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
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
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
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
BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies hav...BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies have shown that Transmembrane protein 176B(TMEM176B)regulates NLRP3 and promotes CRC malignant phenotypes.AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells,BALB/c mice,and primary cultured mouse natural killer(NK)cells.Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells.Fluorescence imaging,Terminal deoxynucleotidyl transferase dUTP nick end labeling assays,immunohistochemistry staining,flow cytometry,and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis,apoptosis,and EMT indicators.RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis,proliferation,and EMT,while activating apoptosis,NLRP3 inflammasome,and NK cell activity.Furthermore,silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion,and promoted apoptosis.The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65,matrix metallopeptidase 9,and transforming growth factor-β.CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.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
Background:Noninfectious uveitis,a chronic ocular inflammatory disease,is char-acterized by the activation of immune cells in the eye,with most studies focusing on the role of the adaptive immune system in the disease...Background:Noninfectious uveitis,a chronic ocular inflammatory disease,is char-acterized by the activation of immune cells in the eye,with most studies focusing on the role of the adaptive immune system in the disease.However,limited data exist on the potential contribution of the innate immune system,specifically the nucleotide-binding oligomerization domain and leucine-rich repeat receptor-3(NLRP3)inflamma-some pathway.This pathway has previously been identified as a driver of inflammation in several low-grade,progressive inflammatory eye diseases such as diabetic retin-opathy.The aim of this study was to determine whether the NLRP3 inflammasome pathway plays a role in the pathogenesis and chronicity of experimental autoimmune uveitis(EAU).Methods:EAU was induced in C57BL/6J mice via intraperitoneal pertussis toxin and subcutaneous interphotoreceptor retinoid-binding protein injections.After 12 weeks,eyes were enucleated,and whole eye sections were assessed for inflammasome,macrophage,and microglial markers in the retina,ciliary body,and cornea using immunohistochemistry.Results:Our study confirmed higher NLRP3 inflammasome activation(increased ex-pression of NLRP3 and cleaved caspase 1 labeling)in EAU mouse retinas compared to controls.This correlated with increased astrogliosis and microglial activation through-out the eye.Migratory innate and adaptive peripheral immune cells(macrophages and leukocytes)were also found within the retina and ciliary body of EAU mice.Connexin43 proteins,which form hexameric hemichannels that can release adeno-sine triphosphate(ATP),an upstream inflammasome priming signal,were also found upregulated in the retina and cornea of EAU mice.Conclusion:Overall,our findings support the idea that in the EAU model there is active inflammation,even 12 weeks post induction,and that it can be correlated to inflammasome activation.This contributes to the pathogenesis and chronicity of non-infectious uveitis,and our results emphasize that targeting the inflammasome path-way could be efficacious for noninfectious uveitis treatment.展开更多
This article provides commentary on the article by Zhang et al.In this original research,Zhang et al investigated the therapeutic potential of teneligliptin for diabetic cardiomyopathy(DCM),which was mediated by targe...This article provides commentary on the article by Zhang et al.In this original research,Zhang et al investigated the therapeutic potential of teneligliptin for diabetic cardiomyopathy(DCM),which was mediated by targeting the NOD-like receptor protein 3(NLRP3)inflammasome.Through the use of both in vivo and in vitro models,the study demonstrated that teneligliptin alleviates cardiac hyper-trophy,reduces myocardial injury,and mitigates the inflammatory responses as-sociated with DCM.These findings suggest that teneligliptin’s cardioprotective effects are mediated through the inhibition of NLRP3 inflammasome activation,positioning it as a promising therapeutic option for managing DCM in diabetic patients.展开更多
Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have...Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.展开更多
Previous studies have demonstrated a bidirectional relationship between inflammation and depression.Activation of the nucleotide-binding oligomerization domain,leucine-rich repeat,and NLR family pyrin domain-containin...Previous studies have demonstrated a bidirectional relationship between inflammation and depression.Activation of the nucleotide-binding oligomerization domain,leucine-rich repeat,and NLR family pyrin domain-containing 3(NLRP3)inflammasomes is closely related to the pathogenesis of various neurological diseases.In patients with major depressive disorder,NLRP3 inflammasome levels are significantly elevated.Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies.In this review,we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome.Moreover,we outlined various therapeutic strategies that target the NLRP3 inflammasome,including NLRP3 inflammatory pathway inhibitors,natural compounds,and other therapeutic compounds that have been shown to be effective in treating depression.Additionally,we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression.Currently,there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment.The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression.Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments.展开更多
Spinal cord injury-induced motor dysfunction is associated with neuroinflammation.Studies have shown that the triterpenoid lupenone,a natural product found in various plants,has a remarkable anti-inflammatory effect i...Spinal cord injury-induced motor dysfunction is associated with neuroinflammation.Studies have shown that the triterpenoid lupenone,a natural product found in various plants,has a remarkable anti-inflammatory effect in the context of chronic inflammation.However,the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown.In this study,we established an impact-induced mouse model of spinal cord injury,and then treated the injured mice with lupenone(8 mg/kg,twice a day)by intrape ritoneal injection.We also treated BV2 cells with lipopolysaccharide and adenosine5’-triphosphate to simulate the inflammatory response after spinal cord injury.Our res ults showed that lupenone reduced IKBa activation and p65 nuclear translocation,inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B,and enhanced the conve rsion of proinflammatory M1 mic roglial cells into anti-inflammatory M2 microglial cells.Furthermore,lupenone decreased NLRP3 inflammasome activation,NLRP3-induced mic roglial cell polarization,and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway.These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.展开更多
Depression ranks among the most common neuropsychiatric disorders globally.Current studies examining the roles of inflammation and mitochondrial autophagy in the antidepressant efficacy of paeoniflorin(PF)are sparse.T...Depression ranks among the most common neuropsychiatric disorders globally.Current studies examining the roles of inflammation and mitochondrial autophagy in the antidepressant efficacy of paeoniflorin(PF)are sparse.This study aimed to elucidate PF’s antidepressant mechanism by promoting autophagy and inhibiting NLRP3 inflammasome activation using chronic unpredictable mild stimulation(CUMS)-induced C57BL/6 mouse models in vivo and corticosterone(CORT)-induced HT22 cell models in vitro.Results demonstrated that PF enhanced the viability of HT22 cells following CORT exposure,restored mitochondrial membrane poten-tial(MMP),reduced reactive oxygen species accumulation,increased LC3 fluorescence intensity,and suppressed inflammatory cy-tokine secretion and inflammation activation.Additionally,PF ameliorated depressive behaviors induced by CUMS and improved damage in hippocampal neurons.It also reduced the expression of NLRP3,ASC,Caspase-1,IL-1β,and the assembly of the NLRP3 in-flammasome.Moreover,PF upregulated the expression of autophagy-related proteins in the hippocampus,facilitating the clearance of damaged mitochondria and enhancing autophagy.The role of autophagy in PF’s antidepressant effects was further confirmed through the use of the autophagy inhibitor 3-methyladenine(3-MA),which reduced the efficacy of PF.In conclusion,PF effectively improved depressive behaviors in CUMS-induced mice and reduced NLRP3-mediated inflammation both in vivo and in vitro,likely via the in-duction of autophagy.展开更多
Microplastics(MPs)have attracted growing attention worldwide as an increasingly prevalent environmental pollutant.In addition,chicken meat is currently the most widely consumed kind of poultry in the global market.Con...Microplastics(MPs)have attracted growing attention worldwide as an increasingly prevalent environmental pollutant.In addition,chicken meat is currently the most widely consumed kind of poultry in the global market.Consumer demand for chicken is on the rise both at home and abroad.As a result,the safety of chicken raising has also received significant attention.The lungs play an essential role in the physiological activities of chickens,and they are also the most vulnerable organs.Lung injury is difficult to repair after the accumulation of contaminants,and the mortality rate is high,which brings huge economic losses to farmers.The research on the toxicity of MPs has mainly focused on the marine ecosystem,while the mechanisms of toxicity and lung damage in chickens have been poorly studied.Thus,this study explored the effects of exposure to polystyrene microplastics(PS-MPs)at various concentrations for 42 d on chicken lungs.PS-MPs could cause lung pathologies and ultrastructural abnormalities,such as endoplasmic reticulum(ER)swelling,inflammatory cell infiltration,chromatin agglutination,and plasma membrane rupture.Simultaneously,PS-MPs increased the expression of genes related to the heat shock protein family(Hsp60,Hsp70,and Hsp90),ER stress signaling(activating) transcription factor 6(ATF0),ATF4,protein kinase RNA-like ER kinase(PERK),and eukaryotic translation initiation factor 2 subunitα(eIF2a),pyroptosis-related genes(NOD)-,LRR-and pyrin domain-containing protein 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC),interleukin-1β(IL-1β),cysteinyl aspartate-specific proteinase 1(Caspasel),and gasdermin-D(GSDMD),and the inflammatory signaling pathway(nuclear factor-kB(NF-kB),inducible nitric oxide synthase(iNOS),and cyclooxygenase-2(COX-2).The above results showed that PS-MP exposure could result in lung stress,ER stress,pyroptosis,and inflammation in broilers.Our findings provide new scientific clues for further research on the mechanisms of physical health and toxicology regardingMPs.展开更多
Ulcerative colitis(UC)is a chronic recurrent inflammatory bowel disease.Despite ongoing advances in our understanding of UC,its pathogenesis is yet unelu-cidated,underscoring the urgent need for novel treatment strate...Ulcerative colitis(UC)is a chronic recurrent inflammatory bowel disease.Despite ongoing advances in our understanding of UC,its pathogenesis is yet unelu-cidated,underscoring the urgent need for novel treatment strategies for patients with UC.Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules,such as proteins,RNAs,DNA,and metabolites.The NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β(IL-1β)and IL-18,triggering the inflammatory response to a pathogenic agent or injury.Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome,with vital roles in the pathological process of UC.Here,recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC.First,the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized.Finally,an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are high-lighted.展开更多
Inulin-type fructan CP-A,a predominant polysaccharide in Codonopsis pilosula,demonstrates regulatory effects on immune activity and anti-inflammation.The efficacy of CP-A in treating ulcerative colitis(UC)is,however,n...Inulin-type fructan CP-A,a predominant polysaccharide in Codonopsis pilosula,demonstrates regulatory effects on immune activity and anti-inflammation.The efficacy of CP-A in treating ulcerative colitis(UC)is,however,not well-established.This study employed an in vitro lipopolysaccharide(LPS)-induced colonic epithelial cell model(NCM460)and an in vivo dextran sulfate sodium(DSS)-induced colitis mouse model to explore CP-A’s protective effects against experimental colitis and its underlying mechanisms.We monitored the clinical symptoms in mice using various parameters:body weight,disease activity index(DAI),colon length,spleen weight,and histopathological scores.Additionally,molecular markers were assessed through enzyme-linked immunosorbent assay(ELISA),quantitative real-time polymerase chain reaction(qRT-PCR),immunofluorescence(IF),immunohistochemistry(IHC),and Western blotting assays.Results showed that CP-A significantly reduced reactive oxygen species(ROS),tumor necrosis factor-alpha(TNF-α),and interleukins(IL-6,IL-1β,IL-18)in LPS-induced cells while increasing IL-4 and IL-10 levels and enhancing the expression of Claudin-1,ZO-1,and occludin proteins in NCM460 cells.Correspondingly,in vivo findings revealed that CPA administration markedly improved DAI,reduced colon shortening,and decreased the production of myeloperoxidase(MPO),malondialdehyde(MDA),ROS,IL-1β,IL-18,and NOD-like receptor protein 3(NLRP3)inflammasome-associated genes/proteins in UC mice.CP-A treatment also elevated glutathione(GSH)and superoxide dismutase(SOD)levels,stimulated autophagy(LC3B,P62,Beclin-1,and ATG5),and reinforced Claudin-1 and ZO-1 expression,thereby aiding in intestinal epithelial barrier repair in colitis mice.Notably,the inhibition of autophagy via chloroquine(CQ)diminished CP-A’s protective impact against colitis in vivo.These findings elucidate that CP-A’s therapeutic effect on experimental colitis possibly involves mitigating intestinal inflammation through autophagymediated NLRP3 inflammasome inactivation.Consequently,inulin-type fructan CP-A emerges as a promising drug candidate for UC treatment.展开更多
Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic ...Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3(NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.展开更多
BACKGROUND Ulcerative colitis(UC)is an inflammatory condition with frequent relapse and recurrence.Evidence suggests the involvement of SLC6A14 in UC pathogenesis,but the central regulator remains unknown.AIM To explo...BACKGROUND Ulcerative colitis(UC)is an inflammatory condition with frequent relapse and recurrence.Evidence suggests the involvement of SLC6A14 in UC pathogenesis,but the central regulator remains unknown.AIM To explore the role of SLC6A14 in UC-associated pyroptosis.METHODS Quantitative real-time polymerase chain reaction(qRT-PCR),immunoblotting,and immunohistochemical were used to assess SLC6A14 in human UC tissues.Lipopolysaccharide(LPS)was used to induce inflammation in FHC and NCM460 cells and model enteritis,and SLC6A14 levels were assessed.Pyroptosis markers were quantified using enzyme-linked immunosorbent assay,Western blotting,and qRT-PCR,and EdU incubation,CCK-8 assays and flow cytometry were used to examine proliferation and apoptosis.Mouse models of UC were used for verification.RESULTS SLC6A14 was increased and correlated with NLRP3 in UC tissues.LPS-induced FHC and NCM460 cells showed increased SLC6A14 levels.Reducing SLC6A14 increased cell proliferation and suppressed apoptosis.Reducing SLC6A14 decreased pyroptosis-associated proteins(ASC,IL-1β,IL-18,NLRP3).NLRP3 overexpression counteracted the effects of sh-SLC6A14 on LPS-induced FHC and NCM460 cell pyroptosis.SLC6A14 improved the mucosa in mice with dextran sulfate sodium-induced colitis.CONCLUSION SLC6A14 promotes UC pyroptosis by regulating NLRP3,suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis.展开更多
Ulcerative colitis(UC)is a common inflammatory disease of the gastrointestinal tract.Traditional Chinese medicine(TCM)has long been used in Asia as a treatment for UC and Puerariae Radix(PR)is a reliable anti-diarrhea...Ulcerative colitis(UC)is a common inflammatory disease of the gastrointestinal tract.Traditional Chinese medicine(TCM)has long been used in Asia as a treatment for UC and Puerariae Radix(PR)is a reliable anti-diarrheal therapy.The aims of this study were to investigate the protective effect of PR using the dextran sulfate sodium salt(DSS)-induced UC model in mice and identify molecular mechanisms of PR action.The chemical constituents of PR via ultra-performance liquid chromatography/tandem mass spectrometry and identified potential PR and UC targets using a network pharmacology(NP)approach were obtained to guide mouse experiments.A total of 180 peaks were identified from PR including 48 flavonoids,46 organic acids,14 amino acids,8 phenols,8 carbohydrates,7 alkaloids,6 coumarins and 43 other constituents.NP results showed that caspase-1 was the most dysregulated of the core genes associated with UC.A PR dose of 0.136 mg/g administered to DSS treated mice reversed weight loss and decreased colon lengths found in UC mice.PR also alleviated intestinal mucosal shedding,inflammatory cell infiltration and mucin loss.PR treatment suppressed upregulation of NOD-like receptor protein 3(NLRP3),cysteinyl aspartate-specific proteases-1(caspase-1),apoptosis-associated speck-like(ASC)and gasdermin D(GSDMD)at both the protein and m RNA expression levels.The addition of a small molecule dual-specificity phosphatase inhibitor NSC 95397 inhibited the positive effects of PR.These results indicated that PR exerts a protective effect on DSS-induced colitis by inhibiting NLRP3 inflammasome activation in mice.展开更多
Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investig...Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investigated the effects of elaidic acid(EA),a typical TFA,on the gut microbiota to understand the underlying mechanisms of TFA-related chronic diseases.16S rDNA gene sequencing on faecal samples from Sprague-Dawley rats were performed to explore the composition change of the gut microbiota by EA gavage for 4 weeks.The results showed that the intake of EA increased the abundance of well-documented harmful bacteria,such as Proteobacteria,Anaerotruncus,Oscillibacter and Desulfovibrionaceae.Plus,EA induced translocation of lipopolysaccharides(LPS) and the above pathogenic bacteria,disrupted the intestinal barrier,led to gut-liver axis derangement and TLR4 pathway activation in the liver.Overall,EA induced intestinal barrier damage and regulated TLR4-MyD88-NF-κB/MAPK pathways in the liver of SD rats,leading to the activation of NLRP3 inflammasome and inflammatory liver damage.展开更多
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 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 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 (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Ministry of Education Industry-University Co-operation Collaborative Education Project,No.202102242020.
文摘BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies have shown that Transmembrane protein 176B(TMEM176B)regulates NLRP3 and promotes CRC malignant phenotypes.AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells,BALB/c mice,and primary cultured mouse natural killer(NK)cells.Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells.Fluorescence imaging,Terminal deoxynucleotidyl transferase dUTP nick end labeling assays,immunohistochemistry staining,flow cytometry,and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis,apoptosis,and EMT indicators.RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis,proliferation,and EMT,while activating apoptosis,NLRP3 inflammasome,and NK cell activity.Furthermore,silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion,and promoted apoptosis.The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65,matrix metallopeptidase 9,and transforming growth factor-β.CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.
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.
基金funded by a Maurice and Phyllis Paykel Trust Grant(203134)supported by a Buchanan Ocular Therapeutics Unit Doctoral Scholarship.Odunayo O.Mugisho is supported by a Neurological Foundation First Postdoctoral Research Fellowship(2001 FFE)+2 种基金an Auckland Medical Research Foundation Grant(1121013)an Auckland Medical Research Foundation Postdoctoral Fellowship(1323001)supported by the Buchanan Charitable Foundation,with part of her salary also supported by the Health Research Council of New Zealand(20/317).
文摘Background:Noninfectious uveitis,a chronic ocular inflammatory disease,is char-acterized by the activation of immune cells in the eye,with most studies focusing on the role of the adaptive immune system in the disease.However,limited data exist on the potential contribution of the innate immune system,specifically the nucleotide-binding oligomerization domain and leucine-rich repeat receptor-3(NLRP3)inflamma-some pathway.This pathway has previously been identified as a driver of inflammation in several low-grade,progressive inflammatory eye diseases such as diabetic retin-opathy.The aim of this study was to determine whether the NLRP3 inflammasome pathway plays a role in the pathogenesis and chronicity of experimental autoimmune uveitis(EAU).Methods:EAU was induced in C57BL/6J mice via intraperitoneal pertussis toxin and subcutaneous interphotoreceptor retinoid-binding protein injections.After 12 weeks,eyes were enucleated,and whole eye sections were assessed for inflammasome,macrophage,and microglial markers in the retina,ciliary body,and cornea using immunohistochemistry.Results:Our study confirmed higher NLRP3 inflammasome activation(increased ex-pression of NLRP3 and cleaved caspase 1 labeling)in EAU mouse retinas compared to controls.This correlated with increased astrogliosis and microglial activation through-out the eye.Migratory innate and adaptive peripheral immune cells(macrophages and leukocytes)were also found within the retina and ciliary body of EAU mice.Connexin43 proteins,which form hexameric hemichannels that can release adeno-sine triphosphate(ATP),an upstream inflammasome priming signal,were also found upregulated in the retina and cornea of EAU mice.Conclusion:Overall,our findings support the idea that in the EAU model there is active inflammation,even 12 weeks post induction,and that it can be correlated to inflammasome activation.This contributes to the pathogenesis and chronicity of non-infectious uveitis,and our results emphasize that targeting the inflammasome path-way could be efficacious for noninfectious uveitis treatment.
文摘This article provides commentary on the article by Zhang et al.In this original research,Zhang et al investigated the therapeutic potential of teneligliptin for diabetic cardiomyopathy(DCM),which was mediated by targeting the NOD-like receptor protein 3(NLRP3)inflammasome.Through the use of both in vivo and in vitro models,the study demonstrated that teneligliptin alleviates cardiac hyper-trophy,reduces myocardial injury,and mitigates the inflammatory responses as-sociated with DCM.These findings suggest that teneligliptin’s cardioprotective effects are mediated through the inhibition of NLRP3 inflammasome activation,positioning it as a promising therapeutic option for managing DCM in diabetic patients.
基金supported the National Natural Science Foundation of China,No.81974178(to CD).
文摘Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.
基金supported by Health Commission of Pudong New Area Health and Family Planning Scientific Research Project,No.PW2020E-4(to GL)Siming Youth Fund Project of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,No.SGKJ-202119(to RH)+5 种基金Medical Innovation Research Special Project of 2021“Science and Technology Innovation Action Plan”of Shanghai,No.21Y21920200(to GL)Shanghai Rising-Star Program and Shanghai Sailing Program,No.23YF1418200(to QH)Shanghai Municipal Health Commission Foundation grant,No.20234Y0294(to QH)Hundred Teacher Talent Program of Shanghai University of Medicine and Health Sciences,No.A1-2601-23-311007-21(to QH)the Scientific and Technological Innovation Program of Higher Education Institution in Shanxi,No.2021L350(to XC)the Fundamental Research Program of Shanxi Province,No.20210302124194(to XC).
文摘Previous studies have demonstrated a bidirectional relationship between inflammation and depression.Activation of the nucleotide-binding oligomerization domain,leucine-rich repeat,and NLR family pyrin domain-containing 3(NLRP3)inflammasomes is closely related to the pathogenesis of various neurological diseases.In patients with major depressive disorder,NLRP3 inflammasome levels are significantly elevated.Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies.In this review,we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome.Moreover,we outlined various therapeutic strategies that target the NLRP3 inflammasome,including NLRP3 inflammatory pathway inhibitors,natural compounds,and other therapeutic compounds that have been shown to be effective in treating depression.Additionally,we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression.Currently,there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment.The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression.Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments.
基金supported by the National Natural Science Foundation of China,Nos.81801226(to QK and XS)and 82101445(to XJ)。
文摘Spinal cord injury-induced motor dysfunction is associated with neuroinflammation.Studies have shown that the triterpenoid lupenone,a natural product found in various plants,has a remarkable anti-inflammatory effect in the context of chronic inflammation.However,the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown.In this study,we established an impact-induced mouse model of spinal cord injury,and then treated the injured mice with lupenone(8 mg/kg,twice a day)by intrape ritoneal injection.We also treated BV2 cells with lipopolysaccharide and adenosine5’-triphosphate to simulate the inflammatory response after spinal cord injury.Our res ults showed that lupenone reduced IKBa activation and p65 nuclear translocation,inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B,and enhanced the conve rsion of proinflammatory M1 mic roglial cells into anti-inflammatory M2 microglial cells.Furthermore,lupenone decreased NLRP3 inflammasome activation,NLRP3-induced mic roglial cell polarization,and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway.These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.
基金supported by the Jilin Science&Technology Development Plan(Nos.20210204001YY,20200404090YY)Jilin Province aid Project for Xinjiang Uygur Autonomous Region(No.0207-202020043).
文摘Depression ranks among the most common neuropsychiatric disorders globally.Current studies examining the roles of inflammation and mitochondrial autophagy in the antidepressant efficacy of paeoniflorin(PF)are sparse.This study aimed to elucidate PF’s antidepressant mechanism by promoting autophagy and inhibiting NLRP3 inflammasome activation using chronic unpredictable mild stimulation(CUMS)-induced C57BL/6 mouse models in vivo and corticosterone(CORT)-induced HT22 cell models in vitro.Results demonstrated that PF enhanced the viability of HT22 cells following CORT exposure,restored mitochondrial membrane poten-tial(MMP),reduced reactive oxygen species accumulation,increased LC3 fluorescence intensity,and suppressed inflammatory cy-tokine secretion and inflammation activation.Additionally,PF ameliorated depressive behaviors induced by CUMS and improved damage in hippocampal neurons.It also reduced the expression of NLRP3,ASC,Caspase-1,IL-1β,and the assembly of the NLRP3 in-flammasome.Moreover,PF upregulated the expression of autophagy-related proteins in the hippocampus,facilitating the clearance of damaged mitochondria and enhancing autophagy.The role of autophagy in PF’s antidepressant effects was further confirmed through the use of the autophagy inhibitor 3-methyladenine(3-MA),which reduced the efficacy of PF.In conclusion,PF effectively improved depressive behaviors in CUMS-induced mice and reduced NLRP3-mediated inflammation both in vivo and in vitro,likely via the in-duction of autophagy.
基金This work was supported by the Key Projects of Natural Science Foundation of Heilongjiang Province of China(No.ZD2020C005).
文摘Microplastics(MPs)have attracted growing attention worldwide as an increasingly prevalent environmental pollutant.In addition,chicken meat is currently the most widely consumed kind of poultry in the global market.Consumer demand for chicken is on the rise both at home and abroad.As a result,the safety of chicken raising has also received significant attention.The lungs play an essential role in the physiological activities of chickens,and they are also the most vulnerable organs.Lung injury is difficult to repair after the accumulation of contaminants,and the mortality rate is high,which brings huge economic losses to farmers.The research on the toxicity of MPs has mainly focused on the marine ecosystem,while the mechanisms of toxicity and lung damage in chickens have been poorly studied.Thus,this study explored the effects of exposure to polystyrene microplastics(PS-MPs)at various concentrations for 42 d on chicken lungs.PS-MPs could cause lung pathologies and ultrastructural abnormalities,such as endoplasmic reticulum(ER)swelling,inflammatory cell infiltration,chromatin agglutination,and plasma membrane rupture.Simultaneously,PS-MPs increased the expression of genes related to the heat shock protein family(Hsp60,Hsp70,and Hsp90),ER stress signaling(activating) transcription factor 6(ATF0),ATF4,protein kinase RNA-like ER kinase(PERK),and eukaryotic translation initiation factor 2 subunitα(eIF2a),pyroptosis-related genes(NOD)-,LRR-and pyrin domain-containing protein 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC),interleukin-1β(IL-1β),cysteinyl aspartate-specific proteinase 1(Caspasel),and gasdermin-D(GSDMD),and the inflammatory signaling pathway(nuclear factor-kB(NF-kB),inducible nitric oxide synthase(iNOS),and cyclooxygenase-2(COX-2).The above results showed that PS-MP exposure could result in lung stress,ER stress,pyroptosis,and inflammation in broilers.Our findings provide new scientific clues for further research on the mechanisms of physical health and toxicology regardingMPs.
基金Supported by Guizhou University of Traditional Chinese Medicine Doctoral Initiation Fund,No.202306and Changshu Municipal Science and Technology Bureau Supporting Project,No.CS202030.
文摘Ulcerative colitis(UC)is a chronic recurrent inflammatory bowel disease.Despite ongoing advances in our understanding of UC,its pathogenesis is yet unelu-cidated,underscoring the urgent need for novel treatment strategies for patients with UC.Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules,such as proteins,RNAs,DNA,and metabolites.The NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β(IL-1β)and IL-18,triggering the inflammatory response to a pathogenic agent or injury.Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome,with vital roles in the pathological process of UC.Here,recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC.First,the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized.Finally,an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are high-lighted.
基金supported by the National Natural Science Foundation of China(No.81904031)National Key Research and Development Program of China(No.2019YFC1710800)+1 种基金the Natural Science Foundation of Shanxi Province(No.201901D211325)the Science Research Start-up Fund for Doctor of Shanxi Medical University(No.XD1802).
文摘Inulin-type fructan CP-A,a predominant polysaccharide in Codonopsis pilosula,demonstrates regulatory effects on immune activity and anti-inflammation.The efficacy of CP-A in treating ulcerative colitis(UC)is,however,not well-established.This study employed an in vitro lipopolysaccharide(LPS)-induced colonic epithelial cell model(NCM460)and an in vivo dextran sulfate sodium(DSS)-induced colitis mouse model to explore CP-A’s protective effects against experimental colitis and its underlying mechanisms.We monitored the clinical symptoms in mice using various parameters:body weight,disease activity index(DAI),colon length,spleen weight,and histopathological scores.Additionally,molecular markers were assessed through enzyme-linked immunosorbent assay(ELISA),quantitative real-time polymerase chain reaction(qRT-PCR),immunofluorescence(IF),immunohistochemistry(IHC),and Western blotting assays.Results showed that CP-A significantly reduced reactive oxygen species(ROS),tumor necrosis factor-alpha(TNF-α),and interleukins(IL-6,IL-1β,IL-18)in LPS-induced cells while increasing IL-4 and IL-10 levels and enhancing the expression of Claudin-1,ZO-1,and occludin proteins in NCM460 cells.Correspondingly,in vivo findings revealed that CPA administration markedly improved DAI,reduced colon shortening,and decreased the production of myeloperoxidase(MPO),malondialdehyde(MDA),ROS,IL-1β,IL-18,and NOD-like receptor protein 3(NLRP3)inflammasome-associated genes/proteins in UC mice.CP-A treatment also elevated glutathione(GSH)and superoxide dismutase(SOD)levels,stimulated autophagy(LC3B,P62,Beclin-1,and ATG5),and reinforced Claudin-1 and ZO-1 expression,thereby aiding in intestinal epithelial barrier repair in colitis mice.Notably,the inhibition of autophagy via chloroquine(CQ)diminished CP-A’s protective impact against colitis in vivo.These findings elucidate that CP-A’s therapeutic effect on experimental colitis possibly involves mitigating intestinal inflammation through autophagymediated NLRP3 inflammasome inactivation.Consequently,inulin-type fructan CP-A emerges as a promising drug candidate for UC treatment.
基金supported by the National Natural Science Foundation of China,No.81971246 (to TM)Opening Foundation of Jiangsu Key Laboratory of Neurodegeneration,Nanjing Medical University,No.KF202204 (to LZ and SF)。
文摘Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3(NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.
基金Supported by The Key Research and Development Projects of Sichuan Science and Technology Department,No.2023YFS0285Natural Science Foundation Project of Sichuan Science and Technology Department,No.2023NSFSC0613.
文摘BACKGROUND Ulcerative colitis(UC)is an inflammatory condition with frequent relapse and recurrence.Evidence suggests the involvement of SLC6A14 in UC pathogenesis,but the central regulator remains unknown.AIM To explore the role of SLC6A14 in UC-associated pyroptosis.METHODS Quantitative real-time polymerase chain reaction(qRT-PCR),immunoblotting,and immunohistochemical were used to assess SLC6A14 in human UC tissues.Lipopolysaccharide(LPS)was used to induce inflammation in FHC and NCM460 cells and model enteritis,and SLC6A14 levels were assessed.Pyroptosis markers were quantified using enzyme-linked immunosorbent assay,Western blotting,and qRT-PCR,and EdU incubation,CCK-8 assays and flow cytometry were used to examine proliferation and apoptosis.Mouse models of UC were used for verification.RESULTS SLC6A14 was increased and correlated with NLRP3 in UC tissues.LPS-induced FHC and NCM460 cells showed increased SLC6A14 levels.Reducing SLC6A14 increased cell proliferation and suppressed apoptosis.Reducing SLC6A14 decreased pyroptosis-associated proteins(ASC,IL-1β,IL-18,NLRP3).NLRP3 overexpression counteracted the effects of sh-SLC6A14 on LPS-induced FHC and NCM460 cell pyroptosis.SLC6A14 improved the mucosa in mice with dextran sulfate sodium-induced colitis.CONCLUSION SLC6A14 promotes UC pyroptosis by regulating NLRP3,suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis.
基金financially supported by the National Natural Science Foundation of China(32172897)Central Significant Changes in the Project at the Corresponding Level(Valuable Resources Capacity-Building for Sustainable Utilization of Traditional Chinese Medicine Program)(2060302)Chinese Herbal Medicine Industry Innovation Team of Shandong Province Agricultural Technology System(SDAIT-20-06)。
文摘Ulcerative colitis(UC)is a common inflammatory disease of the gastrointestinal tract.Traditional Chinese medicine(TCM)has long been used in Asia as a treatment for UC and Puerariae Radix(PR)is a reliable anti-diarrheal therapy.The aims of this study were to investigate the protective effect of PR using the dextran sulfate sodium salt(DSS)-induced UC model in mice and identify molecular mechanisms of PR action.The chemical constituents of PR via ultra-performance liquid chromatography/tandem mass spectrometry and identified potential PR and UC targets using a network pharmacology(NP)approach were obtained to guide mouse experiments.A total of 180 peaks were identified from PR including 48 flavonoids,46 organic acids,14 amino acids,8 phenols,8 carbohydrates,7 alkaloids,6 coumarins and 43 other constituents.NP results showed that caspase-1 was the most dysregulated of the core genes associated with UC.A PR dose of 0.136 mg/g administered to DSS treated mice reversed weight loss and decreased colon lengths found in UC mice.PR also alleviated intestinal mucosal shedding,inflammatory cell infiltration and mucin loss.PR treatment suppressed upregulation of NOD-like receptor protein 3(NLRP3),cysteinyl aspartate-specific proteases-1(caspase-1),apoptosis-associated speck-like(ASC)and gasdermin D(GSDMD)at both the protein and m RNA expression levels.The addition of a small molecule dual-specificity phosphatase inhibitor NSC 95397 inhibited the positive effects of PR.These results indicated that PR exerts a protective effect on DSS-induced colitis by inhibiting NLRP3 inflammasome activation in mice.
基金supported by fund from the National Natural Science Foundation of China (32172322)Shandong Provincial Natural Science Foundation (ZR2023QC291)Shandong Traditional Chinese Medicine Technology Project (Q-2023130)。
文摘Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investigated the effects of elaidic acid(EA),a typical TFA,on the gut microbiota to understand the underlying mechanisms of TFA-related chronic diseases.16S rDNA gene sequencing on faecal samples from Sprague-Dawley rats were performed to explore the composition change of the gut microbiota by EA gavage for 4 weeks.The results showed that the intake of EA increased the abundance of well-documented harmful bacteria,such as Proteobacteria,Anaerotruncus,Oscillibacter and Desulfovibrionaceae.Plus,EA induced translocation of lipopolysaccharides(LPS) and the above pathogenic bacteria,disrupted the intestinal barrier,led to gut-liver axis derangement and TLR4 pathway activation in the liver.Overall,EA induced intestinal barrier damage and regulated TLR4-MyD88-NF-κB/MAPK pathways in the liver of SD rats,leading to the activation of NLRP3 inflammasome and inflammatory liver damage.
