Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this s...Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.展开更多
In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to elimin...In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species.Besides,neutrophils will accumulate at the inflammatory site and release NETs,which are composed of histones,DNA and granular proteins.Traumatic heterotopic ossification(THO)was generally believed to develop through four stages:Inflammation,chondrogenesis,osteogenesis,and bone maturation.Thus,it can be seen that THO was related to inflammation and bone formation.Apart from immune and infectious diseases,recent studies have also shown that NETs play a significant role in the pathogenesis of THO.This article focuses on elaborating the role of NETs in the onset of THO,discussing the existing problems in the current research and outlining future directions.展开更多
BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)is a prevalent chronic liver disorder driven by obesity and metabolic dysfunction.MASLD progresses to metabolic dysfunction-associated steatohe...BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)is a prevalent chronic liver disorder driven by obesity and metabolic dysfunction.MASLD progresses to metabolic dysfunction-associated steatohepatitis,which is characterized by inflammation,hepatocyte injury,and fibrosis,increasing the risk of cirrhosis and liver failure.Recent studies suggest that neutrophil extracellular traps(NETs)and extracellular DNA(ecDNA)contribute to liver inflammation and fibrogenesis.However,their role in MASLD pathogenesis remains incompletely understood.AIM To investigate the dynamics of circulating NETs and ecDNA as potential biomarkers of liver injury in MASLD.METHODS Using three complementary mouse models,thioacetamide(TAA)-induced fibrosis,choline-deficient L-amino acid-defined(CDAA)diet-induced metabolic dysfunction-associated steatohepatitis,and cafeteria(CAF)diet-induced MASLD,we assessed the association between NET-related markers and liver damage.Blood samples were collected biweekly to analyze ecDNA and NET markers,including myeloperoxidase(MPO)and MPO-DNA complexes,using ELISA and real-time PCR.Liver histopathology was assessed for inflammation,fibrosis,and neutrophil infiltration.RESULTS The TAA and CDAA models exhibited significant liver injury,characterized by increased plasma alanine aminotransferase and aspartate aminotransferase levels,hepatocellular damage,and fibrosis.Elevated circulating NET markers(MPO and ecDNA)were observed in these models,with a strong correlation between NET formation and liver pathology.The CAF diet model induced steatosis but failed to elicit significant liver fibrosis or an increase in NET markers,suggesting that NETosis is associated with more severe liver damage.Notably,ecDNA and MPO levels correlated with neutrophil infiltration and fibrosis scores,indicating their potential as biomarkers of MASLD progression.CONCLUSION NETosis and ecDNA levels reflect liver injury severity in MASLD.NET markers and liver fibrosis were strongly associated in TAA and CDAA models,whereas CAF model showed minimal NET involvement.展开更多
Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as...Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.展开更多
Neutrophils are the protagonists of the host immune response,possessing potent antimicrobial and inflammatory capacities.The neutrophil reservoir as well as the development,mobilization,chemotaxis,pro-inflammatory act...Neutrophils are the protagonists of the host immune response,possessing potent antimicrobial and inflammatory capacities.The neutrophil reservoir as well as the development,mobilization,chemotaxis,pro-inflammatory activity,and clearance of neutrophils are strictly regulated to prevent inflammation-induced tissue damage.Inflammation pervades almost every type of cancer.However,there is growing awareness that although the tumor microenvironment has the capacity to recruit neutrophils,the functions are diverse and include roles other than that of sentinels in cancer.This review highlights the heterogeneity of neutrophils in tumors,discusses the dual role of neutrophils as angels and demons in tumorigenesis,invasion,and metastasis,and examines the potential of neutrophils as targets in clinical therapy.展开更多
Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins...Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins released by neutrophils,contribute significantly to both inflammation and thrombosis.This manuscript offers a comprehensive review of the recent literature on the involvement of NET in atherosclerosis,highlighting their interactions with various pathophysiological processes and their potential as biomarkers for CVD.Notably,the impact of radiation on NET formation is explored,emphasising how oxidative stress and inflammatory responses drive NET release,contributing to plaque instability.The role of histones,particularly citrullinated histones,in endothelial dysfunction and plaque progression is discussed,highlighting their significance in the pathophysiology of atherosclerosis.Furthermore,the complex relationship between lipoproteins and NET formation is examined,with a focus on how elevated low-density lipoprotein(LDL)and decreased high-density lipoprotein(HDL)levels facilitate NET release,thus promoting vascular inflammation and plaque instability.The influence of cholesterol on NET formation is also explored,underscoring its contribution to plaque development and stability.The role of Peptidylarginine deiminase 4(PAD4)in the regulation of NETosis is reviewed,with attention given to how PAD4-driven citrullination of histones affects atherosclerosis progression.Moreover,the manuscript examines the potential of NET components—such as double-stranded DNA,myeloperoxidase–DNA complexes,and citrullinated histone H3—as biomarkers for assessing disease severity and predicting adverse cardiovascular events,including ST-elevation myocardial infarction(STEMI)and stroke.Elevated levels of these biomarkers correlate with worse clinical outcomes,suggesting their utility in guiding therapeutic interventions.In contrast to the existing body of work,this review highlights the novelty of integrating recent findings on NET interactions with lipid metabolism,histone modifications,and PAD4 activity in the context of atherosclerosis.Overall,NET plays an integral role in the inflammatory and thrombotic processes underpinning atherosclerosis,and their components hold promise as both diagnostic markers and therapeutic targets in cardiovascular disease management.展开更多
Neutrophil extracellular traps(NETs)have been the subject of research in the field of innate immunity since they were first described two decades ago.NETs are fibrous network structures released by neutrophils under s...Neutrophil extracellular traps(NETs)have been the subject of research in the field of innate immunity since they were first described two decades ago.NETs are fibrous network structures released by neutrophils under specific stimuli,including DNA,histones,and a variety of granular proteins.NETs have been widely studied in the fields of infectious and immune diseases,and new break-throughs have been made in the understanding of disease pathogenesis and treatment.In recent years,studies have found that NETs play an important role in the occurrence and development of osteoarticular diseases.This article reviews the progress in the research of NETs in common osteoarticular diseases such as rheumatoid arthritis,ankylosing spondylitis,gouty arthritis,osteonecrosis of the femoral head,osteoarthritis,and joint fibrosis,including the formation mecha-nism of NETs and its role in inflammation,joint destruction,pain and other pa-thological processes.The problems existing in current research are discussed,along with future research directions,to provide a reference for the in-depth study of osteoarticular diseases and the development of new treatment strategies.展开更多
ABSTRACT:Background:After ischemic stroke,neutrophils hyperactivate,increasing in number and worsening inflammation,causing neural damage.Prior scRNA-seq showed Lrg1 modulates cells subsentence to cerebral ischemiarep...ABSTRACT:Background:After ischemic stroke,neutrophils hyperactivate,increasing in number and worsening inflammation,causing neural damage.Prior scRNA-seq showed Lrg1 modulates cells subsentence to cerebral ischemiareperfusion injury,but its mechanism in regulating neutrophil accumulation/differentiation post-injury is unclear.Methods:Lrg1 knockout impact on neutrophil accumulation was assessed via immunofluorescence and western blot.Three-dimensional reconstruction of immunofluorescent staining analyzed cell-cell interactions among neutrophils and microglia.scRNA-seq of WT and Lrg1^(-/-)mice from GSE245386 and GSE279462 was conducted.Each group conducted oxidative phosphorylation scoring via Gene Set Enrichment Analysis(GSEA),while Metascape was employed to perform GO and KEGG enrichment analyses for elucidating functional mechanisms.CellChat exhibited cell-cell communication.Furthermore,alterations in microglial phagocytic activity were evaluated by immunostaining for CD68,a well-established marker of phagolysosomal activity in phagocytic cells.Brain energy metabolism was evaluated via glutamate dehydrogenase activity and ATP levels with ELISA,and enzyme expression was analyzed by immunofluorescence and western blot.Results:Lrg1 knockout decreased neutrophil accumulation and NET formation in mice.3D immunofluorescence reconstruction confirmed neutrophil co-localization with endothelial cells/microglia.scRNA-seq revealed that the oxidative phosphorylation score was significantly higher in the MCAO/R+WT group compared to both the Sham-operated+WT and Lrg1^(-/-)groups.Notably,the oxidative phosphorylation score was further elevated in the MCAO/R+Lrg1^(-/-)group.Immunostaining showed that Lrg1 knockout elevated CD68+lysosome expression post-MCAO/R,with TMEM119 colocalizing with these lysosomes.MCAO/R raised CD68 expression in ischemic brains,an effect further intensified by Lrg1 knockout.KEGG analysis linked differential genes to oxidative phosphorylation pathways.Validation in MCAO/R vs.sham groups revealed increased ROS production and reduced expression of complex enzymes I-V(NDUFB8,SDHB,UQCRC1,MTCO2,ATP5A1).Lrg1 intervention increased enzyme expression.Immunofluorescence and western blot in brain tissue showed similar patterns in microglia and enzymes I-V.Conclusions:Lrg1 knockout significantly enhances microglial phagocytic activity towards neutrophils subsequent to cerebral ischemia-reperfusion injury,through its regulatory effect on the oxidative phosphorylation pathway.This finding accentuates Lrg1 as a highly potential therapeutic target for intervening in and modulating post-ischemic inflammatory responses.展开更多
This study evaluates the findings of Gu et al,who investigated the role of neutrophil gelatinase-associated lipocalin(NGAL)as a biomarker for predicting neuropsychiatric complications in acute ischemic stroke(AIS)pati...This study evaluates the findings of Gu et al,who investigated the role of neutrophil gelatinase-associated lipocalin(NGAL)as a biomarker for predicting neuropsychiatric complications in acute ischemic stroke(AIS)patients.The results revealed that elevated serum NGAL levels at admission are associated with a higher risk of cognitive impairment,anxiety,and depressive symptoms at discharge.The study analyzed 150 AIS patients(mean age 65.4 years,58%male)using the Mini-Mental State Examination and the Hospital Anxiety and Depression Scale to assess neuropsychiatric outcomes.Multivariate analysis demonstrated that higher NGAL levels were independent predictors of cognitive impairment[odds ratio(OR)=1.42],anxiety(OR=1.28),and depression(OR=1.39).Notably,NGAL exhibited strong predictive power for cognitive impairment,with an area under the curve of 0.78.Despite these promising findings,NGAL’s clinical utility is limited by its non-specificity across various conditions.Nevertheless,NGAL levels could help identify AIS patients at risk for neuropsychiatric complications,enabling timely intervention and comprehensive neuropsychiatric evaluation.The study emphasizes the need for further research to validate NGAL’s predictive accuracy and specificity in diverse AIS populations and advocates for its integration with other diagnostic modalities to enhance clinical decision-making.展开更多
BACKGROUND Gastric cancer(GC)is a leading cause of cancer-related mortality worldwide,with Helicobacter pylori(H.pylori)infection recognized as a major risk factor.Chronic H.pylori-induced inflammation drives carcinog...BACKGROUND Gastric cancer(GC)is a leading cause of cancer-related mortality worldwide,with Helicobacter pylori(H.pylori)infection recognized as a major risk factor.Chronic H.pylori-induced inflammation drives carcinogenesis through neutrophilmediated pathways,in which cytokine-induced neutrophil chemoattractant(CINC)plays a pivotal role.However,the interplay among H.pylori virulence factors,systemic CINC levels,and GC progression remains poorly defined.AIM To investigate the correlation among serum CINC levels,H.pylori infection,and disease severity in patients with GC.METHODS This retrospective cohort study included 258 patients with GC diagnosed between April 2020 and November 2023.H.pylori infection was confirmed via histology,rapid urease test,and serology.Serum CINC levels were quantified using ELISA.Statistical analyses were performed with SPSS 26.0.RESULTS The H.pylori-positive patients exhibited significantly higher serum CINC levels(312.5±120.3 pg/mL)than the H.pylori-negative patients(150.2±95.4 pg/mL;P<0.05).CINC levels were correlated positively with TNM stage in the H.pyloripositive patients(P<0.05),with the highest levels recorded in stage IV(415.7±150.6 pg/mL).The patients infected with cytotoxin-associated gene A/vacuolating cytotoxin-positive H.pylori strains had elevated CINC levels(P<0.05).High CINC levels and H.pylori infection independently predicted poor survival CONCLUSION Elevated serum CINC levels are strongly associated with H.pylori infection,advanced TNM staging,and poor prognosis in GC.CINC serves as a novel prognostic biomarker,underscoring the role of neutrophil-driven inflammation in H.pylori-associated carcinogenesis.展开更多
BACKGROUND Osteoarthritis(OA)involves low-grade inflammation.The neutrophil-to-lym-phocyte ratio(NLR)may serve as a simple biomarker,but its role in OA remains unclear.AIM To review the existing scientific literature ...BACKGROUND Osteoarthritis(OA)involves low-grade inflammation.The neutrophil-to-lym-phocyte ratio(NLR)may serve as a simple biomarker,but its role in OA remains unclear.AIM To review the existing scientific literature on the role of NLR in OA,a classic age-related disorder,to perform a meta-analysis of the available data.METHODS The electronic databases PubMed,ProQuest,and Scopus were systematically searched from inception to March 1,2024.The inclusion criteria were retro-spective and prospective case-control studies involving human subjects with OA and healthy controls.The included studies needed to provide NLR levels for both OA patients and healthy controls and perform a comparative analysis of NLR levels between these groups.RESULTS According to the PRISMA guidelines,fifteen articles were included in the meta-analysis after multiple screenings.The pooled results demonstrated a significant overall elevation of NLR in OA patients compared to healthy controls.(standardized mean difference=0.39,95%confidence interval:0.03-0.75,P=0.03).However,the subgroup analysis shows no significant differences in NLR levels when considering study design(retrospective vs prospective)and OA severity(severe vs mild-moderate).This suggests variability and potential limitations in using NLR as a consistent marker across different study types and OA severity.CONCLUSION Our study found that OA patients have higher NLR than healthy individuals.However,NLR did not significantly differ by study type or disease severity,suggesting its limited use in indicating OA severity.展开更多
Background:SARS-CoV-2,first identified in late 2019,has given rise to numerous variants of concern(VOCs),posing a significant threat to human health.The emer-gence of Omicron BA.1.1 towards the end of 2021 led to a pa...Background:SARS-CoV-2,first identified in late 2019,has given rise to numerous variants of concern(VOCs),posing a significant threat to human health.The emer-gence of Omicron BA.1.1 towards the end of 2021 led to a pandemic in early 2022.At present,the lethal mouse model for the study of SARS-CoV-2 needs supplementation,and the alterations in neutrophils and monocytes caused by different strains remain to be elucidated.Methods:Human ACE2 transgenic mice were inoculated with the SARS-CoV-2 proto-type and Omicron BA.1,respectively.The pathogenicity of the two strains was evalu-ated by observing clinical symptoms,viral load and pathology.Complete blood count,immunohistochemistry and flow cytometry were performed to detect the alterations of neutrophils and monocytes caused by the two strains.Results:Our findings revealed that Omicron BA.1 exhibited significantly lower vir-ulence compared to the SARS-CoV-2 prototype in the mouse model.Additionally,we observed a significant increase in the proportion of neutrophils late in infection with the SARS-CoV-2 prototype and Omicron BA.1.We found that the proportion of monocytes increased at first and then decreased.The trends in the changes in the proportions of neutrophils and monocytes induced by the two strains were similar.Conclusion:Our study provides valuable insights into the utility of mouse models for simulating the severe disease of SARS-CoV-2 prototype infection and the milder manifestation associated with Omicron BA.1.SARS-CoV-2 prototype and Omicron BA.1 resulted in similar trends in the changes in neutrophils and monocytes.展开更多
The increasing aging population and aging-associated diseases have become a global issue for decades.People over 65 show an increased prevalence and greater severity of periodontitis,which poses threats to overall hea...The increasing aging population and aging-associated diseases have become a global issue for decades.People over 65 show an increased prevalence and greater severity of periodontitis,which poses threats to overall health.Studies have demonstrated a significant association between aging and the dysfunction of neutrophils,critical cells in the early stages of periodontitis,and their crosstalk with macrophages and T and B lymphocytes to establish the periodontal lesion.Neutrophils differentiate and mature in the bone marrow before entering the circulation;during an infection,they are recruited to infected tissues guided by the signal from chemokines and cytokines to eliminate invading pathogens.Neutrophils are crucial in maintaining a balanced response between host and microbes to prevent periodontal diseases in periodontal tissues.The impacts of aging on neutrophils'chemotaxis,anti-microbial function,cell activation,and lifespan result in impaired neutrophil functions and excessive neutrophil activation,which could influence periodontitis course.We summarize the roles of neutrophils in periodontal diseases and the aging-related impacts on neutrophil functional responses.We also explore the underlying mechanisms that can contribute to periodontitis manifestation in aging.This review could help us better understand the pathogenesis of periodontitis,which could offer novel therapeutic targets for periodontitis.展开更多
Colorectal cancer(CRC)is a common malignant tumor worldwide,and its tumor microenvironment(TME)plays a crucial role in tumor progression.Neutrophil extracellular traps(NETs),as an important component of the TME,have r...Colorectal cancer(CRC)is a common malignant tumor worldwide,and its tumor microenvironment(TME)plays a crucial role in tumor progression.Neutrophil extracellular traps(NETs),as an important component of the TME,have received widespread attention in recent years.This article explores the biological functions and molecular mechanisms of NETs in CRC and their impact on disease progression,while analyzing the application of single-cell sequencing technology(SCS)in this field.The development of SCS provides a new perspective for understanding the role of NETs in CRC.By combining SCS technology,targeting key regulatory nodes of NETs is expected to reverse the immunosuppressive microenvironment and provide a theoretical basis for developing novel diagnostic biomarkers and targeted therapeutic strategies,thereby promoting the development of precision medicine in CRC and helping enhance patient prognosis.Future research should further explore the integration of SCS technology with complementary methodologies to investigate NETs and develop specific detection methods and therapeutic strategies targeting NETs to enhance early diagnosis and treatment efficacy of tumors.展开更多
Background:Liver metastases are a leading contributor to death among patients with colorectal cancer.Current clinical treatments,such as resection and systemic chemotherapy,are only applicable in a portion of cases.Mo...Background:Liver metastases are a leading contributor to death among patients with colorectal cancer.Current clinical treatments,such as resection and systemic chemotherapy,are only applicable in a portion of cases.More effective medical interventions,including those involving traditional Chinese medicine,could be beneficial for patients with newly diagnosed colorectal cancer to prevent the progression to liver metastasis.Xiaoyaosan(XYS)is a classical prescription in traditional Chinese medicine with a history of hundreds of years.Despite its well-known protective effects against breast cancer,the understanding of its application in colorectal cancer metastases remains limited.The anti-metastasis mechanism of XYS remains to be elucidated.In this research,we explored the impact of XYS against liver metastases of colorectal cancer and its potential mechanisms.Methods:Thirty-six SPF male C57BL/6 mice were randomly assigned to six groups:a control group,a model group,a DNase I group,and three XYS treatment groups receiving high,medium,and low doses,respectively.A mouse model for colorectal cancer liver metastasis was established through the splenic injection of MC38 cells.Twenty-one days after the injection of cancer cells,the number of metastatic foci and the weights of the liver were calculated,and HE staining was performed to evaluate the effect of XYS.Neutrophil extracellular traps(NETs)formation in the liver was detected by immunofluorescence staining,and NETs formation in the serum was detected by ELISA.The levels of CXCL1,CXCL2,G-CSF,and HMGB1 were determined using ELISA kits.The expression levels of the proteins p-p38,p38,p-ERK,and ERK were assessed using Western blot analysis.Results:XYS treatment reduced the number of metastatic foci,the weights of metastatic livers,and the infiltration area of tumor-like cells.XYS could inhibit NETs formation in the liver and serum of mice with metastasis.The concentrations of CXCL1,CXCL2,G-CSF,and HMGB1 were significantly decreased in all XYS-treated groups.Moreover,XYS down-regulated the protein expression levels of phosphorylated p38 and ERK.Conclusion:XYS could attenuate liver metastases of colorectal cancer in vivo.The inhibitory mechanism of XYS may involve the reduction of NETs formation through the regulation of tumor-derived factors and the downstream MAPKs(p38,ERK)signaling pathway.展开更多
Despite suggested shared pathophysiological mechanisms between coronavirus disease 2019(COVID-19)and multiple sclerosis(MS),the molecular pathways underlying their relationship remain unclear.Herein,gene expression pr...Despite suggested shared pathophysiological mechanisms between coronavirus disease 2019(COVID-19)and multiple sclerosis(MS),the molecular pathways underlying their relationship remain unclear.Herein,gene expression profiles of COVID-19(GSE171110,GSE152641)and MS(GSE66573,GSE159225)datasets were analyzed using Gene Ontology(GO)enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,and protein-protein interaction(PPI)network construction.A two-acsample Mendelian randomization(MR)study was performed to establish potential causal relationships.A total of 165 shared differentially expressed genes(DEGs)were identified,with significant enrichment in pathways related to humoral immune response,neutrophil migration,and cytokine-receptor interactions in both conditions.Validation by receiver operating characteristic(ROC)curve analysis demonstrated that the hub genes S100A8,S100A9,S100A12,and ALOX5AP achieved area under the curve(AUC)values above 0.7 for both diseases.Increased neutrophil infiltration was positively correlated with upregulated expression of these genes,particularly demonstrating significant associations between the hub gene expression and neutrophil activity pathways.MR analysis suggested a causal relationship between S100A8 expression and susceptibility to both conditions and neutrophil counts,while ALOX5AP was indicated as a potential MS risk factor.These findings suggest that COVID-19 and MS co-occurrence is associated with neutrophil infiltration,highlighting S100A8 as both a promising biomarker and therapeutic target.展开更多
Objective:Gemcitabine combined with nab-paclitaxel therapy(GnP)represents first-line chemotherapy for advanced pancreatic ductal adenocarcinoma(PDAC).However,the efficacy of GnP is diminished due to chemotherapeutic r...Objective:Gemcitabine combined with nab-paclitaxel therapy(GnP)represents first-line chemotherapy for advanced pancreatic ductal adenocarcinoma(PDAC).However,the efficacy of GnP is diminished due to chemotherapeutic resistance induced by the tumor microenvironment(TME),the underlying mechanisms of which remain poorly understood.Methods:Clinical data from patients with PDAC who underwent GnP therapy were collected and neutrophil infiltration in tumor tissues was assessed.PDAC cell lines and a mouse model of PDAC were utilized to determine the mechanisms underlying GnP resistance and to focus on tumor-associated neutrophils and neutrophil extracellular traps(NETs).Results:GnP therapy recruited neutrophils to the TME,which resulted in the formation of NETs that contributed to therapeutic resistance in the PDAC murine model.The NET inhibitor,PAD4,enhanced the efficacy of GnP by suppressing tumor growth.Furthermore,GnP significantly upregulated CXCL8 secretion in GnP-resistant MIA PaCa-2 cells,which was mediated by increased expression of GPRC5A in PDAC cells.Screening of classic NET-derived molecules identified cell-free DNA(cfDNA)as a pleiotropic factor that promoted tumor cell proliferation and migration and thereby contributed to chemotherapeutic resistance.In vivo experiments revealed that the combination of GnP with si GPRC5A or DNase was more effective in reducing tumor growth and prolonging survival in PDAC-bearing mice than either treatment alone.Conclusion:The GPRC5A-CXCL8-NET-cfDNA axis has a critical role in the development of therapeutic resistance to GnP in PDAC.Targeting this axis may represent a promising strategy for overcoming GnP resistance and thereby enhancing the efficacy of chemotherapy in PDAC.展开更多
Inflammatory cascade critically exacerbates pathological bone loss,however,whether aberrant stimulator of interferon genes(STING)activation is involved has not been clarified.Utilizing STING as a target to alleviate i...Inflammatory cascade critically exacerbates pathological bone loss,however,whether aberrant stimulator of interferon genes(STING)activation is involved has not been clarified.Utilizing STING as a target to alleviate inflammatory osteolysis is worth exploring.Herein,we identified hyperactivated STING signaling as a key driver in the pathogenesis of calvarial osteolysis,suggesting that local inhibition of STING alleviated inflammation-mediated bone loss.A pivotal unmet need lies in achieving rapid organ-specific drug delivery with minimized dosage across anatomically distinct inflammatory bone compartments.We engineered neutrophils(NEs)encapsulated with poly(lactic-co-glycolic acid)(PLGA)containing STING antagonist C176(C176/PLGA@NEs)that leveraged the innate chemotactic proficiency of bone marrow-derived NEs for inflammatory site navigation.The inflammatory transport capacity of live NEs effectively addressed challenges of high systemic doses faced by STING antagonist,and poor spatiotemporal precision in targeting osteolytic lesions.The bioengineered C176/PLGA@NEs exhibited superior biocompatibility,inflammatory chemotaxis and inflammation-responsive release,and were effective in inhibiting STING-NF-κB pathway and remodeling macrophage polarization in vitro.In both calvarial osteolysis and apical periodontitis models,intravenous C176/PLGA@NEs administration achieved greater bone preservation compared to free C176 at equivalent doses,accompanied by reduction in pro-inflammatory cytokines.Notably,this NE-enabled strategy demonstrated targeting efficiency,overcoming anatomical barriers.Our findings establish a paradigm for precision delivery of STING antagonists using endogenous immune vectors,offering a versatile platform to treat systemic inflammatory bone disorders.The integration of cellular tropism with stimuli-responsive nanocarriers opens avenues for adapting this bi ohybrid approach to other immune cells and inflammatory pathologies.展开更多
Metastasis remains the primary cause of cancer-related mortality worldwide.Circulating tumor cells(CTCs)represent critical targets for metastasis prevention and treatment.Traditional Chinese medicine may prevent lung ...Metastasis remains the primary cause of cancer-related mortality worldwide.Circulating tumor cells(CTCs)represent critical targets for metastasis prevention and treatment.Traditional Chinese medicine may prevent lung cancer metastasis through long-term intervention in CTC activity.Tiao-Shen-Zhi-Ai Formular(TSZAF)represents a Chinese medicine compound prescription utilized clinically for lung cancer treatment.This study combined three principal active ingredients from TSZAF into a novel TSZAF monomer combination(TSZAF mc)to investigate its anti-metastatic effects and mechanisms.TSZAF mc demonstrated significant inhibition of proliferation,migration,and invasion in CTC-TJH-01 and LLC cells,while inducing cellular apoptosis in vitro.Moreover,TSZAF mc substantially inhibited LLC cell growth and metastasis in vivo.Mechanistically,TAZSF mc significantly suppressed the Wnt/β-catenin signaling pathway and CXCL5 expression in lung cancer cells and tissues.Additionally,TAZSF mc notably reduced neutrophil infiltration in metastatic lesions.These findings indicate that TSZAF mc inhibits lung cancer growth and metastasis by suppressing the Wnt/β-catenin signaling pathway and reducing CXCL5 secretion,thereby decreasing neutrophil recruitment and infiltration.TSZAF mc demonstrates potential as an effective therapeutic agent for lung cancer metastasis.展开更多
BACKGROUND Neutrophil extracellular traps(NETs)are associated with an immunosuppressive tumor microenvironment and may influence the efficacy of immune-based therapies.However,their role in neoadjuvant chemotherapy co...BACKGROUND Neutrophil extracellular traps(NETs)are associated with an immunosuppressive tumor microenvironment and may influence the efficacy of immune-based therapies.However,their role in neoadjuvant chemotherapy combined with immunotherapy(NACI)for locally advanced gastric cancer(LAGC)remains unclear.AIM To investigate the prognostic and predictive value of NET density in LAGC patients undergoing NACI.METHODS We enrolled 31 LAGC patients treated with NACI.NET density was assessed through dual immunofluorescence staining of citrullinated histone H3 and myeloperoxidase in pretreatment biopsy and post-treatment surgical specimens.Patients were stratified into high and low pre-NACI NET groups based on median NET density.Pathological complete response(pCR)and overall response rates were evaluated in relation to NET density.Logistic regression analyses were performed to identify independent predictors of treatment outcomes.Dynamic changes in NET density during NACI were also analyzed.RESULTS Patients with low pre-NACI NET density demonstrated significantly higher rates of pCR(40%vs 6%,P=0.037)and overall response(53%vs 12%,P=0.023)compared to those with high NET density.Low pre-NACI NET density and higher programmed death protein ligand 1 expression were identified as independent protective factors for achieving pCR and better response rates.NACI increased NET density;however,this increase was primarily observed in non-pCR and nonresponder groups.Patients in the pCR and responder groups showed stable NET density before and after treatment.Higher post-NACI NET density was associated with poorer respond to NACI.High post-NACI NET density was associated with increased infiltration of immunosuppressive FOXP3+T regulatory cells(P=0.025)and CD68+macrophages(P=0.038).CONCLUSION Pre-NACI NET density serves as a prognostic and predictive biomarker for NACI efficacy in LAGC patients.Low pretreatment NET density is associated with favorable outcomes,while increased post-treatment NET density correlates with poorer response.Targeting NET formation may represent a novel therapeutic strategy to enhance NACI efficacy in LAGC.展开更多
基金support from the Open Access Publication Fund of the University of Duisburg-Essensupported by the Deutsche Forschungsgemeinschaft(DFG/JA-2461/7-1)+1 种基金CRC TRR332 project A05 to JJthe Stiftung Tumorforschung Kopf-Hals to CK.
文摘Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.
文摘In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species.Besides,neutrophils will accumulate at the inflammatory site and release NETs,which are composed of histones,DNA and granular proteins.Traumatic heterotopic ossification(THO)was generally believed to develop through four stages:Inflammation,chondrogenesis,osteogenesis,and bone maturation.Thus,it can be seen that THO was related to inflammation and bone formation.Apart from immune and infectious diseases,recent studies have also shown that NETs play a significant role in the pathogenesis of THO.This article focuses on elaborating the role of NETs in the onset of THO,discussing the existing problems in the current research and outlining future directions.
基金Supported by Slovak Research and Development Agency,No.APVV-21-0370Ministry of Education,Science,Research and Sport of the Slovak Republic,No.VEGA 1/0706/25 and No.VEGA 1/0341/23.
文摘BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)is a prevalent chronic liver disorder driven by obesity and metabolic dysfunction.MASLD progresses to metabolic dysfunction-associated steatohepatitis,which is characterized by inflammation,hepatocyte injury,and fibrosis,increasing the risk of cirrhosis and liver failure.Recent studies suggest that neutrophil extracellular traps(NETs)and extracellular DNA(ecDNA)contribute to liver inflammation and fibrogenesis.However,their role in MASLD pathogenesis remains incompletely understood.AIM To investigate the dynamics of circulating NETs and ecDNA as potential biomarkers of liver injury in MASLD.METHODS Using three complementary mouse models,thioacetamide(TAA)-induced fibrosis,choline-deficient L-amino acid-defined(CDAA)diet-induced metabolic dysfunction-associated steatohepatitis,and cafeteria(CAF)diet-induced MASLD,we assessed the association between NET-related markers and liver damage.Blood samples were collected biweekly to analyze ecDNA and NET markers,including myeloperoxidase(MPO)and MPO-DNA complexes,using ELISA and real-time PCR.Liver histopathology was assessed for inflammation,fibrosis,and neutrophil infiltration.RESULTS The TAA and CDAA models exhibited significant liver injury,characterized by increased plasma alanine aminotransferase and aspartate aminotransferase levels,hepatocellular damage,and fibrosis.Elevated circulating NET markers(MPO and ecDNA)were observed in these models,with a strong correlation between NET formation and liver pathology.The CAF diet model induced steatosis but failed to elicit significant liver fibrosis or an increase in NET markers,suggesting that NETosis is associated with more severe liver damage.Notably,ecDNA and MPO levels correlated with neutrophil infiltration and fibrosis scores,indicating their potential as biomarkers of MASLD progression.CONCLUSION NETosis and ecDNA levels reflect liver injury severity in MASLD.NET markers and liver fibrosis were strongly associated in TAA and CDAA models,whereas CAF model showed minimal NET involvement.
基金supported by the National Natural Science Foundation of China(Grant nos.82473157,82460510,82203565,82103388,31960145 and 82560591)the Natural Science Foundation of Beijing(Grant no.L248059)+1 种基金Yunnan Province applied research funds(Grant nos.202201AY070001-011,202201AY070001-043,and 202301AS070018)the Science and Technology Innovation Team of tumor metabolism research at Kunming Medical University(Grant no.CXTD202102).
文摘Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82273449 and 82203663)the Zhejiang Provincial Natural Science Foundation of China(Grant No.LQ23H160013)the Medical and Health Science and Technology Project of Zhejiang Province(Grant Nos.2024KY1039 and 2024KY1250).
文摘Neutrophils are the protagonists of the host immune response,possessing potent antimicrobial and inflammatory capacities.The neutrophil reservoir as well as the development,mobilization,chemotaxis,pro-inflammatory activity,and clearance of neutrophils are strictly regulated to prevent inflammation-induced tissue damage.Inflammation pervades almost every type of cancer.However,there is growing awareness that although the tumor microenvironment has the capacity to recruit neutrophils,the functions are diverse and include roles other than that of sentinels in cancer.This review highlights the heterogeneity of neutrophils in tumors,discusses the dual role of neutrophils as angels and demons in tumorigenesis,invasion,and metastasis,and examines the potential of neutrophils as targets in clinical therapy.
基金supported by NIH grants to MI Bukrinsky(R01NS124477 and P30AI117970)by the“Creation of Experimental Laboratories in the Natural Sciences Program”and Basic Research Programat Higher School of Economics University.
文摘Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins released by neutrophils,contribute significantly to both inflammation and thrombosis.This manuscript offers a comprehensive review of the recent literature on the involvement of NET in atherosclerosis,highlighting their interactions with various pathophysiological processes and their potential as biomarkers for CVD.Notably,the impact of radiation on NET formation is explored,emphasising how oxidative stress and inflammatory responses drive NET release,contributing to plaque instability.The role of histones,particularly citrullinated histones,in endothelial dysfunction and plaque progression is discussed,highlighting their significance in the pathophysiology of atherosclerosis.Furthermore,the complex relationship between lipoproteins and NET formation is examined,with a focus on how elevated low-density lipoprotein(LDL)and decreased high-density lipoprotein(HDL)levels facilitate NET release,thus promoting vascular inflammation and plaque instability.The influence of cholesterol on NET formation is also explored,underscoring its contribution to plaque development and stability.The role of Peptidylarginine deiminase 4(PAD4)in the regulation of NETosis is reviewed,with attention given to how PAD4-driven citrullination of histones affects atherosclerosis progression.Moreover,the manuscript examines the potential of NET components—such as double-stranded DNA,myeloperoxidase–DNA complexes,and citrullinated histone H3—as biomarkers for assessing disease severity and predicting adverse cardiovascular events,including ST-elevation myocardial infarction(STEMI)and stroke.Elevated levels of these biomarkers correlate with worse clinical outcomes,suggesting their utility in guiding therapeutic interventions.In contrast to the existing body of work,this review highlights the novelty of integrating recent findings on NET interactions with lipid metabolism,histone modifications,and PAD4 activity in the context of atherosclerosis.Overall,NET plays an integral role in the inflammatory and thrombotic processes underpinning atherosclerosis,and their components hold promise as both diagnostic markers and therapeutic targets in cardiovascular disease management.
基金Supported by 2024 Suining Health Science and Technology Plan Project,No.24ZDJB03.
文摘Neutrophil extracellular traps(NETs)have been the subject of research in the field of innate immunity since they were first described two decades ago.NETs are fibrous network structures released by neutrophils under specific stimuli,including DNA,histones,and a variety of granular proteins.NETs have been widely studied in the fields of infectious and immune diseases,and new break-throughs have been made in the understanding of disease pathogenesis and treatment.In recent years,studies have found that NETs play an important role in the occurrence and development of osteoarticular diseases.This article reviews the progress in the research of NETs in common osteoarticular diseases such as rheumatoid arthritis,ankylosing spondylitis,gouty arthritis,osteonecrosis of the femoral head,osteoarthritis,and joint fibrosis,including the formation mecha-nism of NETs and its role in inflammation,joint destruction,pain and other pa-thological processes.The problems existing in current research are discussed,along with future research directions,to provide a reference for the in-depth study of osteoarticular diseases and the development of new treatment strategies.
基金supported by the Foundation Project:National Natural Science Foundation of China(Nos.:82460249,82100417,81760094)The Foundation of Jiangxi Provincial Department of Science and Technology Outstanding Youth Fund Project(20242BAB23080).
文摘ABSTRACT:Background:After ischemic stroke,neutrophils hyperactivate,increasing in number and worsening inflammation,causing neural damage.Prior scRNA-seq showed Lrg1 modulates cells subsentence to cerebral ischemiareperfusion injury,but its mechanism in regulating neutrophil accumulation/differentiation post-injury is unclear.Methods:Lrg1 knockout impact on neutrophil accumulation was assessed via immunofluorescence and western blot.Three-dimensional reconstruction of immunofluorescent staining analyzed cell-cell interactions among neutrophils and microglia.scRNA-seq of WT and Lrg1^(-/-)mice from GSE245386 and GSE279462 was conducted.Each group conducted oxidative phosphorylation scoring via Gene Set Enrichment Analysis(GSEA),while Metascape was employed to perform GO and KEGG enrichment analyses for elucidating functional mechanisms.CellChat exhibited cell-cell communication.Furthermore,alterations in microglial phagocytic activity were evaluated by immunostaining for CD68,a well-established marker of phagolysosomal activity in phagocytic cells.Brain energy metabolism was evaluated via glutamate dehydrogenase activity and ATP levels with ELISA,and enzyme expression was analyzed by immunofluorescence and western blot.Results:Lrg1 knockout decreased neutrophil accumulation and NET formation in mice.3D immunofluorescence reconstruction confirmed neutrophil co-localization with endothelial cells/microglia.scRNA-seq revealed that the oxidative phosphorylation score was significantly higher in the MCAO/R+WT group compared to both the Sham-operated+WT and Lrg1^(-/-)groups.Notably,the oxidative phosphorylation score was further elevated in the MCAO/R+Lrg1^(-/-)group.Immunostaining showed that Lrg1 knockout elevated CD68+lysosome expression post-MCAO/R,with TMEM119 colocalizing with these lysosomes.MCAO/R raised CD68 expression in ischemic brains,an effect further intensified by Lrg1 knockout.KEGG analysis linked differential genes to oxidative phosphorylation pathways.Validation in MCAO/R vs.sham groups revealed increased ROS production and reduced expression of complex enzymes I-V(NDUFB8,SDHB,UQCRC1,MTCO2,ATP5A1).Lrg1 intervention increased enzyme expression.Immunofluorescence and western blot in brain tissue showed similar patterns in microglia and enzymes I-V.Conclusions:Lrg1 knockout significantly enhances microglial phagocytic activity towards neutrophils subsequent to cerebral ischemia-reperfusion injury,through its regulatory effect on the oxidative phosphorylation pathway.This finding accentuates Lrg1 as a highly potential therapeutic target for intervening in and modulating post-ischemic inflammatory responses.
基金Supported by the Basic Science Research Program through the National Research Foundation of Korea Funded by the Ministry of Education,No.RS-2023-00237287Regional Innovation Strategy Through the National Research Foundation of Korea Funded by the Ministry of Education,No.2021RIS-003.
文摘This study evaluates the findings of Gu et al,who investigated the role of neutrophil gelatinase-associated lipocalin(NGAL)as a biomarker for predicting neuropsychiatric complications in acute ischemic stroke(AIS)patients.The results revealed that elevated serum NGAL levels at admission are associated with a higher risk of cognitive impairment,anxiety,and depressive symptoms at discharge.The study analyzed 150 AIS patients(mean age 65.4 years,58%male)using the Mini-Mental State Examination and the Hospital Anxiety and Depression Scale to assess neuropsychiatric outcomes.Multivariate analysis demonstrated that higher NGAL levels were independent predictors of cognitive impairment[odds ratio(OR)=1.42],anxiety(OR=1.28),and depression(OR=1.39).Notably,NGAL exhibited strong predictive power for cognitive impairment,with an area under the curve of 0.78.Despite these promising findings,NGAL’s clinical utility is limited by its non-specificity across various conditions.Nevertheless,NGAL levels could help identify AIS patients at risk for neuropsychiatric complications,enabling timely intervention and comprehensive neuropsychiatric evaluation.The study emphasizes the need for further research to validate NGAL’s predictive accuracy and specificity in diverse AIS populations and advocates for its integration with other diagnostic modalities to enhance clinical decision-making.
基金Supported by Hebei Province Medical Science Research Project Plan,No.20210923.
文摘BACKGROUND Gastric cancer(GC)is a leading cause of cancer-related mortality worldwide,with Helicobacter pylori(H.pylori)infection recognized as a major risk factor.Chronic H.pylori-induced inflammation drives carcinogenesis through neutrophilmediated pathways,in which cytokine-induced neutrophil chemoattractant(CINC)plays a pivotal role.However,the interplay among H.pylori virulence factors,systemic CINC levels,and GC progression remains poorly defined.AIM To investigate the correlation among serum CINC levels,H.pylori infection,and disease severity in patients with GC.METHODS This retrospective cohort study included 258 patients with GC diagnosed between April 2020 and November 2023.H.pylori infection was confirmed via histology,rapid urease test,and serology.Serum CINC levels were quantified using ELISA.Statistical analyses were performed with SPSS 26.0.RESULTS The H.pylori-positive patients exhibited significantly higher serum CINC levels(312.5±120.3 pg/mL)than the H.pylori-negative patients(150.2±95.4 pg/mL;P<0.05).CINC levels were correlated positively with TNM stage in the H.pyloripositive patients(P<0.05),with the highest levels recorded in stage IV(415.7±150.6 pg/mL).The patients infected with cytotoxin-associated gene A/vacuolating cytotoxin-positive H.pylori strains had elevated CINC levels(P<0.05).High CINC levels and H.pylori infection independently predicted poor survival CONCLUSION Elevated serum CINC levels are strongly associated with H.pylori infection,advanced TNM staging,and poor prognosis in GC.CINC serves as a novel prognostic biomarker,underscoring the role of neutrophil-driven inflammation in H.pylori-associated carcinogenesis.
文摘BACKGROUND Osteoarthritis(OA)involves low-grade inflammation.The neutrophil-to-lym-phocyte ratio(NLR)may serve as a simple biomarker,but its role in OA remains unclear.AIM To review the existing scientific literature on the role of NLR in OA,a classic age-related disorder,to perform a meta-analysis of the available data.METHODS The electronic databases PubMed,ProQuest,and Scopus were systematically searched from inception to March 1,2024.The inclusion criteria were retro-spective and prospective case-control studies involving human subjects with OA and healthy controls.The included studies needed to provide NLR levels for both OA patients and healthy controls and perform a comparative analysis of NLR levels between these groups.RESULTS According to the PRISMA guidelines,fifteen articles were included in the meta-analysis after multiple screenings.The pooled results demonstrated a significant overall elevation of NLR in OA patients compared to healthy controls.(standardized mean difference=0.39,95%confidence interval:0.03-0.75,P=0.03).However,the subgroup analysis shows no significant differences in NLR levels when considering study design(retrospective vs prospective)and OA severity(severe vs mild-moderate).This suggests variability and potential limitations in using NLR as a consistent marker across different study types and OA severity.CONCLUSION Our study found that OA patients have higher NLR than healthy individuals.However,NLR did not significantly differ by study type or disease severity,suggesting its limited use in indicating OA severity.
基金supported by Beijing Natural Science Foundation(Grant No.Z210014)National Natural Science Foundation of China(Grant No.32070543)+1 种基金National Key Research and Development Project of China(Grant No.2022YFC2303404)CAMS Innovation Fund for Medical Sciences(CIFMS)(Grant No.2022-12M-CoV19-002)
文摘Background:SARS-CoV-2,first identified in late 2019,has given rise to numerous variants of concern(VOCs),posing a significant threat to human health.The emer-gence of Omicron BA.1.1 towards the end of 2021 led to a pandemic in early 2022.At present,the lethal mouse model for the study of SARS-CoV-2 needs supplementation,and the alterations in neutrophils and monocytes caused by different strains remain to be elucidated.Methods:Human ACE2 transgenic mice were inoculated with the SARS-CoV-2 proto-type and Omicron BA.1,respectively.The pathogenicity of the two strains was evalu-ated by observing clinical symptoms,viral load and pathology.Complete blood count,immunohistochemistry and flow cytometry were performed to detect the alterations of neutrophils and monocytes caused by the two strains.Results:Our findings revealed that Omicron BA.1 exhibited significantly lower vir-ulence compared to the SARS-CoV-2 prototype in the mouse model.Additionally,we observed a significant increase in the proportion of neutrophils late in infection with the SARS-CoV-2 prototype and Omicron BA.1.We found that the proportion of monocytes increased at first and then decreased.The trends in the changes in the proportions of neutrophils and monocytes induced by the two strains were similar.Conclusion:Our study provides valuable insights into the utility of mouse models for simulating the severe disease of SARS-CoV-2 prototype infection and the milder manifestation associated with Omicron BA.1.SARS-CoV-2 prototype and Omicron BA.1 resulted in similar trends in the changes in neutrophils and monocytes.
文摘The increasing aging population and aging-associated diseases have become a global issue for decades.People over 65 show an increased prevalence and greater severity of periodontitis,which poses threats to overall health.Studies have demonstrated a significant association between aging and the dysfunction of neutrophils,critical cells in the early stages of periodontitis,and their crosstalk with macrophages and T and B lymphocytes to establish the periodontal lesion.Neutrophils differentiate and mature in the bone marrow before entering the circulation;during an infection,they are recruited to infected tissues guided by the signal from chemokines and cytokines to eliminate invading pathogens.Neutrophils are crucial in maintaining a balanced response between host and microbes to prevent periodontal diseases in periodontal tissues.The impacts of aging on neutrophils'chemotaxis,anti-microbial function,cell activation,and lifespan result in impaired neutrophil functions and excessive neutrophil activation,which could influence periodontitis course.We summarize the roles of neutrophils in periodontal diseases and the aging-related impacts on neutrophil functional responses.We also explore the underlying mechanisms that can contribute to periodontitis manifestation in aging.This review could help us better understand the pathogenesis of periodontitis,which could offer novel therapeutic targets for periodontitis.
基金the Shandong Province Medical and Health Science and Technology Development Plan Project,No.202203030713Yantai Science and Technology Program,No.2024YD005,No.2024YD007 and No.2024YD010and Science and Technology Program of Yantai Affiliated Hospital of Binzhou Medical University,No.YTFY2022KYQD06.
文摘Colorectal cancer(CRC)is a common malignant tumor worldwide,and its tumor microenvironment(TME)plays a crucial role in tumor progression.Neutrophil extracellular traps(NETs),as an important component of the TME,have received widespread attention in recent years.This article explores the biological functions and molecular mechanisms of NETs in CRC and their impact on disease progression,while analyzing the application of single-cell sequencing technology(SCS)in this field.The development of SCS provides a new perspective for understanding the role of NETs in CRC.By combining SCS technology,targeting key regulatory nodes of NETs is expected to reverse the immunosuppressive microenvironment and provide a theoretical basis for developing novel diagnostic biomarkers and targeted therapeutic strategies,thereby promoting the development of precision medicine in CRC and helping enhance patient prognosis.Future research should further explore the integration of SCS technology with complementary methodologies to investigate NETs and develop specific detection methods and therapeutic strategies targeting NETs to enhance early diagnosis and treatment efficacy of tumors.
基金supported by Sichuan Science and Technology Program(grant number 2023NSFSC1809)Hospital of Chengdu University of Traditional Chinese Medicine(grant number 23ZYTS1004,21YY01).
文摘Background:Liver metastases are a leading contributor to death among patients with colorectal cancer.Current clinical treatments,such as resection and systemic chemotherapy,are only applicable in a portion of cases.More effective medical interventions,including those involving traditional Chinese medicine,could be beneficial for patients with newly diagnosed colorectal cancer to prevent the progression to liver metastasis.Xiaoyaosan(XYS)is a classical prescription in traditional Chinese medicine with a history of hundreds of years.Despite its well-known protective effects against breast cancer,the understanding of its application in colorectal cancer metastases remains limited.The anti-metastasis mechanism of XYS remains to be elucidated.In this research,we explored the impact of XYS against liver metastases of colorectal cancer and its potential mechanisms.Methods:Thirty-six SPF male C57BL/6 mice were randomly assigned to six groups:a control group,a model group,a DNase I group,and three XYS treatment groups receiving high,medium,and low doses,respectively.A mouse model for colorectal cancer liver metastasis was established through the splenic injection of MC38 cells.Twenty-one days after the injection of cancer cells,the number of metastatic foci and the weights of the liver were calculated,and HE staining was performed to evaluate the effect of XYS.Neutrophil extracellular traps(NETs)formation in the liver was detected by immunofluorescence staining,and NETs formation in the serum was detected by ELISA.The levels of CXCL1,CXCL2,G-CSF,and HMGB1 were determined using ELISA kits.The expression levels of the proteins p-p38,p38,p-ERK,and ERK were assessed using Western blot analysis.Results:XYS treatment reduced the number of metastatic foci,the weights of metastatic livers,and the infiltration area of tumor-like cells.XYS could inhibit NETs formation in the liver and serum of mice with metastasis.The concentrations of CXCL1,CXCL2,G-CSF,and HMGB1 were significantly decreased in all XYS-treated groups.Moreover,XYS down-regulated the protein expression levels of phosphorylated p38 and ERK.Conclusion:XYS could attenuate liver metastases of colorectal cancer in vivo.The inhibitory mechanism of XYS may involve the reduction of NETs formation through the regulation of tumor-derived factors and the downstream MAPKs(p38,ERK)signaling pathway.
基金Hunan Province College Students Research Learning and Innovative Experiment Project(S202410542120)。
文摘Despite suggested shared pathophysiological mechanisms between coronavirus disease 2019(COVID-19)and multiple sclerosis(MS),the molecular pathways underlying their relationship remain unclear.Herein,gene expression profiles of COVID-19(GSE171110,GSE152641)and MS(GSE66573,GSE159225)datasets were analyzed using Gene Ontology(GO)enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,and protein-protein interaction(PPI)network construction.A two-acsample Mendelian randomization(MR)study was performed to establish potential causal relationships.A total of 165 shared differentially expressed genes(DEGs)were identified,with significant enrichment in pathways related to humoral immune response,neutrophil migration,and cytokine-receptor interactions in both conditions.Validation by receiver operating characteristic(ROC)curve analysis demonstrated that the hub genes S100A8,S100A9,S100A12,and ALOX5AP achieved area under the curve(AUC)values above 0.7 for both diseases.Increased neutrophil infiltration was positively correlated with upregulated expression of these genes,particularly demonstrating significant associations between the hub gene expression and neutrophil activity pathways.MR analysis suggested a causal relationship between S100A8 expression and susceptibility to both conditions and neutrophil counts,while ALOX5AP was indicated as a potential MS risk factor.These findings suggest that COVID-19 and MS co-occurrence is associated with neutrophil infiltration,highlighting S100A8 as both a promising biomarker and therapeutic target.
基金supported by the National Natural Science Foundation of China(Grant Nos.82271883 and 82073195 to Qing.Xiaand 82471775 and 82271800 to Yuli.Lin)+3 种基金the Hospital-pharma Integration Project on Innovative Achievement Translation(Grant No.SHDC2022CRD043 to Qing.Xia)the Shanghai Jiao Tong University School of Medicine Summit Program-“Research Physician”in Clinical Medicine to Qing.Xiathe Young Physician-Scientist Cultivation Program of Shanghai Immune Therapy Institute to Qing.Xiathe Light of the Lintel-young Talents of Huangpu to Qing.Xia。
文摘Objective:Gemcitabine combined with nab-paclitaxel therapy(GnP)represents first-line chemotherapy for advanced pancreatic ductal adenocarcinoma(PDAC).However,the efficacy of GnP is diminished due to chemotherapeutic resistance induced by the tumor microenvironment(TME),the underlying mechanisms of which remain poorly understood.Methods:Clinical data from patients with PDAC who underwent GnP therapy were collected and neutrophil infiltration in tumor tissues was assessed.PDAC cell lines and a mouse model of PDAC were utilized to determine the mechanisms underlying GnP resistance and to focus on tumor-associated neutrophils and neutrophil extracellular traps(NETs).Results:GnP therapy recruited neutrophils to the TME,which resulted in the formation of NETs that contributed to therapeutic resistance in the PDAC murine model.The NET inhibitor,PAD4,enhanced the efficacy of GnP by suppressing tumor growth.Furthermore,GnP significantly upregulated CXCL8 secretion in GnP-resistant MIA PaCa-2 cells,which was mediated by increased expression of GPRC5A in PDAC cells.Screening of classic NET-derived molecules identified cell-free DNA(cfDNA)as a pleiotropic factor that promoted tumor cell proliferation and migration and thereby contributed to chemotherapeutic resistance.In vivo experiments revealed that the combination of GnP with si GPRC5A or DNase was more effective in reducing tumor growth and prolonging survival in PDAC-bearing mice than either treatment alone.Conclusion:The GPRC5A-CXCL8-NET-cfDNA axis has a critical role in the development of therapeutic resistance to GnP in PDAC.Targeting this axis may represent a promising strategy for overcoming GnP resistance and thereby enhancing the efficacy of chemotherapy in PDAC.
基金the financial support from the National Natural Science Foundation of China(Nos.82370948,82170941,82472818,and 82273202)the Fundamental Research Funds for the Central Universities(Nos.2042022dx0003 and 2042021kf0216).
文摘Inflammatory cascade critically exacerbates pathological bone loss,however,whether aberrant stimulator of interferon genes(STING)activation is involved has not been clarified.Utilizing STING as a target to alleviate inflammatory osteolysis is worth exploring.Herein,we identified hyperactivated STING signaling as a key driver in the pathogenesis of calvarial osteolysis,suggesting that local inhibition of STING alleviated inflammation-mediated bone loss.A pivotal unmet need lies in achieving rapid organ-specific drug delivery with minimized dosage across anatomically distinct inflammatory bone compartments.We engineered neutrophils(NEs)encapsulated with poly(lactic-co-glycolic acid)(PLGA)containing STING antagonist C176(C176/PLGA@NEs)that leveraged the innate chemotactic proficiency of bone marrow-derived NEs for inflammatory site navigation.The inflammatory transport capacity of live NEs effectively addressed challenges of high systemic doses faced by STING antagonist,and poor spatiotemporal precision in targeting osteolytic lesions.The bioengineered C176/PLGA@NEs exhibited superior biocompatibility,inflammatory chemotaxis and inflammation-responsive release,and were effective in inhibiting STING-NF-κB pathway and remodeling macrophage polarization in vitro.In both calvarial osteolysis and apical periodontitis models,intravenous C176/PLGA@NEs administration achieved greater bone preservation compared to free C176 at equivalent doses,accompanied by reduction in pro-inflammatory cytokines.Notably,this NE-enabled strategy demonstrated targeting efficiency,overcoming anatomical barriers.Our findings establish a paradigm for precision delivery of STING antagonists using endogenous immune vectors,offering a versatile platform to treat systemic inflammatory bone disorders.The integration of cellular tropism with stimuli-responsive nanocarriers opens avenues for adapting this bi ohybrid approach to other immune cells and inflammatory pathologies.
基金sponsored by the National Natural Science Foundation of China(Nos.81973517,82174245,82174017,and 82305069)Shanghai Shenkang Hospital Development Center’s Second Round of"Three-Year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals"Research Physician Innovation and Translational Ability Training Project(No.SHDC2023CRD01)+2 种基金Shanghai Institute of Traditional Chinese Medicine and Psychosomatic Diseases 2023 Open Research Project(No.SZB2023102)Science and Technology Development Program of Shanghai University of Traditional Chinese Medicine in 2023(No.23KFL096)Traditional Chinese Medicine Science and Technology Development Project of Shanghai Medical Innovation&Development Foundation(No.WL-HBRC-2021001K)。
文摘Metastasis remains the primary cause of cancer-related mortality worldwide.Circulating tumor cells(CTCs)represent critical targets for metastasis prevention and treatment.Traditional Chinese medicine may prevent lung cancer metastasis through long-term intervention in CTC activity.Tiao-Shen-Zhi-Ai Formular(TSZAF)represents a Chinese medicine compound prescription utilized clinically for lung cancer treatment.This study combined three principal active ingredients from TSZAF into a novel TSZAF monomer combination(TSZAF mc)to investigate its anti-metastatic effects and mechanisms.TSZAF mc demonstrated significant inhibition of proliferation,migration,and invasion in CTC-TJH-01 and LLC cells,while inducing cellular apoptosis in vitro.Moreover,TSZAF mc substantially inhibited LLC cell growth and metastasis in vivo.Mechanistically,TAZSF mc significantly suppressed the Wnt/β-catenin signaling pathway and CXCL5 expression in lung cancer cells and tissues.Additionally,TAZSF mc notably reduced neutrophil infiltration in metastatic lesions.These findings indicate that TSZAF mc inhibits lung cancer growth and metastasis by suppressing the Wnt/β-catenin signaling pathway and reducing CXCL5 secretion,thereby decreasing neutrophil recruitment and infiltration.TSZAF mc demonstrates potential as an effective therapeutic agent for lung cancer metastasis.
文摘BACKGROUND Neutrophil extracellular traps(NETs)are associated with an immunosuppressive tumor microenvironment and may influence the efficacy of immune-based therapies.However,their role in neoadjuvant chemotherapy combined with immunotherapy(NACI)for locally advanced gastric cancer(LAGC)remains unclear.AIM To investigate the prognostic and predictive value of NET density in LAGC patients undergoing NACI.METHODS We enrolled 31 LAGC patients treated with NACI.NET density was assessed through dual immunofluorescence staining of citrullinated histone H3 and myeloperoxidase in pretreatment biopsy and post-treatment surgical specimens.Patients were stratified into high and low pre-NACI NET groups based on median NET density.Pathological complete response(pCR)and overall response rates were evaluated in relation to NET density.Logistic regression analyses were performed to identify independent predictors of treatment outcomes.Dynamic changes in NET density during NACI were also analyzed.RESULTS Patients with low pre-NACI NET density demonstrated significantly higher rates of pCR(40%vs 6%,P=0.037)and overall response(53%vs 12%,P=0.023)compared to those with high NET density.Low pre-NACI NET density and higher programmed death protein ligand 1 expression were identified as independent protective factors for achieving pCR and better response rates.NACI increased NET density;however,this increase was primarily observed in non-pCR and nonresponder groups.Patients in the pCR and responder groups showed stable NET density before and after treatment.Higher post-NACI NET density was associated with poorer respond to NACI.High post-NACI NET density was associated with increased infiltration of immunosuppressive FOXP3+T regulatory cells(P=0.025)and CD68+macrophages(P=0.038).CONCLUSION Pre-NACI NET density serves as a prognostic and predictive biomarker for NACI efficacy in LAGC patients.Low pretreatment NET density is associated with favorable outcomes,while increased post-treatment NET density correlates with poorer response.Targeting NET formation may represent a novel therapeutic strategy to enhance NACI efficacy in LAGC.
