Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important...Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important regulator of cellular stress responses and has been confirmed to play a critical role in the occurrence of various diseases.However,the mechanisms by which hypoxia-inducible factor 1αis related to epilepsy and neuronal ferroptosis remain unclear.In this study,we used a pentylentetrazole-induced chronic epilepsy mouse model and treated the mice with intraperitoneal administration of PX-478,a hypoxia-inducible factor-1αinhibitor.Our results showed that PX-478 significantly prolonged the latency of epilepsy,reduced seizure severity,and shortened seizure duration.PX-478 also alleviated neuronal damage in the hippocampal CA1 and CA2 regions,reduced levels of reactive oxygen species and malondialdehyde,and increased levels of superoxide dismutase,catalase,and glutathione peroxidase.Transmission electron microscopy showed that PX-478 treatment reduced mitochondrial damage in the hippocampal neurons of epileptic mice,and significantly improved mitochondrial length and area.Additionally,PX-478 preferentially reduced Fe^(2+)levels and the expression of cyclooxygenase-2,ferritin heavy chain 1 and transferrin in the hippocampus of epileptic mice.It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway.In summary,these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway,alleviating oxidative stress,and reducing ferroptosis in hippocampal neurons.展开更多
Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury respons...Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury response,including inflammation and repair.Although colony-stimulating factor 1 receptor inhibitors such as PLX5622 enable the selective depletion of microglia,their therapeutic potential in neonatal germinal matrix hemorrhage remains underexplored.Here,we used a collagenase-induced germinal matrix hemorrhage model in postnatal day 5 mice,and intraperitoneally administered PLX562272 hours post-germinal matrix hemorrhage to achieve targeted,temporary microglial depletion during the peak injury response.We then assessed the effects of this delayed intervention on oligodendrocyte lineage cell maturation,white matter integrity,and neurobehavioral outcomes.Additionally,RNA sequencing data from a germinal matrix hemorrhage rat model were analyzed using weighted gene co-expression network analysis to identify the critical phases for interventions.RNA sequencing data revealed a critical period in which key synaptic functions declined while immune responses intensified post-germinal matrix hemorrhage,thus pinpointing the critical response phases for potential interventions.Delayed PLX5622 treatment effectively depleted activated microglia,protecting against white matter injury and enhancing oligodendrocyte lineage cell maturation and myelination in subcortical white matter regions.Moreover,magnetic resonance imaging analysis revealed reduced brain lesion volumes in treated mice.Behaviorally,PLX5622-treated mice exhibited significant improvements in motor coordination and reduced hyperactivity compared with vehicle-treated germinal matrix hemorrhage model mice.These findings suggest that,when timed to avoid interference with initial oligodendrocyte lineage cell proliferation,targeted microglial depletion with PLX5622 significantly mitigates white matter damage and improves neurobehavioral outcomes in neonatal germinal matrix hemorrhage.The present study highlights the therapeutic potential of selectively modulating microglial reactivity to support neurodevelopment in preterm infants with brain injury.展开更多
Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genoty...Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[OR_(MEARDS)]=0.84,P=0.008;OR_(MESSI)=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10^(-4)),and improved overall survival in ARDS patients(hazard ratio[HR_(28-day)]=0.49,P=0.009)and sepsis patients(HR_(28-day)=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.展开更多
Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of...Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of interferon regulatory factor 1 in myasthenia gravis,with an aim to understand the underlying mechanisms.Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study.Peripheral blood lymphocytes were extracted from the included patients,and B lymphocyte subsets were isolated.Next,T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis.Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region.Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter.In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180.Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription.Additionally,histone deacetylase 1 promoted B cell activation and T cell differentiation.Finally,in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Collectively,our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Together,these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms.They also provide new ideas and targets for diagnosing and treating myasthenia gravis,which will be both scientifically and clinically valuable.展开更多
Objective:MicroRNAs(miRNAs)are small,non-coding RNAs that play a key role in the development of chemoresistance in various cancer types,including colorectal cancer(CRC).In this study,we aimed to study the underlying m...Objective:MicroRNAs(miRNAs)are small,non-coding RNAs that play a key role in the development of chemoresistance in various cancer types,including colorectal cancer(CRC).In this study,we aimed to study the underlying mechanisms of miRNA in chemotherapy-resistant CRC.Methods:LoVo CRC cell line was exposed to oxaliplatin at an increased dose,and cells were cultured in the presence of oxaliplatin to develop LoVo^(OXR) cells.Microarray and Quantitative Reverse Transcription Polymerase Chain Reaction(qRT-PCR),western blot,and transwell assay were used to evaluate the chemoresistance in LoVo^(OXR) CRC cells.Results:Microarray and qRT-PCR analysis showed an increased expression of miR-100-5p in LoVo^(OXR) cells.MTT assay and flow cytometry analysis revealed less apoptosis and higher cell viability in LoVo^(OXR) cells.mRNA prediction target gene analysis showed C-terminal domain small phosphatase-like(CTDSPL),a phosphatase-like tumor suppressor,as a key target of miR-100-5p.CTDSPL expression was low in LoVo^(OXR) cells compared to LoVoWT cells.miR-100-5p regulates G1/S and S-phase transitions and inhibits differentiation by targeting the CTDSPL/pRB/E2F1 signaling pathway,which involves the modulation of cell cycle effectors in LoVo^(OXR) cells.Further,we found that forkhead box P3(FOXP3),as the upstream target of miR-100-5p,is highly expressed in LoVo^(OXR) cells.Inhibiting miR-100-5p and FOXP3 down-regulates miR-100-5p expression,while increased CTDSPL expression contributed to reduced cell proliferation and promoted cell apoptosis in LoVo^(OXR) CRC cells.Conclusions:miR-100-5p plays an oncogenic role in inducing chemoresistance through modulation of the CTDSPL/retinoblastoma protein(pRB)/E2F transcription factor 1(E2F1)axis in CRC cells.展开更多
Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study invest...Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer(HSPC)through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.Methods:HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation,invasion,migration,and epithelial-mesenchymal transition.Xenograft assays,bioinformatic screening,and analyses of O-GlcNAcylation and protein stability were performed,together with quantitative polymerase chain reaction(qPCR)and Western blotting.Results:ONX-0914 markedly suppressed hormone-sensitive prostate cancer(HSPC)progression through both LMP7-dependent and LMP7-independent mechanisms.Mechanistically,ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation,leading to stabilization of the transcriptional repressor Transcription factor 7-like 1(TCF7L1)and consequent suppression of androgen receptor(AR)expression.Functionally,activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation,invasion,migration,and epithelial-mesenchymal transition in vitro.In vivo,TCF7L1 overexpression,particularly under conditions of enhanced O-GlcNAcylation,significantly suppressed tumor growth and AR expression.Conclusion:This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1,leading to repression of AR signaling and inhibition of HSPC progression.These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.展开更多
Background:To investigate SCL/TAL 1 interrupting locus(STIL)’s role and prognostic significance in lung adenocarcinoma(LUAD)progression,we examined STIL and E2 promoter binding factor 1(E2F1)expression and their impa...Background:To investigate SCL/TAL 1 interrupting locus(STIL)’s role and prognostic significance in lung adenocarcinoma(LUAD)progression,we examined STIL and E2 promoter binding factor 1(E2F1)expression and their impacts on LUAD prognosis using Gene Expression Profiling Interactive Analysis(GEPIA).Methods:Functional assays including CCK-8,wound-healing,5-ethynyl-2-deoxyuridine(EdU),Transwell assays,and flow cytometry,elucidated STIL and E2F1’s effects on cell viability,proliferation,apoptosis,and migration.Gene set enrichment analysis(GSEA)identified potential pathways,while metabolic assays assessed glucose metabolism.Results:Our findings reveal that STIL and E2F1 are overexpressed in LUAD,correlating with adverse outcomes.It enhances cell proliferation,migration,and invasion,and suppresses apoptosis,activating downstream of E2F1.Silencing E2F1 reversed the promotion effect of the STIL overexpression on cell viability and invasiveness.Importantly,STIL modulates glycolysis,influencing glucose consumption,lactate production,and energy balance in LUAD cells.Conclusion:Our model,incorporating STIL,age,and disease stage,robustly predicts patient prognosis,underscored STIL’s pivotal role in LUAD pathogenesis through metabolic reprogramming.This comprehensive approach not only confirms STIL’s prognostic value but also highlights its potential as a therapeutic target in LUAD.展开更多
Objective:Baicalein has been reported to have wide therapeutic effects that act through its antiinflammatory activity.This study examines the effect and mechanism of baicalein on sepsis-induced cardiomyopathy(SIC).Met...Objective:Baicalein has been reported to have wide therapeutic effects that act through its antiinflammatory activity.This study examines the effect and mechanism of baicalein on sepsis-induced cardiomyopathy(SIC).Methods:A thorough screening of a small library of natural products,comprising 100 diverse compounds,was conducted to identify the most effective drug against lipopolysaccharide(LPS)-treated H9C2 cardiomyocytes.The core target proteins and their associated signaling pathways involved in baicalein's efficacy against LPS-induced myocardial injury were predicted by network pharmacology.Results:Baicalein was identified as the most potent protective agent in LPS-exposed H9C2 cardiomyocytes.It exhibited a dose-dependent inhibitory effect on cell injury and inflammation.In the LPSinduced septic mouse model,baicalein demonstrated a significant capacity to mitigate LPS-triggered myocardial deficits,inflammatory responses,and ferroptosis.Network pharmacological analysis and experimental confirmation suggested that hypoxia-inducible factor 1 subunit a(HIF1-a)is likely to be the crucial factor in mediating the impact of baicalein against LPS-induced myocardial ferroptosis and injury.By combining microRNA(miRNA)screening in LPS-treated myocardium with miRNA prediction targeting HIF1-a,we found that miR-299b-5p may serve as a regulator of HIF1-a.The reduction in miR-299b-5p levels in LPS-treated myocardium,compared to the control group,was reversed by baicalein treatment.The reverse transcription quantitative polymerase chain reaction,Western blotting,and dual-luciferase reporter gene analyses together identified HIF1-a as the target of miR-299b-5p in cardiomyocytes.Conclusion:Baicalein mitigates SIC at the miRNA level,suggesting the therapeutic potential of it in treating SIC through the regulation of miR-299b-5p/HIF1-a/ferroptosis pathway.展开更多
BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental...BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental factors.Despite recent therapeutic advances,survival rates remain dismal,underscoring an urgent need for novel therapeutic targets.AIM To investigate the role of hypoxia-inducible factor 1-alpha(HIF1A)in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A(LDHA),which is crucial for the glycolytic pathway in hypoxic tumor environments.METHODS Utilizing transcriptomic data from multiple public databases,we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses.The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines.RESULTS Our findings reveal a significant upregulation of HIF1A in ESCC tissues,associated with poor prognosis.HIF1A directly regulates LDHA,enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness.Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis.CONCLUSION The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target,underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.展开更多
OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen a...OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen and kidney Yang deficiency.METHODS:A total of 100 patients diagnosed with advanced colorectal cancer were randomly divided into two groups:a control group(CON,50)and a Traditional Chinese Medicine(TCM)group(n=50).The control group received treatment with the Capecitabine+Oxaliplatin(CAPEOX)regimen,while the TCM group received the same regimen along with Fuzi Lizhong decoction for six weeks.Changes in intestinal flora were assessed before and after six weeks in both groups.Serum markers,including HIF-1α,vascular endothelial growth factor(VEGF),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α),were measured using enzyme-linked immunosorbent assay.Adverse reactions,clinical efficacy,and TCM syndrome efficacy were also monitored.RESULTS:After six weeks,the levels of Lactobacillus and Bifidobacterium were significantly higher,while the levels of Enterobacter and Enterococcus were significantly lower in the TCM group compared to the control group(P<0.05).Serum levels of HIF-1α,VEGF,IL-6,and TNF-αwere also significantly reduced in the TCM group compared to the control group(P<0.05).Additionally,the incidence of adverse reactions was lower,and the clinical efficacy was higher in the TCM group compared to the control group(P<0.05).CONCLUSION:Fuzi Lizhong decoction effectively improves intestinal microbiota composition,reduces inflammatory factors and HIF-1αexpression,alleviates chemotherapy-related adverse reactions,enhances clinical efficacy,and may inhibit tumor growth in patients with colorectal cancer.展开更多
BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essenti...BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essential to explore novel therapeutic strategies.Curcumol,a sesquiterpenoid derived from traditional Chinese medicine,has shown anti-inflammatory and anti-cancer properties,but its potential role in DR remains unclear.AIM To investigate the therapeutic effects of curcumol on the progression of DR and to elucidate the underlying molecular mechanisms,particularly its impact on the fat mass and obesity-associated(FTO)protein and the long non-coding RNA(lncRNA)MAF transcription factor G antisense RNA 1(MAFG-AS1).METHODS A streptozotocin-induced mouse model of DR was established,followed by treatment with curcumol.Retinal damage and inflammation were evaluated through histological analysis and molecular assays.Human retinal vascular endothelial cells were exposed to high glucose conditions to simulate diabetic environments in vitro.Cell proliferation,migration,and inflammation markers were assessed in curcumoltreated cells.LncRNA microarray analysis identified key molecules regulated by curcumol,and further experiments were conducted to confirm the involvement of FTO and MAFG-AS1 in the progression of DR.RESULTS Curcumol treatment significantly reduced blood glucose levels and alleviated retinal damage in streptozotocininduced DR mouse models.In high-glucose-treated human retinal vascular endothelial cells,curcumol inhibited cell proliferation,migration,and inflammatory responses.LncRNA microarray analysis identified MAFG-AS1 as the most upregulated lncRNA following curcumol treatment.Mechanistically,FTO demethylated MAFG-AS1,stabilizing its expression.Rescue experiments demonstrated that the protective effects of curcumol against DR were mediated through the FTO/MAFG-AS1 signaling pathway.CONCLUSION Curcumol ameliorates the progression of DR by modulating the FTO/MAFG-AS1 axis,providing a novel therapeutic pathway for the treatment of DR.These findings suggest that curcumol-based therapies could offer a promising alternative for managing this debilitating complication of diabetes.展开更多
Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.S...Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.Skeletal muscle,as a major metabolic organ system,undergoes significant remodeling during ALI.However,its specific regulatory contributions remain largely uncharacterized.Methods:Partial(2/3)hepatectomy and acetaminophen were used to induce ALI in male mice.RNA-sequencing(RNA-seq),assay for transposase-accessible chromatin by sequencing(ATAC-seq),chromatin immunoprecipitation,luciferase assay,Western blotting,TUNEL assay,immunohistochemistry,and phase separation assays were performed to reveal the transcriptional axis involved.Serum fibroblast growth factor binding protein 1(FGFBP1)protein levels in ALI patients were assessed via enzyme-linked immunosorbent assay.Results:Integrated analysis of RNA-seq and ATAC-seq following ALI identifies glucocorticoid(GC)signaling-mediated regulation of fibroblast growth factor 6(FGF6)in skeletal muscle metabolism.Muscle-specific knockdown of GC receptor(GR)exacerbates ALI and suppresses liver regeneration.Fgf6-knockout mice exhibited improved ALI and enhanced liver regeneration,with intramuscular injection of FGF6-neutralizing antibody rescuing the detrimental effects induced by GR knockdown.Further analysis of the FGF6 downstream target revealed that FGF6 regulates FGFBP1 expression through extracellular signal regulated kinase-activating transcription factor 3 signaling.Moreover,FGF6 regulates the heparin-dependent release kinetics of FGFBP1 by perturbing its liquid-liquid phase separation(LLPS)-driven condensate dynamics at the plasma membrane.Circulating FGFBP1 subsequently interacts with hepatic FGF5 through LLPS mechanisms to regulate liver regeneration.Conclusion:Our results demonstrate a molecular mechanism by which muscle-liver crosstalk can initiate and sustain liver regeneration via the FGF6-FGFBP1/FGF5 axis,providing a potential therapeutic target and treatment strategy for ALI.展开更多
The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing ...The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species(ROS)levels.Clinical trials have demonstrated that Zhongfeng Xingnao Liquid(ZFXN)ameliorates post-stroke cognitive impairment(PSCI).However,the underlying mechanism,particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway,remains unclear.This study employed an oxygen-glucose deprivation(OGD)cell model using SHSY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation(2VO).The effects of ZFXN on learning and memory,neuroprotective activity,mitochondrial function,oxidative stress,and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro.Results indicated that ZFXN significantly increased the B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)ratio,reduced terminal deoxynucleotidyl transferase-mediated d UTP nickend-labeling(TUNEL)+cells,and markedly improved cognition,synaptic plasticity,and neuronal function in the hippocampus and cortex.Furthermore,ZFXN exhibited potent antioxidant activity,evidenced by decreased ROS and malondialdehyde(MDA)content and increased superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)levels.ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential(MMP),Tom 20 fluorescence intensity,adenosine triphosphate(ATP)and energy charge(EC)levels,and mitochondrial complexⅠandⅢactivity,thereby inhibiting mitochondrial damage.Additionally,ZFXN significantly increased SIRT1 activity and elevated SIRT1,nuclear Nrf2,and HO-1 levels.Notably,these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro.In conclusion,ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.展开更多
A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide,including conditions such as non-alcoholic fatty liver disease,alcoho...A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide,including conditions such as non-alcoholic fatty liver disease,alcoholic liver injury,viral hepatitis,hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.The underlying pathogenic mechanisms are multifactorial,encompassing oxidative stress,inflammatory cascades,mitochondrial impairment,and disturbances in immune homeostasis.Hepatic encephalopathy patients experience cognitive impairment,mood disturbances,and psychomotor dysfunction,significantly reducing quality of life through mechanisms including oxidative stress,neuroinflammation,and neurotransmitter imbalances.The nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway serves as a critical antioxidative defense mechanism in these conditions.Nrf2 regulates the expression of protective enzymes,while HO-1 exerts anti-inflammatory,anti-apoptotic,and antifibrotic effects through heme degradation products.Natural herbal monomers as Nrf2 activators offer advantages of low toxicity,multi-target actions,and extensive traditional use.Various herbal monomers demonstrate specific effects against different liver diseases:In fatty liver,baicalin alleviates lipid accumulation and inflammation;In alcoholic liver disease,curcumin enhances Nrf2 activity reducing oxidative damage;In drug-induced liver injury,dihydromyricetin mitigates oxidative stress;In viral hepatitis,andrographolide inhibits hepatitis C virus replication;In liver fibrosis,multiple compounds inhibit stellate cell activation.These natural compounds simultaneously alleviate hepatic dysfunction and neuropsychiatric symptoms by modulating the Nrf2/HO-1 pathway,though clinical application still faces challenges such as low bioavailability,requiring further research.展开更多
BACKGROUND Keratin 80(KRT80),a type I intermediate filament protein,is a member of the keratin family with specialized functions in epithelial tissues.While KRT80 has been implicated in both normal physiological proce...BACKGROUND Keratin 80(KRT80),a type I intermediate filament protein,is a member of the keratin family with specialized functions in epithelial tissues.While KRT80 has been implicated in both normal physiological processes and various diseases,its role in gastric cancer(GC),particularly its expression and prognostic significance,remains poorly understood.In this study,we investigated the role and underlying molecular mechanisms of KRT80 in oxaliplatin resistance in GC.Our analysis revealed that KRT80 is significantly upregulated in GC tissues and is associated with poor clinical prognosis.The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.AIM To explore the expression of KRT80 in GC and its impact on the prognosis of patients.METHODS KRT80 expression in GC tissues was analyzed using Western blotting,quantitative reverse transcription PCR,multiple immunofluorescence staining,and immunohistochemistry.Survival analysis was conducted using the Kaplan-Meier method with the log-rank test.The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.Immunoprecipitation and mass spectrometry analyses identified elongation factor 1-alpha 1(EEF1A1)as a binding protein of KRT80.RESULTS Integrating our experimental findings with multiple published studies,we found that increased KRT80 expression is associated with poor prognosis in GC and promotes resistance to oxaliplatin.Moreover,we have preliminarily verified the interaction between KRT80 and EEF1A1.Therefore,this study provides a novel perspective on overcoming oxaliplatin resistance in GC.CONCLUSION Increased KRT80 expression predicts poor prognosis and promotes oxaliplatin resistance in GC,suggesting its potential as a novel prognostic biomarker.展开更多
Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancrea...Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancreatic development and insulin biosynthesis in the PCE female offspring and explore the intrauterine programming mechanism.Pregnant rats were orally treated with 120 mg/(kg·day)of caffeine from gestational day(GD)9 to 20.Results showed that fetal pancreaticβ-cells in the PCE group exhibited reduced mass and impaired insulin synthesis function,as evidenced by decreased expression of developmental and functional genes and reduced pancreatic insulin content.At postnatal week(PW)12,the PCE offspring exhibited glucose intolerance,diminishedβ-cell mass,and lower blood insulin levels.However,by PW28,glucose tolerance showed some improvement.Both in vivo and in vitro findings collectively indicated that excessive serum corticosterone(CORT)levels of the PCE fetuses may act through the activation of the pancreatic glucocorticoid receptor(GR)and recruitment of histone deacetylase 9(HDAC9),leading to H3K9 deacetylation in promoter and downregulation of insulin-like growth factor 1(IGF1),thereby inhibiting pancreatic islet morphogenesis and insulin synthesis in fetal rats.Furthermore,the PCE offspring after birth exhibited decreased blood CORT levels,increased H3K9 acetylation in promoter and upregulated gene expression of the pancreatic IGF1 promoter region,accompanied by elevated insulin biosynthesis.However,when exposed to chronic stress,the above changes were totally reversed.Conclusively,“glucocorticoid-insulin like growth factor 1(GC-IGF1)axis”programming may be involved in pancreaticβ-cell dysplasia and dysfunction in the PCE female offspring.展开更多
BACKGROUND Gallbladder cancer(GBC)is a highly aggressive malignant tumor originating from the biliary tract.As one of the most common malignancies in the biliary system,GBC is particularly challenging due to its tende...BACKGROUND Gallbladder cancer(GBC)is a highly aggressive malignant tumor originating from the biliary tract.As one of the most common malignancies in the biliary system,GBC is particularly challenging due to its tendency to remain asymptomatic,which often results in delayed diagnoses even at advanced stages.Combined with its invasive potential and poor response to conventional therapies,GBC has a high mortality rate,highlighting the critical need for innovative therapeutic approaches.Identifying molecular biomarkers for early detection and discovering novel therapeutic targets might be essential to improving outcomes of patients with GBC.AIM To establish a novel GBC cell line to investigate the molecular mechanisms underlying GBC progression and evaluate potential therapeutic targets.METHODS We developed a unique GBC cell line,named OCUG-2,derived from a metastatic peritoneal implant,and verified its authenticity using short tandem repeat(STR)profiling.RT-PCR and RNA sequencing(RNA-seq)were performed to assess gene expression profiles,with functional enrichment analyzed through Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses.The MTT cell proliferation assay and an invasion assay were performed to evaluate response to nine inhibitors.Immunohistochemistry(IHC)was conducted on 34 GBC samples to analyze insulin-like growth factor 1 receptor(IGF1R)expression.RESULTS OCUG-2 cells displayed adhesive growth with dendritic morphology and a 30-hour doubling time.Subcutaneous inoculation of OCUG-2 cells into mice confirmed their tumorigenic potential.STR analysis authenticated the cell line,and there was high mRNA and protein expression of IGF1R in OCUG-2 cells.The IGF1R inhibitor picropodophyllotoxin significantly inhibited OCUG-2 cell proliferation,yielding an IC50 of 0.49μM.RNA-seq analysis identified gene fusions,and GO/KEGG functional enrichment analyses revealed pathways implicated in cancer progression.IHC analysis showed IGF1R positivity in 18 of 34 GBC cases,with significant association between IGF1R expression and poor prognosis.In invasion assays,an IGF1R inhibitor effectively reduced OCUG-2 cell invasiveness.CONCLUSION IGF1R might be a promising target for GBC.The newly established OCUG-2 cell line serves as a valuable model for investigating the molecular mechanisms of GBC and evaluating therapeutic strategies.展开更多
BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity...BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity,but its effects on pancreatic islet quality and function remain poorly understood.This work hypothesized that swimming training enhances glycemic control and insulin secretion by upregulating the insulin-like growth factor 1(IGF-1)/phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)pathway in streptozotocin(STZ)-induced diabetic rats.AIM To investigate the effects of swimming on pancreatic islet quality and function in STZ-induced diabetic rats via the IGF-1/PI3K/AKT pathway.METHODS Twenty-six Sprague-Dawley rats were grouped into diabetic and control groups,with each group further split into exercise and sedentary subgroups.Diabetic rats were induced with STZ.The exercise groups underwent swimming training for 60 minutes/day,5 days/week,for 8 weeks.Body weight,food intake,blood glucose,insulin,lipids,and muscle glycogen were measured.Pancreatic islet morphology and the protein expression levels of IGF-1,PI3K,and AKT were analyzed.Data were analyzed using two-way repeated-measure ANOVA,followed by Tukey’s post-hoc test.RESULTS Exercise training significantly improved body weight[diabetic exercise group(D-Ex):390.66±50.14 g vs diabetic sedentary group(D-Sed):315.89±50.12 g,P<0.05],reduced blood glucose(D-Ex:12.21±4.43 mmol/L vs D-Sed:17.79±2.05 mmol/L,P<0.05),and increased insulin levels(D-Ex:53.50±15.31 pmol/L vs D-Sed:25.31±10.23 pmol/L,P<0.05)in diabetic rats.It also enhanced islet morphology,increased IGF-1 expression,and activated the PI3K/AKT pathway(P<0.05).In-vitro experiments confirmed that IGF-1 positively regulated insulin expression and inhibitedβ-cell apoptosis via the PI3K/AKT pathway.CONCLUSION Exercise training improves pancreatic islet quality and function in diabetic rats by modulating the IGF-1/PI3K/AKT pathway,highlighting its therapeutic potential for diabetes management.展开更多
High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their inve...High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma,demonstrating positive cor-relations between PES1 and programmed death-ligand 1(PD-L1)expression(51.72%for PES1 and 58.62%for PD-L1),as well as associations with lymph node metastasis and tumor invasion depth.However,the relationship between PES1 and PD-L1 remains incompletely defined.To further address this gap,we ana-lyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+T cell infiltration,along-side a positive correlation with PD-L1 expression.Based on prior findings,we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms.While these pathways require experimental validation,our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金supported by the Science and Technology Development Plan Project of Jilin Province,No.YDZJ202401157ZYTS(to SL).
文摘Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important regulator of cellular stress responses and has been confirmed to play a critical role in the occurrence of various diseases.However,the mechanisms by which hypoxia-inducible factor 1αis related to epilepsy and neuronal ferroptosis remain unclear.In this study,we used a pentylentetrazole-induced chronic epilepsy mouse model and treated the mice with intraperitoneal administration of PX-478,a hypoxia-inducible factor-1αinhibitor.Our results showed that PX-478 significantly prolonged the latency of epilepsy,reduced seizure severity,and shortened seizure duration.PX-478 also alleviated neuronal damage in the hippocampal CA1 and CA2 regions,reduced levels of reactive oxygen species and malondialdehyde,and increased levels of superoxide dismutase,catalase,and glutathione peroxidase.Transmission electron microscopy showed that PX-478 treatment reduced mitochondrial damage in the hippocampal neurons of epileptic mice,and significantly improved mitochondrial length and area.Additionally,PX-478 preferentially reduced Fe^(2+)levels and the expression of cyclooxygenase-2,ferritin heavy chain 1 and transferrin in the hippocampus of epileptic mice.It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway.In summary,these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway,alleviating oxidative stress,and reducing ferroptosis in hippocampal neurons.
基金supported by the National Key Research and Development Program of China,No.2022YFC2704801(to CZhu)the National Natural Science Foundation of China,Nos.U21A20347(to CZhu),82203969(to YX),82371472(to XZ)+3 种基金Health Commission of Henan Province,Nos.SBGJ202303039(to XZ),SBGJ202301009(to CZhu),YQRC2024018(to XZ),YQRC2024019(to YX)Henan Science and Technology Department,Nos.242102311054(to XZ),241111521300(to CZhu),GZS2023003(to XW)Swedish Research Council,Nos.2022-01019(to CZhu),2021-01950(to XW)Swedish Governmental Grants to Scientists Working in Healthcare,Nos.ALFGBG-1005209(to CZhu),ALFBG-1005257(to XW),ALFGBG-965197(to CZhu).
文摘Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury response,including inflammation and repair.Although colony-stimulating factor 1 receptor inhibitors such as PLX5622 enable the selective depletion of microglia,their therapeutic potential in neonatal germinal matrix hemorrhage remains underexplored.Here,we used a collagenase-induced germinal matrix hemorrhage model in postnatal day 5 mice,and intraperitoneally administered PLX562272 hours post-germinal matrix hemorrhage to achieve targeted,temporary microglial depletion during the peak injury response.We then assessed the effects of this delayed intervention on oligodendrocyte lineage cell maturation,white matter integrity,and neurobehavioral outcomes.Additionally,RNA sequencing data from a germinal matrix hemorrhage rat model were analyzed using weighted gene co-expression network analysis to identify the critical phases for interventions.RNA sequencing data revealed a critical period in which key synaptic functions declined while immune responses intensified post-germinal matrix hemorrhage,thus pinpointing the critical response phases for potential interventions.Delayed PLX5622 treatment effectively depleted activated microglia,protecting against white matter injury and enhancing oligodendrocyte lineage cell maturation and myelination in subcortical white matter regions.Moreover,magnetic resonance imaging analysis revealed reduced brain lesion volumes in treated mice.Behaviorally,PLX5622-treated mice exhibited significant improvements in motor coordination and reduced hyperactivity compared with vehicle-treated germinal matrix hemorrhage model mice.These findings suggest that,when timed to avoid interference with initial oligodendrocyte lineage cell proliferation,targeted microglial depletion with PLX5622 significantly mitigates white matter damage and improves neurobehavioral outcomes in neonatal germinal matrix hemorrhage.The present study highlights the therapeutic potential of selectively modulating microglial reactivity to support neurodevelopment in preterm infants with brain injury.
基金supported by the National Natural Science Foundation of China(Grant No.82220108002 to F.C.and Grant No.82273737 to R.Z.)the U.S.National Institutes of Health(Grant Nos.CA209414,HL060710,and ES000002 to D.C.C.,Grant Nos.CA209414 and CA249096 to Y.L.)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University.
文摘Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[OR_(MEARDS)]=0.84,P=0.008;OR_(MESSI)=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10^(-4)),and improved overall survival in ARDS patients(hazard ratio[HR_(28-day)]=0.49,P=0.009)and sepsis patients(HR_(28-day)=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.
基金National Natural Science Foundation of China,No.82271440Jiangxi Provincial Health Technology Project,No.202510009(both to LX).
文摘Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of interferon regulatory factor 1 in myasthenia gravis,with an aim to understand the underlying mechanisms.Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study.Peripheral blood lymphocytes were extracted from the included patients,and B lymphocyte subsets were isolated.Next,T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis.Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region.Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter.In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180.Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription.Additionally,histone deacetylase 1 promoted B cell activation and T cell differentiation.Finally,in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Collectively,our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Together,these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms.They also provide new ideas and targets for diagnosing and treating myasthenia gravis,which will be both scientifically and clinically valuable.
基金supported by the China Medical University Hospital,Department of Medical Research(DMR-110-209)the Ministry of Science and Technology,Taiwan(MOST:109-2320-B-303-001-MY2),CMU107-ASIA-08,CMU109-MF-76 and CMU105-ASIA-01Taichung Armed Forces General Hospital:TCAFGH_D_115034.
文摘Objective:MicroRNAs(miRNAs)are small,non-coding RNAs that play a key role in the development of chemoresistance in various cancer types,including colorectal cancer(CRC).In this study,we aimed to study the underlying mechanisms of miRNA in chemotherapy-resistant CRC.Methods:LoVo CRC cell line was exposed to oxaliplatin at an increased dose,and cells were cultured in the presence of oxaliplatin to develop LoVo^(OXR) cells.Microarray and Quantitative Reverse Transcription Polymerase Chain Reaction(qRT-PCR),western blot,and transwell assay were used to evaluate the chemoresistance in LoVo^(OXR) CRC cells.Results:Microarray and qRT-PCR analysis showed an increased expression of miR-100-5p in LoVo^(OXR) cells.MTT assay and flow cytometry analysis revealed less apoptosis and higher cell viability in LoVo^(OXR) cells.mRNA prediction target gene analysis showed C-terminal domain small phosphatase-like(CTDSPL),a phosphatase-like tumor suppressor,as a key target of miR-100-5p.CTDSPL expression was low in LoVo^(OXR) cells compared to LoVoWT cells.miR-100-5p regulates G1/S and S-phase transitions and inhibits differentiation by targeting the CTDSPL/pRB/E2F1 signaling pathway,which involves the modulation of cell cycle effectors in LoVo^(OXR) cells.Further,we found that forkhead box P3(FOXP3),as the upstream target of miR-100-5p,is highly expressed in LoVo^(OXR) cells.Inhibiting miR-100-5p and FOXP3 down-regulates miR-100-5p expression,while increased CTDSPL expression contributed to reduced cell proliferation and promoted cell apoptosis in LoVo^(OXR) CRC cells.Conclusions:miR-100-5p plays an oncogenic role in inducing chemoresistance through modulation of the CTDSPL/retinoblastoma protein(pRB)/E2F transcription factor 1(E2F1)axis in CRC cells.
文摘Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer(HSPC)through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.Methods:HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation,invasion,migration,and epithelial-mesenchymal transition.Xenograft assays,bioinformatic screening,and analyses of O-GlcNAcylation and protein stability were performed,together with quantitative polymerase chain reaction(qPCR)and Western blotting.Results:ONX-0914 markedly suppressed hormone-sensitive prostate cancer(HSPC)progression through both LMP7-dependent and LMP7-independent mechanisms.Mechanistically,ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation,leading to stabilization of the transcriptional repressor Transcription factor 7-like 1(TCF7L1)and consequent suppression of androgen receptor(AR)expression.Functionally,activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation,invasion,migration,and epithelial-mesenchymal transition in vitro.In vivo,TCF7L1 overexpression,particularly under conditions of enhanced O-GlcNAcylation,significantly suppressed tumor growth and AR expression.Conclusion:This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1,leading to repression of AR signaling and inhibition of HSPC progression.These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.
文摘Background:To investigate SCL/TAL 1 interrupting locus(STIL)’s role and prognostic significance in lung adenocarcinoma(LUAD)progression,we examined STIL and E2 promoter binding factor 1(E2F1)expression and their impacts on LUAD prognosis using Gene Expression Profiling Interactive Analysis(GEPIA).Methods:Functional assays including CCK-8,wound-healing,5-ethynyl-2-deoxyuridine(EdU),Transwell assays,and flow cytometry,elucidated STIL and E2F1’s effects on cell viability,proliferation,apoptosis,and migration.Gene set enrichment analysis(GSEA)identified potential pathways,while metabolic assays assessed glucose metabolism.Results:Our findings reveal that STIL and E2F1 are overexpressed in LUAD,correlating with adverse outcomes.It enhances cell proliferation,migration,and invasion,and suppresses apoptosis,activating downstream of E2F1.Silencing E2F1 reversed the promotion effect of the STIL overexpression on cell viability and invasiveness.Importantly,STIL modulates glycolysis,influencing glucose consumption,lactate production,and energy balance in LUAD cells.Conclusion:Our model,incorporating STIL,age,and disease stage,robustly predicts patient prognosis,underscored STIL’s pivotal role in LUAD pathogenesis through metabolic reprogramming.This comprehensive approach not only confirms STIL’s prognostic value but also highlights its potential as a therapeutic target in LUAD.
基金supported by Natural Science Foundation Project of Ningxia Hui Autonomous Region(No.2021AAC03327)Hunan Provincial Natural Science Foundation(No.2021JJ31058)+2 种基金Shanghai Pujiang Program(No.23PJ1403300)Shanghai Science and Technology Commission(No.23ZR1440700)National Natural Science Foundation of China(No.82000797,82102244,31971077,and 82070255)。
文摘Objective:Baicalein has been reported to have wide therapeutic effects that act through its antiinflammatory activity.This study examines the effect and mechanism of baicalein on sepsis-induced cardiomyopathy(SIC).Methods:A thorough screening of a small library of natural products,comprising 100 diverse compounds,was conducted to identify the most effective drug against lipopolysaccharide(LPS)-treated H9C2 cardiomyocytes.The core target proteins and their associated signaling pathways involved in baicalein's efficacy against LPS-induced myocardial injury were predicted by network pharmacology.Results:Baicalein was identified as the most potent protective agent in LPS-exposed H9C2 cardiomyocytes.It exhibited a dose-dependent inhibitory effect on cell injury and inflammation.In the LPSinduced septic mouse model,baicalein demonstrated a significant capacity to mitigate LPS-triggered myocardial deficits,inflammatory responses,and ferroptosis.Network pharmacological analysis and experimental confirmation suggested that hypoxia-inducible factor 1 subunit a(HIF1-a)is likely to be the crucial factor in mediating the impact of baicalein against LPS-induced myocardial ferroptosis and injury.By combining microRNA(miRNA)screening in LPS-treated myocardium with miRNA prediction targeting HIF1-a,we found that miR-299b-5p may serve as a regulator of HIF1-a.The reduction in miR-299b-5p levels in LPS-treated myocardium,compared to the control group,was reversed by baicalein treatment.The reverse transcription quantitative polymerase chain reaction,Western blotting,and dual-luciferase reporter gene analyses together identified HIF1-a as the target of miR-299b-5p in cardiomyocytes.Conclusion:Baicalein mitigates SIC at the miRNA level,suggesting the therapeutic potential of it in treating SIC through the regulation of miR-299b-5p/HIF1-a/ferroptosis pathway.
文摘BACKGROUND Esophageal squamous-cell carcinoma(ESCC)is a highly aggressive cancer,predominantly affecting populations in Eastern Asia and parts of Africa.Its pathogenesis is influenced by both genetic and environmental factors.Despite recent therapeutic advances,survival rates remain dismal,underscoring an urgent need for novel therapeutic targets.AIM To investigate the role of hypoxia-inducible factor 1-alpha(HIF1A)in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A(LDHA),which is crucial for the glycolytic pathway in hypoxic tumor environments.METHODS Utilizing transcriptomic data from multiple public databases,we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses.The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines.RESULTS Our findings reveal a significant upregulation of HIF1A in ESCC tissues,associated with poor prognosis.HIF1A directly regulates LDHA,enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness.Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis.CONCLUSION The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target,underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.
基金Supported by the Guangxi Natural Science Foundation“Controllable Synthesis of Ordered Mesoporous Seafoam-Loaded g-C3N4 Gomposites and Their Mechanism of Adsorption-Photocatalytic Degradation of Antidepressants in Water Bodies”(2017GXNSFBA198216)the Open Fund for the Director of Guangxi Key Laboratory of Spatial Information and Geographic Information“Geographic Spatial Analysis of Regional Urinary Tract Stone Disease”(19-185-10-04)。
文摘OBJECTIVE:To evaluate the effect of Fuzi Lizhong decoction(附子理中汤)on intestinal flora,serum inflammatory factors,and hypoxia inducible factor-1α(HIF-1α)in patients with colorectal cancer associated with spleen and kidney Yang deficiency.METHODS:A total of 100 patients diagnosed with advanced colorectal cancer were randomly divided into two groups:a control group(CON,50)and a Traditional Chinese Medicine(TCM)group(n=50).The control group received treatment with the Capecitabine+Oxaliplatin(CAPEOX)regimen,while the TCM group received the same regimen along with Fuzi Lizhong decoction for six weeks.Changes in intestinal flora were assessed before and after six weeks in both groups.Serum markers,including HIF-1α,vascular endothelial growth factor(VEGF),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α),were measured using enzyme-linked immunosorbent assay.Adverse reactions,clinical efficacy,and TCM syndrome efficacy were also monitored.RESULTS:After six weeks,the levels of Lactobacillus and Bifidobacterium were significantly higher,while the levels of Enterobacter and Enterococcus were significantly lower in the TCM group compared to the control group(P<0.05).Serum levels of HIF-1α,VEGF,IL-6,and TNF-αwere also significantly reduced in the TCM group compared to the control group(P<0.05).Additionally,the incidence of adverse reactions was lower,and the clinical efficacy was higher in the TCM group compared to the control group(P<0.05).CONCLUSION:Fuzi Lizhong decoction effectively improves intestinal microbiota composition,reduces inflammatory factors and HIF-1αexpression,alleviates chemotherapy-related adverse reactions,enhances clinical efficacy,and may inhibit tumor growth in patients with colorectal cancer.
文摘BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essential to explore novel therapeutic strategies.Curcumol,a sesquiterpenoid derived from traditional Chinese medicine,has shown anti-inflammatory and anti-cancer properties,but its potential role in DR remains unclear.AIM To investigate the therapeutic effects of curcumol on the progression of DR and to elucidate the underlying molecular mechanisms,particularly its impact on the fat mass and obesity-associated(FTO)protein and the long non-coding RNA(lncRNA)MAF transcription factor G antisense RNA 1(MAFG-AS1).METHODS A streptozotocin-induced mouse model of DR was established,followed by treatment with curcumol.Retinal damage and inflammation were evaluated through histological analysis and molecular assays.Human retinal vascular endothelial cells were exposed to high glucose conditions to simulate diabetic environments in vitro.Cell proliferation,migration,and inflammation markers were assessed in curcumoltreated cells.LncRNA microarray analysis identified key molecules regulated by curcumol,and further experiments were conducted to confirm the involvement of FTO and MAFG-AS1 in the progression of DR.RESULTS Curcumol treatment significantly reduced blood glucose levels and alleviated retinal damage in streptozotocininduced DR mouse models.In high-glucose-treated human retinal vascular endothelial cells,curcumol inhibited cell proliferation,migration,and inflammatory responses.LncRNA microarray analysis identified MAFG-AS1 as the most upregulated lncRNA following curcumol treatment.Mechanistically,FTO demethylated MAFG-AS1,stabilizing its expression.Rescue experiments demonstrated that the protective effects of curcumol against DR were mediated through the FTO/MAFG-AS1 signaling pathway.CONCLUSION Curcumol ameliorates the progression of DR by modulating the FTO/MAFG-AS1 axis,providing a novel therapeutic pathway for the treatment of DR.These findings suggest that curcumol-based therapies could offer a promising alternative for managing this debilitating complication of diabetes.
基金supported by the NSFC Distinguished Young Scholars Fund(82325010)the National Natural Science Foundation of China(82370874)+4 种基金the Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20212700)the Major Natural Science Project of the Scientific Research and Innovation Plan of Shanghai Municipal Commission of Education(2023ZKZD17)the Shanghai Research Center for Endocrine and Metabolic Diseases(2022ZZ01002)the Shanghai Key Discipline of Public Health Grants Award(GWVI-11.1-20)the Basic Scientific Research Project(General Cultivation Program)of Shanghai Sixth People’s Hospital(ynms202203).
文摘Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.Skeletal muscle,as a major metabolic organ system,undergoes significant remodeling during ALI.However,its specific regulatory contributions remain largely uncharacterized.Methods:Partial(2/3)hepatectomy and acetaminophen were used to induce ALI in male mice.RNA-sequencing(RNA-seq),assay for transposase-accessible chromatin by sequencing(ATAC-seq),chromatin immunoprecipitation,luciferase assay,Western blotting,TUNEL assay,immunohistochemistry,and phase separation assays were performed to reveal the transcriptional axis involved.Serum fibroblast growth factor binding protein 1(FGFBP1)protein levels in ALI patients were assessed via enzyme-linked immunosorbent assay.Results:Integrated analysis of RNA-seq and ATAC-seq following ALI identifies glucocorticoid(GC)signaling-mediated regulation of fibroblast growth factor 6(FGF6)in skeletal muscle metabolism.Muscle-specific knockdown of GC receptor(GR)exacerbates ALI and suppresses liver regeneration.Fgf6-knockout mice exhibited improved ALI and enhanced liver regeneration,with intramuscular injection of FGF6-neutralizing antibody rescuing the detrimental effects induced by GR knockdown.Further analysis of the FGF6 downstream target revealed that FGF6 regulates FGFBP1 expression through extracellular signal regulated kinase-activating transcription factor 3 signaling.Moreover,FGF6 regulates the heparin-dependent release kinetics of FGFBP1 by perturbing its liquid-liquid phase separation(LLPS)-driven condensate dynamics at the plasma membrane.Circulating FGFBP1 subsequently interacts with hepatic FGF5 through LLPS mechanisms to regulate liver regeneration.Conclusion:Our results demonstrate a molecular mechanism by which muscle-liver crosstalk can initiate and sustain liver regeneration via the FGF6-FGFBP1/FGF5 axis,providing a potential therapeutic target and treatment strategy for ALI.
基金supported by the Science&Technology Department of Sichuan Province(No.2019YFS0040)the Improvement Plan of“Xinglin Scholar”Scientific Research Talent,Chengdu University of Traditional Chinese Medicine(No.XKTD2022002)。
文摘The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species(ROS)levels.Clinical trials have demonstrated that Zhongfeng Xingnao Liquid(ZFXN)ameliorates post-stroke cognitive impairment(PSCI).However,the underlying mechanism,particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway,remains unclear.This study employed an oxygen-glucose deprivation(OGD)cell model using SHSY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation(2VO).The effects of ZFXN on learning and memory,neuroprotective activity,mitochondrial function,oxidative stress,and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro.Results indicated that ZFXN significantly increased the B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)ratio,reduced terminal deoxynucleotidyl transferase-mediated d UTP nickend-labeling(TUNEL)+cells,and markedly improved cognition,synaptic plasticity,and neuronal function in the hippocampus and cortex.Furthermore,ZFXN exhibited potent antioxidant activity,evidenced by decreased ROS and malondialdehyde(MDA)content and increased superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)levels.ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential(MMP),Tom 20 fluorescence intensity,adenosine triphosphate(ATP)and energy charge(EC)levels,and mitochondrial complexⅠandⅢactivity,thereby inhibiting mitochondrial damage.Additionally,ZFXN significantly increased SIRT1 activity and elevated SIRT1,nuclear Nrf2,and HO-1 levels.Notably,these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro.In conclusion,ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.
基金Supported by National Natural Science Foundation of China,No.874063.
文摘BACKGROUND Keratin 80(KRT80),a type I intermediate filament protein,is a member of the keratin family with specialized functions in epithelial tissues.While KRT80 has been implicated in both normal physiological processes and various diseases,its role in gastric cancer(GC),particularly its expression and prognostic significance,remains poorly understood.In this study,we investigated the role and underlying molecular mechanisms of KRT80 in oxaliplatin resistance in GC.Our analysis revealed that KRT80 is significantly upregulated in GC tissues and is associated with poor clinical prognosis.The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.AIM To explore the expression of KRT80 in GC and its impact on the prognosis of patients.METHODS KRT80 expression in GC tissues was analyzed using Western blotting,quantitative reverse transcription PCR,multiple immunofluorescence staining,and immunohistochemistry.Survival analysis was conducted using the Kaplan-Meier method with the log-rank test.The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.Immunoprecipitation and mass spectrometry analyses identified elongation factor 1-alpha 1(EEF1A1)as a binding protein of KRT80.RESULTS Integrating our experimental findings with multiple published studies,we found that increased KRT80 expression is associated with poor prognosis in GC and promotes resistance to oxaliplatin.Moreover,we have preliminarily verified the interaction between KRT80 and EEF1A1.Therefore,this study provides a novel perspective on overcoming oxaliplatin resistance in GC.CONCLUSION Increased KRT80 expression predicts poor prognosis and promotes oxaliplatin resistance in GC,suggesting its potential as a novel prognostic biomarker.
基金supported by grants from the National Key Research and Development Program of China(2020YFA0803900)the National Natural Science Foundation of China(U23A20407,82414020,81703631)the Hubei Provincial Natural Science Foundation of China(2024AFB742)。
文摘Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancreatic development and insulin biosynthesis in the PCE female offspring and explore the intrauterine programming mechanism.Pregnant rats were orally treated with 120 mg/(kg·day)of caffeine from gestational day(GD)9 to 20.Results showed that fetal pancreaticβ-cells in the PCE group exhibited reduced mass and impaired insulin synthesis function,as evidenced by decreased expression of developmental and functional genes and reduced pancreatic insulin content.At postnatal week(PW)12,the PCE offspring exhibited glucose intolerance,diminishedβ-cell mass,and lower blood insulin levels.However,by PW28,glucose tolerance showed some improvement.Both in vivo and in vitro findings collectively indicated that excessive serum corticosterone(CORT)levels of the PCE fetuses may act through the activation of the pancreatic glucocorticoid receptor(GR)and recruitment of histone deacetylase 9(HDAC9),leading to H3K9 deacetylation in promoter and downregulation of insulin-like growth factor 1(IGF1),thereby inhibiting pancreatic islet morphogenesis and insulin synthesis in fetal rats.Furthermore,the PCE offspring after birth exhibited decreased blood CORT levels,increased H3K9 acetylation in promoter and upregulated gene expression of the pancreatic IGF1 promoter region,accompanied by elevated insulin biosynthesis.However,when exposed to chronic stress,the above changes were totally reversed.Conclusively,“glucocorticoid-insulin like growth factor 1(GC-IGF1)axis”programming may be involved in pancreaticβ-cell dysplasia and dysfunction in the PCE female offspring.
文摘BACKGROUND Gallbladder cancer(GBC)is a highly aggressive malignant tumor originating from the biliary tract.As one of the most common malignancies in the biliary system,GBC is particularly challenging due to its tendency to remain asymptomatic,which often results in delayed diagnoses even at advanced stages.Combined with its invasive potential and poor response to conventional therapies,GBC has a high mortality rate,highlighting the critical need for innovative therapeutic approaches.Identifying molecular biomarkers for early detection and discovering novel therapeutic targets might be essential to improving outcomes of patients with GBC.AIM To establish a novel GBC cell line to investigate the molecular mechanisms underlying GBC progression and evaluate potential therapeutic targets.METHODS We developed a unique GBC cell line,named OCUG-2,derived from a metastatic peritoneal implant,and verified its authenticity using short tandem repeat(STR)profiling.RT-PCR and RNA sequencing(RNA-seq)were performed to assess gene expression profiles,with functional enrichment analyzed through Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses.The MTT cell proliferation assay and an invasion assay were performed to evaluate response to nine inhibitors.Immunohistochemistry(IHC)was conducted on 34 GBC samples to analyze insulin-like growth factor 1 receptor(IGF1R)expression.RESULTS OCUG-2 cells displayed adhesive growth with dendritic morphology and a 30-hour doubling time.Subcutaneous inoculation of OCUG-2 cells into mice confirmed their tumorigenic potential.STR analysis authenticated the cell line,and there was high mRNA and protein expression of IGF1R in OCUG-2 cells.The IGF1R inhibitor picropodophyllotoxin significantly inhibited OCUG-2 cell proliferation,yielding an IC50 of 0.49μM.RNA-seq analysis identified gene fusions,and GO/KEGG functional enrichment analyses revealed pathways implicated in cancer progression.IHC analysis showed IGF1R positivity in 18 of 34 GBC cases,with significant association between IGF1R expression and poor prognosis.In invasion assays,an IGF1R inhibitor effectively reduced OCUG-2 cell invasiveness.CONCLUSION IGF1R might be a promising target for GBC.The newly established OCUG-2 cell line serves as a valuable model for investigating the molecular mechanisms of GBC and evaluating therapeutic strategies.
文摘BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity,but its effects on pancreatic islet quality and function remain poorly understood.This work hypothesized that swimming training enhances glycemic control and insulin secretion by upregulating the insulin-like growth factor 1(IGF-1)/phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)pathway in streptozotocin(STZ)-induced diabetic rats.AIM To investigate the effects of swimming on pancreatic islet quality and function in STZ-induced diabetic rats via the IGF-1/PI3K/AKT pathway.METHODS Twenty-six Sprague-Dawley rats were grouped into diabetic and control groups,with each group further split into exercise and sedentary subgroups.Diabetic rats were induced with STZ.The exercise groups underwent swimming training for 60 minutes/day,5 days/week,for 8 weeks.Body weight,food intake,blood glucose,insulin,lipids,and muscle glycogen were measured.Pancreatic islet morphology and the protein expression levels of IGF-1,PI3K,and AKT were analyzed.Data were analyzed using two-way repeated-measure ANOVA,followed by Tukey’s post-hoc test.RESULTS Exercise training significantly improved body weight[diabetic exercise group(D-Ex):390.66±50.14 g vs diabetic sedentary group(D-Sed):315.89±50.12 g,P<0.05],reduced blood glucose(D-Ex:12.21±4.43 mmol/L vs D-Sed:17.79±2.05 mmol/L,P<0.05),and increased insulin levels(D-Ex:53.50±15.31 pmol/L vs D-Sed:25.31±10.23 pmol/L,P<0.05)in diabetic rats.It also enhanced islet morphology,increased IGF-1 expression,and activated the PI3K/AKT pathway(P<0.05).In-vitro experiments confirmed that IGF-1 positively regulated insulin expression and inhibitedβ-cell apoptosis via the PI3K/AKT pathway.CONCLUSION Exercise training improves pancreatic islet quality and function in diabetic rats by modulating the IGF-1/PI3K/AKT pathway,highlighting its therapeutic potential for diabetes management.
文摘High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma,demonstrating positive cor-relations between PES1 and programmed death-ligand 1(PD-L1)expression(51.72%for PES1 and 58.62%for PD-L1),as well as associations with lymph node metastasis and tumor invasion depth.However,the relationship between PES1 and PD-L1 remains incompletely defined.To further address this gap,we ana-lyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+T cell infiltration,along-side a positive correlation with PD-L1 expression.Based on prior findings,we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms.While these pathways require experimental validation,our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.
