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
Bone is highly innervated,and its regeneration is significantly nerve-dependent.Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and ...Bone is highly innervated,and its regeneration is significantly nerve-dependent.Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and osteoclast activity.However,the majority of research to date has focused on the direct effects of peripheral nerves and their neurotransmitters on bone regeneration.Emerging studies have begun to reveal a more intricate role of nerves in regulating the immune microenvironment,which is crucial for bone regeneration.This review summarizes how nerves influence bone regeneration through modulation of the immune microenvironment.We first discuss the changes in peripheral nerves during the regenerative process.We then describe conduction and paracrine pathways through which nerves affect the osteogenic immune microenvironment,emphasizing nerves,neural factors,and their impacts.Our goal is to deepen the understanding of the nerve-immune axis in bone regeneration.A better grasp of how nerves influence the osteogenic immune microenvironment may lead to new strategies that integrate the nervous,immune,and skeletal systems to promote bone regeneration.展开更多
Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immun...Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.展开更多
Lung cancer remains the leading cause of cancer-related mortality worldwide,primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells.To adapt to the nutrient-deprived tumor microenv...Lung cancer remains the leading cause of cancer-related mortality worldwide,primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells.To adapt to the nutrient-deprived tumor microenvironment(TME),lung cancer cells undergo profound metabolic reprogramming,characterized by enhanced glycolysis(the Warburg effect),increased glutamine dependency(mediated by GLS1),and accelerated lipid synthesis(involving enzymes such as FASN).These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations(e.g.,Tregs and M2 macrophages)and inhibiting effector functions of CD8^(+)T cells and natural killer(NK)cells.Critically,a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME:metabolic reprogramming drives immune suppression through metabolite accumulation,whereas the immunosuppressive TME,in turn,promotes tumor cell adaptability—thus forming a positive feedback loop that reinforces immune evasion and therapy resistance.This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer—spanning glucose,amino acid,and lipid metabolism—and their dynamic crosstalk with immune regulation,including epigenetic modifications and non-coding RNA-mediated mechanisms.Additionally,it evaluates emerging therapeutic strategies targeting the metabolic-immune axis,such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents,which aim to reverse immunosuppression and improve clinical outcomes.By synthesizing recent advances,this work provides a theoretical framework for precision oncology interventions,highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.展开更多
Ischemic stroke therapy has long been dominated by strategies aimed at restoring cerebral blood flow. Yet, accumulating evidence suggests that neuronal survival and functional recovery depend not only on reperfusion, ...Ischemic stroke therapy has long been dominated by strategies aimed at restoring cerebral blood flow. Yet, accumulating evidence suggests that neuronal survival and functional recovery depend not only on reperfusion, but also on the resolution of postischemic immune dysregulation. This study(Chen et al., Prog Biochem Biophys, 2026, 53(3): 697-710. DOI:10.3724/j.pibb.2025.0541) a dvances this emerging paradigm by proposing a therapeutic strategy that integrates lesion-specific delivery with active modulation of the inflammatory microenvironment.展开更多
Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Method...Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Methods We retrieved data from sepsis patients who underwent Th1/Th2 cytokine testing in Nanfang Hospital,Southern Medical University from June 1,2020,to February 1,2022.An unsupervised K-means clustering method classified participants based on Th1/Th2 cytokine levels,with the primary outcome being the 7-day mortality rate post-ICU admission.Cox proportional hazards and Restricted Mean Survival Time(RMST)analyses were utilized to explore survival outcomes.Results A total of 321 sepsis patients were included.IL-6(HR 1.69,95%CI:1.22,2.34)and IL-10(HR 1.81,95%CI:1.37,2.40)emerged as independent predictors of 7-day mortality.Unsupervised K-means clustering revealed 3 inflammatory/immune subgroups:Cluster 1(n=166,low inflammatory response),Cluster 2(n=99,moderate inflammatory response with immune suppression),and Cluster 3(n=56,strong inflammatory and immune suppression).Compared to Cluster 1,Clusters 2 and 3 had higher 7-day mortality risks(14.4%vs 23.2%,HR=4.30,95%CI:1.51-12.26;14.4%vs 35.7%,HR=7.32,95%CI:2.57-20.79).Conclusion Septic patients in a protective immune response state(Cluster 1)exhibit better short-term prognoses,suggesting the importance of understanding inflammatory/immune states for precise treatment and improved outcomes.展开更多
The interplay between gut microbiota and host health has attracted significant interest in the animal science community.Maintaining gut microbiota homeostasis by supplementing probiotics to treat clinical conditions l...The interplay between gut microbiota and host health has attracted significant interest in the animal science community.Maintaining gut microbiota homeostasis by supplementing probiotics to treat clinical conditions like calf diarrhea is an emerging area of research nowadays because of increased concerns regarding antimicrobial resistance(AMR)and drug residues in animal products.Probiotics reduce the incidence of calf diarrhea by increasing the gut microbiota diversity and richness with more commensal bacteria such as Lactobacillus and Bifidobacterium that produce antimicrobial compounds,as well as modulating the immune response by increasing cytokines,Interleukin-2(IL-2),IL-4,IL-6,IL-10,and reducing tumor necrosis factor-α(TNF-α),by increasing production of antibodies,especially immunoglobulin E(Ig E),also Ig G,differentiating naive Th lymphocytes(Tho)into Th1,hence stimulate innate immunity and prime the adaptive immune response.Specific probiotic strains of bacteria and yeast(Saccharomyces cerevisiae)derived probiotics maintain the integrity of the intestinal barrier.In this review,data are being organized to address the role of probiotics in treating calf diarrhea by modulating gut microbiota and stimulating an immune response against notorious pathogens,to present animal and veterinary scientists and nutritionists with a new concept to treat infectious diseases from the perspective of the gut microbiota,increasing animal health,performance,and welfare.In conclusion,health status and gut microbiome are strongly interlinked.Research data indicated a significant reduction in the incidence of diarrhea after probiotic administration.If interrelations between probiotics and existing gut microbiota are explored more quantitatively,novel antibiotic substitutes can emerge in the future.展开更多
Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the mole...Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.展开更多
Objectives:Postmenopausal osteoporosis is the most common form of osteoporosis in clinical practice,affecting millions of postmenopausal women worldwide.Postmenopausal osteoporosis demands safe and effective therapies...Objectives:Postmenopausal osteoporosis is the most common form of osteoporosis in clinical practice,affecting millions of postmenopausal women worldwide.Postmenopausal osteoporosis demands safe and effective therapies.This study aimed to evaluate the potential of hederagenin(Hed)for treating osteoporosis and to elucidate its underlying mechanisms of action.Methods:The anti-osteoporotic potential of Hed was assessed by investigating its effects on ovariectomy(OVX)-induced bone loss in mice and on receptor activator of NF-kappaB ligand(RANKL)-induced osteoclast differentiation in RAW264.7 cells.Network pharmacology analysis and molecular docking were employed to identify key targets,which were subsequently validated experimentally.Results:In vitro,Hed suppressed osteoclastogenesis by inhibiting the formation of osteoclasts and F-actin rings and by down-regulating osteoclastspecific genes(Atp6v0d2 and Acp5).In vivo,Hed significantly amelioratedOVX-induced bone loss,restoring trabecular bone volume fraction(BV/TV)and trabecular number(Tb.N),while reducing trabecular separation(Tb.Sp).Network pharmacology analysis identified 142 overlapping targets linking Hed to osteoporosis,including tumor necrosis factor alpha(TNF-α),interleukin-6(IL-6),and IL-1β,with enrichment in innate immune signaling and osteoclast differentiation.Molecular docking analysis indicated strong binding affinities between Hed and targets such as TNF-α,IL-6,and IL-1β.Experimentally,Hed was found to decrease RANKL,elevate osteoprotegerin(OPG),and suppress intestinalmRNA levels of pro-inflammatory cytokines such as IL-1β,IL-6,IL-17A,and TNF-α.Conclusion:Hed exerts significant anti-osteoporotic effects inOVX-induced osteoporosis through a dualmechanism involving the suppression of both osteoclastogenesis and innate immune signaling pathways.These findings highlighted Hed’s novel role in modulating immune-bone crosstalk,offering a promising strategy for treating osteolytic diseases without estrogenic side effects.展开更多
Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic releva...Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic relevance of exerkines across cancer types remains unclear,and the molecular determinants of exercise responsiveness are poorly defined.Methods:We systematically profiled 183 curated exerkine-related genes across 33 cancer types from The Cancer Genome Atlas(TCGA)using non-negative matrix factorization(NMF)to define molecular subtypes.Prognostic significance was evaluated via Kaplan-Meier analysis.For five cancers with consistent survival divergence(LGG,KIRC,LUAD,PAAD,ACC),we developed an Exerkine Prognostic Index(EPI)using LASSO Cox regression and validated its predictive performance through time-dependent ROC analysis.Immune cell infiltration(CIBERSORT),stromal/immune scores(ESTIMATE),and immune checkpoint expression were assessed to characterize immune landscape differences between EPI subgroups.Results:Exerkine-based NMF clustering identified prognostically distinct subtypes in 25 cancers.The EPI robustly stratified patients into high-and low-risk groups with significant differences in overall survival(p<0.001).High-EPI subgroups were associated with elevated infiltration of immunosuppressive cells(e.g.,Tregs,M0 macrophages),altered immune/stromal scores,and differential expression of immune checkpoints such as PD-L1 and CTLA4 in a cancer-type-specific manner.Discussion:Our findings reveal that exerkine expression patterns capture biologically and clinically relevant heterogeneity across cancers.The EPI provides a robust molecular tool to stratify patients by prognosis and immune contexture,offering insights into differential exercise responsiveness.Conclusions:Exerkines represent promising biomarkers for risk stratification and precision-guided exercise interventions in oncology.展开更多
Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical applicati...Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical application of multi-omics parameters is still restricted by the expensive and less accessible assays,although they accurately reflect immune status.A comprehensive evaluation framework based on“easy-to-obtain”multi-model clinical parameters is urgently required,incorporating clinical features to establish baseline patient profiles and disease staging;routine blood tests assessing systemic metabolic and functional status;immune cell subsets quantifying subcluster dynamics;imaging features delineating tumor morphology,spatial configuration,and perilesional anatomical relationships;immunohistochemical markers positioning qualitative and quantitative detection of tumor antigens from the cellular and molecular level.This integrated phenomic approach aims to improve prognostic stratification and clinical decision-making in hepatocellular carcinoma management conveniently and practically.展开更多
Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical preced...Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical precedent of SCI being a male-dominated condition.In contrast,most basic science researchers utilize single-sex studies to minimize complications associated with bladder care in males(Stewart et al.,2020).The findings of our recent publication identify sexually dimorphic immune responses to SCI in both mice and pigs(Kumari et al.,2025).Here,we will highlight these findings and discuss the impact of sex on SCI inflammation and recovery.展开更多
AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM...AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas(TCGA)-UVM cohort and an external Gene Expression Omnibus(GEO)microarray dataset(GSE73652;8 non-metastatic vs 5 metastatic cases)were analyzed to identify differentially expressed genes(DEGs).Functional enrichment,proteinprotein interaction(PPI)network construction,and survival analyses identified seven metastasis-and prognosisrelated genes.Their expression was further examined using public single-cell RNA-seq data(GSE139829;11 tumors).Experimental validation was performed in UVM cell lines(92.1,OMM1,MEL270)and adult retinal pigment epithelial(ARPE-19)cells using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting to confirm transcriptomic trends.A LASSO Cox model was applied to construct a metastasis-related risk Score signature.Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis(ssGSEA)and ESTIMATE.Somatic mutation and copy number variation(CNV)profiles were also examined.RESULTS:Seven key genes(UBE2T,KIF20A,DLGAP5,KLC3,TPX2,UBE2C,AURKA)were significantly associated with overall survival and used to construct a metastasisrelated riskScore signature,which effectively stratified patients into high-and low-risk groups and served as an independent prognostic factor.qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells,which were largely consistent with the transcriptomic findings.The high-risk group exhibited reduced immune infiltration and stromal activity.Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential.Mutation and CNV analyses further supported the relevance of these genes to UVM progression.CONCLUSION:This study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM.The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations,and may offer guidance for future mechanistic studies and therapeutic exploration.展开更多
Objective:To investigate the efficacy and mechanism of Ditan Qingnao decoction(DTQND)in alleviating schizophrenia-like symptoms in a maternal immune activation(MIA)-induced rat model.Methods:DTQND components were anal...Objective:To investigate the efficacy and mechanism of Ditan Qingnao decoction(DTQND)in alleviating schizophrenia-like symptoms in a maternal immune activation(MIA)-induced rat model.Methods:DTQND components were analyzed using high-performance liquid chromatography-tandem mass spectrometry.An MIA-induced rat model was established by injecting Poly Ⅰ:C into pregnant dams on gestational day 9.Male offspring were administered DTQND(14.1 g/kg),risperidone(RIS;0.4 mg/kg),or distilled water,while the controls received only distilled water via gavage for 4 weeks.Behavioral assessments were conducted using the open-field,Y-maze,prepulse inhibition,and sucrose preference tests.Serum levels of interleukin(IL)-6,IL-18,IL-1β,and tumor necrosis factor-α(TNF-α)were measured via an enzyme-linked immunosorbent assay.Hippocampal protein levels of nuclear factor kappa B p65(NF-κB p65),phospho-NF-κB p65(p-p65),inhibitor of kappa B-alpha(IκB-α),phospho-IκB-α(p-IκB-α),and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3(NLRP3)were assessed via western blots.Immunohistochemistry detected hippocampal expression of ionized calcium-binding adapter molecule 1(Iba1)and cluster of differentiation 68(CD68).Results:Multiple DTQND compounds were identified,including stachyose,β-syringin,and isofraxidin,among others.DTQND treatment considerably enhanced spontaneous activity,reduced anxiety,improved spatial working memory,and alleviated sensory gating defects in male offspring with MIA.The DTQND group showed significantly lower serum levels of IL-1β(P=.002)and IL-18(P=.046)than the model group,with no discernible variations in IL-6 or TNF-α levels.In the hippocampus,DTQND significantly suppressed the expression of p-p65(P<.001),p-IκB-α(P=.023),and NLRP3(P<.001)compared to the model group.Additionally,DTQND modulated microglial activation markers,decreasing CD68 expression(P=.004)without affecting Iba1 levels.Conclusions:DTQND alleviated schizophrenia-like behavioral deficits and cognitive impairment by inhibiting the NF-κB/NLRP3 pathway,supporting its potential as an alternative therapy for schizophrenia.展开更多
Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regula...Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.展开更多
Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional...Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional therapies.This review comprehensively examines the emerging role of chimeric antigen receptor(CAR)-engineered immune cells,including chimeric antigen receptor-T(CAR-T),CAR-macrophages(CAR-M),and CAR-natural killer(CAR-NK)cells,as innovative immunotherapeutic strategies for PDAC.We delve into the mechanistic foundations of these platforms,highlighting their unique abilities to target tumor-associated antigens,overcome stromal barriers,and remodel the immunosuppressive TME.Recent preclinical and clinical advances demonstrate promising antitumor activity,particularly with targets such as mesothelin,claudin18.2,and human epidermal growth factor 2(HER2),though challenges related to antigen heterogeneity,TME suppression,and cell persistence remain.We further discuss synergistic approaches involving genetic engineering,microenvironment modulation,and combination therapies aimed at enhancing efficacy.Finally,we offer perspectives on the future direction of CARbased therapies,including the development of next-generation constructs,allogeneic“off-the-shelf”products,and personalized combination regimens,underscoring their potential in pancreatic cancer.展开更多
Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly...Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly immune checkpoint blockades(ICBs),has demonstrated considerable therapeutic potential;however,many patients do not exhibit a favorable response.As a result,constructing a predictive model to assess ICBs'responsiveness is essential for enhancing treatment outcomes.Methods:Using consensus clustering based on anoikis-related gene expression,GC patients were stratified into two subclusters.Differences in tumor immune microenvironment,ICB resistance,genomic alterations,methylation profiles,and transcriptional networks were analyzed.A machine learning-based strategy was employed to develop a consensus anoikis-related gene signature(ARGS).Potential therapeutic targets were identified through single-cell RNA sequencing(scRNA-seq),and validation was conducted using multiplex immunofluorescence and immunohistochemistry in an in-house cohort(n=28),including 14 ICB responders and 14 nonresponders.Results:The anoikis-resistant cluster(Cluster A)was associated with poorer survival,immunosuppressive infiltration,lower tumor mutation burden,and ICB resistance.ScRNA-seq revealed high fibroblast and endothelial infiltration,with GLI3+cancer-associated fibroblasts suggesting Hedgehog pathway involvement.The ARGS model effectively stratified patients,with elevated scores associ-ated with immunotherapy resistance,enhanced AR characteristics,and poorer clinical outcomes.展开更多
Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growi...Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growing evidence highlights the immune system’s role in PF,with various immune components participating in inflammatory and fibrotic processes.Different immune cells,including neutrophils,lymphocytes,and macrophages,demonstrate distinct effects on PF progression and development.Furthermore,key immune system cytokines,including the interleukin(IL)family,tumor necrosis factor(TNF)-α,interferon(IFN)-γ,transforming growth factor(TGF)-β,and connective tissue growth factor(CTGF),contribute to PF initiation and progression through independent mechanisms and mutual regulation.Currently,limited effective treatments exist for PF,with several treatments causing severe adverse reactions.Natural products,characterized by multi-target effects,holistic regulation,and low toxicity,have emerged as a research focus.This review compiles the mechanisms,therapeutic potential,and active components of various natural products.These compounds can ameliorate pulmonary inflammation,epithelial-mesenchymal transition,and collagen deposition through diverse immune mechanisms,acting at specific stages or throughout the fibrotic process,thereby supporting PF management.This review examines current scientific understanding of natural products’immunological effects in PF,which is crucial for developing future anti-PF therapeutics.展开更多
Immunotherapy for cardiovascular diseases(CVDs)holds great promise for precision management by modulating localized immune-inflammatory responses.The interplay between focal cardiovascular pathology and panvascular di...Immunotherapy for cardiovascular diseases(CVDs)holds great promise for precision management by modulating localized immune-inflammatory responses.The interplay between focal cardiovascular pathology and panvascular disease,necessitates highly integrated therapeutic strategies.Nano-technology-based theranostic platforms address this challenge by enabling both regulation and real-time imaging of immune cell activity within cardiovascular lesions.These functional nanotherapy systems not only halt disease progression at pathological sites but also reduce secondary cardiovascular events driven by shared inflammatory mechanisms.Additionally,nanoplatform-based dynamic visualization of immune cell responses facilitates adaptive,personalized interventions.This review introduces the role of immune cells in CVDs.It summarizes recent advances in nanomaterial-based immunomodulation strategies,including mechanisms of immune regulation,enhanced imaging,and therapeutic applications in atherosclerosis,myocardial infarction,ischemic stroke,abdominal aortic aneurysm,and myocarditis.Collectively,this integrated nanotheranostic paradigm establishes a robust foundation for the next generation of cardiovascular precision medicine.展开更多
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 grants from the National Natural Science Foundation of China(No.82372382,82002333,32371412,and 32071349)the Central Guidance on Local Science and Technology Development Fund of Zhejiang Province(No.2024ZY01033)+1 种基金the Zhejiang Provincial Natural Science Foundation of China(No.LY24C100001)the Key Research and Development Program of Zhejiang(No.2022C01076).
文摘Bone is highly innervated,and its regeneration is significantly nerve-dependent.Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and osteoclast activity.However,the majority of research to date has focused on the direct effects of peripheral nerves and their neurotransmitters on bone regeneration.Emerging studies have begun to reveal a more intricate role of nerves in regulating the immune microenvironment,which is crucial for bone regeneration.This review summarizes how nerves influence bone regeneration through modulation of the immune microenvironment.We first discuss the changes in peripheral nerves during the regenerative process.We then describe conduction and paracrine pathways through which nerves affect the osteogenic immune microenvironment,emphasizing nerves,neural factors,and their impacts.Our goal is to deepen the understanding of the nerve-immune axis in bone regeneration.A better grasp of how nerves influence the osteogenic immune microenvironment may lead to new strategies that integrate the nervous,immune,and skeletal systems to promote bone regeneration.
基金supported by the National Natural Science Foundation of China(Nos.82573045,82460602,82560459)the Hainan Provincial Graduate Student Innovative Research Project(No.Qhys2024-440).
文摘Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.
基金supported by the Henan Provincial Science and Technology Research and Development Plan Joint Fund(Grant No.242103810035).
文摘Lung cancer remains the leading cause of cancer-related mortality worldwide,primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells.To adapt to the nutrient-deprived tumor microenvironment(TME),lung cancer cells undergo profound metabolic reprogramming,characterized by enhanced glycolysis(the Warburg effect),increased glutamine dependency(mediated by GLS1),and accelerated lipid synthesis(involving enzymes such as FASN).These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations(e.g.,Tregs and M2 macrophages)and inhibiting effector functions of CD8^(+)T cells and natural killer(NK)cells.Critically,a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME:metabolic reprogramming drives immune suppression through metabolite accumulation,whereas the immunosuppressive TME,in turn,promotes tumor cell adaptability—thus forming a positive feedback loop that reinforces immune evasion and therapy resistance.This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer—spanning glucose,amino acid,and lipid metabolism—and their dynamic crosstalk with immune regulation,including epigenetic modifications and non-coding RNA-mediated mechanisms.Additionally,it evaluates emerging therapeutic strategies targeting the metabolic-immune axis,such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents,which aim to reverse immunosuppression and improve clinical outcomes.By synthesizing recent advances,this work provides a theoretical framework for precision oncology interventions,highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.
文摘Ischemic stroke therapy has long been dominated by strategies aimed at restoring cerebral blood flow. Yet, accumulating evidence suggests that neuronal survival and functional recovery depend not only on reperfusion, but also on the resolution of postischemic immune dysregulation. This study(Chen et al., Prog Biochem Biophys, 2026, 53(3): 697-710. DOI:10.3724/j.pibb.2025.0541) a dvances this emerging paradigm by proposing a therapeutic strategy that integrates lesion-specific delivery with active modulation of the inflammatory microenvironment.
文摘Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Methods We retrieved data from sepsis patients who underwent Th1/Th2 cytokine testing in Nanfang Hospital,Southern Medical University from June 1,2020,to February 1,2022.An unsupervised K-means clustering method classified participants based on Th1/Th2 cytokine levels,with the primary outcome being the 7-day mortality rate post-ICU admission.Cox proportional hazards and Restricted Mean Survival Time(RMST)analyses were utilized to explore survival outcomes.Results A total of 321 sepsis patients were included.IL-6(HR 1.69,95%CI:1.22,2.34)and IL-10(HR 1.81,95%CI:1.37,2.40)emerged as independent predictors of 7-day mortality.Unsupervised K-means clustering revealed 3 inflammatory/immune subgroups:Cluster 1(n=166,low inflammatory response),Cluster 2(n=99,moderate inflammatory response with immune suppression),and Cluster 3(n=56,strong inflammatory and immune suppression).Compared to Cluster 1,Clusters 2 and 3 had higher 7-day mortality risks(14.4%vs 23.2%,HR=4.30,95%CI:1.51-12.26;14.4%vs 35.7%,HR=7.32,95%CI:2.57-20.79).Conclusion Septic patients in a protective immune response state(Cluster 1)exhibit better short-term prognoses,suggesting the importance of understanding inflammatory/immune states for precise treatment and improved outcomes.
基金financial support from the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20230718)。
文摘The interplay between gut microbiota and host health has attracted significant interest in the animal science community.Maintaining gut microbiota homeostasis by supplementing probiotics to treat clinical conditions like calf diarrhea is an emerging area of research nowadays because of increased concerns regarding antimicrobial resistance(AMR)and drug residues in animal products.Probiotics reduce the incidence of calf diarrhea by increasing the gut microbiota diversity and richness with more commensal bacteria such as Lactobacillus and Bifidobacterium that produce antimicrobial compounds,as well as modulating the immune response by increasing cytokines,Interleukin-2(IL-2),IL-4,IL-6,IL-10,and reducing tumor necrosis factor-α(TNF-α),by increasing production of antibodies,especially immunoglobulin E(Ig E),also Ig G,differentiating naive Th lymphocytes(Tho)into Th1,hence stimulate innate immunity and prime the adaptive immune response.Specific probiotic strains of bacteria and yeast(Saccharomyces cerevisiae)derived probiotics maintain the integrity of the intestinal barrier.In this review,data are being organized to address the role of probiotics in treating calf diarrhea by modulating gut microbiota and stimulating an immune response against notorious pathogens,to present animal and veterinary scientists and nutritionists with a new concept to treat infectious diseases from the perspective of the gut microbiota,increasing animal health,performance,and welfare.In conclusion,health status and gut microbiome are strongly interlinked.Research data indicated a significant reduction in the incidence of diarrhea after probiotic administration.If interrelations between probiotics and existing gut microbiota are explored more quantitatively,novel antibiotic substitutes can emerge in the future.
基金Natural Science Foundation of Beijing,No.7244428(to WZ)Peking University Medicine Sailing Program for Young Scholars’Scientific and Technological Innovation,No.BMU2023YFJHPY034(to WZ)+1 种基金the National Natural Science Foundation of China,Nos.81873784(to DF),82071426(to DF)Clinical Cohort Construction Program of Peking University Third Hospital,Nos.BYSYDL2019002(to DF)and BYSYZD2021004(to DF).
文摘Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.
基金supported by the Scientific Research Project of Anhui ProvincialHealth Commission(Grant No.AHWJ2021b063)National Natural Scientific Foundation of China(Grant No.82160048)+1 种基金Natural Science Foundation Project of Anhui Province(Grant No.2308085MH265)Major Scientific Research Project of Anhui Provincial Department of Education(Grant No.2024AH040205).
文摘Objectives:Postmenopausal osteoporosis is the most common form of osteoporosis in clinical practice,affecting millions of postmenopausal women worldwide.Postmenopausal osteoporosis demands safe and effective therapies.This study aimed to evaluate the potential of hederagenin(Hed)for treating osteoporosis and to elucidate its underlying mechanisms of action.Methods:The anti-osteoporotic potential of Hed was assessed by investigating its effects on ovariectomy(OVX)-induced bone loss in mice and on receptor activator of NF-kappaB ligand(RANKL)-induced osteoclast differentiation in RAW264.7 cells.Network pharmacology analysis and molecular docking were employed to identify key targets,which were subsequently validated experimentally.Results:In vitro,Hed suppressed osteoclastogenesis by inhibiting the formation of osteoclasts and F-actin rings and by down-regulating osteoclastspecific genes(Atp6v0d2 and Acp5).In vivo,Hed significantly amelioratedOVX-induced bone loss,restoring trabecular bone volume fraction(BV/TV)and trabecular number(Tb.N),while reducing trabecular separation(Tb.Sp).Network pharmacology analysis identified 142 overlapping targets linking Hed to osteoporosis,including tumor necrosis factor alpha(TNF-α),interleukin-6(IL-6),and IL-1β,with enrichment in innate immune signaling and osteoclast differentiation.Molecular docking analysis indicated strong binding affinities between Hed and targets such as TNF-α,IL-6,and IL-1β.Experimentally,Hed was found to decrease RANKL,elevate osteoprotegerin(OPG),and suppress intestinalmRNA levels of pro-inflammatory cytokines such as IL-1β,IL-6,IL-17A,and TNF-α.Conclusion:Hed exerts significant anti-osteoporotic effects inOVX-induced osteoporosis through a dualmechanism involving the suppression of both osteoclastogenesis and innate immune signaling pathways.These findings highlighted Hed’s novel role in modulating immune-bone crosstalk,offering a promising strategy for treating osteolytic diseases without estrogenic side effects.
基金supported by Beijing Sport University Graduate Innovation Programme(2024013).
文摘Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic relevance of exerkines across cancer types remains unclear,and the molecular determinants of exercise responsiveness are poorly defined.Methods:We systematically profiled 183 curated exerkine-related genes across 33 cancer types from The Cancer Genome Atlas(TCGA)using non-negative matrix factorization(NMF)to define molecular subtypes.Prognostic significance was evaluated via Kaplan-Meier analysis.For five cancers with consistent survival divergence(LGG,KIRC,LUAD,PAAD,ACC),we developed an Exerkine Prognostic Index(EPI)using LASSO Cox regression and validated its predictive performance through time-dependent ROC analysis.Immune cell infiltration(CIBERSORT),stromal/immune scores(ESTIMATE),and immune checkpoint expression were assessed to characterize immune landscape differences between EPI subgroups.Results:Exerkine-based NMF clustering identified prognostically distinct subtypes in 25 cancers.The EPI robustly stratified patients into high-and low-risk groups with significant differences in overall survival(p<0.001).High-EPI subgroups were associated with elevated infiltration of immunosuppressive cells(e.g.,Tregs,M0 macrophages),altered immune/stromal scores,and differential expression of immune checkpoints such as PD-L1 and CTLA4 in a cancer-type-specific manner.Discussion:Our findings reveal that exerkine expression patterns capture biologically and clinically relevant heterogeneity across cancers.The EPI provides a robust molecular tool to stratify patients by prognosis and immune contexture,offering insights into differential exercise responsiveness.Conclusions:Exerkines represent promising biomarkers for risk stratification and precision-guided exercise interventions in oncology.
文摘Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical application of multi-omics parameters is still restricted by the expensive and less accessible assays,although they accurately reflect immune status.A comprehensive evaluation framework based on“easy-to-obtain”multi-model clinical parameters is urgently required,incorporating clinical features to establish baseline patient profiles and disease staging;routine blood tests assessing systemic metabolic and functional status;immune cell subsets quantifying subcluster dynamics;imaging features delineating tumor morphology,spatial configuration,and perilesional anatomical relationships;immunohistochemical markers positioning qualitative and quantitative detection of tumor antigens from the cellular and molecular level.This integrated phenomic approach aims to improve prognostic stratification and clinical decision-making in hepatocellular carcinoma management conveniently and practically.
基金supported by University of Kentucky-SCoBIRC Endowed Chair#5Craig H.Neilsen 1173493 and NIH RF1NS135504(to JCG).
文摘Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical precedent of SCI being a male-dominated condition.In contrast,most basic science researchers utilize single-sex studies to minimize complications associated with bladder care in males(Stewart et al.,2020).The findings of our recent publication identify sexually dimorphic immune responses to SCI in both mice and pigs(Kumari et al.,2025).Here,we will highlight these findings and discuss the impact of sex on SCI inflammation and recovery.
基金Supported by the National Natural Science Foundation of China(No.82460215)National Natural Science Foundation of China Pre-experimental Project(No.2025GZRYSY006)+4 种基金2025 Youth Training Project of the Xi’an Municipal Health Commission(No.2025qn05)Xi’an Medical Research-Discipline Capacity Building Project(No.23YXYJ0002)Key R&D Plan of Shaanxi Province:Key Industrial Innovation Chain(Cluster)-Social Development Field(No.2022ZDLSF03-10)Research Incubation Fund of Xi’an People’s Hospital(Xi’an Fourth HospitalNo.LH-13).
文摘AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas(TCGA)-UVM cohort and an external Gene Expression Omnibus(GEO)microarray dataset(GSE73652;8 non-metastatic vs 5 metastatic cases)were analyzed to identify differentially expressed genes(DEGs).Functional enrichment,proteinprotein interaction(PPI)network construction,and survival analyses identified seven metastasis-and prognosisrelated genes.Their expression was further examined using public single-cell RNA-seq data(GSE139829;11 tumors).Experimental validation was performed in UVM cell lines(92.1,OMM1,MEL270)and adult retinal pigment epithelial(ARPE-19)cells using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting to confirm transcriptomic trends.A LASSO Cox model was applied to construct a metastasis-related risk Score signature.Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis(ssGSEA)and ESTIMATE.Somatic mutation and copy number variation(CNV)profiles were also examined.RESULTS:Seven key genes(UBE2T,KIF20A,DLGAP5,KLC3,TPX2,UBE2C,AURKA)were significantly associated with overall survival and used to construct a metastasisrelated riskScore signature,which effectively stratified patients into high-and low-risk groups and served as an independent prognostic factor.qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells,which were largely consistent with the transcriptomic findings.The high-risk group exhibited reduced immune infiltration and stromal activity.Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential.Mutation and CNV analyses further supported the relevance of these genes to UVM progression.CONCLUSION:This study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM.The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations,and may offer guidance for future mechanistic studies and therapeutic exploration.
基金supported by the Beijing Natural Science Foundation(7222274)the Fifth Batch of National Outstanding Talents in Clinical Chinese Medicine(20221)。
文摘Objective:To investigate the efficacy and mechanism of Ditan Qingnao decoction(DTQND)in alleviating schizophrenia-like symptoms in a maternal immune activation(MIA)-induced rat model.Methods:DTQND components were analyzed using high-performance liquid chromatography-tandem mass spectrometry.An MIA-induced rat model was established by injecting Poly Ⅰ:C into pregnant dams on gestational day 9.Male offspring were administered DTQND(14.1 g/kg),risperidone(RIS;0.4 mg/kg),or distilled water,while the controls received only distilled water via gavage for 4 weeks.Behavioral assessments were conducted using the open-field,Y-maze,prepulse inhibition,and sucrose preference tests.Serum levels of interleukin(IL)-6,IL-18,IL-1β,and tumor necrosis factor-α(TNF-α)were measured via an enzyme-linked immunosorbent assay.Hippocampal protein levels of nuclear factor kappa B p65(NF-κB p65),phospho-NF-κB p65(p-p65),inhibitor of kappa B-alpha(IκB-α),phospho-IκB-α(p-IκB-α),and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3(NLRP3)were assessed via western blots.Immunohistochemistry detected hippocampal expression of ionized calcium-binding adapter molecule 1(Iba1)and cluster of differentiation 68(CD68).Results:Multiple DTQND compounds were identified,including stachyose,β-syringin,and isofraxidin,among others.DTQND treatment considerably enhanced spontaneous activity,reduced anxiety,improved spatial working memory,and alleviated sensory gating defects in male offspring with MIA.The DTQND group showed significantly lower serum levels of IL-1β(P=.002)and IL-18(P=.046)than the model group,with no discernible variations in IL-6 or TNF-α levels.In the hippocampus,DTQND significantly suppressed the expression of p-p65(P<.001),p-IκB-α(P=.023),and NLRP3(P<.001)compared to the model group.Additionally,DTQND modulated microglial activation markers,decreasing CD68 expression(P=.004)without affecting Iba1 levels.Conclusions:DTQND alleviated schizophrenia-like behavioral deficits and cognitive impairment by inhibiting the NF-κB/NLRP3 pathway,supporting its potential as an alternative therapy for schizophrenia.
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
基金funded by the National Natural Science Foundation of China(Grant Nos.82204517 to T.Z.and 82404756 to J.Z.)the Science and Technology Program in Medicine and Health of Zhejiang Province(Grant No.2023KY726 to T.Z.).
文摘Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.
文摘Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional therapies.This review comprehensively examines the emerging role of chimeric antigen receptor(CAR)-engineered immune cells,including chimeric antigen receptor-T(CAR-T),CAR-macrophages(CAR-M),and CAR-natural killer(CAR-NK)cells,as innovative immunotherapeutic strategies for PDAC.We delve into the mechanistic foundations of these platforms,highlighting their unique abilities to target tumor-associated antigens,overcome stromal barriers,and remodel the immunosuppressive TME.Recent preclinical and clinical advances demonstrate promising antitumor activity,particularly with targets such as mesothelin,claudin18.2,and human epidermal growth factor 2(HER2),though challenges related to antigen heterogeneity,TME suppression,and cell persistence remain.We further discuss synergistic approaches involving genetic engineering,microenvironment modulation,and combination therapies aimed at enhancing efficacy.Finally,we offer perspectives on the future direction of CARbased therapies,including the development of next-generation constructs,allogeneic“off-the-shelf”products,and personalized combination regimens,underscoring their potential in pancreatic cancer.
基金National Science and Technology Major Project,Grant/Award Number:2024ZD0533300Excellent Doctor Program of Zhongnan Hospital of Wuhan University,Grant/Award Number:ZNYB2021009。
文摘Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly immune checkpoint blockades(ICBs),has demonstrated considerable therapeutic potential;however,many patients do not exhibit a favorable response.As a result,constructing a predictive model to assess ICBs'responsiveness is essential for enhancing treatment outcomes.Methods:Using consensus clustering based on anoikis-related gene expression,GC patients were stratified into two subclusters.Differences in tumor immune microenvironment,ICB resistance,genomic alterations,methylation profiles,and transcriptional networks were analyzed.A machine learning-based strategy was employed to develop a consensus anoikis-related gene signature(ARGS).Potential therapeutic targets were identified through single-cell RNA sequencing(scRNA-seq),and validation was conducted using multiplex immunofluorescence and immunohistochemistry in an in-house cohort(n=28),including 14 ICB responders and 14 nonresponders.Results:The anoikis-resistant cluster(Cluster A)was associated with poorer survival,immunosuppressive infiltration,lower tumor mutation burden,and ICB resistance.ScRNA-seq revealed high fibroblast and endothelial infiltration,with GLI3+cancer-associated fibroblasts suggesting Hedgehog pathway involvement.The ARGS model effectively stratified patients,with elevated scores associ-ated with immunotherapy resistance,enhanced AR characteristics,and poorer clinical outcomes.
基金supported by the National Natural Science Foundation of China(No.82260820)the Natural Science Foundation of Jilin Province,Jilin,China(No.YDZJ202201ZYTS155).
文摘Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growing evidence highlights the immune system’s role in PF,with various immune components participating in inflammatory and fibrotic processes.Different immune cells,including neutrophils,lymphocytes,and macrophages,demonstrate distinct effects on PF progression and development.Furthermore,key immune system cytokines,including the interleukin(IL)family,tumor necrosis factor(TNF)-α,interferon(IFN)-γ,transforming growth factor(TGF)-β,and connective tissue growth factor(CTGF),contribute to PF initiation and progression through independent mechanisms and mutual regulation.Currently,limited effective treatments exist for PF,with several treatments causing severe adverse reactions.Natural products,characterized by multi-target effects,holistic regulation,and low toxicity,have emerged as a research focus.This review compiles the mechanisms,therapeutic potential,and active components of various natural products.These compounds can ameliorate pulmonary inflammation,epithelial-mesenchymal transition,and collagen deposition through diverse immune mechanisms,acting at specific stages or throughout the fibrotic process,thereby supporting PF management.This review examines current scientific understanding of natural products’immunological effects in PF,which is crucial for developing future anti-PF therapeutics.
基金supported by the National Natural Science Foundation of China(32371477,82090051,82301104,and 82300345)the National Key Research and Development Program of China(2021YFA1201000,2023YFC2605000)+2 种基金the National Natural Science Foundation of China Key Project(82430067,32030060)the Natural Science Foundation of Jiangsu Province(BK20230160)the Fundamental Research Funds for the Central Universities,Peking Union Medical College(3332025033).
文摘Immunotherapy for cardiovascular diseases(CVDs)holds great promise for precision management by modulating localized immune-inflammatory responses.The interplay between focal cardiovascular pathology and panvascular disease,necessitates highly integrated therapeutic strategies.Nano-technology-based theranostic platforms address this challenge by enabling both regulation and real-time imaging of immune cell activity within cardiovascular lesions.These functional nanotherapy systems not only halt disease progression at pathological sites but also reduce secondary cardiovascular events driven by shared inflammatory mechanisms.Additionally,nanoplatform-based dynamic visualization of immune cell responses facilitates adaptive,personalized interventions.This review introduces the role of immune cells in CVDs.It summarizes recent advances in nanomaterial-based immunomodulation strategies,including mechanisms of immune regulation,enhanced imaging,and therapeutic applications in atherosclerosis,myocardial infarction,ischemic stroke,abdominal aortic aneurysm,and myocarditis.Collectively,this integrated nanotheranostic paradigm establishes a robust foundation for the next generation of cardiovascular precision medicine.
