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
Regulatory T cells are crucial immunomodulatory cells that play essential roles in both ischemic stroke and intracerebral hemorrhage.These cells are vital in post-stroke inflammation since they suppress immune respons...Regulatory T cells are crucial immunomodulatory cells that play essential roles in both ischemic stroke and intracerebral hemorrhage.These cells are vital in post-stroke inflammation since they suppress immune responses and promote tissue repair.This review thoroughly examines the dynamic changes in the number and function of regulatory T cells and highlights their distinct roles at various stages of stroke progression.In the acute phase(within 5-7 days),regulatory T cells exert neuroprotective effects primarily by reducing inflammation.In the chronic phase(7 days post-onset),these cells support neuroregeneration and functional recovery.The review also explores the emerging role of regulatory T cells in the brain-gut axis,a key mediator of the systemic immune responses following stroke,and discusses its relevance in modulating post-stroke inflammation and repair.Various strategies aimed at enhancing regulatory T cell responses include adoptive transfer of regulatory T cells,administration of pharmacological agents,and induction of mucosal tolerance.All these approaches can potentially enhance the immunomodulatory and repair functions of regulatory T cells.Nevertheless,despite the promising preclinical results,the translation of regulatory T cell-based therapies into clinical practice is associated with challenges related to optimal timing,dosage,and long-term efficacy.Overall,targeting regulatory T cells is a novel and promising immunoregulatory approach for mitigating stroke-induced injury and promoting neural repair.展开更多
Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases.However,whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear.Here,we found that ...Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases.However,whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear.Here,we found that neutrophil-triggered nociceptive ingrowth functioned as negative feedback regulation to inflammation during bone healing.A unique Il4ra^(+)Ccl2^(high) neutrophil subset drove intense postinjury TRPV1^(+)nociceptive ingrowth,which in return dissipated inflammation by activating the production of pro-resolving mediator lipoxin A4(LXA4)in osteoblasts.Mechanistically,osteoblastic autophagy activated by nociceptor-derived calcitonin gene-related peptide(CGRP)suppressed the nuclear translocation of arachidonate 5-lipoxygenase(5-LOX)to favor the LXA4 biosynthesis.Moreover,in alveolar bone from patients with Type Ⅱ diabetes,we found diminished nociceptive innervation correlated with reduced autophagy,increased inflammation,and impaired bone formation.Activating nociceptive nerves by spicy diet or topical administration of a clinical-approved TRPV1 agonist showed therapeutic benefits on alveolar bone healing in diabetic mice.These results reveal a critical neuroimmune interaction underlying the inflammation-regeneration balance during bone repairing and may lead to novel therapeutic strategies for inflammatory bone diseases.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
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
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
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
The immune system is a complex protective network that is tightly controlled to protect and defend the host.Inflammation is a precisely regulated response that is crucial for host defense,while dysregulation can lead ...The immune system is a complex protective network that is tightly controlled to protect and defend the host.Inflammation is a precisely regulated response that is crucial for host defense,while dysregulation can lead to tissue damage and systemic diseases.Defining the mechanisms that initiate,amplify,and resolve inflammation is crucial for understanding our complex immune system.The inflammasome,a multiprotein complex that functions as a sensor,plays a key role in regulating this inflammatory response.Inflammasomes act as molecular platforms that integrate upstream danger signals,catalyze the activation of caspase-1,and drive the maturation and secretion of proinflammatory cytokines such as IL-1βand IL-18.These inflammatory cytokines are released through pyroptosis,a lytic form of programmed cell death that eliminates infected or damaged cells while simultaneously propagating inflammation through the release of cytokines or chemokines[1].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
Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammat...Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs,which have a range of serious adverse effects.As an alternative,naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions.Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models,in the face of neuroinflammatory insults induced by lipopolysaccharide,through a systematic review and meta-analysis.A search of the preclinical literature was conducted across four databases(Pub Med,Web of Science,Scielo,and Google Scholar).Studies were selected based on inclusion and exclusion criteria,assessed for methodological quality using CAMARADES,and risk of bias using the SYRCLE tool,and data were extracted from the studies.The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis.A total of 384 potentially relevant articles were identified,of which 11 studies were included in the analysis.The methodological quality was assessed,resulting in an average score of 5.8/10,and the overall risk of bias analysis revealed a lack of methodological clarity in most studies.Furthermore,through the meta-analysis,it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin 6,interleukin 1β(n=89;SMD=–2.00;95%CI:–3.29 to–0.71),and microgliosis(n=33;SMD=–2.56;95%CI:–4.07 to–1.10).In terms of underlying mechanisms,quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties,possibly through the nuclear factor erythroid 2-related factor 2(Nrf2)/HO-1 pathways,increasing the expression of antioxidant enzymes and reducing reactive species,and modulating the caspase pathway,increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins.Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation.However,despite promising results in animal models,future directions should focus on well-designed clinical studies to assess the safety,bioavailability,and efficacy of quercetin and its derivatives in humans.Additionally,standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.展开更多
Inflammatory markers are elevated in people with the zoonotic disease Mpox(formerly known as monkeypox),but how the monkeypox virus(MPXV)drives these responses has remained largely undefined.A new study published in C...Inflammatory markers are elevated in people with the zoonotic disease Mpox(formerly known as monkeypox),but how the monkeypox virus(MPXV)drives these responses has remained largely undefined.A new study published in Cellular&Molecular Immunology[1]revealed that the cytosolic DNA sensor AIM2 triggers inflammasome responses and pyroptosis in MPXV-infected cells,leading to apoptotic and necroptotic cell death in uninfected bystander macrophages.展开更多
BACKGROUND Coronary microembolization(CME)is the major leading cause of perioperative myocardial injury during coronary revascularization.Semaglutide exerts multiple protective biological activities,but its cardioprot...BACKGROUND Coronary microembolization(CME)is the major leading cause of perioperative myocardial injury during coronary revascularization.Semaglutide exerts multiple protective biological activities,but its cardioprotective effects on CME remain unclear.Thus,this experiment studied the impact of semaglutide on CME-induced myocardial injury.METHODS A rat CME model was generated by injecting microspheres into the left ventricle while clamping the ascending aorta.A H9c2 cardiomyocyte model was constructed by stimulation of lipopolysaccharide combined with hypoxia.Semaglutide or the high mobility group box 1(HMGB1)antagonist glycyrrhizin administrations were ahead of CME and cell modeling.Cardiac function,myocardial injury markers,cell viability and morphological alternations were detected.Apoptotic and inflammatory factors,cytosolic HMGB1 and its translocation,advanced glycosylation end-product specific receptor(RAGE),and nuclear factor kappa B p65(NF-κB p65)were evaluated.RESULTS Semaglutide pretreatment ameliorated CME-induced cardiac systolic dysfunction and relieved the cardiac injury.Semaglutide attenuated myocardial apoptosis and inflammatory response following CME in vivo and in vitro.Moreover,semaglutide downregulated HMGB1 expression and suppressed its nuclear-cytoplasmic translocation.Both glycyrrhizin and semaglutide administration affected the HMGB1/RAGE/NF-κB p65 pathway after CME.CONCLUSIONS Semaglutide pretreatment attenuates CME-induced myocardial injury by suppressing apoptosis and inflammation through the HMGB1/RAGE/NF-κB p65 pathway.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
Microorganisms constitute an essential component in the indoor environment,which is closely related to hu-man health.However,there is limited evidence regarding the associations between indoor airborne microbiome and ...Microorganisms constitute an essential component in the indoor environment,which is closely related to hu-man health.However,there is limited evidence regarding the associations between indoor airborne microbiome and systemic inflammation,as well as whether this association is modified by indoor particulate matter and the underlying mechanisms.In this prospective repeated-measure study among 66 participants,indoor airborne mi-crobiome was characterized using amplicon sequencing and qPCR.Indoor fine particulate matter(PM_(2.5))and inhalable particulate matter(PM10)were measured.Systemic inflammatory biomarkers were assessed,including white blood cell(WBC),neutrophil(NEUT),monocyte,eosinophil counts,and their proportions.Targeted serum amino acid metabolomics were conducted to explore the underlying mechanisms.Linear mixed-effect models re-vealed that bacterial and fungal Simpson diversity were significantly associated with decreased WBC and NEUT.For example,for each interquartile range increase in the bacterial Simpson diversity,WBC and NEUT changed by-4.53%(95%CI:-8.25%,-0.66%)and-5.95%(95%CI:-11.3%,-0.27%),respectively.Notably,increased inflammatory risks of airborne microbial exposure were observed when indoor PM_(2.5) and PM10 levels were below the WHO air quality guidelines.Mediation analyses indicated that dopamine metabolism partially mediated the anti-inflammatory effects of fungal diversity exposure.Overall,our study indicated protection from a diverse indoor microbial environment on cardiovascular health and proposed an underlying mechanism through amino acid metabolism.Additionally,health risks associated with microbial exposure deserve more attention in con-texts of low indoor particulate matter pollution.Further research is necessary to fully disentangle the complex relationships between indoor microbiome,air pollutants,and human health.展开更多
Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,par...Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,particularly palmitic acid,are potent inducers of chronic low-grade inflammation,largely due to disruptions in glucose metabolism and the onset of insulin resistance(Qiu et al.,2022).While many organs are affected,the brain,specifically the hypothalamus,is among the first to exhibit inflammation in response to an unhealthy diet,suggesting that obesity may,in fact,be a brain-centered disease with neuroinflammation as a central factor(Thaler et al., 2012).展开更多
OBJECTIVE:To investigate the therapeutic effect of Weimishu prescription(胃糜舒方,WMSP)on chronic gastritis with liver-stomach disharmony(CG-LSD)and elucidate its molecular mechanisms involved in regulating the nuclea...OBJECTIVE:To investigate the therapeutic effect of Weimishu prescription(胃糜舒方,WMSP)on chronic gastritis with liver-stomach disharmony(CG-LSD)and elucidate its molecular mechanisms involved in regulating the nuclear factor kappa-B(NF-κB)inflammatory response and gastric stem cell(GSC)differentiation.METHODS:A CG-LSD rat model was established through a combined protocol involving 56%ethanol and tail-clip stimulation.Rats were administered with low-,medium-,or high-dose WMSP,the positive control drug omeprazole,or high-dose WMSP with the NF-κB agonist phorbol 12-myristate 13-acetate(PMA).Histopathological changes were assessed via hematoxylin and eosin and Td T-mediated d UTP nick end labeling staining.Flow cytometry,immunofluorescence,real-time quantitative polymerase chain reaction,Western blotting,and enzyme-linked immunosorbent assay were performed to evaluate the underlying mechanisms.RESULTS:WMSP significantly increased rat locomotor activity,improved Traditional Chinese Medicine syndrome scores,and ameliorated pathological damage to the gastric mucosa while reducing gastric mucosal epithelial cells apoptosis.WMSP also increased the proportion of Lgr5+Ki67+cells;upregulated muscle,intestine,and stomach specific transcript 1,sex determining region Y-box 2,sex determining region Y-box 9,and homing cell adhesion molecule;and enhanced the levels of pepsinogen C,somatostatin,mucin-6,H+-K+ATPase,and E-cadherin proteins,thereby promoting gastric stem cell survival and differentiation.Furthermore,WMSP alleviated systemic and gastric mucosal inflammation in CG-LSD rats.Mechanistically,WMSP suppressed NF-κB expression,thereby reducing Smadspecific E3 ubiquitin ligase 2 levels,which enhancedβ-catenin and subsequently increased myelocytomatosis oncogene,and axis inhibition protein 2 expression.PMA administration reversed the protective effect of WMSP on CG-LSD rats.CONCLUSIONS:WMSP ameliorated gastric mucosal injury in CG-LSD rats by regulating the NF-κB/β-catenin signaling pathway,thereby suppressing inflammation and promoting gastric stem cell differentiation.These findings highlight the therapeutic potential of WMSP,providing the foundation for further clinical evaluations of WMSP in CGLSD treatment.展开更多
Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson'...Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).展开更多
AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)ce...AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)cells through regulating snail family transcriptional repressor 1(SNAI1),and to validate its role in a proliferative vitreoretinopathy(PVR)mouse model.METHODS:Human RPE cell line ARPE-19 cells were treated with TGF-β2 to construct an EMT model.Western blot detected VRK1 level.The effects of VRK1 on SNAI1 expression and biological behavior of ARPE-19 cells were detected by immunofluorescence,ELISA,Transwell,and scratch assay,and the interaction between VRK1 and SNAI1 was confirmed through immunoprecipitation.A PVR mouse model was constructed,and the effects of VRK1 or/and SNAI1 on retinal damage were assessed by pathologic staining.Inflammatory factors and EMT-related proteins were assessed with ELISA and Western blot.RESULTS:VRK1 was upregulated in ARPE-19 cells after TGF-β2 treatment.Overexpression of VRK1 increased cell viability,promoted cell migration and EMT,and the levels of inflammatory factors.Silencing of VRK1 reversed the above indexes.There was a direct interaction between VRK1 and SNAI1,and overexpresssion SNAI1 weakened the impacts of silencing of VRK1.In PVR mice,silencing of VRK1 ameliorated retinal structural damage,decreased proinflammatory factor levels,and suppressed SNAI1 and mesenchymal marker expression.SNAI1 overexpression antagonized the protective effects of silencing VRK1 and exacerbated EMT and inflammatory responses.CONCLUSION:VRK1 plays a key role in retinal structural and inflammatory damage in PVR mice by regulating SNAI1 and mediating TGF-β2-caused EMT and inflammatory responses in RPE cells.展开更多
Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated ...Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.展开更多
G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR3...G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).展开更多
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 National Key R&D Program:Key Special Project on Research for the Prevention and Treatment of Common Diseases-2022 Annual Project,Nos.2022YFC2504900,2022YFC2504902(both to ZL).
文摘Regulatory T cells are crucial immunomodulatory cells that play essential roles in both ischemic stroke and intracerebral hemorrhage.These cells are vital in post-stroke inflammation since they suppress immune responses and promote tissue repair.This review thoroughly examines the dynamic changes in the number and function of regulatory T cells and highlights their distinct roles at various stages of stroke progression.In the acute phase(within 5-7 days),regulatory T cells exert neuroprotective effects primarily by reducing inflammation.In the chronic phase(7 days post-onset),these cells support neuroregeneration and functional recovery.The review also explores the emerging role of regulatory T cells in the brain-gut axis,a key mediator of the systemic immune responses following stroke,and discusses its relevance in modulating post-stroke inflammation and repair.Various strategies aimed at enhancing regulatory T cell responses include adoptive transfer of regulatory T cells,administration of pharmacological agents,and induction of mucosal tolerance.All these approaches can potentially enhance the immunomodulatory and repair functions of regulatory T cells.Nevertheless,despite the promising preclinical results,the translation of regulatory T cell-based therapies into clinical practice is associated with challenges related to optimal timing,dosage,and long-term efficacy.Overall,targeting regulatory T cells is a novel and promising immunoregulatory approach for mitigating stroke-induced injury and promoting neural repair.
基金The National Natural Science Foundation of China(No.82130027,82301020,82100966)Young Elite Scientists Sponsorship Program by CAST(2024QNRC001)+5 种基金The China Postdoctoral Science Foundation(2023M732283)The National Key Research and Development Program of China(No.2023YFC2413600)The Shanghai Sailing Program(23YF1422000,21YF1424400)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZLCX20212400)Young Elite Scientists Sponsorship Program by CAST(2021QNRC001)Shanghai Pujiang Program(24PJD054).
文摘Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases.However,whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear.Here,we found that neutrophil-triggered nociceptive ingrowth functioned as negative feedback regulation to inflammation during bone healing.A unique Il4ra^(+)Ccl2^(high) neutrophil subset drove intense postinjury TRPV1^(+)nociceptive ingrowth,which in return dissipated inflammation by activating the production of pro-resolving mediator lipoxin A4(LXA4)in osteoblasts.Mechanistically,osteoblastic autophagy activated by nociceptor-derived calcitonin gene-related peptide(CGRP)suppressed the nuclear translocation of arachidonate 5-lipoxygenase(5-LOX)to favor the LXA4 biosynthesis.Moreover,in alveolar bone from patients with Type Ⅱ diabetes,we found diminished nociceptive innervation correlated with reduced autophagy,increased inflammation,and impaired bone formation.Activating nociceptive nerves by spicy diet or topical administration of a clinical-approved TRPV1 agonist showed therapeutic benefits on alveolar bone healing in diabetic mice.These results reveal a critical neuroimmune interaction underlying the inflammation-regeneration balance during bone repairing and may lead to novel therapeutic strategies for inflammatory bone diseases.
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 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.
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.
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 a National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(2022R1C1C1007544,2024M3A9H5043152 to S.L.)a grant from the Korea Drug Development Fund funded by the Ministry of Science and ICT+7 种基金the Ministry of Trade,Industry,and Energythe Ministry of Health and Welfare(RS-2025--02222987 to S.L.)a grant from the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea,under the Korea Health Technology R&D Project(RS-2022--KH128422(HV22C015600)to S.L.)the Institute for Basic Science(IBS),Republic of Korea(IBS-R801--D9-A09,IBS-R801-D1-2025-a02 to S.L.)supported by the Circle Foundation(Republic of Korea)through the selection of the UNIST Pandemic Treatment Research Center as the 2023 Circle Foundation Innovative Science Technology Center(2023 TCF Innovative Science Project-01 to S.L.)Additionally,this study received funding from the Republic of Korea’s National Institute of Health(Project No.#2025ER160200,#2025ER240100 to S.L.)Additional support was provided by research funds from the Ulsan National Institute of Science&Technology(UNIST)(1.220112.01,1.220107.01 to S.L.)a grant from Yuhan Corporation(S.L.).
文摘The immune system is a complex protective network that is tightly controlled to protect and defend the host.Inflammation is a precisely regulated response that is crucial for host defense,while dysregulation can lead to tissue damage and systemic diseases.Defining the mechanisms that initiate,amplify,and resolve inflammation is crucial for understanding our complex immune system.The inflammasome,a multiprotein complex that functions as a sensor,plays a key role in regulating this inflammatory response.Inflammasomes act as molecular platforms that integrate upstream danger signals,catalyze the activation of caspase-1,and drive the maturation and secretion of proinflammatory cytokines such as IL-1βand IL-18.These inflammatory cytokines are released through pyroptosis,a lytic form of programmed cell death that eliminates infected or damaged cells while simultaneously propagating inflammation through the release of cytokines or chemokines[1].
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.
基金supported by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil(CAPES)[Finance Code 001](to MGS)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)fellowship[research grants 309840/2022-8]。
文摘Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions.The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs,which have a range of serious adverse effects.As an alternative,naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions.Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models,in the face of neuroinflammatory insults induced by lipopolysaccharide,through a systematic review and meta-analysis.A search of the preclinical literature was conducted across four databases(Pub Med,Web of Science,Scielo,and Google Scholar).Studies were selected based on inclusion and exclusion criteria,assessed for methodological quality using CAMARADES,and risk of bias using the SYRCLE tool,and data were extracted from the studies.The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis.A total of 384 potentially relevant articles were identified,of which 11 studies were included in the analysis.The methodological quality was assessed,resulting in an average score of 5.8/10,and the overall risk of bias analysis revealed a lack of methodological clarity in most studies.Furthermore,through the meta-analysis,it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin 6,interleukin 1β(n=89;SMD=–2.00;95%CI:–3.29 to–0.71),and microgliosis(n=33;SMD=–2.56;95%CI:–4.07 to–1.10).In terms of underlying mechanisms,quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties,possibly through the nuclear factor erythroid 2-related factor 2(Nrf2)/HO-1 pathways,increasing the expression of antioxidant enzymes and reducing reactive species,and modulating the caspase pathway,increasing levels of anti-apoptotic proteins and decreasing proapoptotic proteins.Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation.However,despite promising results in animal models,future directions should focus on well-designed clinical studies to assess the safety,bioavailability,and efficacy of quercetin and its derivatives in humans.Additionally,standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.
基金HB is supported by an Australian Government Research Training Program(RTP)Stipend ScholarshipAP is supported by a Medical Research Future Fund(MRFF)Early to Mid-Career Researchers grant(2041535)+3 种基金an ANU Hansen Scandinavian Friendship GrantSMM is supported by the National Health and Medical Research Council(NHMRC)of Australia(under Investigator Grant 2026910)the Australian Government Australia-India Strategic Research Fund and Collaborative Research Project(AIRXV000005)a CSL Centenary Fellowship。
文摘Inflammatory markers are elevated in people with the zoonotic disease Mpox(formerly known as monkeypox),but how the monkeypox virus(MPXV)drives these responses has remained largely undefined.A new study published in Cellular&Molecular Immunology[1]revealed that the cytosolic DNA sensor AIM2 triggers inflammasome responses and pyroptosis in MPXV-infected cells,leading to apoptotic and necroptotic cell death in uninfected bystander macrophages.
文摘BACKGROUND Coronary microembolization(CME)is the major leading cause of perioperative myocardial injury during coronary revascularization.Semaglutide exerts multiple protective biological activities,but its cardioprotective effects on CME remain unclear.Thus,this experiment studied the impact of semaglutide on CME-induced myocardial injury.METHODS A rat CME model was generated by injecting microspheres into the left ventricle while clamping the ascending aorta.A H9c2 cardiomyocyte model was constructed by stimulation of lipopolysaccharide combined with hypoxia.Semaglutide or the high mobility group box 1(HMGB1)antagonist glycyrrhizin administrations were ahead of CME and cell modeling.Cardiac function,myocardial injury markers,cell viability and morphological alternations were detected.Apoptotic and inflammatory factors,cytosolic HMGB1 and its translocation,advanced glycosylation end-product specific receptor(RAGE),and nuclear factor kappa B p65(NF-κB p65)were evaluated.RESULTS Semaglutide pretreatment ameliorated CME-induced cardiac systolic dysfunction and relieved the cardiac injury.Semaglutide attenuated myocardial apoptosis and inflammatory response following CME in vivo and in vitro.Moreover,semaglutide downregulated HMGB1 expression and suppressed its nuclear-cytoplasmic translocation.Both glycyrrhizin and semaglutide administration affected the HMGB1/RAGE/NF-κB p65 pathway after CME.CONCLUSIONS Semaglutide pretreatment attenuates CME-induced myocardial injury by suppressing apoptosis and inflammation through the HMGB1/RAGE/NF-κB p65 pathway.
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 National Key Research and Development Program of China(No.2022YFC3702704)the National Natural Science Foundation of China(Nos.22376005,22076006 and 82073506).
文摘Microorganisms constitute an essential component in the indoor environment,which is closely related to hu-man health.However,there is limited evidence regarding the associations between indoor airborne microbiome and systemic inflammation,as well as whether this association is modified by indoor particulate matter and the underlying mechanisms.In this prospective repeated-measure study among 66 participants,indoor airborne mi-crobiome was characterized using amplicon sequencing and qPCR.Indoor fine particulate matter(PM_(2.5))and inhalable particulate matter(PM10)were measured.Systemic inflammatory biomarkers were assessed,including white blood cell(WBC),neutrophil(NEUT),monocyte,eosinophil counts,and their proportions.Targeted serum amino acid metabolomics were conducted to explore the underlying mechanisms.Linear mixed-effect models re-vealed that bacterial and fungal Simpson diversity were significantly associated with decreased WBC and NEUT.For example,for each interquartile range increase in the bacterial Simpson diversity,WBC and NEUT changed by-4.53%(95%CI:-8.25%,-0.66%)and-5.95%(95%CI:-11.3%,-0.27%),respectively.Notably,increased inflammatory risks of airborne microbial exposure were observed when indoor PM_(2.5) and PM10 levels were below the WHO air quality guidelines.Mediation analyses indicated that dopamine metabolism partially mediated the anti-inflammatory effects of fungal diversity exposure.Overall,our study indicated protection from a diverse indoor microbial environment on cardiovascular health and proposed an underlying mechanism through amino acid metabolism.Additionally,health risks associated with microbial exposure deserve more attention in con-texts of low indoor particulate matter pollution.Further research is necessary to fully disentangle the complex relationships between indoor microbiome,air pollutants,and human health.
文摘Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,particularly palmitic acid,are potent inducers of chronic low-grade inflammation,largely due to disruptions in glucose metabolism and the onset of insulin resistance(Qiu et al.,2022).While many organs are affected,the brain,specifically the hypothalamus,is among the first to exhibit inflammation in response to an unhealthy diet,suggesting that obesity may,in fact,be a brain-centered disease with neuroinflammation as a central factor(Thaler et al., 2012).
基金Supported by the 2023 Traditional Chinese Medicine Innovation Capability Enhancement Project from the National Administration of Traditional Chinese Medicine(no number)2024 Qinghai Province“Kunlun Talents·High-End Innovative and Entrepreneurial Talents”Top Notch Talent Project(No.QHKLYC-GDCXCY-2024-152)both for Study the Mechanism of Weimishu Prescription in the Treatment of Chronic Gastritis with Liver-Stomach Disharmony。
文摘OBJECTIVE:To investigate the therapeutic effect of Weimishu prescription(胃糜舒方,WMSP)on chronic gastritis with liver-stomach disharmony(CG-LSD)and elucidate its molecular mechanisms involved in regulating the nuclear factor kappa-B(NF-κB)inflammatory response and gastric stem cell(GSC)differentiation.METHODS:A CG-LSD rat model was established through a combined protocol involving 56%ethanol and tail-clip stimulation.Rats were administered with low-,medium-,or high-dose WMSP,the positive control drug omeprazole,or high-dose WMSP with the NF-κB agonist phorbol 12-myristate 13-acetate(PMA).Histopathological changes were assessed via hematoxylin and eosin and Td T-mediated d UTP nick end labeling staining.Flow cytometry,immunofluorescence,real-time quantitative polymerase chain reaction,Western blotting,and enzyme-linked immunosorbent assay were performed to evaluate the underlying mechanisms.RESULTS:WMSP significantly increased rat locomotor activity,improved Traditional Chinese Medicine syndrome scores,and ameliorated pathological damage to the gastric mucosa while reducing gastric mucosal epithelial cells apoptosis.WMSP also increased the proportion of Lgr5+Ki67+cells;upregulated muscle,intestine,and stomach specific transcript 1,sex determining region Y-box 2,sex determining region Y-box 9,and homing cell adhesion molecule;and enhanced the levels of pepsinogen C,somatostatin,mucin-6,H+-K+ATPase,and E-cadherin proteins,thereby promoting gastric stem cell survival and differentiation.Furthermore,WMSP alleviated systemic and gastric mucosal inflammation in CG-LSD rats.Mechanistically,WMSP suppressed NF-κB expression,thereby reducing Smadspecific E3 ubiquitin ligase 2 levels,which enhancedβ-catenin and subsequently increased myelocytomatosis oncogene,and axis inhibition protein 2 expression.PMA administration reversed the protective effect of WMSP on CG-LSD rats.CONCLUSIONS:WMSP ameliorated gastric mucosal injury in CG-LSD rats by regulating the NF-κB/β-catenin signaling pathway,thereby suppressing inflammation and promoting gastric stem cell differentiation.These findings highlight the therapeutic potential of WMSP,providing the foundation for further clinical evaluations of WMSP in CGLSD treatment.
基金supported by grants from the Deutsche Forschungsgemeinschaft(HU 2614/1-1(Project No.462650276))the Fritz Thyssen Foundation(10.21.1.021MN)the Medical faculty of the University of Saarland(HOMFOR2016,HOMFORexzellent2017,HOMFOR2024 Anschubfinanzierung)to WH。
文摘Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).
文摘AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)cells through regulating snail family transcriptional repressor 1(SNAI1),and to validate its role in a proliferative vitreoretinopathy(PVR)mouse model.METHODS:Human RPE cell line ARPE-19 cells were treated with TGF-β2 to construct an EMT model.Western blot detected VRK1 level.The effects of VRK1 on SNAI1 expression and biological behavior of ARPE-19 cells were detected by immunofluorescence,ELISA,Transwell,and scratch assay,and the interaction between VRK1 and SNAI1 was confirmed through immunoprecipitation.A PVR mouse model was constructed,and the effects of VRK1 or/and SNAI1 on retinal damage were assessed by pathologic staining.Inflammatory factors and EMT-related proteins were assessed with ELISA and Western blot.RESULTS:VRK1 was upregulated in ARPE-19 cells after TGF-β2 treatment.Overexpression of VRK1 increased cell viability,promoted cell migration and EMT,and the levels of inflammatory factors.Silencing of VRK1 reversed the above indexes.There was a direct interaction between VRK1 and SNAI1,and overexpresssion SNAI1 weakened the impacts of silencing of VRK1.In PVR mice,silencing of VRK1 ameliorated retinal structural damage,decreased proinflammatory factor levels,and suppressed SNAI1 and mesenchymal marker expression.SNAI1 overexpression antagonized the protective effects of silencing VRK1 and exacerbated EMT and inflammatory responses.CONCLUSION:VRK1 plays a key role in retinal structural and inflammatory damage in PVR mice by regulating SNAI1 and mediating TGF-β2-caused EMT and inflammatory responses in RPE cells.
基金supported by FWO(Fonds voor Wetenschappelijk Onderzoek),grant number G07562NFWO(to BB)。
文摘Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.
基金FEDER/Ministerio de Ciencia,Innovacióny Universidades-Agencia Estatal de Investigación(PID2023-147425OB-I00 to FC)Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)-Generalitat de Catalunya(2021 SGR 00698 to FC).
文摘G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).
