The sensor virus is a serious threat,as an attacker can simply send a single packet to compromise the entire sensor network.Epidemics become drastic with link additions among sensors when the small world phenomena occ...The sensor virus is a serious threat,as an attacker can simply send a single packet to compromise the entire sensor network.Epidemics become drastic with link additions among sensors when the small world phenomena occur.Two immunization strategies,uniform immunization and temporary immunization,are conducted on small worlds of tree-based wireless sensor networks to combat the sensor viruses.With the former strategy,the infection extends exponentially,although the immunization effectively reduces the contagion speed.With the latter strategy,recurrent contagion oscillations occur in the small world when the spatial-temporal dynamics of the epidemic are considered.The oscillations come from the small-world structure and the temporary immunization.Mathematical analyses on the small world of the Cayley tree are presented to reveal the epidemic dynamics with the two immunization strategies.展开更多
Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted t...Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.展开更多
Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have rev...Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.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
In a series of experiments,Phelps et al.1provided novel data linking moderate-to-vigorous physical activity (MVPA),gut microbiota composition changes and the release of the short chain fatty acid (SCFA) formate,and en...In a series of experiments,Phelps et al.1provided novel data linking moderate-to-vigorous physical activity (MVPA),gut microbiota composition changes and the release of the short chain fatty acid (SCFA) formate,and enhanced antitumor immunity via the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in cytotoxic CD8+T cells.These data support the growing awareness that the clinical benefits of MVPA are achieved at least in part through enhanced immunity with support from the gut microbiome.展开更多
The central nervous system(CNS)does not function in isolation-it engages in continuous molecular dialogue with the vascular and immune systems.Traditionally,the blood-brain barrier(BBB)was portrayed solely as an imper...The central nervous system(CNS)does not function in isolation-it engages in continuous molecular dialogue with the vascular and immune systems.Traditionally,the blood-brain barrier(BBB)was portrayed solely as an impermeable wall,safeguarding the CNS by excluding blood-derived molecules and circulating cells.However,this view has evolved.The BBB is now recognized as a dynamic interface that selectively regulates the exchange of signals,cells.展开更多
Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune check...Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.展开更多
Probiotics can regulate the body’s immune system through both non-specific and specific immunity,thereby regulating host health.In terms of non-specific immune regulation,probiotics can activate the intrinsic immune ...Probiotics can regulate the body’s immune system through both non-specific and specific immunity,thereby regulating host health.In terms of non-specific immune regulation,probiotics can activate the intrinsic immune system,regulate the mucosal barrier function,and play an immune role by influencing the activity of intrinsic immune cells such as macrophages,dendritic cells and natural killer cells,as well as their differentiation and maturation;in terms of specific immune regulation,probiotics play a role in regulating the immunoglobulin level and the maturation of B cells.Probiotics can also regulate T-cell differentiation according to the condition of the body,thus regulating specific immunity.Many studies have focused on the role of probiotics in metabolism and nutrition,and the mechanisms involved in the immunomodulatory role of probiotics have only been partially described.This review summarises the role of common probiotics such as Lactobacillus plantarum and Lactobacillus rhamnosus in immunomodulation as well as their mechanisms,describing the currently known mechanisms of immunomodulation by probiotics in improving the host immune system.A deeper understanding of probiotics and their specific mechanisms of action will facilitate the use of probiotics for immunomodulation in clinical medicine,functional foods,and other areas.This will also contribute to the development and research of engineered probiotics,next-generation probiotics,and other new functional probiotics with immunomodulatory effects.展开更多
Colorectal cancer(CRC)is ranked as the third most common tumor globally,representing approximately 10%of all cancer cases,and is the second primary cause of cancer-associated mortality.Existing therapeutic approaches ...Colorectal cancer(CRC)is ranked as the third most common tumor globally,representing approximately 10%of all cancer cases,and is the second primary cause of cancer-associated mortality.Existing therapeutic approaches demonstrate limited efficacy against CRC,partially due to the immunosuppressive tumor microenvironment(TME).In recent years,substantial evidence indicates that dysbiosis of the gut microbiota and its metabolic products is closely associated with the initiation,progression,and prognostic outcomes of CRC.In this minireview,we systematically elaborate on how these microbes and their metabolites directly impair intestinal epithelial integrity,activate cancer-associated fibroblasts,remodel tumor vasculature,and critically,sculpt an immunosuppressive landscape by modulating T cells,dendritic cells,and tumor-associated macrophages.We highlight the translational potential of targeting the gut microbiota,including fecal microbiota transplantation,probiotics,and engineered microbial systems,to reprogram the TME and overcome resistance to immunotherapy and chemotherapy.A deeper understanding of the microbiota-TME axis is essential for developing novel diagnostic and therapeutic paradigms for CRC.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
ADPr-ATP is a natural nucleotide with three sugar rings and five pentavalent phosphorus,and can be produced through TIR-catalyzed ADP-ribosylation reactions for plant immunity.Here,we report the first total synthesis ...ADPr-ATP is a natural nucleotide with three sugar rings and five pentavalent phosphorus,and can be produced through TIR-catalyzed ADP-ribosylation reactions for plant immunity.Here,we report the first total synthesis of ADPr-ATP(1)with a total yield of 6.4%through 14 steps,featuring late-stage P(V)−N activation reaction of pyrophosphate(4)and 5′-phosphoromorpholidate(25).The protected adenosine 5′-phosphoromorpholidate(24)was prepared on the basis of a scalable to adenosine 5′′-monophosphate(2).The construction of P(V)−N bond in phosphoramidate is esteemed as a critical step as they are sufficiently stable in deprotection reactions.The chemical synthesis of ADPr-ATP can offer an appealing alternative to traditional enzymatic synthesis and fractionation methods.Furthermore,the pRib-AMP and its prodrug are also synthesized to evaluate cytotoxicity and anti-influenza activity in vitro.展开更多
The red imported fire ant,Solenopsis invicta Buren,is a highly invasive eusocial insect pest that threatens native biodiversity,agriculture,and human health.The innate immune system and intricate social immune respons...The red imported fire ant,Solenopsis invicta Buren,is a highly invasive eusocial insect pest that threatens native biodiversity,agriculture,and human health.The innate immune system and intricate social immune responses of S.invicta pose challenges to the development of effective control strategies.Micro RNAs(mi RNAs)play critical roles in the post-transcriptional regulation of gene expression,which influences various biological processes,including immunity and host-pathogen interactions.While the mi RNA-mediated response of insects to pathogens has been extensively studied in solitary insects,little is known about the innate immune responses of individual members within a colony.To address this gap,we constructed small RNA libraries from Metarhizium anisopliae-infected S.invicta workers and investigated the temporal dynamics of mi RNA-mediated immune responses to the entomopathogen.Several differentially expressed mi RNAs were identified,and they were found to regulate genes involved in the Toll,IMD,and melanization immune pathways.Quantitative real-time PCR(q RT-PCR)was employed to analyze the spatiotemporal dynamics of key mi RNAs/target genes,specifically mi R-71/Mod SP1-Relish and mi R-7/Lysozyme2-Serine protease7.A dual luciferase assay(in vitro)was performed to validate the interactions between mi RNAs and their target genes.Overexpression of mi R-71 and mi R-7(via mi RNA mimics)efficiently suppressed their target genes,impaired the antifungal immune response of S.invicta and increased the susceptibility to M.anisopliae infection compared to controls.Furthermore,RNA interference-based gene silencing elucidated the roles of these immune genes in regulating fungal susceptibility,thus providing vital clues for developing virulent and effective mycoinsecticides using modern genetic engineering tools.展开更多
Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanis...Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA(dsDNA)-sensing cyclic GMP-AMP synthase(cGAS)signaling warrant further study.Using middle cerebral artery occlusion mice,we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation.Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release,as reflected byγH2AX staining,as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway,both of which were notably suppressed by melatonin treatment.Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome activation and nuclear factor(NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke,while exhibiting the capacity to attenuate the immune response to ischemia in mice.This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain.Specifically,melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-αby microglia.Regarding neurological outcomes,melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice.Notably,the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity.We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles(Mф-MLT@FNGs),which exhibited therapeutic properties in middle cerebral artery occlusion mice.Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway.By doing so,melatonin rescues damaged brain tissue and protects neurological function,highlighting its potential as a neuroprotective treatment for ischemic stroke.展开更多
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
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
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
Objective: This review aims to explore the efficacy of exercise in the treatment of anxiety disorders and its underlying mechanisms, summarizing recent research advances and focusing on the potential biological and ps...Objective: This review aims to explore the efficacy of exercise in the treatment of anxiety disorders and its underlying mechanisms, summarizing recent research advances and focusing on the potential biological and psychological pathways through which exercise exerts its anxiolytic effects.Methods: To ensure comprehensive coverage of relevant studies, we conducted a systematic search in databases such as PubMed, Web of Science, and Embase, combining MeSH terms with free-text terms. Keywords included“exercise,” “physical activity,” and “anxiety disorder.”Results and conclusions: Current research widely supports exercise as a safe and effective intervention for anxiety.Both aerobic exercise and resistance training have shown significant anxiety-reducing effects across various populations. The mechanisms of action can be categorized into three main types: cellular and molecular mechanisms, systemic immune effects, and behavioral and cognitive pathways. Different forms of exercise have distinct advantages: aerobic exercise is suitable for the general population, resistance training is beneficial for individuals with coexisting physical conditions, and low-intensity exercises such as yoga and Tai Chi are suitable for pregnant women, the elderly, or postoperative recovery patients. Given its good safety profile and broad applicability, moderate exercise should be considered a first-line treatment for mild anxiety and an adjunctive intervention for moderate to severe anxiety. Future research should further clarify the mechanistic differences between various exercise modalities and promote the development of individualized exercise prescriptions.展开更多
Objective:To investigate the correlation between the expression of glucose-6-phosphate dehydrogenase(G6PD)and the clinicopathological characteristics,prognosis and immune cell infiltration of hepatocellular carcinoma(...Objective:To investigate the correlation between the expression of glucose-6-phosphate dehydrogenase(G6PD)and the clinicopathological characteristics,prognosis and immune cell infiltration of hepatocellular carcinoma(HCC).Methods:The expression of G6PD in liver cancer tissues and normal tissues is extracted from TCGA and GEO databases,validated by immunohistochemistry,and the correlation between G6PD expression and clinical features is analyzed.The clinical significance of G6PD in liver cancer is assessed by Kaplan-Meier,Cox regression,and prognostic line graph models.Functional enrichment analysis is performed by protein-protein interaction(PPI)network,GO/KEGG,GSEA and for G6PD-associated differentially expressed genes(DEGs).TIMER and ssGSEA packages are used to assess the correlation between expression and the level of immune cell infiltration.Results:Analysis of TCGA and GEO datasets revealed that G6PD expression is significantly upregulated in hepatocellular carcinoma tissues(P<0.001).G6PD expression is associated with histological grade,pathological stage,T-stage,vascular infiltration,and AFP level(P<0.05);HCC patients in the low G6PD expression group had longer overall survival and better prognosis compared with the high G6PD expression group(P<0.05).The level of G6PD expression affects the levels of macrophages,dendritic cells,B cells,and follicular helper T cells in the tumor microenvironment.Conclusion:High expression of G6PD is a potential biomarker for poor prognosis of hepatocellular carcinoma,and G6PD may be a target for immunotherapy of HCC.展开更多
Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifyi...Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifying the underlying mechanisms are essential.Methods:In vitro screening was performed to identify tumor types that are sensitive to STING agonists.The non-nucleotide agonist,SR-717,and the macrocyclic agonist,E7766,were compared for efficacy.Complementary in vivo and in vitro studies,including gene-knockout models,HMGN2-knockout Neuro-2A and CT-2A cells apoptosis assays,and murine tumor models,were then performed.These experiments focused on the mechanism by which SR-717 mediates antitumor effects and emphasized the role of STING signaling-induced high-mobility group nucleosome-binding protein 2(HMGN2).In addition,the potential of HMGN2 as a prognostic biomarker was assessed.Results:Neuroblastomas and glioblastomas,two nervous system tumors,were shown to be sensitive to STING agonists.SR-717 exhibited greater antitumor efficacy compared to E7766.Mechanistic studies indicated that STING agonists promote apoptosis through activation of the intrinsic STING-signal transducer and activator of transcription 1(STAT1)-HMGN2 axis within tumor cells.Ectopic expression of HMGN2 in melanoma cells,which naturally lack HMGN2,led to significant apoptosis.Furthermore,analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases revealed positive correlation between elevated HMGN2 expression and patient survival,supporting the utility of HMGN2 as a prognostic biomarker.Conclusions:This study clarified the mechanism underlying the potent antitumor activity of SR-717 in nervous system tumors through activation of the STING-STAT1-HMGN2 signaling pathway and demonstrated that SR-717 has superior efficacy compared to E7766.In addition,HMGN2 was shown to exhibit translational potential as a prognostic biomarker for patient survival.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
文摘The sensor virus is a serious threat,as an attacker can simply send a single packet to compromise the entire sensor network.Epidemics become drastic with link additions among sensors when the small world phenomena occur.Two immunization strategies,uniform immunization and temporary immunization,are conducted on small worlds of tree-based wireless sensor networks to combat the sensor viruses.With the former strategy,the infection extends exponentially,although the immunization effectively reduces the contagion speed.With the latter strategy,recurrent contagion oscillations occur in the small world when the spatial-temporal dynamics of the epidemic are considered.The oscillations come from the small-world structure and the temporary immunization.Mathematical analyses on the small world of the Cayley tree are presented to reveal the epidemic dynamics with the two immunization strategies.
基金supported by the National Natural Science Foundation of China,Nos.32271389,31900987(both to PY)the Natural Science Foundation of Jiangsu Province,No.BK20230608(to JJ)。
文摘Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.
基金supported by the Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030045(to HS)Presidential Foundation of Zhujiang Hospital of Southern Medical University,No.yzjj2022ms4(to HS)。
文摘Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.
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.
文摘In a series of experiments,Phelps et al.1provided novel data linking moderate-to-vigorous physical activity (MVPA),gut microbiota composition changes and the release of the short chain fatty acid (SCFA) formate,and enhanced antitumor immunity via the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in cytotoxic CD8+T cells.These data support the growing awareness that the clinical benefits of MVPA are achieved at least in part through enhanced immunity with support from the gut microbiome.
基金supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K02NS110973 and R01NS126498(to MAP).
文摘The central nervous system(CNS)does not function in isolation-it engages in continuous molecular dialogue with the vascular and immune systems.Traditionally,the blood-brain barrier(BBB)was portrayed solely as an impermeable wall,safeguarding the CNS by excluding blood-derived molecules and circulating cells.However,this view has evolved.The BBB is now recognized as a dynamic interface that selectively regulates the exchange of signals,cells.
基金supported by the National Natural Science Foundation of China(82472842 and 82473350)and Wuxi Double-Hundred Talent Fund Project(BJ2023075).
文摘Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.
基金funded by Ausnutria-kabrita Research Fund(RS2022-14).
文摘Probiotics can regulate the body’s immune system through both non-specific and specific immunity,thereby regulating host health.In terms of non-specific immune regulation,probiotics can activate the intrinsic immune system,regulate the mucosal barrier function,and play an immune role by influencing the activity of intrinsic immune cells such as macrophages,dendritic cells and natural killer cells,as well as their differentiation and maturation;in terms of specific immune regulation,probiotics play a role in regulating the immunoglobulin level and the maturation of B cells.Probiotics can also regulate T-cell differentiation according to the condition of the body,thus regulating specific immunity.Many studies have focused on the role of probiotics in metabolism and nutrition,and the mechanisms involved in the immunomodulatory role of probiotics have only been partially described.This review summarises the role of common probiotics such as Lactobacillus plantarum and Lactobacillus rhamnosus in immunomodulation as well as their mechanisms,describing the currently known mechanisms of immunomodulation by probiotics in improving the host immune system.A deeper understanding of probiotics and their specific mechanisms of action will facilitate the use of probiotics for immunomodulation in clinical medicine,functional foods,and other areas.This will also contribute to the development and research of engineered probiotics,next-generation probiotics,and other new functional probiotics with immunomodulatory effects.
基金Supported by National Natural Science Foundation of China,No.82170638Natural Science Foundation of the Science and Technology Commission of Shanghai Municipality,No.23ZR1458300+1 种基金Key Discipline Project of Shanghai Municipal Health System,No.2024ZDXK0004and Pujiang Project of Shanghai Magnolia Talent Plan,No.24PJD098.
文摘Colorectal cancer(CRC)is ranked as the third most common tumor globally,representing approximately 10%of all cancer cases,and is the second primary cause of cancer-associated mortality.Existing therapeutic approaches demonstrate limited efficacy against CRC,partially due to the immunosuppressive tumor microenvironment(TME).In recent years,substantial evidence indicates that dysbiosis of the gut microbiota and its metabolic products is closely associated with the initiation,progression,and prognostic outcomes of CRC.In this minireview,we systematically elaborate on how these microbes and their metabolites directly impair intestinal epithelial integrity,activate cancer-associated fibroblasts,remodel tumor vasculature,and critically,sculpt an immunosuppressive landscape by modulating T cells,dendritic cells,and tumor-associated macrophages.We highlight the translational potential of targeting the gut microbiota,including fecal microbiota transplantation,probiotics,and engineered microbial systems,to reprogram the TME and overcome resistance to immunotherapy and chemotherapy.A deeper understanding of the microbiota-TME axis is essential for developing novel diagnostic and therapeutic paradigms for CRC.
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 National Natural Science Foundation of China(Nos.82204209 and 82130103)Natural Science Foundation of Henna Province(No.242300421084).
文摘ADPr-ATP is a natural nucleotide with three sugar rings and five pentavalent phosphorus,and can be produced through TIR-catalyzed ADP-ribosylation reactions for plant immunity.Here,we report the first total synthesis of ADPr-ATP(1)with a total yield of 6.4%through 14 steps,featuring late-stage P(V)−N activation reaction of pyrophosphate(4)and 5′-phosphoromorpholidate(25).The protected adenosine 5′-phosphoromorpholidate(24)was prepared on the basis of a scalable to adenosine 5′′-monophosphate(2).The construction of P(V)−N bond in phosphoramidate is esteemed as a critical step as they are sufficiently stable in deprotection reactions.The chemical synthesis of ADPr-ATP can offer an appealing alternative to traditional enzymatic synthesis and fractionation methods.Furthermore,the pRib-AMP and its prodrug are also synthesized to evaluate cytotoxicity and anti-influenza activity in vitro.
基金supported by grants from the National Natural Science Foundation of China(32172498 and W2433052)the National Key R&D Program of China(2021YFD1000500)the Natural Science Foundation of Guangdong,China(2023A1515010305)。
文摘The red imported fire ant,Solenopsis invicta Buren,is a highly invasive eusocial insect pest that threatens native biodiversity,agriculture,and human health.The innate immune system and intricate social immune responses of S.invicta pose challenges to the development of effective control strategies.Micro RNAs(mi RNAs)play critical roles in the post-transcriptional regulation of gene expression,which influences various biological processes,including immunity and host-pathogen interactions.While the mi RNA-mediated response of insects to pathogens has been extensively studied in solitary insects,little is known about the innate immune responses of individual members within a colony.To address this gap,we constructed small RNA libraries from Metarhizium anisopliae-infected S.invicta workers and investigated the temporal dynamics of mi RNA-mediated immune responses to the entomopathogen.Several differentially expressed mi RNAs were identified,and they were found to regulate genes involved in the Toll,IMD,and melanization immune pathways.Quantitative real-time PCR(q RT-PCR)was employed to analyze the spatiotemporal dynamics of key mi RNAs/target genes,specifically mi R-71/Mod SP1-Relish and mi R-7/Lysozyme2-Serine protease7.A dual luciferase assay(in vitro)was performed to validate the interactions between mi RNAs and their target genes.Overexpression of mi R-71 and mi R-7(via mi RNA mimics)efficiently suppressed their target genes,impaired the antifungal immune response of S.invicta and increased the susceptibility to M.anisopliae infection compared to controls.Furthermore,RNA interference-based gene silencing elucidated the roles of these immune genes in regulating fungal susceptibility,thus providing vital clues for developing virulent and effective mycoinsecticides using modern genetic engineering tools.
基金supported by the Natural Science Foundation of Heilongjiang Province,No.YQ2021H011(to QL)China Postdoctoral Science Foundation,Nos.2020M670925,2022T150172(to QL)+2 种基金Postdoctoral Foundation of Heilongjiang Province,Nos.LBH‐Z19027,LBH‐TZ2019(to QL)Institute Cultivation Fund,No.PYMS2023-1(to QL)Natural Science Foundation of Jiangsu Province,No.BK20241233(to YL).
文摘Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA(dsDNA)-sensing cyclic GMP-AMP synthase(cGAS)signaling warrant further study.Using middle cerebral artery occlusion mice,we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation.Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release,as reflected byγH2AX staining,as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway,both of which were notably suppressed by melatonin treatment.Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome activation and nuclear factor(NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke,while exhibiting the capacity to attenuate the immune response to ischemia in mice.This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain.Specifically,melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-αby microglia.Regarding neurological outcomes,melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice.Notably,the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity.We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles(Mф-MLT@FNGs),which exhibited therapeutic properties in middle cerebral artery occlusion mice.Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway.By doing so,melatonin rescues damaged brain tissue and protects neurological function,highlighting its potential as a neuroprotective treatment for ischemic stroke.
基金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.
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Suppored by Nanjing Municipal Bureau of Physical Education and Sports Research Bureau Management Subjects (NJTY2023-104)Nanjing "Sports and Health Integration" New Model (JSYGY-3-2023-505)。
文摘Objective: This review aims to explore the efficacy of exercise in the treatment of anxiety disorders and its underlying mechanisms, summarizing recent research advances and focusing on the potential biological and psychological pathways through which exercise exerts its anxiolytic effects.Methods: To ensure comprehensive coverage of relevant studies, we conducted a systematic search in databases such as PubMed, Web of Science, and Embase, combining MeSH terms with free-text terms. Keywords included“exercise,” “physical activity,” and “anxiety disorder.”Results and conclusions: Current research widely supports exercise as a safe and effective intervention for anxiety.Both aerobic exercise and resistance training have shown significant anxiety-reducing effects across various populations. The mechanisms of action can be categorized into three main types: cellular and molecular mechanisms, systemic immune effects, and behavioral and cognitive pathways. Different forms of exercise have distinct advantages: aerobic exercise is suitable for the general population, resistance training is beneficial for individuals with coexisting physical conditions, and low-intensity exercises such as yoga and Tai Chi are suitable for pregnant women, the elderly, or postoperative recovery patients. Given its good safety profile and broad applicability, moderate exercise should be considered a first-line treatment for mild anxiety and an adjunctive intervention for moderate to severe anxiety. Future research should further clarify the mechanistic differences between various exercise modalities and promote the development of individualized exercise prescriptions.
文摘Objective:To investigate the correlation between the expression of glucose-6-phosphate dehydrogenase(G6PD)and the clinicopathological characteristics,prognosis and immune cell infiltration of hepatocellular carcinoma(HCC).Methods:The expression of G6PD in liver cancer tissues and normal tissues is extracted from TCGA and GEO databases,validated by immunohistochemistry,and the correlation between G6PD expression and clinical features is analyzed.The clinical significance of G6PD in liver cancer is assessed by Kaplan-Meier,Cox regression,and prognostic line graph models.Functional enrichment analysis is performed by protein-protein interaction(PPI)network,GO/KEGG,GSEA and for G6PD-associated differentially expressed genes(DEGs).TIMER and ssGSEA packages are used to assess the correlation between expression and the level of immune cell infiltration.Results:Analysis of TCGA and GEO datasets revealed that G6PD expression is significantly upregulated in hepatocellular carcinoma tissues(P<0.001).G6PD expression is associated with histological grade,pathological stage,T-stage,vascular infiltration,and AFP level(P<0.05);HCC patients in the low G6PD expression group had longer overall survival and better prognosis compared with the high G6PD expression group(P<0.05).The level of G6PD expression affects the levels of macrophages,dendritic cells,B cells,and follicular helper T cells in the tumor microenvironment.Conclusion:High expression of G6PD is a potential biomarker for poor prognosis of hepatocellular carcinoma,and G6PD may be a target for immunotherapy of HCC.
文摘Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifying the underlying mechanisms are essential.Methods:In vitro screening was performed to identify tumor types that are sensitive to STING agonists.The non-nucleotide agonist,SR-717,and the macrocyclic agonist,E7766,were compared for efficacy.Complementary in vivo and in vitro studies,including gene-knockout models,HMGN2-knockout Neuro-2A and CT-2A cells apoptosis assays,and murine tumor models,were then performed.These experiments focused on the mechanism by which SR-717 mediates antitumor effects and emphasized the role of STING signaling-induced high-mobility group nucleosome-binding protein 2(HMGN2).In addition,the potential of HMGN2 as a prognostic biomarker was assessed.Results:Neuroblastomas and glioblastomas,two nervous system tumors,were shown to be sensitive to STING agonists.SR-717 exhibited greater antitumor efficacy compared to E7766.Mechanistic studies indicated that STING agonists promote apoptosis through activation of the intrinsic STING-signal transducer and activator of transcription 1(STAT1)-HMGN2 axis within tumor cells.Ectopic expression of HMGN2 in melanoma cells,which naturally lack HMGN2,led to significant apoptosis.Furthermore,analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases revealed positive correlation between elevated HMGN2 expression and patient survival,supporting the utility of HMGN2 as a prognostic biomarker.Conclusions:This study clarified the mechanism underlying the potent antitumor activity of SR-717 in nervous system tumors through activation of the STING-STAT1-HMGN2 signaling pathway and demonstrated that SR-717 has superior efficacy compared to E7766.In addition,HMGN2 was shown to exhibit translational potential as a prognostic biomarker for patient survival.
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.
