Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,...Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.展开更多
Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in...Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiqui...The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.展开更多
Diabetic retinopathy(DR),a common complication of diabetes,is characterized by retinal angiogenesis and inflammation.The role of hepatoma-derived growth factor(HDGF)in mediating inflammation during DR remains unclear....Diabetic retinopathy(DR),a common complication of diabetes,is characterized by retinal angiogenesis and inflammation.The role of hepatoma-derived growth factor(HDGF)in mediating inflammation during DR remains unclear.We measured HDGF levels in the aqueous humor and found that HDGF was increased in DR but decreased after anti-angiogenesis treatment.Using public single-cell RNA sequencing datasets,we found that elevated HDGF in DR was mainly produced by Müller cells and targeted microglia.Additionally,integrin beta 2(Itgb2),a target gene of HDGF that induces microglial activation,was significantly upregulated in DR.To verify these results,we performed enzyme-linked immunosorbent assays,quantitative reverse transcription-PCR,Western blotting,and fluorescence immunostaining in cultured Müller and microglial cells treated with HDGF or anti-HDGF,as well as in DR mice receiving intravitreal injections of HDGF or its antibody.Exogenous HDGF further promoted microglial activation,migration,and secretion of pro-inflammatory cytokines,while neutralization of HDGF suppressed these effects caused by high glucose.Furthermore,the HDGF receptor nucleolin was overexpressed in microglia under high glucose stimulation.Therefore,blocking HDGF from Müller cells in DR reduced the excessive inflammatory response in microglia,highlighting HDGF as a potential therapeutic target.展开更多
Micro/nanoplastics(M/NPs)have become pervasive environmental pollutants,posing significant risks to human health through various exposure routes,including ingestion,inhalation,and direct contact.This review systematic...Micro/nanoplastics(M/NPs)have become pervasive environmental pollutants,posing significant risks to human health through various exposure routes,including ingestion,inhalation,and direct contact.This review systematically examined the potential impacts of M/NPs on ocular health,focusing on exposure pathways,toxicological mechanisms,and resultant damage to the eye.Ocular exposure to M/NPs can occur via direct contact and oral ingestion,with the latter potentially leading to the penetration of particles through ocular biological barriers into ocular tissues.The review highlighted that M/NPs can induce adverse effects on the ocular surface,elevate intraocular pressure,and cause abnormalities in the vitreous and retina.Mechanistically,oxidative stress and inflammation are central to M/NP-induced ocular damage,with smaller particles often exhibiting greater toxicity.Overall,this review underscored the potential risks of M/NPs to ocular health and emphasized the need for further research to elucidate exposure mechanisms,toxicological pathways,and mitigation strategies.展开更多
BACKGROUND Perimenopausal women are prone to anxiety and depression due to fluctuating hormone levels,which significantly impair their quality of life.The current treatments have certain limitations.In traditional Chi...BACKGROUND Perimenopausal women are prone to anxiety and depression due to fluctuating hormone levels,which significantly impair their quality of life.The current treatments have certain limitations.In traditional Chinese medicine,liver-soothing formulas are commonly prescribed for mood-related disorders,but their overall efficacy in perimenopausal anxiety and depression remains uncertain and requires verification through meta-analysis.AIM To provide evidence-based support for clinical decision-making and research,a meta-analysis was conducted to evaluate the effectiveness of liver-soothing formulas in treating perimenopausal anxiety and depression.METHODS Relevant studies published up to April 2025 were retrieved from ClinicalTrials.gov,PubMed,Web of Science,EMBASE,and the Cochrane Library.Eligible studies were screened according to predefined inclusion and exclusion criteria.Data were extracted and analyzed using the Stata 12.0 software.RESULTS After searching and screening,12 articles involving 1798 patients(922 in the treatment group and 876 in the control group)were included in the analysis.Meta-analysis showed that the standardized scores for anxiety[standardized mean difference(SMD)=-0.71,95%confidence interval(95%CI):-1.06 to-0.36]and depression(SMD=-0.67,95%CI:-1.06 to-0.27)of the treatment group were lower than those of the control group.Subgroup analysis results revealed that for anxiety,liver-soothing formulas used alone(SMD=-0.34,95%CI:-0.50 to-0.18)or in combination(SMD=-0.88,95%CI:-1.43 to-0.34)both significantly reduced scores compared with the control group.For depression,monotherapy of liversoothing formulas showed no significant statistical difference between the treatment and control groups(SMD=-0.47,95%CI:-1.11 to 0.17),whereas combination therapy produced significantly lower standardized scale scores in the treatment group than in the control group,with a statistically significant difference(SMD=-0.83,95%CI:-1.39 to-0.28).Regarding Greene scores,no statistically significant difference was observed with monotherapy(SMD=0.87,95%CI:-0.32 to 2.06),whereas combination therapy had significantly lower Greene scores(SMD=-0.24,95%CI:-0.44 to-0.04).No statistically significant difference was found between the groups in the occurrence of adverse reactions(odds ratio=0.90,95%CI:0.57-1.43).However,liver-soothing formulas did not affect estrogen levels in perimenopausal women.CONCLUSION Compared with placebo,conventional Western medicine,or other interventions,the monotherapy of liver-soothing formulas demonstrates superior efficacy in treating perimenopausal anxiety.When used as an adjuvant,they exert a synergistic effect in alleviating negative emotions and improving overall perimenopausal symptoms.展开更多
Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in hu...Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in humans remain unclear,including cell viability,distribution,migration,and fate.Conventional cell tracing methods cannot be used in the clinic.The use of superparamagnetic iron oxide nanoparticles as contrast agents allows for the observation of transplanted cells using magnetic resonance imaging.In 2016,the National Medical Products Administration of China approved a new superparamagnetic iron oxide nanoparticle,Ruicun,for use as a contrast agent in clinical trials.In the present study,an acute hemi-transection spinal cord injury model was established in beagle dogs.The injury was then treated by transplantation of Ruicun-labeled mesenchymal stromal cells.The results indicated that Ruicunlabeled mesenchymal stromal cells repaired damaged spinal cord fibers and partially restored neurological function in animals with acute spinal cord injury.T2*-weighted imaging revealed low signal areas on both sides of the injured spinal cord.The results of quantitative susceptibility mapping with ultrashort echo time sequences indicated that Ruicun-labeled mesenchymal stromal cells persisted stably within the injured spinal cord for over 4 weeks.These findings suggest that magnetic resonance imaging has the potential to effectively track the migration of Ruicun-labeled mesenchymal stromal cells and assess their ability to repair spinal cord injury.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
BACKGROUND Non-suicidal self-injury(NSSI)is common among adolescents with depressive disorders and poses a major public health challenge.Rumination,a key cognitive feature of depression,includes different subtypes tha...BACKGROUND Non-suicidal self-injury(NSSI)is common among adolescents with depressive disorders and poses a major public health challenge.Rumination,a key cognitive feature of depression,includes different subtypes that may relate to NSSI through distinct psychological mechanisms.However,how these subtypes interact with specific NSSI behaviors remains unclear.AIM To examine associations between rumination subtypes and specific NSSI behaviors in adolescents.METHODS We conducted a cross-sectional study with 305 hospitalized adolescents diagnosed with depressive disorders.The subjects ranged from 12-18 years in age.Rumi-nation subtypes were assessed using the Ruminative Response Scale,and 12 NSSI behaviors were evaluated using a validated questionnaire.Network analysis was applied to explore symptom-level associations and identify central symptoms.RESULTS The network analysis revealed close connections between rumination subtypes and NSSI behaviors.Brooding was linked to behaviors such as hitting objects and burning.Scratching emerged as the most influential NSSI symptom.Symptomfocused rumination served as a key bridge connecting rumination and NSSI.CONCLUSION Symptom-focused rumination and scratching were identified as potential intervention targets.These findings highlight the psychological significance of specific cognitive-behavioral links in adolescent depression and suggest directions for tailored prevention and treatment.However,the cross-sectional,single-site design limits causal inference and generalizability.Future longitudinal and multi-center studies are needed to confirm causal pathways and verify the generalizability of the findings to broader adolescent populations.展开更多
Myelosuppression is a common and severe side effect of cancer chemotherapy,with current treatments hindered by limitations such as depletion of hematopoietic reserves,poor patient compliance,delayed therapeutic onset,...Myelosuppression is a common and severe side effect of cancer chemotherapy,with current treatments hindered by limitations such as depletion of hematopoietic reserves,poor patient compliance,delayed therapeutic onset,and high cost.To overcome these challenges,we developed Epimedium-derived nanovesicles(ENVs)from the traditional Chinese medicinal herb Epimedium,addressing the solubility and bioavailability issues associated with conventional extracts.ENVs encapsulate bioactive constituents,including icariin and hematopoiesis-promoting ceramides.In a cyclophosphamide(CTX)-induced myelosuppression mouse model,prophylactic and therapeutic oral administration of ENVs effectively alleviated hematopoietic suppression,significantly outperforming the Epimedium-based herbal extract“Joungal”(Shengbai Formula)despite equivalent icariin content.Notably,ENVs promoted hematopoietic stem cell(HSC)proliferation—an outcome rarely achieved with existing therapies.Mechanistically,ENVs modulated the gut microbiota,enriching lactobacillus species and enhancing lactate production.This microbiota-driven lactate signaling stimulated LepR+mesenchymal stem cells(MSCs)in the bone marrow niche to secrete stromal cellderived factor-1(SDF-1)and stem cell factor(SCF),thereby supporting HSC expansion and restoring hematopoietic function.In vivo safety evaluations confirmed the excellent biocompatibility of ENVs.Our findings uncover a gut-lactate-bone marrow axis through which ENVs enhance hematopoiesis and promote HSC regeneration.This work introduces a cost-effective,scalable,and orally administrable biomaterial platform with strong translational potential for the prevention and treatment of chemotherapy-induced myelosuppression.展开更多
AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyse...AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.展开更多
BACKGROUND Major depressive disorder(MDD)and obesity(OB)are bidirectionally comorbid conditions with common neurobiological underpinnings.However,the neurocognitive mechanisms of their comorbidity remain poorly unders...BACKGROUND Major depressive disorder(MDD)and obesity(OB)are bidirectionally comorbid conditions with common neurobiological underpinnings.However,the neurocognitive mechanisms of their comorbidity remain poorly understood.AIM To examine regional abnormalities in spontaneous brain activity among patients with MDD-OB comorbidity.METHODS This study adopted a regional homogeneity(ReHo)analysis of resting-state functional magnetic resonance imaging.The study included 149 hospital patients divided into four groups:Patients experiencing their first episode of drug-naive MDD with OB,patients with MDD without OB,and age-and sex-matched healthy individuals with and without OB.Whole-brain ReHo analysis was conducted using SPM12 software and RESTplus toolkits,with group comparisons via ANOVA and post-hoc tests.Correlations between ReHo values and behavioral measures were examined.RESULTS ANOVA revealed significant whole-brain ReHo differences among the four groups in four key regions:The left middle temporal gyrus(MTG.L),right cuneus,left precuneus,and left thalamus.Post-hoc analyses confirmed pairwise differences between all groups across these regions(P<0.05).OB was associated with ReHo alterations in the MTG.L,right cuneus,and left thalamus,whereas abnormalities in the precuneus suggested synergistic pathological mechanisms between MDD and OB.Statistically significant correlations were found between the drive and fun-seeking dimensions of the behavioral activation system,as well as behavioral inhibition and the corresponding ReHo values.CONCLUSION Our findings provide novel evidence for the neuroadaptive mechanisms underlying the MDD-OB comorbidity.Further validation could lead to personalized interventions targeting MTG.L hyperactivity and targeting healthy food cues.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
Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)...Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.展开更多
Effective control of inflammatory cytokines is crucial for controlling ankylosing spondylitis(AS).However,due to the complexity of cytokine networks,current therapies targeting individual cytokines often fall short of...Effective control of inflammatory cytokines is crucial for controlling ankylosing spondylitis(AS).However,due to the complexity of cytokine networks,current therapies targeting individual cytokines often fall short of achieving satisfactory outcomes.Here,we developed mesenchymal stem cell(MSC)-like nanodecoys(denoted“MSC-NDs”)and evaluated their potential as a versatile anti-inflammatory therapeutic for AS.To improve membrane yield,microvesicles derived from MSCs via cytochalasin B(CB)stimulation were employed as substitutes for traditional membrane extractions.Proteomic analysis confirmed that CBinduced microvesicles retained a membrane protein profile comparable to that of conventionally isolated MSC membranes,while offering over twice the production efficiency.The resulting MSC-NDs effectively neutralized multiple proinflammatory cytokines and suppressed cytokine-induced osteogenic differentiation of MSCs in vitro.In a mouse model of AS,MSC-NDs significantly reduced systemic cytokine levels and effectively delayed pathological new bone formation.RNA sequencing of lumbar spine tissue further revealed widespread downregulation of genes involved in bone metabolism and inflammation.These findings underscore the therapeutic potential of MSC-like nanodecoys as a versatile anti-inflammatory platform for the treatment of AS and potentially other inflammatory disorders.展开更多
Metabolic diseases have emerged as a paramount global health threat amidst evolving lifestyles,with mechanistic investigations and therapeutic advancements impeded by the absence of physiologically relevant human expe...Metabolic diseases have emerged as a paramount global health threat amidst evolving lifestyles,with mechanistic investigations and therapeutic advancements impeded by the absence of physiologically relevant human experimental models.Organoids,self-organizing threedimensional cultures of self-renewing cells,recapitulate in vivo tissue architecture and function by spontaneously forming structures analogous to native organs.Notably,this technology has demonstrated transformative utility across diverse biomedical fields,including disease modeling,developmental biology,regenerative medicine,and precision oncology,garnering substantial attention as a nextgeneration biological platform.In this review,we summarize recent progress in organoid-based metabolic monitoring and the generation of metabolic disease-associated organoids,detailing their construction methodologies and research milestones.We further discuss the current challenges and the future opportunities of the development and application of organoid technology in metabolic research.展开更多
This study addresses the intractable“infectioninflammation-injury”vicious cycle in MRSA pneumonia therapy.We have designed a glycosylated mesoporous polydopamine nanoaerosols(MPDA/B@M),which achieves effective treat...This study addresses the intractable“infectioninflammation-injury”vicious cycle in MRSA pneumonia therapy.We have designed a glycosylated mesoporous polydopamine nanoaerosols(MPDA/B@M),which achieves effective treatment of MRSA infected pneumonia through multi mechanism synergistic effects.The aerosol encapsulates bufalin,an active component of traditional Chinese medicine,within MPDA carriers.Surface modification with mannose enables macrophage-targeted delivery.Upon inhalation,the aerosol accumulates efficiently in pulmonary lesions,directly killing pathogens via photothermal effects while releasing bufalin to suppress inflammation.Furthermore,MPDA/B@M scavenges excess reactive oxygen species(ROS)and upregulates heat shock protein 70(HSP70)expression,providing dual cell-protective and antiinflammatory effects.In vitro and in vivo studies demonstrate that MPDA/B@M nanoaerosols achieves 98.2%antibacterial efficacy against MRSA.In MRSA-infected murine pneumonia models,it significantly reduces pulmonary bacterial loads and reprograms macrophage phenotypes to modulate inflammatory responses.This integrated strategy synergizes targeted delivery,antibacterial action,oxidative stress modulation,and anti-inflammatory effects,offering an innovative solution for drug-resistant bacterial pneumonia.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
The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR...The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR.However,their clinical translation is hindered by their inherently low immunogenicity,often requiring potent adjuvants and advanced delivery systems.Biomembrane nanostructures(e.g.,liposomes,exosomes,and cell membrane-derived nanostructures),characterized by superior biocompatibility,intrinsic targeting ability,and immune-modulating properties,could serve as versatile platforms that potentiate vaccine efficacy by increasing antigen stability,enabling codelivery of immunostimulants,and facilitating targeted delivery to lymphoid tissues/antigen-presenting cells.This intrinsic immunomodulation promotes robust humoral and cellular immune responses to combat bacteria.This review critically reviews(1)key biomembrane nanostructure classes for bacterial protein antigens,(2)design strategies leveraging biomembrane nanostructures to enhance humoral and cellular immune responses,(3)preclinical efficacy against diverse pathogens,and(4)translational challenges and prospects.Biomembrane nanostructure-driven approaches represent a paradigm shift in the development of next-generation bacterial protein vaccines against resistant infections.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82172196(to KX),82372507(to KX)the Natural Science Foundation of Hunan Province,China,No.2023JJ40804(to QZ)the Key Laboratory of Emergency and Trauma(Hainan Medical University)of the Ministry of Education,China,No.KLET-202210(to QZ)。
文摘Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.
基金supported by the National Natural Science Foundation of China,Nos.82371310(to YJ),82271306(to JP)the Sichuan Science and Technology Support Program,Nos.2023YFH0069(to JP),2023NSFSC0028(to YJ),2023NSFSC1559(to YJ),2022YFS0615(to JP),2022NSFSC1421(to JP)+1 种基金Scientific Research Project of Sichuan Provincial Health Commission,No.23LCYJ040(to YJ)Youth Foundation of Southwestern Medical University and Southwest Medical University Project,Nos.2020ZRQNA038(to JP),2021ZKZD013(to JP),2021LZXNYD-P01(to YJ),2023QN014(to JP).
文摘Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
基金supported by grants from the Major Projects of Health Science Research Foundation for Middle-Aged and Young Scientist of Fujian Province,China,No.2022ZQNZD01010010the National Natural Science Foundation of China,No.82371390Fujian Province Scientific Foundation,No.2023J01725(all to XC).
文摘The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.
基金supported by National Natural Science Foundation of China(Grant No.81900873 to A.Q.)the Jiangsu Provincial Key Research and Development Programme-social development(Grant No.BE2023777 to W.Z.)+1 种基金the Key Medical Research Project of Jiangsu Commission of Health(Grant No.H2022185 to W.Z.)the Clinical Capacity Enhancement Project of Jiangsu Province Hospital(Grant No.JSPH-MB-2023-18 to W.Z.)。
文摘Diabetic retinopathy(DR),a common complication of diabetes,is characterized by retinal angiogenesis and inflammation.The role of hepatoma-derived growth factor(HDGF)in mediating inflammation during DR remains unclear.We measured HDGF levels in the aqueous humor and found that HDGF was increased in DR but decreased after anti-angiogenesis treatment.Using public single-cell RNA sequencing datasets,we found that elevated HDGF in DR was mainly produced by Müller cells and targeted microglia.Additionally,integrin beta 2(Itgb2),a target gene of HDGF that induces microglial activation,was significantly upregulated in DR.To verify these results,we performed enzyme-linked immunosorbent assays,quantitative reverse transcription-PCR,Western blotting,and fluorescence immunostaining in cultured Müller and microglial cells treated with HDGF or anti-HDGF,as well as in DR mice receiving intravitreal injections of HDGF or its antibody.Exogenous HDGF further promoted microglial activation,migration,and secretion of pro-inflammatory cytokines,while neutralization of HDGF suppressed these effects caused by high glucose.Furthermore,the HDGF receptor nucleolin was overexpressed in microglia under high glucose stimulation.Therefore,blocking HDGF from Müller cells in DR reduced the excessive inflammatory response in microglia,highlighting HDGF as a potential therapeutic target.
基金Supported by the Guangdong Provincial Natural Science Foundation(No.2114050001527).
文摘Micro/nanoplastics(M/NPs)have become pervasive environmental pollutants,posing significant risks to human health through various exposure routes,including ingestion,inhalation,and direct contact.This review systematically examined the potential impacts of M/NPs on ocular health,focusing on exposure pathways,toxicological mechanisms,and resultant damage to the eye.Ocular exposure to M/NPs can occur via direct contact and oral ingestion,with the latter potentially leading to the penetration of particles through ocular biological barriers into ocular tissues.The review highlighted that M/NPs can induce adverse effects on the ocular surface,elevate intraocular pressure,and cause abnormalities in the vitreous and retina.Mechanistically,oxidative stress and inflammation are central to M/NP-induced ocular damage,with smaller particles often exhibiting greater toxicity.Overall,this review underscored the potential risks of M/NPs to ocular health and emphasized the need for further research to elucidate exposure mechanisms,toxicological pathways,and mitigation strategies.
文摘BACKGROUND Perimenopausal women are prone to anxiety and depression due to fluctuating hormone levels,which significantly impair their quality of life.The current treatments have certain limitations.In traditional Chinese medicine,liver-soothing formulas are commonly prescribed for mood-related disorders,but their overall efficacy in perimenopausal anxiety and depression remains uncertain and requires verification through meta-analysis.AIM To provide evidence-based support for clinical decision-making and research,a meta-analysis was conducted to evaluate the effectiveness of liver-soothing formulas in treating perimenopausal anxiety and depression.METHODS Relevant studies published up to April 2025 were retrieved from ClinicalTrials.gov,PubMed,Web of Science,EMBASE,and the Cochrane Library.Eligible studies were screened according to predefined inclusion and exclusion criteria.Data were extracted and analyzed using the Stata 12.0 software.RESULTS After searching and screening,12 articles involving 1798 patients(922 in the treatment group and 876 in the control group)were included in the analysis.Meta-analysis showed that the standardized scores for anxiety[standardized mean difference(SMD)=-0.71,95%confidence interval(95%CI):-1.06 to-0.36]and depression(SMD=-0.67,95%CI:-1.06 to-0.27)of the treatment group were lower than those of the control group.Subgroup analysis results revealed that for anxiety,liver-soothing formulas used alone(SMD=-0.34,95%CI:-0.50 to-0.18)or in combination(SMD=-0.88,95%CI:-1.43 to-0.34)both significantly reduced scores compared with the control group.For depression,monotherapy of liversoothing formulas showed no significant statistical difference between the treatment and control groups(SMD=-0.47,95%CI:-1.11 to 0.17),whereas combination therapy produced significantly lower standardized scale scores in the treatment group than in the control group,with a statistically significant difference(SMD=-0.83,95%CI:-1.39 to-0.28).Regarding Greene scores,no statistically significant difference was observed with monotherapy(SMD=0.87,95%CI:-0.32 to 2.06),whereas combination therapy had significantly lower Greene scores(SMD=-0.24,95%CI:-0.44 to-0.04).No statistically significant difference was found between the groups in the occurrence of adverse reactions(odds ratio=0.90,95%CI:0.57-1.43).However,liver-soothing formulas did not affect estrogen levels in perimenopausal women.CONCLUSION Compared with placebo,conventional Western medicine,or other interventions,the monotherapy of liver-soothing formulas demonstrates superior efficacy in treating perimenopausal anxiety.When used as an adjuvant,they exert a synergistic effect in alleviating negative emotions and improving overall perimenopausal symptoms.
基金supported by the National Key R&D Program of China,Nos.2017YFA0104302(to NG and XM)and 2017YFA0104304(to BW and ZZ)
文摘Mesenchymal stromal cell transplantation is an effective and promising approach for treating various systemic and diffuse diseases.However,the biological characteristics of transplanted mesenchymal stromal cells in humans remain unclear,including cell viability,distribution,migration,and fate.Conventional cell tracing methods cannot be used in the clinic.The use of superparamagnetic iron oxide nanoparticles as contrast agents allows for the observation of transplanted cells using magnetic resonance imaging.In 2016,the National Medical Products Administration of China approved a new superparamagnetic iron oxide nanoparticle,Ruicun,for use as a contrast agent in clinical trials.In the present study,an acute hemi-transection spinal cord injury model was established in beagle dogs.The injury was then treated by transplantation of Ruicun-labeled mesenchymal stromal cells.The results indicated that Ruicunlabeled mesenchymal stromal cells repaired damaged spinal cord fibers and partially restored neurological function in animals with acute spinal cord injury.T2*-weighted imaging revealed low signal areas on both sides of the injured spinal cord.The results of quantitative susceptibility mapping with ultrashort echo time sequences indicated that Ruicun-labeled mesenchymal stromal cells persisted stably within the injured spinal cord for over 4 weeks.These findings suggest that magnetic resonance imaging has the potential to effectively track the migration of Ruicun-labeled mesenchymal stromal cells and assess their ability to repair spinal cord injury.
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.
基金Supported by Key Research and Development Program of Shaanxi Province,China,No.2024SF-YBXM-078.
文摘BACKGROUND Non-suicidal self-injury(NSSI)is common among adolescents with depressive disorders and poses a major public health challenge.Rumination,a key cognitive feature of depression,includes different subtypes that may relate to NSSI through distinct psychological mechanisms.However,how these subtypes interact with specific NSSI behaviors remains unclear.AIM To examine associations between rumination subtypes and specific NSSI behaviors in adolescents.METHODS We conducted a cross-sectional study with 305 hospitalized adolescents diagnosed with depressive disorders.The subjects ranged from 12-18 years in age.Rumi-nation subtypes were assessed using the Ruminative Response Scale,and 12 NSSI behaviors were evaluated using a validated questionnaire.Network analysis was applied to explore symptom-level associations and identify central symptoms.RESULTS The network analysis revealed close connections between rumination subtypes and NSSI behaviors.Brooding was linked to behaviors such as hitting objects and burning.Scratching emerged as the most influential NSSI symptom.Symptomfocused rumination served as a key bridge connecting rumination and NSSI.CONCLUSION Symptom-focused rumination and scratching were identified as potential intervention targets.These findings highlight the psychological significance of specific cognitive-behavioral links in adolescent depression and suggest directions for tailored prevention and treatment.However,the cross-sectional,single-site design limits causal inference and generalizability.Future longitudinal and multi-center studies are needed to confirm causal pathways and verify the generalizability of the findings to broader adolescent populations.
基金supported by National Natural Science Foundation of China(Nos.82104445 and 82470182]Basic Scientific Research Funds of Department of Education of Zhejiang Province(No.KYZD2024013)+2 种基金The Startup Foundation of Zhejiang Provincial People’s Hospital(Nos.C-2023-QDJJ12 and C-2024-ZZJJ05)Science and Technology Plan Project of Traditional Chinese Medicine in Zhejiang Province(No.2025ZR007)The National Administration of Traditional Chinese Medicine(No.GZY-ZJ-KJ-24044).
文摘Myelosuppression is a common and severe side effect of cancer chemotherapy,with current treatments hindered by limitations such as depletion of hematopoietic reserves,poor patient compliance,delayed therapeutic onset,and high cost.To overcome these challenges,we developed Epimedium-derived nanovesicles(ENVs)from the traditional Chinese medicinal herb Epimedium,addressing the solubility and bioavailability issues associated with conventional extracts.ENVs encapsulate bioactive constituents,including icariin and hematopoiesis-promoting ceramides.In a cyclophosphamide(CTX)-induced myelosuppression mouse model,prophylactic and therapeutic oral administration of ENVs effectively alleviated hematopoietic suppression,significantly outperforming the Epimedium-based herbal extract“Joungal”(Shengbai Formula)despite equivalent icariin content.Notably,ENVs promoted hematopoietic stem cell(HSC)proliferation—an outcome rarely achieved with existing therapies.Mechanistically,ENVs modulated the gut microbiota,enriching lactobacillus species and enhancing lactate production.This microbiota-driven lactate signaling stimulated LepR+mesenchymal stem cells(MSCs)in the bone marrow niche to secrete stromal cellderived factor-1(SDF-1)and stem cell factor(SCF),thereby supporting HSC expansion and restoring hematopoietic function.In vivo safety evaluations confirmed the excellent biocompatibility of ENVs.Our findings uncover a gut-lactate-bone marrow axis through which ENVs enhance hematopoiesis and promote HSC regeneration.This work introduces a cost-effective,scalable,and orally administrable biomaterial platform with strong translational potential for the prevention and treatment of chemotherapy-induced myelosuppression.
文摘AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.
基金Supported by Provincial Key Research Project of Henan Province,No.232102310081.
文摘BACKGROUND Major depressive disorder(MDD)and obesity(OB)are bidirectionally comorbid conditions with common neurobiological underpinnings.However,the neurocognitive mechanisms of their comorbidity remain poorly understood.AIM To examine regional abnormalities in spontaneous brain activity among patients with MDD-OB comorbidity.METHODS This study adopted a regional homogeneity(ReHo)analysis of resting-state functional magnetic resonance imaging.The study included 149 hospital patients divided into four groups:Patients experiencing their first episode of drug-naive MDD with OB,patients with MDD without OB,and age-and sex-matched healthy individuals with and without OB.Whole-brain ReHo analysis was conducted using SPM12 software and RESTplus toolkits,with group comparisons via ANOVA and post-hoc tests.Correlations between ReHo values and behavioral measures were examined.RESULTS ANOVA revealed significant whole-brain ReHo differences among the four groups in four key regions:The left middle temporal gyrus(MTG.L),right cuneus,left precuneus,and left thalamus.Post-hoc analyses confirmed pairwise differences between all groups across these regions(P<0.05).OB was associated with ReHo alterations in the MTG.L,right cuneus,and left thalamus,whereas abnormalities in the precuneus suggested synergistic pathological mechanisms between MDD and OB.Statistically significant correlations were found between the drive and fun-seeking dimensions of the behavioral activation system,as well as behavioral inhibition and the corresponding ReHo values.CONCLUSION Our findings provide novel evidence for the neuroadaptive mechanisms underlying the MDD-OB comorbidity.Further validation could lead to personalized interventions targeting MTG.L hyperactivity and targeting healthy food cues.
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 Guangdong Province Basic and Applied Basic Research Fund Project(2023A1515220104)Open Fund of Key Laboratory of Hepatoaplenic Surgery,Ministry of Education(Award Number:GPKF202407).
文摘Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.
基金supported by funding from the Science and Technology Planning Project of Guangdong Province(No.2023B1111030002)the Guangdong Clinical Research Center of Immune disease(No.2020B1111170008).
文摘Effective control of inflammatory cytokines is crucial for controlling ankylosing spondylitis(AS).However,due to the complexity of cytokine networks,current therapies targeting individual cytokines often fall short of achieving satisfactory outcomes.Here,we developed mesenchymal stem cell(MSC)-like nanodecoys(denoted“MSC-NDs”)and evaluated their potential as a versatile anti-inflammatory therapeutic for AS.To improve membrane yield,microvesicles derived from MSCs via cytochalasin B(CB)stimulation were employed as substitutes for traditional membrane extractions.Proteomic analysis confirmed that CBinduced microvesicles retained a membrane protein profile comparable to that of conventionally isolated MSC membranes,while offering over twice the production efficiency.The resulting MSC-NDs effectively neutralized multiple proinflammatory cytokines and suppressed cytokine-induced osteogenic differentiation of MSCs in vitro.In a mouse model of AS,MSC-NDs significantly reduced systemic cytokine levels and effectively delayed pathological new bone formation.RNA sequencing of lumbar spine tissue further revealed widespread downregulation of genes involved in bone metabolism and inflammation.These findings underscore the therapeutic potential of MSC-like nanodecoys as a versatile anti-inflammatory platform for the treatment of AS and potentially other inflammatory disorders.
基金supported by grants from the National Natural Science Foundation of China(No.32170561)the Natural Science Foundation of Jiangsu Province(No.BK20241935)+2 种基金Natural Science Foundation of Jiangsu Province(No.BK20241838)Jiangsu Provincial Medical Key Discipline Cultivation Unit(No.BK20241838)Jiangsu Provincial Research Hospital(No.YJXYY202204).
文摘Metabolic diseases have emerged as a paramount global health threat amidst evolving lifestyles,with mechanistic investigations and therapeutic advancements impeded by the absence of physiologically relevant human experimental models.Organoids,self-organizing threedimensional cultures of self-renewing cells,recapitulate in vivo tissue architecture and function by spontaneously forming structures analogous to native organs.Notably,this technology has demonstrated transformative utility across diverse biomedical fields,including disease modeling,developmental biology,regenerative medicine,and precision oncology,garnering substantial attention as a nextgeneration biological platform.In this review,we summarize recent progress in organoid-based metabolic monitoring and the generation of metabolic disease-associated organoids,detailing their construction methodologies and research milestones.We further discuss the current challenges and the future opportunities of the development and application of organoid technology in metabolic research.
基金supported by the National Natural Science Foundation of China(No.22173029)the Natural Science Foundation of Nantong Municipal Science and Technology Bureau(No.JC2024011)+2 种基金Excellent Young and Middle-aged Science and Technology Innovation Team Program of Universities in Hubei Province(No.T2024014)the Talent Introduction Project of Hubei Normal University(No.HS2023RC078)the Open Research Fund of Hubei Key Laboratory of Pollutant Analysis&Reuse Technology(No.PA230213).
文摘This study addresses the intractable“infectioninflammation-injury”vicious cycle in MRSA pneumonia therapy.We have designed a glycosylated mesoporous polydopamine nanoaerosols(MPDA/B@M),which achieves effective treatment of MRSA infected pneumonia through multi mechanism synergistic effects.The aerosol encapsulates bufalin,an active component of traditional Chinese medicine,within MPDA carriers.Surface modification with mannose enables macrophage-targeted delivery.Upon inhalation,the aerosol accumulates efficiently in pulmonary lesions,directly killing pathogens via photothermal effects while releasing bufalin to suppress inflammation.Furthermore,MPDA/B@M scavenges excess reactive oxygen species(ROS)and upregulates heat shock protein 70(HSP70)expression,providing dual cell-protective and antiinflammatory effects.In vitro and in vivo studies demonstrate that MPDA/B@M nanoaerosols achieves 98.2%antibacterial efficacy against MRSA.In MRSA-infected murine pneumonia models,it significantly reduces pulmonary bacterial loads and reprograms macrophage phenotypes to modulate inflammatory responses.This integrated strategy synergizes targeted delivery,antibacterial action,oxidative stress modulation,and anti-inflammatory effects,offering an innovative solution for drug-resistant bacterial pneumonia.
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the National Natural Science Foundation of China(82573571)the Shanghai 2025 Basic Research Plan Natural Science Foundation(25ZR1401393)the First Batch of Open Topics of the Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices(2025QN13)。
文摘The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR.However,their clinical translation is hindered by their inherently low immunogenicity,often requiring potent adjuvants and advanced delivery systems.Biomembrane nanostructures(e.g.,liposomes,exosomes,and cell membrane-derived nanostructures),characterized by superior biocompatibility,intrinsic targeting ability,and immune-modulating properties,could serve as versatile platforms that potentiate vaccine efficacy by increasing antigen stability,enabling codelivery of immunostimulants,and facilitating targeted delivery to lymphoid tissues/antigen-presenting cells.This intrinsic immunomodulation promotes robust humoral and cellular immune responses to combat bacteria.This review critically reviews(1)key biomembrane nanostructure classes for bacterial protein antigens,(2)design strategies leveraging biomembrane nanostructures to enhance humoral and cellular immune responses,(3)preclinical efficacy against diverse pathogens,and(4)translational challenges and prospects.Biomembrane nanostructure-driven approaches represent a paradigm shift in the development of next-generation bacterial protein vaccines against resistant infections.
