The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections(XNJ) on cerebral ischemia injury and blood-brain barrier(BBB) disruption. Middle cerebral artery occlusion(MCAO) ...The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections(XNJ) on cerebral ischemia injury and blood-brain barrier(BBB) disruption. Middle cerebral artery occlusion(MCAO) method was applicated to establish the model of cerebral ischemia/reperfusion(I/R) injury in rats. BBB permeability after I/R injury was assessed with the leaking amount of Evans Blue and the expression of occludin and ZO-1. The expression of NOD-like receptor family, pyrin domain containing(NLRP3) was checked to explore the inhibition of inflammation by XNJ. The results showed that XNJ could significantly increase the survival percent, decrease the infarct area and ameliorate neurological deficits and brain damage after I/R injury. Leaking amount of Evans Blue was reduced by XNJ, and the expression of tight junction protein, occludin and ZO-1 was also up-regulated by XNJ, which showed a role of protection on BBB disruption. The expression of NLRP3 was inhibited after exposure of XNJ, which was associated with inhibition of the inflammatory response. In summary, XNJ could suppress NLRP3 inflammasomes and improve BBB disruption and brain damage in rats after cerebral I/R injury, which provided a beneficial insight to further explore XNJ.展开更多
Streptococcus mutans(S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin(IL...Streptococcus mutans(S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin(IL)-1β, a proinflammatory cytokine, is related to the host defences against pathogens, and its synthesis, maturation, and secretion are tightly regulated by the activation of the inflammasome, an inflammatory signalling complex. This study examined the signalling mechanism of IL-1β secretion and the inflammasome pathway induced by S. mutans to explain the molecular mechanism through which systemic infection by oral streptococci can occur. After infection of THP-1 cells with S. mutans, the expression of inflammasome components was detected using various methods. S. mutans induced IL-1β secretion via caspase-1 activation, and S. mutans-induced IL-1β secretion required absent in melanoma(AIM2), NLR family pyrin domain-containing 3(NLRP3) and NLR family CARD domain-containing 4(NLRC4)inflammasome activation. In particular, the S. mutans-induced NLRP3 inflammasome was mediated by adenosine triphosphate(ATP) release, potassium depletion and lysosomal damage. Our study provides novel insight into the innate immune response against S. mutans infection.展开更多
Inflammation plays an important role in atherosclerosis.Inflammasomes play a crucial role in innate immunity,which mediates the body’s response to various pathogens.Of the different types of inflammasomes,NLRP3 has b...Inflammation plays an important role in atherosclerosis.Inflammasomes play a crucial role in innate immunity,which mediates the body’s response to various pathogens.Of the different types of inflammasomes,NLRP3 has been implicated in atherosclerosis through the production of proinfl ammatory cytokines,IL-1β and IL-18.This review describes the role of the NLRP3 infl ammasome in atherosclerosis and discusses potential therapeutic targets in the infl ammasome pathway.展开更多
Major depressive disorder(MDD)is highly prevalent and is a significant cause of mortality and morbidity worldwide.Currently,conventional pharmacological treatments for MDD produce temporary remission in<50%of patie...Major depressive disorder(MDD)is highly prevalent and is a significant cause of mortality and morbidity worldwide.Currently,conventional pharmacological treatments for MDD produce temporary remission in<50%of patients;therefore,there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms.Accumulated evidence has shown that immune inflammation,particularly inflammasome activity,plays an important role in the pathophysiology of MDD.In this review,we summarize the evidence on nuclear receptors(NRs),such as glucocorticoid receptor,mineralocorticoid receptor,estrogen receptor,aryl hydrocarbon receptor,and peroxisome proliferator-activated receptor,in modulating the inflammasome activity and depression-associated behaviors.This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD,and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.展开更多
Autoimmune diseases are immune disorders in which the immune system mistakenly targets and attacks the normal cells,tissues,and organs of the patients.The etiology of autoimmune diseases is complex and multifactorial....Autoimmune diseases are immune disorders in which the immune system mistakenly targets and attacks the normal cells,tissues,and organs of the patients.The etiology of autoimmune diseases is complex and multifactorial.This review aims to provide a general introduction to the immunological functions of inflammasomes and describe the role of inflammasomes in disorders characterized by self-directed inflammation,with a particular focus on several common autoimmune diseases.We reviewed current research on the mechanisms of inflammasome activation and inflammasomes'contribution to autoimmune diseases.Inhibitors targeting inflammasome components were also explored for their potential in therapeutic applications.With increasing research on mechanisms of inflammation of the pathologic conditions,accumulated evidence suggests that the aberrant or uncontrolled activation of inflammasomes contributes to the pathogenesis and development of autoimmune diseases.Additionally,inflammasome-targeting drugs have shown promise in treating autoimmune diseases.Insights into the mechanisms governing inflammasome activation and their roles in autoimmune diseases could contribute to the development of novel anti-inflammatory drugs for the prevention and treatment of autoimmune diseases with enhanced targeting precision and reduced adverse reactions.展开更多
Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a...Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a Food and Drug Administration(FDA)-approved cannabidiol(CBD),in improving brain function in a rat model of chronic GWI.Methods:Six months after exposure to low doses of GWI-related chemicals[pyridostigmine bromide,N,N-diethyl-meta-toluamide(DEET),and permethrin(PER)]along with moderate stress,rats with chronic GWI were administered either vehicle(VEH)or CBD(20 mg/kg,oral)for 16 weeks.Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory,object location memory,pattern separation,and sucrose preference.The effect of CBD on hyperalgesia was also examined.The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.Results:GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia,whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia.Additionally,CBD treatment alleviated hyperalgesia in GWI rats.Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription(JAK/STAT)signaling.Furthermore,there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis.In contrast,the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling,normalized concentrations of proinflammatory cytokines and oxidative stress markers,and improved neurogenesis.Notably,CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.Conclusions:The use of an FDA-approved CBD(Epidiolex®)has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI.Importantly,the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.展开更多
Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela ...Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.展开更多
Inflammasomes represent a crucial component of the innate immune system,which respond to threats by recognizing different molecules.These are known as pathogen-associated molecular patterns(PAMPs)or host-derived damag...Inflammasomes represent a crucial component of the innate immune system,which respond to threats by recognizing different molecules.These are known as pathogen-associated molecular patterns(PAMPs)or host-derived damage-associated molecular patterns(DAMPs).In neurodegenerative diseases and neuroinflammation,the accumulation of misfolded proteins,such as beta-amyloid and alpha-synuclein,can lead to inflammasome activation,resulting in the release of interleukin(IL)-1βand IL-18.This activation also induces pyroptosis,the release of inflammatory mediators,and exacerbates neuroinflammation.Increasing evidence suggests that inflammasomes play a pivotal role in neurodegenerative diseases.Therefore,elucidating and investigating the activation and regulation of inflammasomes in these diseases is of paramount importance.This review is primarily focused on evidence indicating that inflammasomes are activated through the canonical pathway in these diseases.Inflammasomes as potential targets for treating neurodegenerative diseases are also discussed.展开更多
AIM:To determine the therapeutic benefits of fenofibrate(Feno)on the dysfunction of high glucose(HG)-induced human retinal microvascular endothelial cells(HRMECs)and to elucidate the underlying molecular mechanism.MET...AIM:To determine the therapeutic benefits of fenofibrate(Feno)on the dysfunction of high glucose(HG)-induced human retinal microvascular endothelial cells(HRMECs)and to elucidate the underlying molecular mechanism.METHODS:HRMEC dysfunction model was established by 48h glucose(30 mmol/L)treatment and treated with Feno/NOD-like receptor thermal protein domain associated protein 3(NLRP3)inflammasome activator(Nigericin).Cell viability/apoptosis were assessed by cell counting kit-8(CCK-8)/terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay(TUNEL)staining and flow cytometry assays.Levels of apoptosis-(Bcl-2-associated X protein,Bax/B-cell lymphoma 2,Bcl-2),vascular permeability-(vascular endothelial growth factor,VEGF)and inflammasome activation-related proteins(NLRP3/cleaved caspase-1/apoptosis-associated speck-like protein containing a CARD,ASC),as well as inflammatory factors(interleukin,IL-6/IL-1β/tumor necrosis factor,TNF-α/IL-18)were determined with Western blot/enzyme linked immunosorbent assay(ELISA).Cell permeability/reactive oxygen species(ROS)level/superoxide dismutase(SOD)activity/malondialdehyde(MDA)content were assessed by Evans blue staining/2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA)fluorescent probe/SOD kit/MDA kit.RESULTS:HRMEC dysfunction was successfully induced by HG,evidenced by decreased viability(P<0.001),increased apoptosis(P<0.001),permeability(P<0.001),and inflammatory factor levels(P<0.001).Feno treatment significantly ameliorated HG-induced HRMEC dysfunction(P<0.01).Meanwhile,HG induction increased ROS production(P<0.001)and MDA content(P<0.001)in HRMECs,while reducing SOD activity(P<0.001),indicative of oxidative stress.This was,however,abolished by Feno(P<0.05).Moreover,Feno eliminated activation of NLRP3 inflammasomes(P<0.05)in HG-induced HRMECs.Strikingly,activation of NLRP3 inflammasomes partially averted the inhibition of Feno on HG-induced HRMEC dysfunction(P<0.05).CONCLUSION:Feno represses oxidative stress and NLRP3 inflammasome activation,consequently alleviating HG-induced HRMEC dysfunction.展开更多
Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release f...In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.展开更多
Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangle...Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangles,in the brain.The NLRP3 inflammasome may play a role in the transition from amyloid-βdeposition to tau phosphorylation and aggregation.Because NLRP3 is primarily found in brain microglia,and tau is predominantly located in neurons,it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines.Here,we found that neurons also express NLRP3 in vitro and in vivo,and that neuronal NLRP3 regulates tau phosphorylation.Using biochemical methods,we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons.In primary neurons and the neuroblastoma cell line Neuro2A,FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-βis present.In the brains of aged wild-type mice and a mouse model of Alzheimer's disease,FUBP3 expression was markedly increased in cortical neurons.Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses.We also found that FUBP3 trimmed the 5′end of DNA fragments that it bound,implying that FUBP3 functions in stress-induced responses.These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3,and that amyloid-βfundamentally alters the regulatory mechanism of NLRP3 expression in neurons.Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice,FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.展开更多
The NOD-like receptor protein 3(NLRP3)inflammasome is essential in innate immune-mediated inflammation,with its overactivation implicated in various autoinflammatory,metabolic,and neurodegenerative diseases.Pharmacolo...The NOD-like receptor protein 3(NLRP3)inflammasome is essential in innate immune-mediated inflammation,with its overactivation implicated in various autoinflammatory,metabolic,and neurodegenerative diseases.Pharmacological inhibition of NLRP3 offers a promising treatment strategy for inflammatory conditions,although no medications targeting the NLRP3 inflammasome are currently available.This study demonstrates that clioquinol(CQ),a clinical drug with chelating properties,effectively inhibits NLRP3 activation,resulting in reduced cytokine secretion and cell pyroptosis in both human and mouse macrophages,with a half maximal inhibitory concentration(IC_(50))of 0.478 mM.Additionally,CQ mitigates experimental acute peritonitis,gouty arthritis,sepsis,and colitis by lowering serum levels of interleukin-1β(IL-1β),IL-6,and tumor necrosis factor-α(TNF-α).Mechanistically,CQ covalently binds to Arginine 335(R335)in the NACHT domain,inhibiting NLRP3 inflammasome assembly and blocking the interaction between NLRP3 and its component protein.Collectively,this study identifies CQ as an effective natural NLRP3 inhibitor and a potential therapeutic agent for NLRP3-driven diseases.展开更多
Background:Recent research showed that the NLRP3 inflammasome was activated in the central nervous system of mice administered chronic ethanol(EtOH).Dictyophora polysaccharides(DIPs)are essential components of the val...Background:Recent research showed that the NLRP3 inflammasome was activated in the central nervous system of mice administered chronic ethanol(EtOH).Dictyophora polysaccharides(DIPs)are essential components of the valuable edible fungus Dictyophora,which has antioxidant properties that can delay the aging process of the body.This study aimed to investigate the roles of NLRP3 in chronic EtOH-induced cerebellar Purkinje cell(PC)degeneration and behavioral changes.Methods:C57BL/6J normal and NLRP3 knockout mice were exposed to EtOH for 14 days.Dictyophora polysaccharide(DIP)and NLRP3 inhibitor were administered to the EtOH mice.The pathology and NLRP3-ASC-caspase-1 signaling pathway proteins were analyzed in EtOH mice cerebellar tissues and behavioral performance was assessed in the mice.Results:In the EtOH mouse model,we observed increases in the NLRP3 inflammasome proteins,including NLRP3,ASC,caspase-1,mature IL-1βand pro IL-1β,loss of PCs,and motor coordination disorders.We found that DIPs could suppress the NLRP3-ASC-caspase-1 signaling pathway,and alleviate the motor deficits and cerebellar pathological changes in chronic EtOH mice.Next,we used MCC950,a NLRP3 inhibitor,and an NLRP3 knockout strategy to further verify the effects of NLRP3-ASC-caspase-1 signaling in chronic EtOH mice.MCC950 or NLRP3 knockout alleviated the EtOH-induced latency to decreases in fall time,increases in stride width and decreases in stride length.MCC950 or NLRP3 knockout also attenuated PC number loss and suppressed NLRP3 inflammation induced by EtOH.Taken together,pharmacologically or genetically inhibiting NLRP3 alleviated EtOH-induced cerebellar degeneration and behavioral deficits.Conclusion:These findings indicated that DIPs might diminish EtOH-induced cerebellar degeneration and behavioral deficits through the NLRP3-ASC-caspase-1 signaling pathway,which provides a potential therapeutic target for the prevention and treatment of alcoholism and EtOH-induced cerebellar pathology.展开更多
Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and t...Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing.There are currently no effective strategies for slowing the progression of AD.Herein,we spotlight the dysregulation of lipid metabolism,particularly the elevation of ceramides(Cers),as a critical yet underexplored facet of AD pathogenesis.Our study delineates the role of Cers in promoting microglial pyroptosis,a form of programmed cell death distinct from apoptosis and necroptosis,characterized by cellular swelling,and membrane rupture mediated by the NLRP3 inflammasome pathway.Utilizing both in vivo experiments with amyloid precursor protein(APP)/presenilin 1(PS1)transgenic mice and in vitro assays with BV-2 microglial cells,we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin(ICA),a flavonoid with known antioxidant and anti-inflammatory properties.Our findings reveal a significant increase in Cers levels and pyroptosis markers(NOD-like receptor family,pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain,caspase-1,gasdermin D(GSDMD),and interleukin-18(IL-18))in the brains of AD model mice,indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis.Conversely,ICA treatment effectively reduces these pyroptotic markers and Cer levels,thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD.This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy,capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2(COX-2)-NLRP3 inflammasome-gasdermin D(GSDMD)axis.Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.展开更多
NLRP3 inflammasome activation is pivotal for cytokine secretion and pyroptosis in response to diverse stimuli,playing a crucial role in innate immunity.While extensively studied in mammals,the regulatory mechanisms go...NLRP3 inflammasome activation is pivotal for cytokine secretion and pyroptosis in response to diverse stimuli,playing a crucial role in innate immunity.While extensively studied in mammals,the regulatory mechanisms governing NLRP3 activation in non-mammalian vertebrates remain largely unexplored.Teleosts,as basal vertebrates,represent an ideal model for exploring the evolutionary trajectory of inflammasome regulation.In this study,ABE assays,confocal microscopy,and biochemical analyses were applied to systematically characterize the mechanisms underlying NLRP3 inflammasome in teleosts,using large yellow croakers(Larimichthys crocea,Lc)and zebrafish(Danio rerio,Dr)as representative models.Our findings revealed a previously unrecognized palmitoylation-dependent regulatory mechanism essential for teleost NLRP3 activation.Specifically,zDHHC18-mediated palmitoylation at a teleost-specific cysteine residue(C946 in LcNLRP3,C1037 in DrNLRP3)was required for the translocation of NLRP3 to the dispersed trans-Golgi network,facilitating its subsequent recruitment to the microtubule-organizing center.This membrane trafficking was crucial for inflammasome assembly and downstream inflammatory responses.These findings provide new insights into the distinct regulatory mechanisms of NLRP3 activation in teleosts,highlighting an evolutionary divergence that contributes to innate immunity adaptation in early vertebrates.展开更多
AIM:To investigate whether pyroptosis contributes to retinal ganglion cell(RGC)degeneration in aged TgAPPswePS1 transgenic mice and to explore the relationship between amyloid-beta(Aβ)accumulation and activation of t...AIM:To investigate whether pyroptosis contributes to retinal ganglion cell(RGC)degeneration in aged TgAPPswePS1 transgenic mice and to explore the relationship between amyloid-beta(Aβ)accumulation and activation of the pyroptotic pathway in the retina.METHODS:The twelve 18-month-old TgAPPswePS1 transgenic mice and twelve 18-month-old wild-type C57BL/6J mice were used to investigate amyloid precursor protein(APP)and Aβexpression,retinal structural changes,and activation of pyroptosis in RGCs.Immunohistochemical analyses were performed to detect APP,Aβ,and pyroptosisrelated proteins[NOD-like receptor thermal protein domain associated protein 3(NLRP3),caspase-1,gasdermin D(GSDMD),interleukin(IL)-1β,and IL-18].Quantitative assessments of retinal nerve fiber layer(RNFL)thickness were conducted to evaluate retinal integrity.RESULTS:Compared to age-matched wild-type controls,TgAPPswePS1 transgenic mice exhibited significant upregulation of APP and Aβwithin RGCs.Histological analysis revealed reduced RNFL thickness,indicating structural degeneration.Notably,RGCs in transgenic mice showed robust immunoreactivity for NLRP3,caspase-1,and GSDMD,alongside elevated levels of IL-1βand IL-18,supporting the activation of pyroptosis.CONCLUSION:Aβaccumulation in RGCs is associated with retinal degeneration and activation of the pyroptosis pathway in aged TgAPPswePS1 mice.This study provides new insights into the inflammatory mechanisms underlying Aβ-related retinal neurodegeneration and suggests that targeting pyroptosis may represent a promising therapeutic strategy for retinal disorders linked to amyloid pathology.展开更多
Background:Alzheimer's disease(AD)is a progressive neurodegenerative disease with no effective therapies.It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD.Wel...Background:Alzheimer's disease(AD)is a progressive neurodegenerative disease with no effective therapies.It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD.Well-balanced neuronal-microglial interactions are essential for brain functions.However,determining the role of microglia—the primary immune cells in the brain—in neuroinflammation in AD and the associated molecular basis has been challenging.Methods:Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed.The mechanism for microglial inflammation was investigated.IL6 and TNF-α were found to be significantly increased in the AD stage.Results:Our analysis revealed that microglia were extensively activated in AD cerebra,releasing sufficient amounts of cytokines to impair the neural stem cells(NSCs)function.Moreover,the ApoD-induced NLRC4 inflammasome was activated in microglia,which gave rise to the proinflammatory phenotype.Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis.These findings demonstrate the critical role of ApoD in microglial inflammasome activation,and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation.Conclusion:Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD),characterized by fatty acid overload,secondary chronic inflammation,and fibrosis,has become the most prevalent chronic liver disease globally.While no effect...Metabolic dysfunction-associated fatty liver disease(MAFLD),characterized by fatty acid overload,secondary chronic inflammation,and fibrosis,has become the most prevalent chronic liver disease globally.While no effective pharmacotherapy exists for MAFLD,mitigating inflammatory responses represents a promising approach to preventing the progression from steatosis to severe steatohepatitis.The NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome,which detects endogenous danger and stress signals,has emerged as a significant target for inflammatory disease treatment,as transcriptional inactivation of its components demonstrates the therapeutic potential for MAFLD.Natural products targeting NLRP3 inflammasome activation have shown promising efficacy in MAFLD therapy.This review synthesizes the current understanding of NLRP3 inflammasome activation and therapeutic targets for NLRP3 homeostasis.Additionally,natural products reported to inhibit NLRP3 inflammasome for MAFLD improvement are categorized according to their mechanisms of action.The review also addresses limitations and future directions regarding natural products targeting NLRP3 inflammasome in MAFLD treatment.Enhanced understanding of NLRP3 inflammasome activation mechanisms in MAFLD and the identification of novel natural products supported by mechanistic research will significantly advance MAFLD treatment.展开更多
基金surported by the National Natural Science Foundation of China(No.81803608)the Administration of Traditional Chinese Medicine of Jilin Province,China(No.2019133)
文摘The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections(XNJ) on cerebral ischemia injury and blood-brain barrier(BBB) disruption. Middle cerebral artery occlusion(MCAO) method was applicated to establish the model of cerebral ischemia/reperfusion(I/R) injury in rats. BBB permeability after I/R injury was assessed with the leaking amount of Evans Blue and the expression of occludin and ZO-1. The expression of NOD-like receptor family, pyrin domain containing(NLRP3) was checked to explore the inhibition of inflammation by XNJ. The results showed that XNJ could significantly increase the survival percent, decrease the infarct area and ameliorate neurological deficits and brain damage after I/R injury. Leaking amount of Evans Blue was reduced by XNJ, and the expression of tight junction protein, occludin and ZO-1 was also up-regulated by XNJ, which showed a role of protection on BBB disruption. The expression of NLRP3 was inhibited after exposure of XNJ, which was associated with inhibition of the inflammatory response. In summary, XNJ could suppress NLRP3 inflammasomes and improve BBB disruption and brain damage in rats after cerebral I/R injury, which provided a beneficial insight to further explore XNJ.
基金A National Research Foundation of Korea (NRF) grant funded by the government of South Korea (MEST no. 2012R1A2A2A01015470) supported this research
文摘Streptococcus mutans(S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin(IL)-1β, a proinflammatory cytokine, is related to the host defences against pathogens, and its synthesis, maturation, and secretion are tightly regulated by the activation of the inflammasome, an inflammatory signalling complex. This study examined the signalling mechanism of IL-1β secretion and the inflammasome pathway induced by S. mutans to explain the molecular mechanism through which systemic infection by oral streptococci can occur. After infection of THP-1 cells with S. mutans, the expression of inflammasome components was detected using various methods. S. mutans induced IL-1β secretion via caspase-1 activation, and S. mutans-induced IL-1β secretion required absent in melanoma(AIM2), NLR family pyrin domain-containing 3(NLRP3) and NLR family CARD domain-containing 4(NLRC4)inflammasome activation. In particular, the S. mutans-induced NLRP3 inflammasome was mediated by adenosine triphosphate(ATP) release, potassium depletion and lysosomal damage. Our study provides novel insight into the innate immune response against S. mutans infection.
文摘Inflammation plays an important role in atherosclerosis.Inflammasomes play a crucial role in innate immunity,which mediates the body’s response to various pathogens.Of the different types of inflammasomes,NLRP3 has been implicated in atherosclerosis through the production of proinfl ammatory cytokines,IL-1β and IL-18.This review describes the role of the NLRP3 infl ammasome in atherosclerosis and discusses potential therapeutic targets in the infl ammasome pathway.
基金the National Natural Science Foundation of China,No.31650005.
文摘Major depressive disorder(MDD)is highly prevalent and is a significant cause of mortality and morbidity worldwide.Currently,conventional pharmacological treatments for MDD produce temporary remission in<50%of patients;therefore,there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms.Accumulated evidence has shown that immune inflammation,particularly inflammasome activity,plays an important role in the pathophysiology of MDD.In this review,we summarize the evidence on nuclear receptors(NRs),such as glucocorticoid receptor,mineralocorticoid receptor,estrogen receptor,aryl hydrocarbon receptor,and peroxisome proliferator-activated receptor,in modulating the inflammasome activity and depression-associated behaviors.This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD,and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.
基金supported by the Ministry of Science and Technology of the People's Republic of China,Grant/Award Number:2023YFC2306102National Natural Science Foundation of China,Grant/Award Number:32130038.
文摘Autoimmune diseases are immune disorders in which the immune system mistakenly targets and attacks the normal cells,tissues,and organs of the patients.The etiology of autoimmune diseases is complex and multifactorial.This review aims to provide a general introduction to the immunological functions of inflammasomes and describe the role of inflammasomes in disorders characterized by self-directed inflammation,with a particular focus on several common autoimmune diseases.We reviewed current research on the mechanisms of inflammasome activation and inflammasomes'contribution to autoimmune diseases.Inhibitors targeting inflammasome components were also explored for their potential in therapeutic applications.With increasing research on mechanisms of inflammation of the pathologic conditions,accumulated evidence suggests that the aberrant or uncontrolled activation of inflammasomes contributes to the pathogenesis and development of autoimmune diseases.Additionally,inflammasome-targeting drugs have shown promise in treating autoimmune diseases.Insights into the mechanisms governing inflammasome activation and their roles in autoimmune diseases could contribute to the development of novel anti-inflammatory drugs for the prevention and treatment of autoimmune diseases with enhanced targeting precision and reduced adverse reactions.
基金supported by grants from Jazz Pharmaceuticals Inc.the Texas A&M University of School of Medicine to AKS
文摘Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a Food and Drug Administration(FDA)-approved cannabidiol(CBD),in improving brain function in a rat model of chronic GWI.Methods:Six months after exposure to low doses of GWI-related chemicals[pyridostigmine bromide,N,N-diethyl-meta-toluamide(DEET),and permethrin(PER)]along with moderate stress,rats with chronic GWI were administered either vehicle(VEH)or CBD(20 mg/kg,oral)for 16 weeks.Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory,object location memory,pattern separation,and sucrose preference.The effect of CBD on hyperalgesia was also examined.The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.Results:GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia,whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia.Additionally,CBD treatment alleviated hyperalgesia in GWI rats.Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription(JAK/STAT)signaling.Furthermore,there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis.In contrast,the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling,normalized concentrations of proinflammatory cytokines and oxidative stress markers,and improved neurogenesis.Notably,CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.Conclusions:The use of an FDA-approved CBD(Epidiolex®)has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI.Importantly,the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.
文摘Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.
基金supported by grants from National Natural Science Foundation of China(82003973)National Natural Science Foundation of China(82304750)Hunan University of Chinese Medicine Research Fund Outstanding Youth Project(Z2023XJYQ02).
文摘Inflammasomes represent a crucial component of the innate immune system,which respond to threats by recognizing different molecules.These are known as pathogen-associated molecular patterns(PAMPs)or host-derived damage-associated molecular patterns(DAMPs).In neurodegenerative diseases and neuroinflammation,the accumulation of misfolded proteins,such as beta-amyloid and alpha-synuclein,can lead to inflammasome activation,resulting in the release of interleukin(IL)-1βand IL-18.This activation also induces pyroptosis,the release of inflammatory mediators,and exacerbates neuroinflammation.Increasing evidence suggests that inflammasomes play a pivotal role in neurodegenerative diseases.Therefore,elucidating and investigating the activation and regulation of inflammasomes in these diseases is of paramount importance.This review is primarily focused on evidence indicating that inflammasomes are activated through the canonical pathway in these diseases.Inflammasomes as potential targets for treating neurodegenerative diseases are also discussed.
基金Supported by grants from the Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-037A).
文摘AIM:To determine the therapeutic benefits of fenofibrate(Feno)on the dysfunction of high glucose(HG)-induced human retinal microvascular endothelial cells(HRMECs)and to elucidate the underlying molecular mechanism.METHODS:HRMEC dysfunction model was established by 48h glucose(30 mmol/L)treatment and treated with Feno/NOD-like receptor thermal protein domain associated protein 3(NLRP3)inflammasome activator(Nigericin).Cell viability/apoptosis were assessed by cell counting kit-8(CCK-8)/terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay(TUNEL)staining and flow cytometry assays.Levels of apoptosis-(Bcl-2-associated X protein,Bax/B-cell lymphoma 2,Bcl-2),vascular permeability-(vascular endothelial growth factor,VEGF)and inflammasome activation-related proteins(NLRP3/cleaved caspase-1/apoptosis-associated speck-like protein containing a CARD,ASC),as well as inflammatory factors(interleukin,IL-6/IL-1β/tumor necrosis factor,TNF-α/IL-18)were determined with Western blot/enzyme linked immunosorbent assay(ELISA).Cell permeability/reactive oxygen species(ROS)level/superoxide dismutase(SOD)activity/malondialdehyde(MDA)content were assessed by Evans blue staining/2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA)fluorescent probe/SOD kit/MDA kit.RESULTS:HRMEC dysfunction was successfully induced by HG,evidenced by decreased viability(P<0.001),increased apoptosis(P<0.001),permeability(P<0.001),and inflammatory factor levels(P<0.001).Feno treatment significantly ameliorated HG-induced HRMEC dysfunction(P<0.01).Meanwhile,HG induction increased ROS production(P<0.001)and MDA content(P<0.001)in HRMECs,while reducing SOD activity(P<0.001),indicative of oxidative stress.This was,however,abolished by Feno(P<0.05).Moreover,Feno eliminated activation of NLRP3 inflammasomes(P<0.05)in HG-induced HRMECs.Strikingly,activation of NLRP3 inflammasomes partially averted the inhibition of Feno on HG-induced HRMEC dysfunction(P<0.05).CONCLUSION:Feno represses oxidative stress and NLRP3 inflammasome activation,consequently alleviating HG-induced HRMEC dysfunction.
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金supported by the National Natural Science Foundation of China,No.81971269 (to DP)the Science and Technology Commission of Shanghai,No.YDZX20213100001003 (to DP)。
文摘In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.
基金supported by a grant from Key Laboratory of Alzheimer's Disease of Zhejiang Province,Institute of Aging,Wenzhou Medical University,No.ZJAD-2021002(to ZW)。
文摘Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangles,in the brain.The NLRP3 inflammasome may play a role in the transition from amyloid-βdeposition to tau phosphorylation and aggregation.Because NLRP3 is primarily found in brain microglia,and tau is predominantly located in neurons,it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines.Here,we found that neurons also express NLRP3 in vitro and in vivo,and that neuronal NLRP3 regulates tau phosphorylation.Using biochemical methods,we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons.In primary neurons and the neuroblastoma cell line Neuro2A,FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-βis present.In the brains of aged wild-type mice and a mouse model of Alzheimer's disease,FUBP3 expression was markedly increased in cortical neurons.Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses.We also found that FUBP3 trimmed the 5′end of DNA fragments that it bound,implying that FUBP3 functions in stress-induced responses.These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3,and that amyloid-βfundamentally alters the regulatory mechanism of NLRP3 expression in neurons.Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice,FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82101417,81920108017,and 82130036)the STI2030-Major Projects(Project No.:2022ZD0211800)+2 种基金Jiangsu Province Key Medical Discipline(Grant No.:ZDXK202216)the Key Research and Development Program of Jiangsu Province of China(Program No.:BE2020620)Nanjing Medical Science and technology development Foundation,China(Grant No.:YKK20061).
文摘The NOD-like receptor protein 3(NLRP3)inflammasome is essential in innate immune-mediated inflammation,with its overactivation implicated in various autoinflammatory,metabolic,and neurodegenerative diseases.Pharmacological inhibition of NLRP3 offers a promising treatment strategy for inflammatory conditions,although no medications targeting the NLRP3 inflammasome are currently available.This study demonstrates that clioquinol(CQ),a clinical drug with chelating properties,effectively inhibits NLRP3 activation,resulting in reduced cytokine secretion and cell pyroptosis in both human and mouse macrophages,with a half maximal inhibitory concentration(IC_(50))of 0.478 mM.Additionally,CQ mitigates experimental acute peritonitis,gouty arthritis,sepsis,and colitis by lowering serum levels of interleukin-1β(IL-1β),IL-6,and tumor necrosis factor-α(TNF-α).Mechanistically,CQ covalently binds to Arginine 335(R335)in the NACHT domain,inhibiting NLRP3 inflammasome assembly and blocking the interaction between NLRP3 and its component protein.Collectively,this study identifies CQ as an effective natural NLRP3 inhibitor and a potential therapeutic agent for NLRP3-driven diseases.
基金Guizhou Provincial Science and Technology Projects,Grant/Award Number:Qian Science Foundation-ZK[2023]General 328Guizhou Provincial Education Department Young Scientific Talent,Grant/Award Number:Qianjiaoji[2024]93+3 种基金National Natural Science Foundation of China,Grant/Award Number:42077313Natural Science Foundation of Guizhou Medical University Incubation Program,Grant/Award Number:20NSP084Research Foundation for Advanced Talents of Guizhou Medical University,Grant/Award Number:University Contract of Doctors J[2021]014Guizhou Provincial 2020 Science and Technology Subsidies,Grant/Award Number:GZ 2020SIG。
文摘Background:Recent research showed that the NLRP3 inflammasome was activated in the central nervous system of mice administered chronic ethanol(EtOH).Dictyophora polysaccharides(DIPs)are essential components of the valuable edible fungus Dictyophora,which has antioxidant properties that can delay the aging process of the body.This study aimed to investigate the roles of NLRP3 in chronic EtOH-induced cerebellar Purkinje cell(PC)degeneration and behavioral changes.Methods:C57BL/6J normal and NLRP3 knockout mice were exposed to EtOH for 14 days.Dictyophora polysaccharide(DIP)and NLRP3 inhibitor were administered to the EtOH mice.The pathology and NLRP3-ASC-caspase-1 signaling pathway proteins were analyzed in EtOH mice cerebellar tissues and behavioral performance was assessed in the mice.Results:In the EtOH mouse model,we observed increases in the NLRP3 inflammasome proteins,including NLRP3,ASC,caspase-1,mature IL-1βand pro IL-1β,loss of PCs,and motor coordination disorders.We found that DIPs could suppress the NLRP3-ASC-caspase-1 signaling pathway,and alleviate the motor deficits and cerebellar pathological changes in chronic EtOH mice.Next,we used MCC950,a NLRP3 inhibitor,and an NLRP3 knockout strategy to further verify the effects of NLRP3-ASC-caspase-1 signaling in chronic EtOH mice.MCC950 or NLRP3 knockout alleviated the EtOH-induced latency to decreases in fall time,increases in stride width and decreases in stride length.MCC950 or NLRP3 knockout also attenuated PC number loss and suppressed NLRP3 inflammation induced by EtOH.Taken together,pharmacologically or genetically inhibiting NLRP3 alleviated EtOH-induced cerebellar degeneration and behavioral deficits.Conclusion:These findings indicated that DIPs might diminish EtOH-induced cerebellar degeneration and behavioral deficits through the NLRP3-ASC-caspase-1 signaling pathway,which provides a potential therapeutic target for the prevention and treatment of alcoholism and EtOH-induced cerebellar pathology.
基金supported by the National Natural Science Foundation of China(Grant No.:82374552)Hunan Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.:2024JJ2086)+1 种基金the Science and Technology Innovation Program of Hunan Province,China(Grant No.:2022RC1220)Support Plan for High-level Health and Medical Talents in Hunan Province,China.
文摘Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing.There are currently no effective strategies for slowing the progression of AD.Herein,we spotlight the dysregulation of lipid metabolism,particularly the elevation of ceramides(Cers),as a critical yet underexplored facet of AD pathogenesis.Our study delineates the role of Cers in promoting microglial pyroptosis,a form of programmed cell death distinct from apoptosis and necroptosis,characterized by cellular swelling,and membrane rupture mediated by the NLRP3 inflammasome pathway.Utilizing both in vivo experiments with amyloid precursor protein(APP)/presenilin 1(PS1)transgenic mice and in vitro assays with BV-2 microglial cells,we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin(ICA),a flavonoid with known antioxidant and anti-inflammatory properties.Our findings reveal a significant increase in Cers levels and pyroptosis markers(NOD-like receptor family,pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain,caspase-1,gasdermin D(GSDMD),and interleukin-18(IL-18))in the brains of AD model mice,indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis.Conversely,ICA treatment effectively reduces these pyroptotic markers and Cer levels,thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD.This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy,capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2(COX-2)-NLRP3 inflammasome-gasdermin D(GSDMD)axis.Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.
基金supported by the National Natural Science Foundation of China (32473194)Natural Science Foundation of Zhejiang Province (LY23C190002)+1 种基金Natural Science Foundation of Ningbo City (202003N4011)One Health Interdisciplinary Research Project of Ningbo University (HZ202201)。
文摘NLRP3 inflammasome activation is pivotal for cytokine secretion and pyroptosis in response to diverse stimuli,playing a crucial role in innate immunity.While extensively studied in mammals,the regulatory mechanisms governing NLRP3 activation in non-mammalian vertebrates remain largely unexplored.Teleosts,as basal vertebrates,represent an ideal model for exploring the evolutionary trajectory of inflammasome regulation.In this study,ABE assays,confocal microscopy,and biochemical analyses were applied to systematically characterize the mechanisms underlying NLRP3 inflammasome in teleosts,using large yellow croakers(Larimichthys crocea,Lc)and zebrafish(Danio rerio,Dr)as representative models.Our findings revealed a previously unrecognized palmitoylation-dependent regulatory mechanism essential for teleost NLRP3 activation.Specifically,zDHHC18-mediated palmitoylation at a teleost-specific cysteine residue(C946 in LcNLRP3,C1037 in DrNLRP3)was required for the translocation of NLRP3 to the dispersed trans-Golgi network,facilitating its subsequent recruitment to the microtubule-organizing center.This membrane trafficking was crucial for inflammasome assembly and downstream inflammatory responses.These findings provide new insights into the distinct regulatory mechanisms of NLRP3 activation in teleosts,highlighting an evolutionary divergence that contributes to innate immunity adaptation in early vertebrates.
基金Supported by Natural Science Foundation of Zhejiang Province(No.LY18H120009)Wenzhou Basic Scientific Research Project(No.2025K0279)+1 种基金Xi’an Health and Wellness Committee General Cultivation Project(No.2023ms08)Shaanxi Province Health and Health High-Level Talents(Team)Training Program Young Talents Project.
文摘AIM:To investigate whether pyroptosis contributes to retinal ganglion cell(RGC)degeneration in aged TgAPPswePS1 transgenic mice and to explore the relationship between amyloid-beta(Aβ)accumulation and activation of the pyroptotic pathway in the retina.METHODS:The twelve 18-month-old TgAPPswePS1 transgenic mice and twelve 18-month-old wild-type C57BL/6J mice were used to investigate amyloid precursor protein(APP)and Aβexpression,retinal structural changes,and activation of pyroptosis in RGCs.Immunohistochemical analyses were performed to detect APP,Aβ,and pyroptosisrelated proteins[NOD-like receptor thermal protein domain associated protein 3(NLRP3),caspase-1,gasdermin D(GSDMD),interleukin(IL)-1β,and IL-18].Quantitative assessments of retinal nerve fiber layer(RNFL)thickness were conducted to evaluate retinal integrity.RESULTS:Compared to age-matched wild-type controls,TgAPPswePS1 transgenic mice exhibited significant upregulation of APP and Aβwithin RGCs.Histological analysis revealed reduced RNFL thickness,indicating structural degeneration.Notably,RGCs in transgenic mice showed robust immunoreactivity for NLRP3,caspase-1,and GSDMD,alongside elevated levels of IL-1βand IL-18,supporting the activation of pyroptosis.CONCLUSION:Aβaccumulation in RGCs is associated with retinal degeneration and activation of the pyroptosis pathway in aged TgAPPswePS1 mice.This study provides new insights into the inflammatory mechanisms underlying Aβ-related retinal neurodegeneration and suggests that targeting pyroptosis may represent a promising therapeutic strategy for retinal disorders linked to amyloid pathology.
基金supported by the Guiding Science and Technology Development Grant in the Social Sector of Luoyang(2101083A)。
文摘Background:Alzheimer's disease(AD)is a progressive neurodegenerative disease with no effective therapies.It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD.Well-balanced neuronal-microglial interactions are essential for brain functions.However,determining the role of microglia—the primary immune cells in the brain—in neuroinflammation in AD and the associated molecular basis has been challenging.Methods:Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed.The mechanism for microglial inflammation was investigated.IL6 and TNF-α were found to be significantly increased in the AD stage.Results:Our analysis revealed that microglia were extensively activated in AD cerebra,releasing sufficient amounts of cytokines to impair the neural stem cells(NSCs)function.Moreover,the ApoD-induced NLRC4 inflammasome was activated in microglia,which gave rise to the proinflammatory phenotype.Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis.These findings demonstrate the critical role of ApoD in microglial inflammasome activation,and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation.Conclusion:Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.
基金supported by the National Natural Science Foundation of China(No.82304587)Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology(No.2025HYTP076)+2 种基金Introduction Program Project of Henan Province for Foreign Expert(No.HNGD2022032)Henan Science and Technology Project(No.242102310507,No.252102310496)China Postdoctoral Science Foundation(No.2024M750816)。
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD),characterized by fatty acid overload,secondary chronic inflammation,and fibrosis,has become the most prevalent chronic liver disease globally.While no effective pharmacotherapy exists for MAFLD,mitigating inflammatory responses represents a promising approach to preventing the progression from steatosis to severe steatohepatitis.The NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome,which detects endogenous danger and stress signals,has emerged as a significant target for inflammatory disease treatment,as transcriptional inactivation of its components demonstrates the therapeutic potential for MAFLD.Natural products targeting NLRP3 inflammasome activation have shown promising efficacy in MAFLD therapy.This review synthesizes the current understanding of NLRP3 inflammasome activation and therapeutic targets for NLRP3 homeostasis.Additionally,natural products reported to inhibit NLRP3 inflammasome for MAFLD improvement are categorized according to their mechanisms of action.The review also addresses limitations and future directions regarding natural products targeting NLRP3 inflammasome in MAFLD treatment.Enhanced understanding of NLRP3 inflammasome activation mechanisms in MAFLD and the identification of novel natural products supported by mechanistic research will significantly advance MAFLD treatment.
