Dual Synthetic Jets (DSJ) can directly affect the development of spray through the complex vortex structure. The mechanism of flow control on spray and its thermal management application are studied by combining exper...Dual Synthetic Jets (DSJ) can directly affect the development of spray through the complex vortex structure. The mechanism of flow control on spray and its thermal management application are studied by combining experiment and simulation. The spray characteristics under different injection angles are studied, and the results show that the angle should be controlled in the range of 45°–60°, so that sufficient momentum transfer can be obtained, and meanwhile spray impingement area narrowing can be avoided. The spray characteristics under flow control of DSJ with different Reynolds numbers are studied, and the results show that Reynolds number should be controlled in the range of 2859–3574, so that strong particle streamwise acceleration and wall film disturbing can be achieved. In addition, the DSJ kinetic energy is utilized more efficiently. On the basis of previous research, this paper proposes a novel active heat pipe based on spray controlled by DSJ. The space occupancy has been reduced by more than 60%. Even in a sealed state, the active heat pipe is able to cool a hot surface with heat flux of 22.2 kW/m^(2) from 111℃ to 57℃ only in 20 s. The noise of DSJ is reduced from 85 dB to 60 dB, which is expected to promote the practical application of DSJ in thermal management.展开更多
Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant...Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.展开更多
This editorial examines a recent study that used radiomics based on computed tomography(CT)to predict the expression of the fibroblast-related gene enhancer of zeste homolog 2(EZH2)and its correlation with the surviva...This editorial examines a recent study that used radiomics based on computed tomography(CT)to predict the expression of the fibroblast-related gene enhancer of zeste homolog 2(EZH2)and its correlation with the survival of patients with hepatocellular carcinoma(HCC).By integrating radiomics with molecular analysis,the study presented a strategy for accurately predicting the expression of EZH2 from CT scans.The findings demonstrated a strong link between the radiomics model,EZH2 expression,and patient prognosis.This noninvasive approach provides valuable insights into the therapeutic management of HCC.展开更多
Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways...Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.展开更多
The increasing challenges of environmental degradation,soil erosion,and climate change have driven interest in sustainable solutions like enhanced weathering(EW)and phytoremediation.Elephant Grass(Cenchrus purpureus),...The increasing challenges of environmental degradation,soil erosion,and climate change have driven interest in sustainable solutions like enhanced weathering(EW)and phytoremediation.Elephant Grass(Cenchrus purpureus),a fast-growing perennial species,shows promise as a bioaccumulator and agent for soil weathering.This study assessed the potential of C.purpureus to improve soil quality through heavy metal(HM)uptake and EW facilitation.A 60-day greenhouse pot experiment at Jackson State University evaluated plant performance in soils amended with metabasalt rock powder at 1:1 and 2:1 rock-to-soil ratios.Biomass,growth,and HM concentrations in roots and shoots were measured via ICP-MS after wet digestion.Soil pH and magnesium(Mg)release were also monitored to assess weathering and carbon drawdown.Results showed that C.purpureus accumulated more HMs in roots at higher amendment levels,while at lower levels,metals like As,Cd,and Cr were more translocated to shoots,enhancing phytoextraction potential.High treatment favored Fe and Al uptake,possibly reducing toxic metal accumulation in edible parts.Notably,C.purpureus contributed to the weathering of 38%of metabasalt rock,leading to a 42%increase in Mg release.With high biomass,HM tolerance,and weathering capacity,C.purpureus offers a sustainable strategy for soil remediation,improved soil health,and potential support for renewable energy systems.展开更多
Objective:In recent decades,studies have underscored nuclear proteins and signaling pathways in prostate cancer(PCa)development.Key biomarkers like Enhancer of zeste homolog 2(EZH2)and Forkhead box M1(FOXM1)are expres...Objective:In recent decades,studies have underscored nuclear proteins and signaling pathways in prostate cancer(PCa)development.Key biomarkers like Enhancer of zeste homolog 2(EZH2)and Forkhead box M1(FOXM1)are expressed in both healthy and malignant prostate cells.This study aimed to demonstrate the relationship between pathological characteristics,survival,recurrence,and tissue expression of EZH2 and FOXM1 in high-risk PCa patients.Methods:PCa tissues were used in a retrospective analysis that spanned from September 2009 to August 2019.Inclusion criteria comprised pathological tumor stage(pT)3 patients with positive surgical margins or tumor proximity to inked margins within 5 mm.After case selection,tissue slides were stained for EZH2 and FOXM1 antibodies,and Allred scores were calculated.Patients or relatives of deceased patients were contacted for signed agreements and disease follow-ups.Results:The pT3b,ductal carcinoma component,and moderate EZH2 expression were associated with relapse(odds ratio[OR]6.21,95%confidence interval[CI]1.41-27.27,p=0.016;OR 7.29,95%CI 1.03-51.43,p=0.046;OR 5.96,95%CI 1.09-32.48,p=0.039;respectively).The unilateral and bilateral seminal vesicle invasion increased the likelihood of recurrence by 9.98 times and 5.36 times,and the risk of death by around 9.78 times and 10.79 times,respectively.The pT3b was linked to higher death likelihood(OR 7.16,95%CI 1.38-37.23,p=0.019),while moderate EZH2 expression did not show statistical significance(OR 4.54,95%CI 0.87-23.60,p=0.072,marginally).Pathological regional lymph node stage(pN)1 had significantly higher probability of mortality than pN unknown(3.9%vs.27%,p<0.001).PCa in the neck and apex of the prostate gland increased death risk tenfold.Conclusion:Sufficient immunoexpression of EZH2,ductal carcinoma component,and neoplastic proliferation in the seminal vesicles,apex and neck of the prostate gland correlates with elevated risks of recurrence and mortality.Clinicians should use these criteria for appropriate patient referrals,and a multicenter trial could provide accurate classifications.展开更多
BACKGROUND Stem cells from apical papilla(SCAPs)represent promising candidates for bone regenerative therapies due to their osteogenic potential.However,enhancing their differentiation capacity remains a critical chal...BACKGROUND Stem cells from apical papilla(SCAPs)represent promising candidates for bone regenerative therapies due to their osteogenic potential.However,enhancing their differentiation capacity remains a critical challenge.Enhancer of zeste homolog 2(EZH2),a histone H3 lysine 27 methyltransferase,regulates osteogenesis through epigenetic mechanisms,but its role in SCAPs remains unclear.We hypothesized that EZH2 modulates SCAP osteogenic differentiation via interaction with lysine demethylase 2B(KDM2B),offering a target for therapeutic intervention.AIM To investigate the functional role and molecular mechanism of EZH2 in SCAP osteogenic differentiation.METHODS SCAPs were isolated from healthy human third molars(n=6 donors).Osteogenic differentiation was assessed via Alizarin red staining and alkaline phosphatase assays.EZH2 overexpression/knockdown models were established using lentiviral vectors.Protein interactions were analyzed by co-immunoprecipitation,transcriptomic changes via microarray(Affymetrix platform),and chromatin binding by chromatin immunoprecipitation-quantitative polymerase chain reaction.In vivo bone formation was evaluated in immunodeficient mice(n=8/group)transplanted with SCAPs-hydroxyapatite scaffolds.Data were analyzed using Student’s t-test and ANOVA.RESULTS EZH2 overexpression increased osteogenic markers and mineralized nodule formation.In vivo,EZH2-overexpressing SCAPs generated 10%more bone/dentin-like tissue.Co-immunoprecipitation confirmed EZH2-KDM2B interaction,and peptide-mediated disruption of this binding enhanced osteogenesis.Transcriptome analysis identified 1648 differentially expressed genes(971 upregulated;677 downregulated),with pathway enrichment in Wnt/β-catenin signaling.CONCLUSION EZH2 promotes SCAP osteogenesis via antagonistic interaction with KDM2B,and targeted disruption of this axis offers a translatable strategy for bone regeneration.展开更多
Flight feathers represent a hallmark innovation of avian evolution.Recent comparative genomic analyses identified a 284 bp avian-specific highly conserved element(ASHCE)located within the eighth intron of the SIM bHLH...Flight feathers represent a hallmark innovation of avian evolution.Recent comparative genomic analyses identified a 284 bp avian-specific highly conserved element(ASHCE)located within the eighth intron of the SIM bHLH transcription factor 1(Sim1)gene,postulated to act as a cis-regulatory element governing flight feather morphogenesis.To investigate its functional significance,genome-edited(GE)primordial germ cell(PGC)lines carrying targeted ASHCE deletions were generated using CRISPR/Cas9-mediated editing,with germline chimeric males subsequently mated with wild-type(WT)hens to obtain GE progeny.The resulting GE chickens harbored 257-260 bp deletions,excising approximately half of the Sim1-ASHCE sequence.Reverse transcription-quantitative real-time polymerase chain reaction(RT-qPCR)analysis showed an average 0.32-fold reduction in Sim1 expression in the forelimbs of GE embryos at day 8(E8)compared to WT counterparts.Despite this,GE chickens developed structurally normal flight and tail feathers.In situ hybridization localized Sim1 expression to the posterior mesenchyme surrounding flight feather buds in E8 WT embryos,but not within the buds themselves.These results suggest that partial deletion of Sim1-ASHCE,despite diminishing Sim1 expression,does not disrupt flight feather formation.The excised region appears to possess enhancer activity toward Sim1 but is dispensable for flight feather development.Complete ablation of the ASHCE will be necessary to fully resolve the regulatory role of Sim1 in avian feather morphogenesis.展开更多
Plp1-lineage Schwann cells(SCs)of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing,and the abnormal plasticity of SCs would jeopardize ...Plp1-lineage Schwann cells(SCs)of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing,and the abnormal plasticity of SCs would jeopardize the bone regeneration.However,how Plp1-lineage cells respond to injury and initiate the vascularized osteogenesis remains incompletely understood.Here,by employing single-cell transcriptional profiling combined with lineage-specific tracing models,we uncover that Plp1-lineage cells undergoing injury-induced glia-to-MSCs transition contributed to osteogenesis and revascularization in the initial stage of bone injury.Importantly,our data demonstrated that the Sonic hedgehog(Shh)signaling was responsible for the transition process initiation,which was strongly activated by c-Jun/SIRT6/BAF170 complex-driven Shh enhancers.Collectively,these findings depict an injuryspecific niche signal-mediated Plp1-lineage cells transition towards Gli1+MSCs and may be instructive for approaches to promote bone regeneration during aging or other bone diseases.展开更多
BACKGROUND The mortality rate for severe cases of acute pancreatitis(AP),a common gastrointestinal emergency,is as high as 30%.Our previous study has shown that rutaecarpine(Rut)has a therapeutic effect on AP.AIM To i...BACKGROUND The mortality rate for severe cases of acute pancreatitis(AP),a common gastrointestinal emergency,is as high as 30%.Our previous study has shown that rutaecarpine(Rut)has a therapeutic effect on AP.AIM To investigate the role of F-box and WD repeat domain containing 11(FBXW11)in AP models and to assess whether Rut mitigates AP by regulating FBXW11.METHODS AP rat model was established and treated with Rut,followed by biochemical analysis of serum amylase and lipase,hematoxylin and eosin staining of pancreatic tissue,and immunohistochemistry detection of pancreatic Ly6G,CD11b,and myeloperoxidase.Assay kits were used to detect oxidative stress-related indicators in pancreatic tissue and inflammatory factors in serum.AR42J cells were treated with cerulein to model AP and subjected to Cell Counting Kit-8 viability assay,flow cytometry apoptosis assay,and immunofluorescence detection of reactive oxygen species to elucidate the mechanistic involvement of the enhancer of zeste homolog 2(EZH2)-FBXW11 axis in Rut-mediated protection against AP.The EZH2-histone H3 binding and H3 methylation were evaluated using co-immunoprecipitation.RESULTS Rut treatment ameliorated AP severity,as evidenced by reduced serum levels of pancreatic enzymes(amylase and lipase)and attenuated histological damage.Rut also decreased inflammatory markers(interleukin-1 beta,interleukin-6,and tumor necrosis factor alpha),tissue oxidative stress(malondialdehyde),and neutrophil infiltration(Ly6G,CD11b,and myeloperoxidase)levels in rats with AP.Moreover,Rut restored pancreatic antioxidant capacity(glutathione and superoxide dismutase).In vitro,Rut pre-incubation enhanced cell viability and suppressed cerulein-induced apoptosis and oxidative stress.Rut increased EZH2 expression while decreasing FBXW11 expression.FBXW11 overexpression eliminated the protective effect of Rut against AP.Further analysis revealed that EZH2 binds to H3 and upregulates H3 methylation levels,thereby inhibiting FBXW11 expression.CONCLUSION Collectively,our findings demonstrate that Rut ameliorates AP by upregulating EZH2,thereby enhancing H3 methylation and suppressing FBXW11 expression.展开更多
Backgrounds:As cancer progresses through various stages of malignancy,metastasis,and drug resistance,the Wnt/-catenin signaling is frequently dysregulated.Despite advancements in medical technology and therapeutic str...Backgrounds:As cancer progresses through various stages of malignancy,metastasis,and drug resistance,the Wnt/-catenin signaling is frequently dysregulated.Despite advancements in medical technology and therapeutic strategies,the prognosis for numerous gastric cancer patients remains unfavorable.Methods:For the analysis of prognostic signature genes associated with Wnt signaling in GC,we used LASSO(least absolute shrinkage and selection operator)regression.To explore the function,cell specificity,and transcriptional regulation of the signature gene Carboxypeptidase Z(CPZ),we conducted co-expression analysis,single-cell RNA sequencing data analysis,transcription factor prediction,and dual luciferase reporter assay.The knockdown and overexpression experiments were also performed to observe the changes in the downstream gene expression,as well as the influence on the biological functions of GC cells.Results:We identified a five-gene signature,including CPZ,Collagen Triple Helix Repeat Containing-1(CTHRC1),Dickkopf-1(DKK1),Epidermal Growth Factor(EGF),and Glypican Proteoglycan-3(GPC3),with risk scores predictive of the prognosis of GC patients.We found that the adipocyte enhancer binding protein 1(AEBP1)and transcription factor 3(TCF3)could interact in the nucleus and synergistically enhance the expression of Wnt signaling-associated genes,including WNT2/FZD2(Wnt family member 2/frizzled class receptor 2)and VIM(vimentin),thus promoting the invasion,migration,and malignant metastasis of GC.Conclusions:Our study offers a precise gene-signature prediction method for the prognosis of GC.We discovered the synergistic effect of AEBP1 and TCF3 in the nucleus on GC metastasis.GC may benefit from the identification of this potential therapeutic target.展开更多
Background:Dysregulation of enhancer transcription occurs in multiple cancers.Enhancer RNAs(eRNAs)are transcribed products from enhancers that play critical roles in transcriptional control.Characterizing the genetic ...Background:Dysregulation of enhancer transcription occurs in multiple cancers.Enhancer RNAs(eRNAs)are transcribed products from enhancers that play critical roles in transcriptional control.Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers.Methods:Initially,a comprehensive analysis of eRNA quantitative trait loci(eRNAQTLs)was performed in The Cancer Genome Atlas(TCGA),and functional features were characterized using multi-omics data.To establish the first eRNAQTL profiles for colorectal cancer(CRC)in China,epigenomic data were used to define active enhancers,which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples.Finally,largescale case-control studies(34,585 cases and 69,544 controls)were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk.Results:A total of 300,112 eRNAQTLs were identified across 30 different cancer types,which exert their influence on eRNA transcription by modulating chromatin status,binding affinity to transcription factors and RNA-binding proteins.These eRNAQTLs were found to be significantly enriched in cancer risk loci,explaining a substantial proportion of cancer heritability.Additionally,tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer.Moreover,the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer,highlighting their potential as therapeutic targets.Furthermore,multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China(OR=0.91,95%CI 0.88–0.95,P=2.92×10^(-7))and Europe(OR=0.92,95%CI 0.88–0.95,P=4.61×10^(-6)).Mechanistically,rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786,which functioned as a transcriptional activator promoting the expression of its target gene SENP7.These two genes synergistically suppressed tumor cell proliferation.Our curated list of variants,genes,and drugs has been made available in CancereRNAQTL(http://canernaqtl.whu.edu.cn/#/)to serve as an informative resource for advancing this field.Conclusion:Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability,pinpointing the potential of eRNA-based therapeutic strategies in cancers.展开更多
BACKGROUND Colorectal cancer(CRC)is a malignant tumor characterized by high global incidence and mortality rates.Contemporary therapeutic modalities remain limited by suboptimal efficacy and adverse effects,thereby ne...BACKGROUND Colorectal cancer(CRC)is a malignant tumor characterized by high global incidence and mortality rates.Contemporary therapeutic modalities remain limited by suboptimal efficacy and adverse effects,thereby necessitating the pursuit of more efficacious treatment strategies.Within traditional Chinese medicine,spleen deficiency is regarded as a central pathogenic mechanism in CRC,persisting throughout the entire disease course.AIM To elucidate the mechanism by which modified Yigong San confers therapeutic efficacy against CRC,potentially exerting its effects through apoptosis regulation mediated by the enhancer of zeste homolog 2(EZH2)/methyltransferase-like 3(METTL3)/SRY-box transcription factor 4(SOX4)axis.METHODS In the clinical study,CRC tissues and corresponding adjacent normal samples that fulfilled inclusion criteria were procured.Quantitative reverse transcription polymerase chain reaction was employed to determine the transcriptional expression of EZH2 and METTL3 mRNA.For in vitro experimentation,SW-480 cells were allocated into five experimental conditions:Control,control+serum,control+negative control,control+overexpressing-EZH2,and control+overexpressing-EZH2+serum.The mRNA expression levels of EZH2,METTL3,SOX4,B-cell lymphoma 2,and Bax across groups were quantified via quantitative reverse transcription polymerase chain reaction,while protein levels were assessed using western blot analysis.The presence of EZH2 binding sites within the METTL3 promoter region was verified through chromatin immunoprecipitation polymerase chain reaction.The optimal concentration of drug-containing serum(5%,10%,15%)was determined using the Cell Counting Kit-8 assay.Cell migratory ability was evaluated via scratch assays,and apoptotic activity was quantified by flow cytometry.RESULTS The clinical findings demonstrated significantly elevated transcriptional levels of METTL3 and EZH2 mRNA in tumor tissues compared to their adjacent normal counterparts(P<0.05).In vitro,cells treated with modified Yigong San exhibited a substantial downregulation of EZH2,METTL3,SOX4,B-cell lymphoma 2,and Bax mRNA and protein levels(P<0.05),relative to the control group.Apoptotic rates were markedly increased,while migratory capacity was significantly attenuated.Furthermore,in EZH2-overexpressing cells treated with modified Yigong San,similar reductions in both mRNA and protein levels of the aforementioned targets were observed(P<0.05),concomitant with enhanced apoptosis and reduced migration.Chromatin immunoprecipitation polymerase chain reaction analysis confirmed EZH2 occupancy at specific loci within the METTL3 promoter.CONCLUSION Modified Yigong San exhibits both preventive and therapeutic potential against CRC,likely mediated through the regulation of apoptosis via the EZH2/METTL3/SOX4 signaling pathway.展开更多
The abnormality of the p53 tumor suppressor is crucial in lung cancer development,because p53 regulates target gene promoters to combat cancer.Recent studies have shown extensive p53 binding to enhancer elements.Howev...The abnormality of the p53 tumor suppressor is crucial in lung cancer development,because p53 regulates target gene promoters to combat cancer.Recent studies have shown extensive p53 binding to enhancer elements.However,whether p53 exerts a tumor suppressor role by shaping the enhancer landscape remains poorly understood.In the current study,we employed several functional genomics approaches to assess the enhancer activity at p53 binding sites throughout the genome based on our established TP53 knockout(KO)human bronchial epithelial cells(BEAS-2B).A total of 943 active regular enhancers and 370 super-enhancers(SEs)disappeared upon the deletion of p53,indicating that p53 modulates the activity of hundreds of enhancer elements.We found that one p53-dependent SE,located on chromosome 9 and designated as KLF4-SE,regulated the expression of the Krüppel-like factor 4(KLF4)gene.Furthermore,the deletion of p53 significantly decreased the KLF4-SE enhancer activity and the KLF4 expression,but increased colony formation ability in the nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced cell transformation model.Subsequently,in TP53 KO cells,the overexpression of KLF4 partially reversed the increased clonogenic capacity caused by p53 deficiency.Consistently,KLF4 expression also decreased in lung cancer tissues and cell lines.It appeared that overexpression of KLF4 significantly suppressed the proliferation and migration of lung cancer cells.Collectively,our results suggest that the regulation of enhancer formation and activity by p53 is an integral component of the p53 tumor suppressor function.Therefore,our findings offer some novel insights into the regulation mechanism of p53 in lung oncogenesis and introduce a new strategy for screening therapeutic targets.展开更多
Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were establi...Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.展开更多
Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related deaths worldwide.Major treatments include liver transplantation,resection,and chemotherapy,but the 5-year recurrence rate remains high.Late dia...Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related deaths worldwide.Major treatments include liver transplantation,resection,and chemotherapy,but the 5-year recurrence rate remains high.Late diagnosis often prevents surgical intervention,contributing to poor patient survival rates.Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones.Enhancer of zeste homolog 2(EZH2),a key regulator of cell cycle progression,is frequently upregulated in HCC and is associated with advanced stages and poor prognosis,making it a potential biomarker.Additionally,signal transducer and activator of transcription 3,which binds to EZH2,affects disease staging and outcomes.Targeting EZH2 presents a promising therapeutic strategy.On the other hand,abnormal lipid metabolism is a hallmark of HCC and impacts prognosis.Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes,suggesting its potential as a biomarker.Other genes such as guanine monophosphate synthase,cell division cycle associated 5,and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC,offering potential as biomarkers and therapeutic targets.展开更多
We propose a joint look-up-table(LUT)-based nonlinear predistortion and digital resolution enhancement scheme to achieve high-speed and low-cost optical interconnects using low-resolution digital-to-analog converters(...We propose a joint look-up-table(LUT)-based nonlinear predistortion and digital resolution enhancement scheme to achieve high-speed and low-cost optical interconnects using low-resolution digital-to-analog converters(DACs).The LUT-based predistortion is employed to mitigate the patterndependent effect(PDE)of a semiconductor optical amplifier(SOA),while the digital resolution enhancer(DRE)is utilized to shape the quantization noise,lowering the requirement for the resolution of DAC.We experimentally demonstrate O-band intensity modulation and direct detection(IM/DD)transmission of 124-GBd 4∕6-level pulse-amplitude modulation ePAMT-4∕6 and 112-GBd PAM-8 signals over a 2-km standard single-mode fiber(SSMF)with 3∕3.5∕4-bit DACs.In the case of 40-km SSMF transmission with an SOAbased preamplifier,124-GBd on-off-keying(OOK)/PAM-3/PAM-4 signals are successfully transmitted with 1.5∕2∕3-bit DACs.To the best of our knowledge,we have achieved the highest net data rates of 235.3-Gb∕s PAM-4,289.7-Gb∕s PAM-6,and 294.7 Gb∕s PAM-8 signals over 2-km SSMF,as well as 117.6-Gb∕s OOK,173.8-Gb∕s PAM-3,and−231.8 Gb∕s PAM-4 signals over 40-km SSMF,employing low-resolution DACs.The experimental results reveal that the joint LUT-based predistortion and DRE effectively mitigate the PDE and improve the signal-to-quantization noise ratio by shaping the noise.The proposed scheme can provide a powerful solution for low-cost IM/DD optical interconnects beyond 200 Gb∕s.展开更多
The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for n...The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease.Through a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell development.FAM46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific enhancer.We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner.Furthermore,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis.In conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.展开更多
Borneol, as a traditional natural permeation enhancer, has been widely used to promote the transdermal absorption of active ingredients. In this review, the mechanism of borneol in promoting permeation by destroying t...Borneol, as a traditional natural permeation enhancer, has been widely used to promote the transdermal absorption of active ingredients. In this review, the mechanism of borneol in promoting permeation by destroying the highly ordered lipid structure of the lipid layer and by destroying the hydrogen-bond network was described. The application of borneol in promoting the transdermal absorption of the active ingredients of traditional Chinese medicine and chemical drugs was introduced. The application of borneol as a natural ingredient added to functional cosmetics was summarized, and its effects on skin-spot treatment, acne skin care, eczema skin care, skin repair and anti-oxidation were introduced. Finally, the possible problems in the application of borneol in cosmetics were put forward, and the application prospect of borneol in the development of cosmetics was given.展开更多
基金supported by the National Natural Science Foundation of China(Nos.U2341202,12402333).
文摘Dual Synthetic Jets (DSJ) can directly affect the development of spray through the complex vortex structure. The mechanism of flow control on spray and its thermal management application are studied by combining experiment and simulation. The spray characteristics under different injection angles are studied, and the results show that the angle should be controlled in the range of 45°–60°, so that sufficient momentum transfer can be obtained, and meanwhile spray impingement area narrowing can be avoided. The spray characteristics under flow control of DSJ with different Reynolds numbers are studied, and the results show that Reynolds number should be controlled in the range of 2859–3574, so that strong particle streamwise acceleration and wall film disturbing can be achieved. In addition, the DSJ kinetic energy is utilized more efficiently. On the basis of previous research, this paper proposes a novel active heat pipe based on spray controlled by DSJ. The space occupancy has been reduced by more than 60%. Even in a sealed state, the active heat pipe is able to cool a hot surface with heat flux of 22.2 kW/m^(2) from 111℃ to 57℃ only in 20 s. The noise of DSJ is reduced from 85 dB to 60 dB, which is expected to promote the practical application of DSJ in thermal management.
基金supported by the National Natural Science Foundation of China(Nos.82171552 and 82170479)the Natural Science Foundation of Shanghai Ctiy(No.21ZR1457500)the Science and Technology Bureau of Shanghai Putuo District(No.ptkwws202102).
文摘Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.
文摘This editorial examines a recent study that used radiomics based on computed tomography(CT)to predict the expression of the fibroblast-related gene enhancer of zeste homolog 2(EZH2)and its correlation with the survival of patients with hepatocellular carcinoma(HCC).By integrating radiomics with molecular analysis,the study presented a strategy for accurately predicting the expression of EZH2 from CT scans.The findings demonstrated a strong link between the radiomics model,EZH2 expression,and patient prognosis.This noninvasive approach provides valuable insights into the therapeutic management of HCC.
基金supported by the German Research Council(Deutsche Forschungsgemeinschaft,HA3309/3-1/2,HA3309/6-1,HA3309/7-1)。
文摘Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.
文摘The increasing challenges of environmental degradation,soil erosion,and climate change have driven interest in sustainable solutions like enhanced weathering(EW)and phytoremediation.Elephant Grass(Cenchrus purpureus),a fast-growing perennial species,shows promise as a bioaccumulator and agent for soil weathering.This study assessed the potential of C.purpureus to improve soil quality through heavy metal(HM)uptake and EW facilitation.A 60-day greenhouse pot experiment at Jackson State University evaluated plant performance in soils amended with metabasalt rock powder at 1:1 and 2:1 rock-to-soil ratios.Biomass,growth,and HM concentrations in roots and shoots were measured via ICP-MS after wet digestion.Soil pH and magnesium(Mg)release were also monitored to assess weathering and carbon drawdown.Results showed that C.purpureus accumulated more HMs in roots at higher amendment levels,while at lower levels,metals like As,Cd,and Cr were more translocated to shoots,enhancing phytoextraction potential.High treatment favored Fe and Al uptake,possibly reducing toxic metal accumulation in edible parts.Notably,C.purpureus contributed to the weathering of 38%of metabasalt rock,leading to a 42%increase in Mg release.With high biomass,HM tolerance,and weathering capacity,C.purpureus offers a sustainable strategy for soil remediation,improved soil health,and potential support for renewable energy systems.
文摘Objective:In recent decades,studies have underscored nuclear proteins and signaling pathways in prostate cancer(PCa)development.Key biomarkers like Enhancer of zeste homolog 2(EZH2)and Forkhead box M1(FOXM1)are expressed in both healthy and malignant prostate cells.This study aimed to demonstrate the relationship between pathological characteristics,survival,recurrence,and tissue expression of EZH2 and FOXM1 in high-risk PCa patients.Methods:PCa tissues were used in a retrospective analysis that spanned from September 2009 to August 2019.Inclusion criteria comprised pathological tumor stage(pT)3 patients with positive surgical margins or tumor proximity to inked margins within 5 mm.After case selection,tissue slides were stained for EZH2 and FOXM1 antibodies,and Allred scores were calculated.Patients or relatives of deceased patients were contacted for signed agreements and disease follow-ups.Results:The pT3b,ductal carcinoma component,and moderate EZH2 expression were associated with relapse(odds ratio[OR]6.21,95%confidence interval[CI]1.41-27.27,p=0.016;OR 7.29,95%CI 1.03-51.43,p=0.046;OR 5.96,95%CI 1.09-32.48,p=0.039;respectively).The unilateral and bilateral seminal vesicle invasion increased the likelihood of recurrence by 9.98 times and 5.36 times,and the risk of death by around 9.78 times and 10.79 times,respectively.The pT3b was linked to higher death likelihood(OR 7.16,95%CI 1.38-37.23,p=0.019),while moderate EZH2 expression did not show statistical significance(OR 4.54,95%CI 0.87-23.60,p=0.072,marginally).Pathological regional lymph node stage(pN)1 had significantly higher probability of mortality than pN unknown(3.9%vs.27%,p<0.001).PCa in the neck and apex of the prostate gland increased death risk tenfold.Conclusion:Sufficient immunoexpression of EZH2,ductal carcinoma component,and neoplastic proliferation in the seminal vesicles,apex and neck of the prostate gland correlates with elevated risks of recurrence and mortality.Clinicians should use these criteria for appropriate patient referrals,and a multicenter trial could provide accurate classifications.
基金Supported by National Key Research and Development Program,No.2022YFA1104401Beijing Natural Science Foundation,No.7222075+1 种基金CAMS Innovation Fund for Medical Sciences,No.2019RU020Innovation Research Team Project of Beijing Stomatological Hospital,No.CXTD202204.
文摘BACKGROUND Stem cells from apical papilla(SCAPs)represent promising candidates for bone regenerative therapies due to their osteogenic potential.However,enhancing their differentiation capacity remains a critical challenge.Enhancer of zeste homolog 2(EZH2),a histone H3 lysine 27 methyltransferase,regulates osteogenesis through epigenetic mechanisms,but its role in SCAPs remains unclear.We hypothesized that EZH2 modulates SCAP osteogenic differentiation via interaction with lysine demethylase 2B(KDM2B),offering a target for therapeutic intervention.AIM To investigate the functional role and molecular mechanism of EZH2 in SCAP osteogenic differentiation.METHODS SCAPs were isolated from healthy human third molars(n=6 donors).Osteogenic differentiation was assessed via Alizarin red staining and alkaline phosphatase assays.EZH2 overexpression/knockdown models were established using lentiviral vectors.Protein interactions were analyzed by co-immunoprecipitation,transcriptomic changes via microarray(Affymetrix platform),and chromatin binding by chromatin immunoprecipitation-quantitative polymerase chain reaction.In vivo bone formation was evaluated in immunodeficient mice(n=8/group)transplanted with SCAPs-hydroxyapatite scaffolds.Data were analyzed using Student’s t-test and ANOVA.RESULTS EZH2 overexpression increased osteogenic markers and mineralized nodule formation.In vivo,EZH2-overexpressing SCAPs generated 10%more bone/dentin-like tissue.Co-immunoprecipitation confirmed EZH2-KDM2B interaction,and peptide-mediated disruption of this binding enhanced osteogenesis.Transcriptome analysis identified 1648 differentially expressed genes(971 upregulated;677 downregulated),with pathway enrichment in Wnt/β-catenin signaling.CONCLUSION EZH2 promotes SCAP osteogenesis via antagonistic interaction with KDM2B,and targeted disruption of this axis offers a translatable strategy for bone regeneration.
基金supported by the Ministry of Agriculture and Rural Affairs of the People's Republic of China(125A0607)Department of Science and Technology of Yunnan Province(XDYC-KJLJ-2022-0004)。
文摘Flight feathers represent a hallmark innovation of avian evolution.Recent comparative genomic analyses identified a 284 bp avian-specific highly conserved element(ASHCE)located within the eighth intron of the SIM bHLH transcription factor 1(Sim1)gene,postulated to act as a cis-regulatory element governing flight feather morphogenesis.To investigate its functional significance,genome-edited(GE)primordial germ cell(PGC)lines carrying targeted ASHCE deletions were generated using CRISPR/Cas9-mediated editing,with germline chimeric males subsequently mated with wild-type(WT)hens to obtain GE progeny.The resulting GE chickens harbored 257-260 bp deletions,excising approximately half of the Sim1-ASHCE sequence.Reverse transcription-quantitative real-time polymerase chain reaction(RT-qPCR)analysis showed an average 0.32-fold reduction in Sim1 expression in the forelimbs of GE embryos at day 8(E8)compared to WT counterparts.Despite this,GE chickens developed structurally normal flight and tail feathers.In situ hybridization localized Sim1 expression to the posterior mesenchyme surrounding flight feather buds in E8 WT embryos,but not within the buds themselves.These results suggest that partial deletion of Sim1-ASHCE,despite diminishing Sim1 expression,does not disrupt flight feather formation.The excised region appears to possess enhancer activity toward Sim1 but is dispensable for flight feather development.Complete ablation of the ASHCE will be necessary to fully resolve the regulatory role of Sim1 in avian feather morphogenesis.
基金supported by the National Natural Science Foundation of China(grants 81970910 and 82370931)Jiangsu Province Capability Improvement Project through Science,Technology and Education-Jiangsu Provincial Research Hospital Cultivation Unit(YJXYYJSDW4)Jiangsu Provincial Medical Innovation Center(CXZX202227).
文摘Plp1-lineage Schwann cells(SCs)of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing,and the abnormal plasticity of SCs would jeopardize the bone regeneration.However,how Plp1-lineage cells respond to injury and initiate the vascularized osteogenesis remains incompletely understood.Here,by employing single-cell transcriptional profiling combined with lineage-specific tracing models,we uncover that Plp1-lineage cells undergoing injury-induced glia-to-MSCs transition contributed to osteogenesis and revascularization in the initial stage of bone injury.Importantly,our data demonstrated that the Sonic hedgehog(Shh)signaling was responsible for the transition process initiation,which was strongly activated by c-Jun/SIRT6/BAF170 complex-driven Shh enhancers.Collectively,these findings depict an injuryspecific niche signal-mediated Plp1-lineage cells transition towards Gli1+MSCs and may be instructive for approaches to promote bone regeneration during aging or other bone diseases.
基金Supported by Hunan Provincial Natural Science Foundation of China,No.2022JJ40836the Key Project of Research and Development Plan of Hunan Province,No.2023DK2002the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation,No.GZC20242045.
文摘BACKGROUND The mortality rate for severe cases of acute pancreatitis(AP),a common gastrointestinal emergency,is as high as 30%.Our previous study has shown that rutaecarpine(Rut)has a therapeutic effect on AP.AIM To investigate the role of F-box and WD repeat domain containing 11(FBXW11)in AP models and to assess whether Rut mitigates AP by regulating FBXW11.METHODS AP rat model was established and treated with Rut,followed by biochemical analysis of serum amylase and lipase,hematoxylin and eosin staining of pancreatic tissue,and immunohistochemistry detection of pancreatic Ly6G,CD11b,and myeloperoxidase.Assay kits were used to detect oxidative stress-related indicators in pancreatic tissue and inflammatory factors in serum.AR42J cells were treated with cerulein to model AP and subjected to Cell Counting Kit-8 viability assay,flow cytometry apoptosis assay,and immunofluorescence detection of reactive oxygen species to elucidate the mechanistic involvement of the enhancer of zeste homolog 2(EZH2)-FBXW11 axis in Rut-mediated protection against AP.The EZH2-histone H3 binding and H3 methylation were evaluated using co-immunoprecipitation.RESULTS Rut treatment ameliorated AP severity,as evidenced by reduced serum levels of pancreatic enzymes(amylase and lipase)and attenuated histological damage.Rut also decreased inflammatory markers(interleukin-1 beta,interleukin-6,and tumor necrosis factor alpha),tissue oxidative stress(malondialdehyde),and neutrophil infiltration(Ly6G,CD11b,and myeloperoxidase)levels in rats with AP.Moreover,Rut restored pancreatic antioxidant capacity(glutathione and superoxide dismutase).In vitro,Rut pre-incubation enhanced cell viability and suppressed cerulein-induced apoptosis and oxidative stress.Rut increased EZH2 expression while decreasing FBXW11 expression.FBXW11 overexpression eliminated the protective effect of Rut against AP.Further analysis revealed that EZH2 binds to H3 and upregulates H3 methylation levels,thereby inhibiting FBXW11 expression.CONCLUSION Collectively,our findings demonstrate that Rut ameliorates AP by upregulating EZH2,thereby enhancing H3 methylation and suppressing FBXW11 expression.
基金funded by the Natural Science Research Project of Anhui Educational Committee(2023AH050650)the Research Fund Program of Anhui Medical University(2023xkj176).
文摘Backgrounds:As cancer progresses through various stages of malignancy,metastasis,and drug resistance,the Wnt/-catenin signaling is frequently dysregulated.Despite advancements in medical technology and therapeutic strategies,the prognosis for numerous gastric cancer patients remains unfavorable.Methods:For the analysis of prognostic signature genes associated with Wnt signaling in GC,we used LASSO(least absolute shrinkage and selection operator)regression.To explore the function,cell specificity,and transcriptional regulation of the signature gene Carboxypeptidase Z(CPZ),we conducted co-expression analysis,single-cell RNA sequencing data analysis,transcription factor prediction,and dual luciferase reporter assay.The knockdown and overexpression experiments were also performed to observe the changes in the downstream gene expression,as well as the influence on the biological functions of GC cells.Results:We identified a five-gene signature,including CPZ,Collagen Triple Helix Repeat Containing-1(CTHRC1),Dickkopf-1(DKK1),Epidermal Growth Factor(EGF),and Glypican Proteoglycan-3(GPC3),with risk scores predictive of the prognosis of GC patients.We found that the adipocyte enhancer binding protein 1(AEBP1)and transcription factor 3(TCF3)could interact in the nucleus and synergistically enhance the expression of Wnt signaling-associated genes,including WNT2/FZD2(Wnt family member 2/frizzled class receptor 2)and VIM(vimentin),thus promoting the invasion,migration,and malignant metastasis of GC.Conclusions:Our study offers a precise gene-signature prediction method for the prognosis of GC.We discovered the synergistic effect of AEBP1 and TCF3 in the nucleus on GC metastasis.GC may benefit from the identification of this potential therapeutic target.
基金supported by the National Science Fund for Excellent Young Scholars(NSFC-82322058)the Program of National Natural Science Foundation of China(NSFC-82103929,NSFC-82273713)+10 种基金the Young Elite Scientists Sponsorship Program by CAST(2022QNRC001)the National Science Fund for Distinguished Young Scholars of Hubei Province of China(2023AFA046)the Fundamental Research Funds for the Central Universities(WHU:2042022kf1205)Fundamental Research Funds for the Central Universities(WHU:2042022kf1031)for Ying Zhuthe Fundamental Research Funds for the Central Universities(2042022rc0026,2042023kf1005)for Xiao-Ping Miaothe Knowledge Innovation Program of Wuhan(whkxjsj011,2023020201010073)for Jian-Bo Tianthe Science and Technology Innovation Seed Fund of Zhongnan Hospital of Wuhan University(znpy2019060)for Yong-Chang Weithe Distinguished Young Scholars of China(NSFC-81925032)the Key Program of National Natural Science Foundation of China(NSFC-82130098)the Youth Program of National Natural Science Foundation of China(NSFC-82003547)the Program of Health Commission of Hubei Province(WJ2023M045)。
文摘Background:Dysregulation of enhancer transcription occurs in multiple cancers.Enhancer RNAs(eRNAs)are transcribed products from enhancers that play critical roles in transcriptional control.Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers.Methods:Initially,a comprehensive analysis of eRNA quantitative trait loci(eRNAQTLs)was performed in The Cancer Genome Atlas(TCGA),and functional features were characterized using multi-omics data.To establish the first eRNAQTL profiles for colorectal cancer(CRC)in China,epigenomic data were used to define active enhancers,which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples.Finally,largescale case-control studies(34,585 cases and 69,544 controls)were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk.Results:A total of 300,112 eRNAQTLs were identified across 30 different cancer types,which exert their influence on eRNA transcription by modulating chromatin status,binding affinity to transcription factors and RNA-binding proteins.These eRNAQTLs were found to be significantly enriched in cancer risk loci,explaining a substantial proportion of cancer heritability.Additionally,tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer.Moreover,the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer,highlighting their potential as therapeutic targets.Furthermore,multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China(OR=0.91,95%CI 0.88–0.95,P=2.92×10^(-7))and Europe(OR=0.92,95%CI 0.88–0.95,P=4.61×10^(-6)).Mechanistically,rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786,which functioned as a transcriptional activator promoting the expression of its target gene SENP7.These two genes synergistically suppressed tumor cell proliferation.Our curated list of variants,genes,and drugs has been made available in CancereRNAQTL(http://canernaqtl.whu.edu.cn/#/)to serve as an informative resource for advancing this field.Conclusion:Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability,pinpointing the potential of eRNA-based therapeutic strategies in cancers.
基金Supported by Liaoning Provincial Science and Technology Department Project,No.2023JH2/101700149Open Fund Project of Liaoning University of Traditional Chinese Medicine,No.zyzx2205.
文摘BACKGROUND Colorectal cancer(CRC)is a malignant tumor characterized by high global incidence and mortality rates.Contemporary therapeutic modalities remain limited by suboptimal efficacy and adverse effects,thereby necessitating the pursuit of more efficacious treatment strategies.Within traditional Chinese medicine,spleen deficiency is regarded as a central pathogenic mechanism in CRC,persisting throughout the entire disease course.AIM To elucidate the mechanism by which modified Yigong San confers therapeutic efficacy against CRC,potentially exerting its effects through apoptosis regulation mediated by the enhancer of zeste homolog 2(EZH2)/methyltransferase-like 3(METTL3)/SRY-box transcription factor 4(SOX4)axis.METHODS In the clinical study,CRC tissues and corresponding adjacent normal samples that fulfilled inclusion criteria were procured.Quantitative reverse transcription polymerase chain reaction was employed to determine the transcriptional expression of EZH2 and METTL3 mRNA.For in vitro experimentation,SW-480 cells were allocated into five experimental conditions:Control,control+serum,control+negative control,control+overexpressing-EZH2,and control+overexpressing-EZH2+serum.The mRNA expression levels of EZH2,METTL3,SOX4,B-cell lymphoma 2,and Bax across groups were quantified via quantitative reverse transcription polymerase chain reaction,while protein levels were assessed using western blot analysis.The presence of EZH2 binding sites within the METTL3 promoter region was verified through chromatin immunoprecipitation polymerase chain reaction.The optimal concentration of drug-containing serum(5%,10%,15%)was determined using the Cell Counting Kit-8 assay.Cell migratory ability was evaluated via scratch assays,and apoptotic activity was quantified by flow cytometry.RESULTS The clinical findings demonstrated significantly elevated transcriptional levels of METTL3 and EZH2 mRNA in tumor tissues compared to their adjacent normal counterparts(P<0.05).In vitro,cells treated with modified Yigong San exhibited a substantial downregulation of EZH2,METTL3,SOX4,B-cell lymphoma 2,and Bax mRNA and protein levels(P<0.05),relative to the control group.Apoptotic rates were markedly increased,while migratory capacity was significantly attenuated.Furthermore,in EZH2-overexpressing cells treated with modified Yigong San,similar reductions in both mRNA and protein levels of the aforementioned targets were observed(P<0.05),concomitant with enhanced apoptosis and reduced migration.Chromatin immunoprecipitation polymerase chain reaction analysis confirmed EZH2 occupancy at specific loci within the METTL3 promoter.CONCLUSION Modified Yigong San exhibits both preventive and therapeutic potential against CRC,likely mediated through the regulation of apoptosis via the EZH2/METTL3/SOX4 signaling pathway.
基金the National Natural Science Foundation of China(Grant No.82072580).
文摘The abnormality of the p53 tumor suppressor is crucial in lung cancer development,because p53 regulates target gene promoters to combat cancer.Recent studies have shown extensive p53 binding to enhancer elements.However,whether p53 exerts a tumor suppressor role by shaping the enhancer landscape remains poorly understood.In the current study,we employed several functional genomics approaches to assess the enhancer activity at p53 binding sites throughout the genome based on our established TP53 knockout(KO)human bronchial epithelial cells(BEAS-2B).A total of 943 active regular enhancers and 370 super-enhancers(SEs)disappeared upon the deletion of p53,indicating that p53 modulates the activity of hundreds of enhancer elements.We found that one p53-dependent SE,located on chromosome 9 and designated as KLF4-SE,regulated the expression of the Krüppel-like factor 4(KLF4)gene.Furthermore,the deletion of p53 significantly decreased the KLF4-SE enhancer activity and the KLF4 expression,but increased colony formation ability in the nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced cell transformation model.Subsequently,in TP53 KO cells,the overexpression of KLF4 partially reversed the increased clonogenic capacity caused by p53 deficiency.Consistently,KLF4 expression also decreased in lung cancer tissues and cell lines.It appeared that overexpression of KLF4 significantly suppressed the proliferation and migration of lung cancer cells.Collectively,our results suggest that the regulation of enhancer formation and activity by p53 is an integral component of the p53 tumor suppressor function.Therefore,our findings offer some novel insights into the regulation mechanism of p53 in lung oncogenesis and introduce a new strategy for screening therapeutic targets.
基金supported by the National Natural Science Foundation of China(81971875,82300661)Natural Science Foundation of Anhui province(2308085QH246)+3 种基金Natural Science Foundation of the Anhui Higher Education Institutions(KJ2021A0205)Basic and Clinical Cooperative Research Program of Anhui Medical University(2019xkjT002,2019xkjT022,2022xkjT013)Talent Training Program,School of Basic Medical Sciences,Anhui Medical University(2022YPJH102)National College Students Innovation and Entrepreneurship Training Program of China(202210366024)。
文摘Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.
文摘Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related deaths worldwide.Major treatments include liver transplantation,resection,and chemotherapy,but the 5-year recurrence rate remains high.Late diagnosis often prevents surgical intervention,contributing to poor patient survival rates.Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones.Enhancer of zeste homolog 2(EZH2),a key regulator of cell cycle progression,is frequently upregulated in HCC and is associated with advanced stages and poor prognosis,making it a potential biomarker.Additionally,signal transducer and activator of transcription 3,which binds to EZH2,affects disease staging and outcomes.Targeting EZH2 presents a promising therapeutic strategy.On the other hand,abnormal lipid metabolism is a hallmark of HCC and impacts prognosis.Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes,suggesting its potential as a biomarker.Other genes such as guanine monophosphate synthase,cell division cycle associated 5,and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC,offering potential as biomarkers and therapeutic targets.
基金supported by the National Key R&D Program of China(Grant No.2020YFB1806400)the China Scholarship Council(Grant No.202306230183)the National Natural Science Foundation of China(Grant Nos.62271305 and 62001287).
文摘We propose a joint look-up-table(LUT)-based nonlinear predistortion and digital resolution enhancement scheme to achieve high-speed and low-cost optical interconnects using low-resolution digital-to-analog converters(DACs).The LUT-based predistortion is employed to mitigate the patterndependent effect(PDE)of a semiconductor optical amplifier(SOA),while the digital resolution enhancer(DRE)is utilized to shape the quantization noise,lowering the requirement for the resolution of DAC.We experimentally demonstrate O-band intensity modulation and direct detection(IM/DD)transmission of 124-GBd 4∕6-level pulse-amplitude modulation ePAMT-4∕6 and 112-GBd PAM-8 signals over a 2-km standard single-mode fiber(SSMF)with 3∕3.5∕4-bit DACs.In the case of 40-km SSMF transmission with an SOAbased preamplifier,124-GBd on-off-keying(OOK)/PAM-3/PAM-4 signals are successfully transmitted with 1.5∕2∕3-bit DACs.To the best of our knowledge,we have achieved the highest net data rates of 235.3-Gb∕s PAM-4,289.7-Gb∕s PAM-6,and 294.7 Gb∕s PAM-8 signals over 2-km SSMF,as well as 117.6-Gb∕s OOK,173.8-Gb∕s PAM-3,and−231.8 Gb∕s PAM-4 signals over 40-km SSMF,employing low-resolution DACs.The experimental results reveal that the joint LUT-based predistortion and DRE effectively mitigate the PDE and improve the signal-to-quantization noise ratio by shaping the noise.The proposed scheme can provide a powerful solution for low-cost IM/DD optical interconnects beyond 200 Gb∕s.
基金funded by the Starting Fund from Zhejiang University to N.L.and grants to X.L.from National Natural Science Foundation of China(82170120 and 81670108)CAMS Initiative for Innovative Medicine(2017-12M-B&R-04)+2 种基金Medical Epigenetics Research Cen-ter,CAMS(2018PT31015)the State Key Laboratory of Medical Molecular Biology(2060204)Haihe L aboratory of Cell Ecosystem Innovation Fund(22HHXBSS00008).
文摘The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease.Through a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell development.FAM46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific enhancer.We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner.Furthermore,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis.In conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.
文摘Borneol, as a traditional natural permeation enhancer, has been widely used to promote the transdermal absorption of active ingredients. In this review, the mechanism of borneol in promoting permeation by destroying the highly ordered lipid structure of the lipid layer and by destroying the hydrogen-bond network was described. The application of borneol in promoting the transdermal absorption of the active ingredients of traditional Chinese medicine and chemical drugs was introduced. The application of borneol as a natural ingredient added to functional cosmetics was summarized, and its effects on skin-spot treatment, acne skin care, eczema skin care, skin repair and anti-oxidation were introduced. Finally, the possible problems in the application of borneol in cosmetics were put forward, and the application prospect of borneol in the development of cosmetics was given.
