Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen...Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.展开更多
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications wit...Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.展开更多
Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response pla...Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response plays a crucial role in worsening brain injury.Neuroinflammation,a key player in the pathophysiology of stroke,has a dual role.In the acute phase of stroke,neuroinflammation exacerbates brain injury,contributing to neuronal damage and blood–brain barrier disruption.This aspect of neuroinflammation is associated with poor neurological outcomes.Conversely,in the recovery phase following stroke,neuroinflammation facilitates brain repair processes,including neurogenesis,angiogenesis,and synaptic plasticity.The transition of neuroinflammation from a harmful to a reparative role is not well understood.Therefore,this review seeks to explore the mechanisms underlying this transition,with the goal of informing the development of therapeutic interventions that are both time-and context-specific.This review aims to elucidate the complex and dual role of neuroinflammation in stroke,highlighting the main actors,biomarkers of the disease,and potential therapeutic approaches.展开更多
Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the curr...Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the current understanding of the bidirectional relationship between blood-brain barrier disruption and neuroinflammation in traumatic brain injury,along with emerging combination therapeutic strategies.Literature review indicates that blood-brain barrier disruption and neuroinflammatory responses are key pathological features following traumatic brain injury.In the acute phase after traumatic brain injury,the pathological characteristics include primary blood-brain barrier disruption and the activation of inflammatory cascades.In the subacute phase,the pathological features are characterized by repair mechanisms and inflammatory modulation.In the chronic phase,the pathological features show persistent low-grade inflammation and incomplete recovery of the blood-brain barrier.Various physiological changes,such as structural alterations of the blood-brain barrier,inflammatory cascades,and extracellular matrix remodeling,interact with each other and are influenced by genetic,age,sex,and environmental factors.The dynamic balance between blood-brain barrier permeability and neuroinflammation is regulated by hormones,particularly sex hormones and stress-related hormones.Additionally,the role of gastrointestinal hormones is receiving increasing attention.Current treatment strategies for traumatic brain injury include various methods such as conventional drug combinations,multimodality neuromonitoring,hyperbaric oxygen therapy,and non-invasive brain stimulation.Artificial intelligence also shows potential in treatment decision-making and personalized therapy.Emerging sequential combination strategies and precision medicine approaches can help improve treatment outcomes;however,challenges remain,such as inadequate research on the mechanisms of the chronic phase traumatic brain injury and difficulties with technology integration.Future research on traumatic brain injury should focus on personalized treatment strategies,the standardization of techniques,costeffectiveness evaluations,and addressing the needs of patients with comorbidities.A multidisciplinary approach should be used to enhance treatment and improve patient outcomes.展开更多
To explore the material basis and mechanisms of the anti-inflammatory effects of Hibiscus mutabilis L..The active ingredients and potential targets of Hibiscus mutabilis L.were obtained through the literature review a...To explore the material basis and mechanisms of the anti-inflammatory effects of Hibiscus mutabilis L..The active ingredients and potential targets of Hibiscus mutabilis L.were obtained through the literature review and SwissADME platform.Genes related to the inflammation were collected using Genecards and OMIM databases,and the intersection genes were submitted on STRING and DAVID websites.Then,the protein interaction network(PPI),gene ontology(GO)and pathway(KEGG)were analyzed.Cytoscape 3.7.2 software was used to construct the“Hibiscus mutabilis L.-active ingredient-target-inflammation”network diagram,and AutoDockTools-1.5.6 software was used for the molecular docking verification.The antiinflammatory effect of Hibiscus mutabilis L.active ingredient was verified by the RAW264.7 inflammatory cell model.The results showed that 11 active components and 94 potential targets,1029 inflammatory targets and 24 intersection targets were obtained from Hibiscus mutabilis L..The key anti-inflammatory active ingredients of Hibiscus mutabilis L.are quercetin,apigenin and luteolin.Its action pathway is mainly related to NF-κB,cancer pathway and TNF signaling pathway.Cell experiments showed that total flavonoids of Hibiscus mutabilis L.could effectively inhibit the expression of tumor necrosis factor(TNF-α),interleukin 8(IL-8)and epidermal growth factor receptor(EGFR)in LPS-induced RAW 264.7 inflammatory cells.It also downregulates the phosphorylation of human nuclear factor ĸB inhibitory protein α(IĸBα)and NF-κB p65 subunit protein(p65).Overall,the anti-inflammatory effect of Hibiscus mutabilis L.is related to many active components,many signal pathways and targets,which provides a theoretical basis for its further development and application.展开更多
Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cuta...Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cutaneous vasculopathy,and pulmonary inflammation.We sequenced a candidate gene,TMEM173,encoding the stimulator of interferon genes(STING),in this patient and in five unrelated children with similar clinical phenotypes.展开更多
AIM:To evaluate the predictive value of pan-immuneinflammation value(PIV)in the diagnosis of proliferative diabetic retinopathy(PDR)and its association with the stage of PDR.METHODS:This observational case-control stu...AIM:To evaluate the predictive value of pan-immuneinflammation value(PIV)in the diagnosis of proliferative diabetic retinopathy(PDR)and its association with the stage of PDR.METHODS:This observational case-control study included participants who underwent routine complete blood count testing.Inflammation-related indices,including neutrophil-to-lymphocyte ratio,systemic immune-inflammation index(SII),and PIV,were derived and analyzed.Receiver operating characteristic curve(ROC)analysis was applied to assess the diagnostic performance of these indices in distinguishing patients with PDR,with sensitivity,specificity,area under ROC,and optimal threshold values calculated.In addition,binary logistic regression analysis was performed to evaluate the association between inflammatory indices and PDR stage.RESULTS:This study included 205 patients:60 with diabetes without retinopathy(mean age:61.81±10.76y),80 with PDR(mean age:61.63±10.03y)and 65 healthy controls(mean age:59.52±5.88y).The PDR group had significantly higher white blood cell(WBC,P<0.001),monocyte(MONO,P=0.009)and neutrophil(NEU)counts(P<0.001).SII and PIV had the highest sensitivity and area under ROC for predicting patients with PDR(0.822,0.846,respectively).The optimal cut-off values for discriminating patients with PDR were determined to be>527.12 and>299.08 for SII and PIV,respectively.The logistic regression analysis demonstrated that a decrease in lymphocyte(LYM)count and an increase in platelet count(PLT),glycated haemoglobin(HbA1c),SII,and PIV were all significantly associated with the development of high-risk PDR(all P<0.05).PIV was more stable than independent MONO,LYM,PLT and NEU levels in predicting both the diagnosis and stage of PDR.The optimal cut-off value for PIV to discriminate patients with high-risk PDR was found to be>345.87 area under ROC=0.871,with sensitivity of 0.827 and specificity of 0.812.CONCLUSION:PIV is a reliable,valuable,and inexpensive blood index that can be used for early detection and staging of PDR.PIV may therefore be essential to be used for the follow-up of diabetic patients.展开更多
Dear Editor,Idiopathic orbital inflammation(IOI),also known as orbital inflammatory pseudotumor,is a relatively common orbital disorder[1].Its pathogenesis remains unclear,often regarded as a nonspecific immune-mediat...Dear Editor,Idiopathic orbital inflammation(IOI),also known as orbital inflammatory pseudotumor,is a relatively common orbital disorder[1].Its pathogenesis remains unclear,often regarded as a nonspecific immune-mediated response[2].IOI presents with symptoms such as pain,photophobia,proptosis,eyelid swelling,edema,conjunctival congestion,and diplopia,with possible vision loss occurring in some cases.Based on the soft tissue structures involved,IOI can be classified into subtypes such as myositis,optic neuritis,dacryoadenitis,diffuse orbital inflammation,and orbital inflammatory masses[2].展开更多
Globally,glaucoma stands as a primary cause of irreversible blindness,marked by intricate pathophysiological processes in which neuroinflammation plays a pivotal role.As the principal immune cells within the central n...Globally,glaucoma stands as a primary cause of irreversible blindness,marked by intricate pathophysiological processes in which neuroinflammation plays a pivotal role.As the principal immune cells within the central nervous system,microglia play a dual function in the progression of glaucoma.Under standard physiological states,microglia safeguard the retina by offering neurotrophic support and removing cellular debris.In the pathological progression of glaucoma,microglia become activated and release significant levels of inflammatory factors,resulting in retinal ganglion cell injury,cell death,and impaired neuroregeneration.This review focuses on examining the dual functions of microglia in glaucoma,evaluating their influence on retinal neurodegeneration and repair,and suggesting that modulating microglial activity could serve as a promising therapeutic strategy.Understanding the mechanisms of microglial action in glaucoma is crucial for unveiling the complex pathophysiological processes of the disease and developing new therapeutic strategies.展开更多
Neutrophil extracellular trap(NET)formation or NETosis is a specialized innate immune process in which neutrophils release chromatin fibers decorated with histones and antimicrobial proteins.Although pivotal for patho...Neutrophil extracellular trap(NET)formation or NETosis is a specialized innate immune process in which neutrophils release chromatin fibers decorated with histones and antimicrobial proteins.Although pivotal for pathogen clearance,aberrant NETosis has emerged as a critical modulator of acute and chronic respiratory pathologies,including acute respiratory distress syndrome,asthma,and chronic obstructive pulmonary disease.Dysregulated NET release exacerbates airway inflammation by inducing epithelial injury,mucus hypersecretion,and the recruitment of inflammatory leukocytes,thereby accelerating tissue remodeling and functional decline.Mechanistically,NETosis is governed by peptidyl arginine deiminase 4(PADI4)-mediated histone citrullination,NADPH oxidase-dependent reactive oxygen species production,mitochondrial metabolic reprogramming,and activation of toll-like receptors and inflammasomes.These molecular events perpetuate inflammation and prevent its resolution.Emerging evidence indicates that natural bioactive compounds,such as flavonoids,terpenoids,and polyphenols,attenuate NETosis by modulating oxidative stress,inhibiting PADI4 activation,or suppressing downstream pro-inflammatory cascades.Collectively,these findings highlight the therapeutic potential of targetingNETosis tomitigate neutrophil-driven airway pathology.This review aims to comprehensively synthesize recent mechanistic insights into NETosis and to delineate how modulation of NET formation contributes to the prevention and treatment of inflammatory respiratory diseases.展开更多
Moringa oleifera(MO)is traditionally used to mitigate inflammatory-mediated disorders;however,the influence of ecotypic variation on its anti-inflammatory activity remains poorly understood.In this study,we compared t...Moringa oleifera(MO)is traditionally used to mitigate inflammatory-mediated disorders;however,the influence of ecotypic variation on its anti-inflammatory activity remains poorly understood.In this study,we compared the phytochemical composition and anti-inflammatory activity of ethanolic extracts obtained from fresh and dried leaves of four MO ecotypes(India,Paraguay,Mozambique,and Pakistan),all grown under the same outdoor conditions,as well as two commercial powders(Just Moringa and WISSA),using LPS-stimulated RAW 264.7 macrophages.Extracts from fresh leaves were 19-43%more cytotoxic than those from dried leaves,depending on the ecotype,likely due to higher cyanogenic glycoside content.Extracts from the India and Paraguay ecotypes,characterized by high levels of quercetin derivatives and caffeic acids,as well as Just Moringa,enriched in kaempferol derivatives,significantly inhibited LPS-induced nitric oxide(NO)production(p<0.05).Just Moringa and Paraguay extracts also reduced iNOS gene expression(p<0.05 and p<0.01,respectively),whereas only the Paraguay extract decreased iNOS protein levels(p<0.05).In contrast,quercetin-3-O-glucoside and rutin showed significant effects only at concentrations approximately 100-fold higher than those present in the extracts,indicating that the phytocomplex displays greater bioactivity than individual compounds.Overall,these results demonstrate that ecotypic variation strongly affects the polyphenolic composition and anti-inflammatory properties of MO leaves,highlighting the importance of reporting both origin and phytochemical composition in MO-based products.展开更多
Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanis...Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA(dsDNA)-sensing cyclic GMP-AMP synthase(cGAS)signaling warrant further study.Using middle cerebral artery occlusion mice,we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation.Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release,as reflected byγH2AX staining,as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway,both of which were notably suppressed by melatonin treatment.Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome activation and nuclear factor(NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke,while exhibiting the capacity to attenuate the immune response to ischemia in mice.This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain.Specifically,melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-αby microglia.Regarding neurological outcomes,melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice.Notably,the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity.We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles(Mф-MLT@FNGs),which exhibited therapeutic properties in middle cerebral artery occlusion mice.Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway.By doing so,melatonin rescues damaged brain tissue and protects neurological function,highlighting its potential as a neuroprotective treatment for ischemic stroke.展开更多
Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, ...Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood–brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood–brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.展开更多
Objectives Neutrophil extracellular traps(NETs)have emerged as critical effectors in immune defense but also as potential drivers of tissue damage in chronic inflammatory diseases.Their role in periodontitis,a highly ...Objectives Neutrophil extracellular traps(NETs)have emerged as critical effectors in immune defense but also as potential drivers of tissue damage in chronic inflammatory diseases.Their role in periodontitis,a highly prevalent condition characterized by dysregulated host–microbe interactions,remains incompletely defined.This systematic review aimed to synthesize,for the first time,ex vivo human evidence on the presence,activity,and clinical significance of NETs in periodontitis.Methods A comprehensive search of Medline,Web of Science,and Scopus was conducted up to August 2025.Eligible studies included ex vivo human investigations assessing NETs or NET markers in gingival tissues,gingival crevicular fluid,saliva,blood,or biofilms from patients with periodontitis.Study selection,data extraction,and risk-of-bias assessment were conducted in duplicate,and the protocol was registered in PROSPERO(CRD420251109174).Results Seventeen studies met the inclusion criteria.NET markers such as citrullinated histone H3(CitH3),myeloperoxidase(MPO),and neutrophil elastase were consistently elevated in periodontitis samples compared with controls.Several studies reported a reduction in NET levels or improved NET degradation following periodontal therapy.NETs were also implicated in biofilm stability and in systemic associations with rheumatoid arthritis and chronic kidney disease.However,heterogeneity in methodologies,small sample sizes,and inconsistent marker use limited comparability across studies.Conclusions Ex vivo evidence indicates that aberrant NET formation and impaired clearance contribute to periodontal inflammation and tissue destruction.Nonetheless,methodological variability and risk of bias constrain definitive conclusions.Standardization of detection methods,consensus on marker panels,and exploration of neutrophil subsets and systemic confounders are essential to establish NETs as reliable biomarkers and therapeutic targets in periodontitis.展开更多
AIM:To report and analyze cases of sterile intraocular inflammation(IOI)following intravitreal faricimab injections in patients treated for neovascular age-related macular degeneration(nAMD)and diabetic macular edema(...AIM:To report and analyze cases of sterile intraocular inflammation(IOI)following intravitreal faricimab injections in patients treated for neovascular age-related macular degeneration(nAMD)and diabetic macular edema(DME).METHODS:This double-center case series included nine eyes of six patients who developed uveitis after faricimab therapy.Comprehensive clinical evaluation was performed,including slit-lamp examination,intraocular pressure(IOP)measurement,fluorescein and indocyanine green angiography(ICGA),and laboratory tests.Inflammatory responses were treated with topical or systemic corticosteroids,and patients were monitored for visual acuity and inflammatory activity.RESULTS:The incidence of IOI was 0.8%per patient(Innsbruck)and 0.23%(Czechia),with inflammation typically occurring between the third and sixth injection(mean interval:10d post-injection).Inflammator y presentations ranged from anterior uveitis to posterior segment involvement.One notable case demonstrated novel choroidal hypofluorescent lesions on angiography,suggesting deeper ocular involvement.The mean patient age was 76y;five of six affected patients were female.All cases responded to local and systemic corticosteroids,with full recovery of initial visual acuity.CONCLUSION:Sterile IOI after faricimab appears to be a rare but relevant adverse event.Although the incidence falls within expected ranges for anti-vascular endothelial growth factor(anti-VEGF)agents,the observed choroidal involvement represents a potentially new safety signal.Prompt diagnosis and corticosteroid therapy are effective in all cases.Our findings support the need for vigilant post-marketing surveillance and further studies to better understand the underlying mechanisms and risk factors of faricimab-associated inflammation.展开更多
AIM:To investigate the impact of depression-like behavior on ocular surface homeostasis in a mouse model,with a focus on dry eye-like alterations.METHODS:Male C57BL/6J mice(10-12 weeks old)were randomly assigned to co...AIM:To investigate the impact of depression-like behavior on ocular surface homeostasis in a mouse model,with a focus on dry eye-like alterations.METHODS:Male C57BL/6J mice(10-12 weeks old)were randomly assigned to control or restraint stress(RS)groups.The RS group underwent three intermittent 24-hour restraint sessions to induce depressive-like behavior.Behavioral testing,tear secretion measurement,and corneal Oregon Green Dextran(OGD)staining were performed.Postmortem analyses included histological evaluation of lacrimal glands,goblet cell quantification using periodic acid-Schiff staining,and assessment of key inflammatory and apoptotic markers:interleukin(IL)-17,matrix metalloproteinases(MMP)-3,MMP-9,IL-13,interferon(IFN)-γ,and cleaved caspase-3 and-8.RESULTS:Repeated RS induced depression-like behavior and significant ocular surface changes.RStreated mice showed increased corneal OGD uptake and upregulation of gene/protein expression of IL-17,MMP-3,and MMP-9(P<0.05).Goblet cell density and IL-13 protein expression were reduced,while IFN-γprotein expression was elevated(P<0.05).Cleaved caspase-3 and-8 levels were significantly increased in both cornea and conjunctiva.Tear volume and lacrimal gland size were unchanged;however,mild inflammatory infiltration was observed in lacrimal glands.CONCLUSION:Repeated RS leads to ocular surface inflammation and dry eye-like pathology,including corneal barrier disruption,goblet cell loss,and epithelial apoptosis.These findings suggest that depression contributes to the pathogenesis of dry eye disease via immune-mediated mechanisms.展开更多
To explore the mechanisms underlying ocular infection by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),we conducted a comprehensive review of current literature,focusing on viral entry pathways,receptor ...To explore the mechanisms underlying ocular infection by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),we conducted a comprehensive review of current literature,focusing on viral entry pathways,receptor expression in ocular tissues,and associated clinical manifestations.This review encompasses studies published within the last five years with a focus on original research and systematic reviews that provide molecular,histological,or clinical evidence.The findings show that SARS-CoV-2 can infect ocular tissues through multiple receptors beyond angiotensin-converting enzyme 2(ACE2),including transmembrane serine protease 2(TMPRSS2),CD147,alanyl aminopeptidase N(ANPEP),dipeptidyl peptidase 4(DPP4),angiotensin II receptor type 2(AGTR2),and polymeric immunoglobulin receptor(PIGR),which are expressed in retinal,conjunctival,corneal,limbal,and photoreceptor cells.The virus may also reach ocular structures via neurovascular invasion.Clinically,patients with coronavirus disease 2019(COVID-19)may present with a broad spectrum of ophthalmic manifestations,including conjunctivitis,hyperreflective lesions in the inner retinal layers,flame-shaped hemorrhages,cottonwool spots,retinal pallor,hard exudates,and various forms of maculopathy,such as paracentral acute middle maculopathy and acute macular neuroretinopathy(AMN).These signs reflect both direct viral damage and secondary effects of systemic inflammation and microvascular injury.Understanding the molecular and clinical spectrum of ocular involvement is essential for early diagnosis,appropriate ophthalmologic care,and the prevention of long-term visual sequelae in patients affected by COVID-19.展开更多
Background:Acute kidney injury(AKI),characterized by rapid renal dysfunction(KDIGO 2022 criteria:48-hour doubling of serum creatinine or<0.5 mL/kg/h urine output for>6 h),affects 13.3 million people annually wit...Background:Acute kidney injury(AKI),characterized by rapid renal dysfunction(KDIGO 2022 criteria:48-hour doubling of serum creatinine or<0.5 mL/kg/h urine output for>6 h),affects 13.3 million people annually with>20%mortality.Its progression involves metabolic imbalances,toxin accumulation,and multiorgan failure,often culminating in chronic kidney disease.Current therapies(fluid resuscitation,diuretics,renal replacement therapy)remain limited.Inflammation drives AKI pathogenesis:renal insults(ischemia,toxins)trigger tubular cell release of pro-inflammatory mediators(TNF-α,IL-1β,IL-6),activating neutrophil gelatinase-associated lipocalin(NGAL)and dysregulating P38 MAPK/ERK pathways.This cascade promotes leukocyte infiltration,oxidative stress,and apoptosis,exacerbating renal damage.Ononin,a flavonoid from Astragali Radix,shows multi-target potential by suppressing pro-inflammatory cytokines,modulating signaling,and mitigating oxidative stress.Its dual anti-inflammatory/antioxidant properties position it as a promising candidate for AKI intervention.Exploring the ameliorative effect of ononin on the inflammatory response Ameliorative effect of ononin on the inflammatory response in doxorubicin-induced AKI mice.Methods:We used network pharmacology to explore ononin’s target molecules and AKI-related disease molecules,identified their intersections,and predicted potential mechanisms via enrichment analysis,followed by molecular docking verification.For in-vivo validation,50 mice were randomly divided into five groups(n=10/group):Control,Model,Ononin-L(15 mg/kg),Ononin-H(60 mg/kg),and Dexamethasone(2.6 mg/kg).An AKI model was established by intravenous tail-vein injection of Doxorubicin(15 mg/kg).Samples were collected 12 h post-induction.We calculated the renal coefficient,examined renal histopathology using hematoxylin and eosin(HE),periodic acid-Schiff(PAS),and Masson’s trichrome(MASSON)staining,and observed mitochondrial morphology by electron microscopy(EM).ELISA was used to measure NGAL,serum creatinine(Scr),and blood urea nitrogen(BUN)levels in serum.Immunofluorescence(IF)evaluated the expression of P-P38,P-ERK,NGAL,and KIM-1 in renal tissues.RT-qPCR assessed the gene expression of pro-inflammatory cytokines,MAPK pathway components,and renal injury markers in kidney tissues.Western Blot(WB)quantified P-P38,P38 MAPK,P-ERK,ERK,NGAL,and KIM-1 in renal tissues.Results:Network pharmacology analysis suggested that ononin could attenuate AKI through its anti-inflammatory properties and regulation of the MAPK signaling pathway.The Model group exhibited a significantly elevated renal coefficient(P<0.05),severe histopathological damage,and mitochondrial dysfunction compared to controls.Serum levels of NGAL,Scr,and BUN were markedly increased(P<0.05),indicating impaired renal function.Enhanced fluorescence signals of P-P38 MAPK,P-ERK,NGAL,and KIM-1 suggested activation of MAPK pathways and renal injury.Upregulation of pro-inflammatory cytokines(IL-1β,IL-6,TNF-α)and MAPK-related genes(P38 MAPK,ERK)alongside injury markers(NGAL,KIM-1)(P<0.05).Increased ratios of phosphorylated-to-total proteins(P-P38/P38,P-ERK/ERK)and elevated NGAL/KIM-1 protein levels confirmed pathway dysregulation.Treatment significantly reduced the renal coefficient(P<0.05),attenuated histological damage,and restored mitochondrial integrity.NGAL,Scr,and BUN levels were lowered,reflecting functional recovery.Diminished fluorescence intensities of P-P38,P-ERK,NGAL,and KIM-1 indicated suppression of injury pathways.Downregulation of inflammatory cytokines(IL-1β,IL-6,TNF-α),MAPK components(P38 MAPK,ERK),and injury markers(NGAL,KIM-1)(P<0.05).Reduced phosphorylation ratios(P-P38/P38,P-ERK/ERK)and decreased NGAL/KIM-1 protein expression demonstrated therapeutic efficacy.Conclusion:Ononin ameliorates inflammatory responses in AKI mice via the P38 MAPK/ERK pathway.展开更多
Spinal cord injury is a severe neurological condition characterized by the permanent loss of nerve cell function and a failure in neural circuit reconstruction-key factors contributing to disability.Therefore,explorin...Spinal cord injury is a severe neurological condition characterized by the permanent loss of nerve cell function and a failure in neural circuit reconstruction-key factors contributing to disability.Therefore,exploring effective strategies to promote the repair and regeneration of nerve cells after spinal cord injury is crucial for optimizing patient prognosis.The purpose of this paper is to conduct an in-depth review of the pathological changes in nerve cells after spinal cord injury and to present the state of research on the role of exercise training in promoting the repair and regeneration of nerve cells after spinal cord injury.In terms of the intrinsic growth capacity of neurons,disruptions in the dynamic balance between growth cones and the cytoskeleton,the dysregulation of transcription factors,abnormal protein signaling transduction,and altered epigenetic modifications collectively hinder axonal regeneration.Additionally,the microenvironment of neurons undergoes a series of complex changes,initially manifesting as edema,which may be exacerbated by spinal cord ischemia-reperfusion injury,further increasing the extent of nerve cell damage.The abnormal proliferation of astrocytes leads to the formation of glial scars,creating a physical barrier to nerve regeneration.The inflammatory response triggered by the excessive activation of microglia negatively impacts the process of nerve repair.Non-invasive interventions involving exercise training have shown significant potential in promoting nerve repair as part of a comprehensive treatment strategy for spinal cord injury.Specifically,exercise training can reshape the growth cone and cytoskeletal structures of neurons,regulate transcription factor activity,modulate protein signaling pathways,and influence epigenetic modifications,thereby activating the intrinsic repair mechanisms of neurons.Moreover,exercise training can regulate the activation state of astrocytes,optimize the inflammatory response and metabolic processes,promote astrocyte polarization,enhance angiogenesis,reduce glial scar formation,and modulate the expression levels of nerve growth factors.It also effectively helps regulate microglial activation,promotes axonal regeneration,and improves phagocytic function,thereby optimizing the microenvironment for nerve repair.In terms of clinical translation,we summarize the preliminary results of new drug research and development efforts,the development of innovative devices,and the use of exercise training in promoting clinical advancements in nerve repair following spinal cord injury,while considering their limitations and future application prospects.In summary,this review systematically analyzes findings relating to the pathological changes occurring in nerve cells after spinal cord injury and emphasizes the critical role of exercise training in facilitating the repair and regeneration of nerve cells.This work is expected to provide new ideas and methods for the rehabilitation of patients with spinal cord injury.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82171387 and 31830111(both to SL).
文摘Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.82071383,82371392(to BN)the Natural Science Foundation of Shandong Province of China(Key Project),No.ZR2020KH007(to BN)+1 种基金“Taishan Scholar Distinguished Expert Program”of Shandong Province,No.tstp20231257(to BN)Health Commission Science and Technology Plan Project of Jinan,No.2023-1-8(to YZ).
文摘Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.
基金supported by European Union-NextGeneration EU under the Italian University and Research(MUR)National Innovation Ecosystem grant ECS00000041-VITALITY-CUP E13C22001060006(to MdA)。
文摘Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response plays a crucial role in worsening brain injury.Neuroinflammation,a key player in the pathophysiology of stroke,has a dual role.In the acute phase of stroke,neuroinflammation exacerbates brain injury,contributing to neuronal damage and blood–brain barrier disruption.This aspect of neuroinflammation is associated with poor neurological outcomes.Conversely,in the recovery phase following stroke,neuroinflammation facilitates brain repair processes,including neurogenesis,angiogenesis,and synaptic plasticity.The transition of neuroinflammation from a harmful to a reparative role is not well understood.Therefore,this review seeks to explore the mechanisms underlying this transition,with the goal of informing the development of therapeutic interventions that are both time-and context-specific.This review aims to elucidate the complex and dual role of neuroinflammation in stroke,highlighting the main actors,biomarkers of the disease,and potential therapeutic approaches.
基金supported by Open Scientific Research Program of Military Logistics,No.BLB20J009(to YZhao).
文摘Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the current understanding of the bidirectional relationship between blood-brain barrier disruption and neuroinflammation in traumatic brain injury,along with emerging combination therapeutic strategies.Literature review indicates that blood-brain barrier disruption and neuroinflammatory responses are key pathological features following traumatic brain injury.In the acute phase after traumatic brain injury,the pathological characteristics include primary blood-brain barrier disruption and the activation of inflammatory cascades.In the subacute phase,the pathological features are characterized by repair mechanisms and inflammatory modulation.In the chronic phase,the pathological features show persistent low-grade inflammation and incomplete recovery of the blood-brain barrier.Various physiological changes,such as structural alterations of the blood-brain barrier,inflammatory cascades,and extracellular matrix remodeling,interact with each other and are influenced by genetic,age,sex,and environmental factors.The dynamic balance between blood-brain barrier permeability and neuroinflammation is regulated by hormones,particularly sex hormones and stress-related hormones.Additionally,the role of gastrointestinal hormones is receiving increasing attention.Current treatment strategies for traumatic brain injury include various methods such as conventional drug combinations,multimodality neuromonitoring,hyperbaric oxygen therapy,and non-invasive brain stimulation.Artificial intelligence also shows potential in treatment decision-making and personalized therapy.Emerging sequential combination strategies and precision medicine approaches can help improve treatment outcomes;however,challenges remain,such as inadequate research on the mechanisms of the chronic phase traumatic brain injury and difficulties with technology integration.Future research on traumatic brain injury should focus on personalized treatment strategies,the standardization of techniques,costeffectiveness evaluations,and addressing the needs of patients with comorbidities.A multidisciplinary approach should be used to enhance treatment and improve patient outcomes.
文摘To explore the material basis and mechanisms of the anti-inflammatory effects of Hibiscus mutabilis L..The active ingredients and potential targets of Hibiscus mutabilis L.were obtained through the literature review and SwissADME platform.Genes related to the inflammation were collected using Genecards and OMIM databases,and the intersection genes were submitted on STRING and DAVID websites.Then,the protein interaction network(PPI),gene ontology(GO)and pathway(KEGG)were analyzed.Cytoscape 3.7.2 software was used to construct the“Hibiscus mutabilis L.-active ingredient-target-inflammation”network diagram,and AutoDockTools-1.5.6 software was used for the molecular docking verification.The antiinflammatory effect of Hibiscus mutabilis L.active ingredient was verified by the RAW264.7 inflammatory cell model.The results showed that 11 active components and 94 potential targets,1029 inflammatory targets and 24 intersection targets were obtained from Hibiscus mutabilis L..The key anti-inflammatory active ingredients of Hibiscus mutabilis L.are quercetin,apigenin and luteolin.Its action pathway is mainly related to NF-κB,cancer pathway and TNF signaling pathway.Cell experiments showed that total flavonoids of Hibiscus mutabilis L.could effectively inhibit the expression of tumor necrosis factor(TNF-α),interleukin 8(IL-8)and epidermal growth factor receptor(EGFR)in LPS-induced RAW 264.7 inflammatory cells.It also downregulates the phosphorylation of human nuclear factor ĸB inhibitory protein α(IĸBα)and NF-κB p65 subunit protein(p65).Overall,the anti-inflammatory effect of Hibiscus mutabilis L.is related to many active components,many signal pathways and targets,which provides a theoretical basis for its further development and application.
文摘Background:The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.Methods:We analyzed the DNA of an index patient with early-onset systemic inflammation,cutaneous vasculopathy,and pulmonary inflammation.We sequenced a candidate gene,TMEM173,encoding the stimulator of interferon genes(STING),in this patient and in five unrelated children with similar clinical phenotypes.
文摘AIM:To evaluate the predictive value of pan-immuneinflammation value(PIV)in the diagnosis of proliferative diabetic retinopathy(PDR)and its association with the stage of PDR.METHODS:This observational case-control study included participants who underwent routine complete blood count testing.Inflammation-related indices,including neutrophil-to-lymphocyte ratio,systemic immune-inflammation index(SII),and PIV,were derived and analyzed.Receiver operating characteristic curve(ROC)analysis was applied to assess the diagnostic performance of these indices in distinguishing patients with PDR,with sensitivity,specificity,area under ROC,and optimal threshold values calculated.In addition,binary logistic regression analysis was performed to evaluate the association between inflammatory indices and PDR stage.RESULTS:This study included 205 patients:60 with diabetes without retinopathy(mean age:61.81±10.76y),80 with PDR(mean age:61.63±10.03y)and 65 healthy controls(mean age:59.52±5.88y).The PDR group had significantly higher white blood cell(WBC,P<0.001),monocyte(MONO,P=0.009)and neutrophil(NEU)counts(P<0.001).SII and PIV had the highest sensitivity and area under ROC for predicting patients with PDR(0.822,0.846,respectively).The optimal cut-off values for discriminating patients with PDR were determined to be>527.12 and>299.08 for SII and PIV,respectively.The logistic regression analysis demonstrated that a decrease in lymphocyte(LYM)count and an increase in platelet count(PLT),glycated haemoglobin(HbA1c),SII,and PIV were all significantly associated with the development of high-risk PDR(all P<0.05).PIV was more stable than independent MONO,LYM,PLT and NEU levels in predicting both the diagnosis and stage of PDR.The optimal cut-off value for PIV to discriminate patients with high-risk PDR was found to be>345.87 area under ROC=0.871,with sensitivity of 0.827 and specificity of 0.812.CONCLUSION:PIV is a reliable,valuable,and inexpensive blood index that can be used for early detection and staging of PDR.PIV may therefore be essential to be used for the follow-up of diabetic patients.
基金Supported by the National Natural Science Foundation of China(No.82388101,No.81930024)the Science and Technology Commission of Shanghai(No.22YS1400400,No.20DZ2270800).
文摘Dear Editor,Idiopathic orbital inflammation(IOI),also known as orbital inflammatory pseudotumor,is a relatively common orbital disorder[1].Its pathogenesis remains unclear,often regarded as a nonspecific immune-mediated response[2].IOI presents with symptoms such as pain,photophobia,proptosis,eyelid swelling,edema,conjunctival congestion,and diplopia,with possible vision loss occurring in some cases.Based on the soft tissue structures involved,IOI can be classified into subtypes such as myositis,optic neuritis,dacryoadenitis,diffuse orbital inflammation,and orbital inflammatory masses[2].
基金supported by the Deutsche Forschungsgemeinschaft(DFG)with grants PR1569/1-1 and PR 1569/1-3(to VP).
文摘Globally,glaucoma stands as a primary cause of irreversible blindness,marked by intricate pathophysiological processes in which neuroinflammation plays a pivotal role.As the principal immune cells within the central nervous system,microglia play a dual function in the progression of glaucoma.Under standard physiological states,microglia safeguard the retina by offering neurotrophic support and removing cellular debris.In the pathological progression of glaucoma,microglia become activated and release significant levels of inflammatory factors,resulting in retinal ganglion cell injury,cell death,and impaired neuroregeneration.This review focuses on examining the dual functions of microglia in glaucoma,evaluating their influence on retinal neurodegeneration and repair,and suggesting that modulating microglial activity could serve as a promising therapeutic strategy.Understanding the mechanisms of microglial action in glaucoma is crucial for unveiling the complex pathophysiological processes of the disease and developing new therapeutic strategies.
基金supported by the Main Research Program(E0210202-05)of the Korea Food Research Institute(KFRI),funded by the Korean Ministry of Science and ICT.
文摘Neutrophil extracellular trap(NET)formation or NETosis is a specialized innate immune process in which neutrophils release chromatin fibers decorated with histones and antimicrobial proteins.Although pivotal for pathogen clearance,aberrant NETosis has emerged as a critical modulator of acute and chronic respiratory pathologies,including acute respiratory distress syndrome,asthma,and chronic obstructive pulmonary disease.Dysregulated NET release exacerbates airway inflammation by inducing epithelial injury,mucus hypersecretion,and the recruitment of inflammatory leukocytes,thereby accelerating tissue remodeling and functional decline.Mechanistically,NETosis is governed by peptidyl arginine deiminase 4(PADI4)-mediated histone citrullination,NADPH oxidase-dependent reactive oxygen species production,mitochondrial metabolic reprogramming,and activation of toll-like receptors and inflammasomes.These molecular events perpetuate inflammation and prevent its resolution.Emerging evidence indicates that natural bioactive compounds,such as flavonoids,terpenoids,and polyphenols,attenuate NETosis by modulating oxidative stress,inhibiting PADI4 activation,or suppressing downstream pro-inflammatory cascades.Collectively,these findings highlight the therapeutic potential of targetingNETosis tomitigate neutrophil-driven airway pathology.This review aims to comprehensively synthesize recent mechanistic insights into NETosis and to delineate how modulation of NET formation contributes to the prevention and treatment of inflammatory respiratory diseases.
文摘Moringa oleifera(MO)is traditionally used to mitigate inflammatory-mediated disorders;however,the influence of ecotypic variation on its anti-inflammatory activity remains poorly understood.In this study,we compared the phytochemical composition and anti-inflammatory activity of ethanolic extracts obtained from fresh and dried leaves of four MO ecotypes(India,Paraguay,Mozambique,and Pakistan),all grown under the same outdoor conditions,as well as two commercial powders(Just Moringa and WISSA),using LPS-stimulated RAW 264.7 macrophages.Extracts from fresh leaves were 19-43%more cytotoxic than those from dried leaves,depending on the ecotype,likely due to higher cyanogenic glycoside content.Extracts from the India and Paraguay ecotypes,characterized by high levels of quercetin derivatives and caffeic acids,as well as Just Moringa,enriched in kaempferol derivatives,significantly inhibited LPS-induced nitric oxide(NO)production(p<0.05).Just Moringa and Paraguay extracts also reduced iNOS gene expression(p<0.05 and p<0.01,respectively),whereas only the Paraguay extract decreased iNOS protein levels(p<0.05).In contrast,quercetin-3-O-glucoside and rutin showed significant effects only at concentrations approximately 100-fold higher than those present in the extracts,indicating that the phytocomplex displays greater bioactivity than individual compounds.Overall,these results demonstrate that ecotypic variation strongly affects the polyphenolic composition and anti-inflammatory properties of MO leaves,highlighting the importance of reporting both origin and phytochemical composition in MO-based products.
基金supported by the Natural Science Foundation of Heilongjiang Province,No.YQ2021H011(to QL)China Postdoctoral Science Foundation,Nos.2020M670925,2022T150172(to QL)+2 种基金Postdoctoral Foundation of Heilongjiang Province,Nos.LBH‐Z19027,LBH‐TZ2019(to QL)Institute Cultivation Fund,No.PYMS2023-1(to QL)Natural Science Foundation of Jiangsu Province,No.BK20241233(to YL).
文摘Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA(dsDNA)-sensing cyclic GMP-AMP synthase(cGAS)signaling warrant further study.Using middle cerebral artery occlusion mice,we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation.Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release,as reflected byγH2AX staining,as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway,both of which were notably suppressed by melatonin treatment.Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome activation and nuclear factor(NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke,while exhibiting the capacity to attenuate the immune response to ischemia in mice.This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain.Specifically,melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-αby microglia.Regarding neurological outcomes,melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice.Notably,the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity.We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles(Mф-MLT@FNGs),which exhibited therapeutic properties in middle cerebral artery occlusion mice.Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway.By doing so,melatonin rescues damaged brain tissue and protects neurological function,highlighting its potential as a neuroprotective treatment for ischemic stroke.
文摘Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood–brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood–brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.
文摘Objectives Neutrophil extracellular traps(NETs)have emerged as critical effectors in immune defense but also as potential drivers of tissue damage in chronic inflammatory diseases.Their role in periodontitis,a highly prevalent condition characterized by dysregulated host–microbe interactions,remains incompletely defined.This systematic review aimed to synthesize,for the first time,ex vivo human evidence on the presence,activity,and clinical significance of NETs in periodontitis.Methods A comprehensive search of Medline,Web of Science,and Scopus was conducted up to August 2025.Eligible studies included ex vivo human investigations assessing NETs or NET markers in gingival tissues,gingival crevicular fluid,saliva,blood,or biofilms from patients with periodontitis.Study selection,data extraction,and risk-of-bias assessment were conducted in duplicate,and the protocol was registered in PROSPERO(CRD420251109174).Results Seventeen studies met the inclusion criteria.NET markers such as citrullinated histone H3(CitH3),myeloperoxidase(MPO),and neutrophil elastase were consistently elevated in periodontitis samples compared with controls.Several studies reported a reduction in NET levels or improved NET degradation following periodontal therapy.NETs were also implicated in biofilm stability and in systemic associations with rheumatoid arthritis and chronic kidney disease.However,heterogeneity in methodologies,small sample sizes,and inconsistent marker use limited comparability across studies.Conclusions Ex vivo evidence indicates that aberrant NET formation and impaired clearance contribute to periodontal inflammation and tissue destruction.Nonetheless,methodological variability and risk of bias constrain definitive conclusions.Standardization of detection methods,consensus on marker panels,and exploration of neutrophil subsets and systemic confounders are essential to establish NETs as reliable biomarkers and therapeutic targets in periodontitis.
文摘AIM:To report and analyze cases of sterile intraocular inflammation(IOI)following intravitreal faricimab injections in patients treated for neovascular age-related macular degeneration(nAMD)and diabetic macular edema(DME).METHODS:This double-center case series included nine eyes of six patients who developed uveitis after faricimab therapy.Comprehensive clinical evaluation was performed,including slit-lamp examination,intraocular pressure(IOP)measurement,fluorescein and indocyanine green angiography(ICGA),and laboratory tests.Inflammatory responses were treated with topical or systemic corticosteroids,and patients were monitored for visual acuity and inflammatory activity.RESULTS:The incidence of IOI was 0.8%per patient(Innsbruck)and 0.23%(Czechia),with inflammation typically occurring between the third and sixth injection(mean interval:10d post-injection).Inflammator y presentations ranged from anterior uveitis to posterior segment involvement.One notable case demonstrated novel choroidal hypofluorescent lesions on angiography,suggesting deeper ocular involvement.The mean patient age was 76y;five of six affected patients were female.All cases responded to local and systemic corticosteroids,with full recovery of initial visual acuity.CONCLUSION:Sterile IOI after faricimab appears to be a rare but relevant adverse event.Although the incidence falls within expected ranges for anti-vascular endothelial growth factor(anti-VEGF)agents,the observed choroidal involvement represents a potentially new safety signal.Prompt diagnosis and corticosteroid therapy are effective in all cases.Our findings support the need for vigilant post-marketing surveillance and further studies to better understand the underlying mechanisms and risk factors of faricimab-associated inflammation.
基金Supported by the Key Program of the National Natural Science Foundation of China(No.82530034)the National Natural Science Foundation of China(No.82271054)the Nature Science Foundation of Xiamen,China(No.3502Z20227121).
文摘AIM:To investigate the impact of depression-like behavior on ocular surface homeostasis in a mouse model,with a focus on dry eye-like alterations.METHODS:Male C57BL/6J mice(10-12 weeks old)were randomly assigned to control or restraint stress(RS)groups.The RS group underwent three intermittent 24-hour restraint sessions to induce depressive-like behavior.Behavioral testing,tear secretion measurement,and corneal Oregon Green Dextran(OGD)staining were performed.Postmortem analyses included histological evaluation of lacrimal glands,goblet cell quantification using periodic acid-Schiff staining,and assessment of key inflammatory and apoptotic markers:interleukin(IL)-17,matrix metalloproteinases(MMP)-3,MMP-9,IL-13,interferon(IFN)-γ,and cleaved caspase-3 and-8.RESULTS:Repeated RS induced depression-like behavior and significant ocular surface changes.RStreated mice showed increased corneal OGD uptake and upregulation of gene/protein expression of IL-17,MMP-3,and MMP-9(P<0.05).Goblet cell density and IL-13 protein expression were reduced,while IFN-γprotein expression was elevated(P<0.05).Cleaved caspase-3 and-8 levels were significantly increased in both cornea and conjunctiva.Tear volume and lacrimal gland size were unchanged;however,mild inflammatory infiltration was observed in lacrimal glands.CONCLUSION:Repeated RS leads to ocular surface inflammation and dry eye-like pathology,including corneal barrier disruption,goblet cell loss,and epithelial apoptosis.These findings suggest that depression contributes to the pathogenesis of dry eye disease via immune-mediated mechanisms.
文摘To explore the mechanisms underlying ocular infection by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),we conducted a comprehensive review of current literature,focusing on viral entry pathways,receptor expression in ocular tissues,and associated clinical manifestations.This review encompasses studies published within the last five years with a focus on original research and systematic reviews that provide molecular,histological,or clinical evidence.The findings show that SARS-CoV-2 can infect ocular tissues through multiple receptors beyond angiotensin-converting enzyme 2(ACE2),including transmembrane serine protease 2(TMPRSS2),CD147,alanyl aminopeptidase N(ANPEP),dipeptidyl peptidase 4(DPP4),angiotensin II receptor type 2(AGTR2),and polymeric immunoglobulin receptor(PIGR),which are expressed in retinal,conjunctival,corneal,limbal,and photoreceptor cells.The virus may also reach ocular structures via neurovascular invasion.Clinically,patients with coronavirus disease 2019(COVID-19)may present with a broad spectrum of ophthalmic manifestations,including conjunctivitis,hyperreflective lesions in the inner retinal layers,flame-shaped hemorrhages,cottonwool spots,retinal pallor,hard exudates,and various forms of maculopathy,such as paracentral acute middle maculopathy and acute macular neuroretinopathy(AMN).These signs reflect both direct viral damage and secondary effects of systemic inflammation and microvascular injury.Understanding the molecular and clinical spectrum of ocular involvement is essential for early diagnosis,appropriate ophthalmologic care,and the prevention of long-term visual sequelae in patients affected by COVID-19.
基金supported by Hebei Province Natural Science Foundation(H2023423037)The Government Funded Clinical Program of Hebei Province(No.ZF2025287)+1 种基金Special Project of Hebei Industrial Technology Institute for Traditional Chinese Medicine Preparation(No.YJY2024001)Chinese Medicine Scientific Research Program of Hebei Province(No.2025222).
文摘Background:Acute kidney injury(AKI),characterized by rapid renal dysfunction(KDIGO 2022 criteria:48-hour doubling of serum creatinine or<0.5 mL/kg/h urine output for>6 h),affects 13.3 million people annually with>20%mortality.Its progression involves metabolic imbalances,toxin accumulation,and multiorgan failure,often culminating in chronic kidney disease.Current therapies(fluid resuscitation,diuretics,renal replacement therapy)remain limited.Inflammation drives AKI pathogenesis:renal insults(ischemia,toxins)trigger tubular cell release of pro-inflammatory mediators(TNF-α,IL-1β,IL-6),activating neutrophil gelatinase-associated lipocalin(NGAL)and dysregulating P38 MAPK/ERK pathways.This cascade promotes leukocyte infiltration,oxidative stress,and apoptosis,exacerbating renal damage.Ononin,a flavonoid from Astragali Radix,shows multi-target potential by suppressing pro-inflammatory cytokines,modulating signaling,and mitigating oxidative stress.Its dual anti-inflammatory/antioxidant properties position it as a promising candidate for AKI intervention.Exploring the ameliorative effect of ononin on the inflammatory response Ameliorative effect of ononin on the inflammatory response in doxorubicin-induced AKI mice.Methods:We used network pharmacology to explore ononin’s target molecules and AKI-related disease molecules,identified their intersections,and predicted potential mechanisms via enrichment analysis,followed by molecular docking verification.For in-vivo validation,50 mice were randomly divided into five groups(n=10/group):Control,Model,Ononin-L(15 mg/kg),Ononin-H(60 mg/kg),and Dexamethasone(2.6 mg/kg).An AKI model was established by intravenous tail-vein injection of Doxorubicin(15 mg/kg).Samples were collected 12 h post-induction.We calculated the renal coefficient,examined renal histopathology using hematoxylin and eosin(HE),periodic acid-Schiff(PAS),and Masson’s trichrome(MASSON)staining,and observed mitochondrial morphology by electron microscopy(EM).ELISA was used to measure NGAL,serum creatinine(Scr),and blood urea nitrogen(BUN)levels in serum.Immunofluorescence(IF)evaluated the expression of P-P38,P-ERK,NGAL,and KIM-1 in renal tissues.RT-qPCR assessed the gene expression of pro-inflammatory cytokines,MAPK pathway components,and renal injury markers in kidney tissues.Western Blot(WB)quantified P-P38,P38 MAPK,P-ERK,ERK,NGAL,and KIM-1 in renal tissues.Results:Network pharmacology analysis suggested that ononin could attenuate AKI through its anti-inflammatory properties and regulation of the MAPK signaling pathway.The Model group exhibited a significantly elevated renal coefficient(P<0.05),severe histopathological damage,and mitochondrial dysfunction compared to controls.Serum levels of NGAL,Scr,and BUN were markedly increased(P<0.05),indicating impaired renal function.Enhanced fluorescence signals of P-P38 MAPK,P-ERK,NGAL,and KIM-1 suggested activation of MAPK pathways and renal injury.Upregulation of pro-inflammatory cytokines(IL-1β,IL-6,TNF-α)and MAPK-related genes(P38 MAPK,ERK)alongside injury markers(NGAL,KIM-1)(P<0.05).Increased ratios of phosphorylated-to-total proteins(P-P38/P38,P-ERK/ERK)and elevated NGAL/KIM-1 protein levels confirmed pathway dysregulation.Treatment significantly reduced the renal coefficient(P<0.05),attenuated histological damage,and restored mitochondrial integrity.NGAL,Scr,and BUN levels were lowered,reflecting functional recovery.Diminished fluorescence intensities of P-P38,P-ERK,NGAL,and KIM-1 indicated suppression of injury pathways.Downregulation of inflammatory cytokines(IL-1β,IL-6,TNF-α),MAPK components(P38 MAPK,ERK),and injury markers(NGAL,KIM-1)(P<0.05).Reduced phosphorylation ratios(P-P38/P38,P-ERK/ERK)and decreased NGAL/KIM-1 protein expression demonstrated therapeutic efficacy.Conclusion:Ononin ameliorates inflammatory responses in AKI mice via the P38 MAPK/ERK pathway.
基金supported by the National Natural Science Foundation of China,No.81641048Research Project of Yan’an University,No.2023JBZR-011(both to LZ).
文摘Spinal cord injury is a severe neurological condition characterized by the permanent loss of nerve cell function and a failure in neural circuit reconstruction-key factors contributing to disability.Therefore,exploring effective strategies to promote the repair and regeneration of nerve cells after spinal cord injury is crucial for optimizing patient prognosis.The purpose of this paper is to conduct an in-depth review of the pathological changes in nerve cells after spinal cord injury and to present the state of research on the role of exercise training in promoting the repair and regeneration of nerve cells after spinal cord injury.In terms of the intrinsic growth capacity of neurons,disruptions in the dynamic balance between growth cones and the cytoskeleton,the dysregulation of transcription factors,abnormal protein signaling transduction,and altered epigenetic modifications collectively hinder axonal regeneration.Additionally,the microenvironment of neurons undergoes a series of complex changes,initially manifesting as edema,which may be exacerbated by spinal cord ischemia-reperfusion injury,further increasing the extent of nerve cell damage.The abnormal proliferation of astrocytes leads to the formation of glial scars,creating a physical barrier to nerve regeneration.The inflammatory response triggered by the excessive activation of microglia negatively impacts the process of nerve repair.Non-invasive interventions involving exercise training have shown significant potential in promoting nerve repair as part of a comprehensive treatment strategy for spinal cord injury.Specifically,exercise training can reshape the growth cone and cytoskeletal structures of neurons,regulate transcription factor activity,modulate protein signaling pathways,and influence epigenetic modifications,thereby activating the intrinsic repair mechanisms of neurons.Moreover,exercise training can regulate the activation state of astrocytes,optimize the inflammatory response and metabolic processes,promote astrocyte polarization,enhance angiogenesis,reduce glial scar formation,and modulate the expression levels of nerve growth factors.It also effectively helps regulate microglial activation,promotes axonal regeneration,and improves phagocytic function,thereby optimizing the microenvironment for nerve repair.In terms of clinical translation,we summarize the preliminary results of new drug research and development efforts,the development of innovative devices,and the use of exercise training in promoting clinical advancements in nerve repair following spinal cord injury,while considering their limitations and future application prospects.In summary,this review systematically analyzes findings relating to the pathological changes occurring in nerve cells after spinal cord injury and emphasizes the critical role of exercise training in facilitating the repair and regeneration of nerve cells.This work is expected to provide new ideas and methods for the rehabilitation of patients with spinal cord injury.
