivity in microglia sustains neuroinflammation"published in Nature,delves into the intricate dynamics between mitochondrial function within microglia and the perpetuation of chronic neuroinflammation,specifically in MS.The core point of their investigation is the hypothesis that mitochondrial complexⅠ(CI) activity,through a mechanism known as reverse electron transport (RET),generates reactive oxygen species (ROS) in microglia,thereby sustaining inflammatory response in the CNS.This increases ROS production from the mitochondria,which is thought to be a crucial factor in the maintenance of a pro-inflammatory state in the microglia,contributing to the pathology of MS and similar neuroinflammatory diseases.
基金Supported by National Research Foundation of Korea,No.RS-2024-00409554,No.2023R1A2C2006894,and No.2021R1A6A3A01088243.
文摘BACKGROUND Human mesenchymal stromal cells(MSCs)possess regenerative potential due to pluripotency and paracrine functions.However,their stemness and immunomod-ulatory capabilities are sub-optimal in conventional two-dimensional(2D)culture.AIM To enhance the efficiency and therapeutic efficacy of MSCs,an in vivo-like 3D culture condition was applied.METHODS MSCs were cultured on polystyrene(2D)or in a gellan gum-based 3D system.In vitro,prostaglandin-endoperoxide synthase 2,indoleamine-2,3-dioxygenase,heme oxygenase 1,and prostaglandin E synthase gene expression was quantified by quantitative real-time polymerase chain reaction.MSCs were incubated with lipopolysaccharide(LPS)-treated mouse splenocytes,and prostaglandin E2 and tumor necrosis factor-alpha levels were measured by enzyme linked immuno-sorbent assay.In vivo,LPS was injected into the lateral ventricle of mouse brain,and MSCs were administered intravenously the next day.Animals were sacrificed and analyzed on days 2 and 6.RESULTS Gellan gum polymer-based 3D culture significantly increased expression of octamer-binding transcription factor 4 and Nanog homeobox stemness markers in human MSCs compared to 2D culture.This 3D environment also heightened expression of cyclooxygenase-2 and heme-oxygenase 1,enzymes known for immunomodulatory functions,including production of prostaglandins and heme degradation,respectively.MSCs in 3D culture secreted more prostaglandin E2 and effectively suppressed tumor necrosis factor-alpha release from LPS-stimulated splenocytes and surpassed the efficiency of MSCs cultured in 2D.In a murine neuroinflammation model,intravenous injection of 3D-cultured MSCs significantly reduced ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein expression,mitigating chronic inflammation more effectively than 2D-cultured MSCs.CONCLUSION The microenvironment established in 3D culture serves as an in vivo mimetic,enhancing the immunomodulatory function of MSCs.This suggests that engineered MSCs hold significant promise a potent tool for cell therapy.
文摘BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,over 30%of patients suffer from drug-resistant epilepsy,which can lead to severe cognitive impairments and adverse psychosocial outcomes.AIM To explore the role of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy,providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each,and the TLE model group was established by injecting kainic acid.BMSCs were isolated from the mice,and exosomes were purified using ultracentrifugation.Exosomal miR-203 was identified and characterized using highthroughput sequencing and quantitative reverse-transcription polymerase chain reaction.The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice.In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons,resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway,ultimately leading to enhanced secretion of pro-inflammatory cytokines.CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy.The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway,thus providing a potential avenue for the development of cell-free therapeutics.
基金supported by the National Natural Science Foundation of China(Nos.81920108017 and 82130036)the Key Research and Development Program of Jiangsu Province of China(No.BE2020620)Jiangsu Province Key Medical Discipline(No.ZDXKA2016020)。
文摘Microglia,the resident immune cells in the central nervous system(CNS),rapidly transition from a resting to an active state in the acute phase of ischemic brain injury.This active state mediates a pro-inflammatory response that can exacerbate the injury.Targeting the pro-inflammatory response of microglia in the semi-dark band during this acute phase may effectively reduce brain injury.Shionone(SH),an active ingredient extracted from the dried roots and rhizomes of the genus Aster(Asteraceae),has been reported to regulate the inflammatory response of macrophages in sepsis-induced acute lung injury.However,its function in post-stroke neuroinflammation,particularly microglia-mediated neuroinflammation,remains uninvestigated.This study found that SH significantly inhibited lipopolysaccharide(LPS)-induced elevation of inflammatory cytokines,including interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and inducible nitric oxide synthase(iNOS),in microglia in vitro.Furthermore,the results demonstrated that SH alleviated infarct volume and improved behavioral performance in middle cerebral artery occlusion(MCAO)mice,which may be attributed to the inhibition of the microglial inflammatory response induced by SH treatment.Mechanistically,SH potently inhibited the phosphorylation of serine-threonine protein kinase B(AKT),mammalian target of rapamycin(mTOR),and signal transducer and activator of transcription 3(STAT3).These findings suggest that SH may be a potential therapeutic agent for relieving ischemic stroke(IS)by alleviating microglia-associated neuroinflammation.
