目的探讨糖尿病肾病(diabetic nephropathy,DN)患者外周血单个核细胞中miR-92b-5p水平与高迁移率族蛋白Box1(high mobility group protein box1,HMGB1)/核因子κB(nuclear factor-κB,NF-κB)通路的相关性。方法选择2020年3月-2021年2...目的探讨糖尿病肾病(diabetic nephropathy,DN)患者外周血单个核细胞中miR-92b-5p水平与高迁移率族蛋白Box1(high mobility group protein box1,HMGB1)/核因子κB(nuclear factor-κB,NF-κB)通路的相关性。方法选择2020年3月-2021年2月在河南省老干部康复医院就诊的197例2型糖尿病患者作为研究对象,合并DN患者96例作为DN组,无DN患者101例作为单纯糖尿病组,选择健康受检者100例作为对照组。采用实时定量PCR检测外周血单个核细胞中miR-92b-5p相对表达量,采用酶联免疫吸附法检测血清中HMGB1、NF-κB水平。采用受试者工作特征曲线分析miR-92b-5p对DN的诊断价值。结果DN组和单纯糖尿病组患者外周血单个核细胞中miR-92b-5p相对表达量显著低于对照组,DN组患者外周血单个核细胞中miR-92b-5p相对表达量显著低于单纯糖尿病组,差异有统计学意义(P<0.05)。DN组和单纯糖尿病组患者血清中HMGB1、NF-κB水平显著高于对照组,DN组患者血清中HMGB1、NF-κB水平显著高于单纯糖尿病组,差异有统计学意义(P<0.05)。受试者工作特征曲线结果显示,曲线下面积为0.935(95%CI 0.900~0.971,P<0.01)。DN患者miR-92-5p相对表达量与血清HMGB1、NF-κB水平均成负相关(r值分别为-0.376、-0.417,P<0.05)。结论miR-92-5p参与DN的疾病调控过程,且与HMGB1/NF-κB通路表达密切相关,可作为DN潜在的诊断靶标。展开更多
Objective: Ethyl Pyruvate (EP) has been shown to be an effective anti-inflammatory agent in a variety of model systems. The aim of this study was to investigate the effects of EP on High Mobility Group Box1(HMGB1) gen...Objective: Ethyl Pyruvate (EP) has been shown to be an effective anti-inflammatory agent in a variety of model systems. The aim of this study was to investigate the effects of EP on High Mobility Group Box1(HMGB1) genes expression and the possible mechanisms of EP protecting against acute lung injury induced by sepsis. Methods: Forty Wistar rats were randomly divided into normal controls,sham operation,acute lung injury,and EP treatment (40 mg/kg intra-peritoneally every 6 hrs) groups. At the time points of 24 hours the animals in each group were sacrificed, and the lungs were harvested. Wet/dry lung weight ratio, the protein in the bronchoalveolar lavage fluid(BALF),and pulmonary permeability index(PPI) were determined. The histological morphology of lung was observed under microscope. The expression of HMGB1 mRNA was measured using semi-quantitative RT-PCR. Results: EP treatment decreased wet/dry lung weight ratio, the protein in the BALF,and PPI (P<0.01). The histological morphology of lung injury was ameliorated. EP significantly inhibited the HMGB1 mRNA expression(P<0.01). HMGB1 mRNA expression in lungs positively correlation with wet/dry lung weight ratio, the protein in the BALF,and PPI. Conclusion: EP administered inhibits HMGB1 mRNA expression, and protects the lungs against acute injury induced by sepsis.展开更多
High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the ex...High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.展开更多
BACKGROUND Accumulating studies indicated that maintain nuclei homeostasis was deemed to the protective factors for the occurrence of cancer.Thus,high-mobility group box 1(HMGB1)might influence the risk and poorer pro...BACKGROUND Accumulating studies indicated that maintain nuclei homeostasis was deemed to the protective factors for the occurrence of cancer.Thus,high-mobility group box 1(HMGB1)might influence the risk and poorer prognoses of colorectal cancer(CRC).AIM This study was designed to investigate whether HMGB1 polymorphisms influence the risk and lymph node metastasis(LNM)of CRC.METHODS Firstly,we designed an investigation with 1003 CRC patients and 1303 cancer-free controls to observe whether HMGB1 rs1412125 T>C and rs1045411 C>T SNPs could influence the risk of cancer.Subsequently,we carried out a correlation-analysis to assess whether these SNPs could alter the risk of LNM.RESULTS The current investigation suggested a relationship of HMGB1 rs1412125 SNP with the increased susceptibility of CRC.In a subgroup analysis,our findings suggested that this SNP could enhance an occurrence of CRC in≥61 years,non-drinker and body mass index<24 kg/m2 subgroups.However,we found that there was null association between HMGB1 rs1412125 SNP and LNM,even in different CRC region.These observations were confirmed by calculating the power value(more than 0.8).The association of HMGB1 rs1045411 C>T SNP with CRC risk and LNM was not found in any compare.CONCLUSION This study highlights a possible association between HMGB1 rs1412125 polymorphism and the increased risk of CRC.In the future,more studies should be conducted to explore HMGB1 rs1412125 polymorphism in relation to CRC development.展开更多
High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental auto...High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.展开更多
Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the...Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the role of high mobility group box 1(HMGB1)in oligodendrocyte precursor cells(OPCs)in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier(BBB)by using OPC-specific HMGB1 knockout(KO)mice.We found that HMGB1 released from OPCs promotes BBB disruption,subsequently allowing increased immune cell infiltration.The migration of CD4+T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes(OLs).OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS,leading to less damage to the myelin sheath and mitigated EAE progression.CD4+T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs.Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.展开更多
OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions a...OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions and important signaling pathways of the Rab27-and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database,gene ontology database,Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis.Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results.Colon length,body weight,and disease activity index were measured.Hematoxylin and eosin staining was applied to validate the histopathology.Tight junction proteins were detected by immunohistochemistry.The proportions of T helper 17 cells(Th17)and regulatory T cells(Treg)in mesenteric lymph nodes were measured viaflow cytometry.Proinflammatory cytokines like interleukin(IL)17(IL-17),IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factorβand IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction,respectively.The expression levels of high mobility group box 1(HMGB1),P53 and phospho-P53(P-P53)in colonic tissues were detected by immunofluorescence and Western blotting.RESULTS:Bioinformatics analysis revealed that compared with normal tissues,the expression of Rab27 was significantly increased in UC tissues.Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity.Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport,nutrient metabolism,transmembrane transport and the downstream pathway of P53.According to animal experiments,the expression of Rab27 was increased in UC tissues,which aggravated the colonic pathological damage,activated the expression of HMGB1,and also leaded to the imbalance of Th17 and Treg cells.After CAD intervention,Rab27 overexpression,weight loss,colon shortening,and pathological damage were substantial reduced,the expression of tight junction proteins,zona occludens 1 and Occludin were increased.The effect of CAD at high-dose was more obvious.In addition,CAD upgraded the number of Treg cells and the production of TGF-βand IL-10,while decreasing the number of Th17 cells and the expression of inflammatory cytokines(IL-17,IL-21,and IL-22).Moreover,colon inflammation was alleviated by CAD,as indicated by the regulation of HMGB1 and P-P53 expression.CONCLUSION:The expression of Rab27,HMGB1 and P-P53 could be decreased by CAD,and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.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
Objective:The World Health Organization(WHO)grading based on histopathology cannot always accurately predict tumor behavior of meningiomas.To overcome the limitations of the WHO grading,the study aims to propose a nov...Objective:The World Health Organization(WHO)grading based on histopathology cannot always accurately predict tumor behavior of meningiomas.To overcome the limitations of the WHO grading,the study aims to propose a novel oxidative stress-based molecular classification for WHO grade 2/3 meningiomas.Methods:Differentially expressed oxidative stress-related genes were analyzed between 86 WHO grade 1(low grade)meningiomas and 99 grade 2/3(high grade)meningiomas.An oxidative stress-based molecular classification was developed in high-grade meningiomas through consensus clustering analysis.Immune microenvironment features,responses to immunotherapy and chemotherapy,and targeted drugs were evaluated.Three machine learning models:logistic regression,support vector machine,and random forest,were built for differentiating the classification.Key oxidative stress-related geneswere verified in humanmeningeal cells(HMC)and two meningioma cells(CH-157MN and IOMMLee)via reverse transcription quantitative polymerase chain reaction(RT-qPCR)and western blot.After knockdown of Forkhead Box M1(FOXM1)or Prion Protein(PRNP),cell growth,migration,and reactive oxygen species(ROS)levels were measured through cell counting kit-8(CCK-8),transwell,and immunofluorescence,respectively.Results:We classified high-grade meningiomas into two oxidative stress-based clusters,termed cluster 1 and cluster 2.Cluster 1 exhibited higher infiltrations of immune and stromal cells and higher expression of classic immune checkpoints:Cluster of Differentiation 86(CD86),Programmed Cell Death 1(PDCD1),and Leukocyte-Associated Immunoglobulin-Like Receptor 1(LAIR1),indicating that cluster 1 meningiomas might respond to immunotherapy.Drug sensitivity was heterogeneous between the two clusters.Three classifiers were established,which could accurately differentiate this molecular classification.FOXM1 and PRNP were experimentally evidenced to be highly expressed inmeningioma cells,and their knockdown hindered cell growth and migration and triggered ROS accumulation.Conclusion:In summary,our findings established a novel oxidative stress-based molecular classification and identified potential treatment vulnerabilities in high-grade meningiomas,which might assist personalized clinical management.展开更多
BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but th...BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but the detailed mechanism is still unclear.Most studies ofβ-cell dedifferentiation rely on rodent models and human pathological specimens.The development of in vitro systems can facilitate the exploration ofβ-cell dedifferentiation.AIM To investigate the molecular mechanism ofβ-cell dedifferentiation.Hence,an in vitro model ofβ-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1832/13 cell line.METHODS The study was further analyzed using RNA-sequencing,transmission electron microscopy,quantitative real-time polymerase chain reaction and Western blot.RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulatedβ-cell forbidden genes and endocrine precursor cell marker genes,and down-regulated the expression ofβ-cell specific markers.Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum(ER)stressrelated genes.Moreover,the results also showed that forkhead box O1(Foxo1)inhibition potentiated genetic changes inβ-cell dedifferentiation induced by palmitic acid and high glucose.CONCLUSION ER stress is sufficient to triggerβ-cell dedifferentiation and is necessary for palmitic acid and high glucose-inducedβ-cell dedifferentiation.Foxo1 inhibition can further enhance these phenomena.展开更多
BACKGROUND Cervical cancer(CC)stem cell-like cells(CCSLCs),defined by the capacity of differentiation and self-renewal and proliferation,play a significant role in the progression of CC.However,the molecular mechanism...BACKGROUND Cervical cancer(CC)stem cell-like cells(CCSLCs),defined by the capacity of differentiation and self-renewal and proliferation,play a significant role in the progression of CC.However,the molecular mechanisms regulating their self-renewal are poorly understood.Therefore,elucidation of the epigenetic mechanisms that drive cancer stem cell self-renewal will enhance our ability to improve the effectiveness of targeted therapies for cancer stem cells.AIM To explore how DNA methyltransferase 1(DNMT1)/miR-342-3p/Forkhead box M1(FoxM1),which have been shown to have abnormal expression in CCSLCs,and their signaling pathways could stimulate self-renewal-related stemness in CCSLCs.METHODS Sphere-forming cells derived from CC cell lines HeLa,SiHa and CaSki served as CCSLCs.Self-renewal-related stemness was identified by determining sphere and colony formation efficiency,CD133 and CD49f protein level,and SRY-box transcription factor 2 and octamer-binding transcription factor 4 mRNA level.The microRNA expression profiles between HeLa cells and HeLa-derived CCSLCs or mRNA expression profiles that HeLaderived CCSLCs were transfected with or without miR-342-3p mimic were compared using quantitative PCR analysis.The expression levels of DNMT1 mRNA,miR-342-3p,and FoxM1 protein were examined by quantitative real-time PCR and western blotting.In vivo carcinogenicity was assessed using a mouse xenograft model.The functional effects of the DNMT1/miR-342-3p/FoxM1 axis were examined by in vivo and in vitro gain-of-activity and loss-of-activity assessments.Interplay among DNMT1,miR-342-3p,and FoxM1 was tested by methylationspecific PCR and a respective luciferase reporter assay.RESULTS CCSLCs derived from the established HeLa cell lines displayed higher self-renewal-related stemness,including enhanced sphere and colony formation efficiency,increased CD133 and CD49f protein level,and heightened transcriptional quantity of stemness-related factors SRY-box transcription factor 2 and octamer-binding transcription factor 4 in vitro as well as a stronger tumorigenic potential in vivo compared to their parental cells.Moreover,quantitative PCR showed that the miR-342-3p level was downregulated in HeLa-derived CCSLCs compared to HeLa cells.Its mimic significantly decreased DNMT1 and FoxM1 mRNA expression levels in CCSLCs.Knockdown of DNMT1 or miR-342-3p mimic transfection suppressed DNMT1 expression,increased miR-342-3p quantity by promoter demethylation,and inhibited CCSLC self-renewal.Inhibition of FoxM1 by shRNA transfection also resulted in the attenuation of CCSLC self-renewal but had little effect on the DNMT1 activity and miR-342-3p expression.Furthermore,the loss of CCSLC self-renewal exerted by miR-342-3p mimic was inverted by the overexpression of DNMT1 or FoxM1.Furthermore,DNMT1 and FoxM1 were recognized as straight targets by miR-342-3p in HeLa-derived CCSLCs.CONCLUSION Our findings suggested that a novel DNMT1/miR-342-3p/FoxM1 signal axis promotes CCSLC self-renewal and presented a potential target for the treatment of CC through suppression of CCSLC self-renewal.However,this pathway has been previously implicated in CC,as evidenced by prior studies showing miR-342-3p-mediated downregulation of FoxM1 in cervical cancer cells.Additionally,research on liver cancer further supports the involvement of miR-342-3p in suppressing FoxM1 expression.While our study contributed to this body of knowledge,we did not present a completely novel axis but reinforced the therapeutic potential of targeting the DNMT1/miR-342-3p/FoxM1 axis to suppress CCSLC self-renewal in CC treatment.展开更多
目的:探究宫腔粘连(Intrauterine adhesion,IUA)患者子宫内膜组织中高迁移率族蛋白B1(High mobility group box1,HMGB1)、高迁移率族蛋白A2(High mobility group protein A2,HMGA2)和表皮生长因子受体(Epidermal growth factor receptor...目的:探究宫腔粘连(Intrauterine adhesion,IUA)患者子宫内膜组织中高迁移率族蛋白B1(High mobility group box1,HMGB1)、高迁移率族蛋白A2(High mobility group protein A2,HMGA2)和表皮生长因子受体(Epidermal growth factor receptor,EGFR)表达与病情及预后关系。方法:选取2021年8月-2023年8月本院收治的68例IUA患者(IUA组)和60例正常宫腔患者(对照组),采用免疫组化法检测HMGB1、HMGA2和EGFR表达,分析其与病情严重程度及预后不良的关系。结果:IUA组HMGB1阳性表达率低于对照组,HMGA2和EGFR阳性表达率显著升高(P<0.05)。随着病情加重,IUA患者子宫内膜组织中HMGB1阳性表达率依次降低,HMGA2和EGFR阳性表达率依次升高(P<0.05)。单因素分析显示,患者预后不良与流产史、术前月经量、粘连范围、粘连性质、HMGB1、HMGA2及EGFR表达情况有关(P<0.05),与年龄和病程无关(P>0.05)。多因素Logistic回归分析显示,流产史>3次、术前闭经、粘连范围>2/3、粘连性质肌性、HMGB1阴性表达、HMGA2及EGFR阳性表达是患者术后复发的危险因素(P<0.05)。结论:IUA患者子宫内膜组织中HMGB1低表达及HMGA2和EGFR高表达与患者病情程度及预后有关,可作为患者患病程度及不良预后的评估指标。展开更多
Objective Non-small cell lung cancer(NSCLC)is a leading cause of cancer-associated mortality.This study aimed to investigate the role of checkpoint kinase 1(CHEK1)in NSCLC progression and its regulatory relationship w...Objective Non-small cell lung cancer(NSCLC)is a leading cause of cancer-associated mortality.This study aimed to investigate the role of checkpoint kinase 1(CHEK1)in NSCLC progression and its regulatory relationship with forkhead box protein M1(FOXM1).Methods Transwell assays were used to evaluate the migration and invasion capabilities of NSCLC cells with either CHEK1 overexpression or knockdown.The expression of epithelial−mesenchymal transition(EMT)markers in NSCLC cells under CHEK1 overexpression or knockdown conditions was analyzed via Western blotting.Proliferative capacity was assessed using CCK-8 assays in NSCLC cells with modulated CHEK1 expression.Additionally,real-time quantitative PCR was employed to measure CHEK1 and FOXM1 expression levels in NSCLC tissues.The effects of CHEK1 knockdown on tumor growth were further validated in animal models.The binding of FOXM1 to the CHEK1 promoter region was examined using dual-luciferase reporter assays and chromatin immunoprecipitation(ChIP)assays.Results FOXM1 and CHEK1 were upregulated in NSCLC tissues.CHEK1 overexpression promoted NSCLC cell proliferation,while its knockdown suppressed proliferation,inhibited EMT,and reduced tumor growth in vivo.FOXM1 was shown to directly bind to CHEK1 promoter,thereby upregulating CHEK1 expression.Conclusion CHEK1 promotes NSCLC cell proliferation and tumor growth,and its expression is regulated by FOXM1.These findings suggest CHEK1 and FOXM1 are potential therapeutic targets for NSCLC treatment.展开更多
In this editorial,we highlight the study by Wang et al published in a recent issue of the World Journal of Diabetes.Type 2 diabetes is increasingly recognized as a β-cell dysfunction disorder,with apoptosis and dedif...In this editorial,we highlight the study by Wang et al published in a recent issue of the World Journal of Diabetes.Type 2 diabetes is increasingly recognized as a β-cell dysfunction disorder,with apoptosis and dedifferentiation being key factors in insulin secretion loss.β-cell dedifferentiation is a regression from a mature insulin-secretory phenotype to a progenitor-like state,characterized by the loss of key transcription factors such as pancreatic and duodenal homeobox 1 and MAF bZIP transcription factor A,and the ectopic expression of developmental markers such as neurogenin 3 and aldehyde dehydrogenase 1 family member A3.This editorial discusses the key role of metabolic stress-saturated fatty acids and high glucose-in triggering dedifferentiation through endoplasmic reticulum(ER)stress and repression of the forkhead box protein O1(FoxO1)transcription factor.The study by Wang et al demonstrated how ER dysfunction and FoxO1 suppression collaborate to destabilizeβ-cell identity.Notably,evidence suggests that this process can be reversed under certain circumstances,with potential for therapies aiming to redifferentiateβ-cells or prevent identity loss.We also outline the therapeutic potential of modulating ER stress pathways,controlling FoxO1 activity,and developing biomarkers to trackβ-cell plasticity in patients.Overall,β-cell dedifferentiation knowledge and manipulation offer new avenues for the treatment of diabetes by restoring functionalβ-cell mass.展开更多
Objective Innate lymphoid cells(ILCs)are a class of newly discovered immunocytes.Group 1 ILCs(ILC1s)are identified in the decidua of humans and mice.High mobility group box 1(HMGB1)is predicted to be one of the target...Objective Innate lymphoid cells(ILCs)are a class of newly discovered immunocytes.Group 1 ILCs(ILC1s)are identified in the decidua of humans and mice.High mobility group box 1(HMGB1)is predicted to be one of the target genes of miR-142-3p,which is closely related to pregnancy-related diseases.Furthermore,miR-142-3p and HMGB1 are involved in regulating the NF-κB signaling pathway.This study aimed to examine the regulatory effect of miR-142-3p on ILC1s and the underlying mechanism involving HMGB1 and the NF-κB signaling pathway.Methods Mouse models of normal pregnancy and abortion were constructed,and the alterations of ILC1s,miR-142-3p,ILC1 transcription factor(T-bet),and pro-inflammatory cytokines of ILC1s(TNF-α,IFN-γand IL-2)were detected in mice from different groups.The targeting regulation of HMGB1 by miR-142-3p in ILC1s,and the expression of HMGB1 in normal pregnant mice and abortive mice were investigated.In addition,the regulatory effects of miR-142-3p and HMGB1 on ILC1s were detected in vitro by CCK-8,Annexin-V/PI,ELISA,and RT-PCR,respectively.Furthermore,changes of the NF-κB signaling pathway in ILC1s were examined in the different groups.For the in vivo studies,miR-142-3p-Agomir was injected in the uterus of abortive mice to evaluate the abortion rate and alterations of ILC1s at the maternal-fetal interface,and further detect the expression of HMGB1,pro-inflammatory cytokines,and the NF-κB signaling pathway.Results The number of ILC1s was significantly increased,the level of HMGB1 was significantly upregulated,and that of miR-142-3p was considerably downregulated in the abortive mice as compared with the normal pregnant mice(all P<0.05).In addition,miR-142-3p was found to drastically inhibit the activation of the NF-κB signaling pathway(P<0.05).The number of ILC1s and the levels of pro-inflammatory cytokines were significantly downregulated and the activation of the NF-κB signaling pathway was inhibited in the miR-142-3p Agomir group(all P<0.05).Conclusion miR-142-3p can regulate ILC1s by targeting HMGB1 via the NF-κB signaling pathway,and attenuate the inflammation at the maternal-fetal interface in abortive mice.展开更多
BACKGROUND Diabetic intracerebral hemorrhage(ICH)is a serious complication of diabetes.The role and mechanism of bone marrow mesenchymal stem cell(BMSC)-derived exosomes(BMSC-exo)in neuroinflammation post-ICH in patie...BACKGROUND Diabetic intracerebral hemorrhage(ICH)is a serious complication of diabetes.The role and mechanism of bone marrow mesenchymal stem cell(BMSC)-derived exosomes(BMSC-exo)in neuroinflammation post-ICH in patients with diabetes are unknown.In this study,we investigated the regulation of BMSC-exo on hyperglycemia-induced neuroinflammation.AIM To study the mechanism of BMSC-exo on nerve function damage after diabetes complicated with cerebral hemorrhage.METHODS BMSC-exo were isolated from mouse BMSC media.This was followed by transfection with microRNA-129-5p(miR-129-5p).BMSC-exo or miR-129-5poverexpressing BMSC-exo were intravitreally injected into a diabetes mouse model with ICH for in vivo analyses and were cocultured with high glucoseaffected BV2 cells for in vitro analyses.The dual luciferase test and RNA immunoprecipitation test verified the targeted binding relationship between miR-129-5p and high-mobility group box 1(HMGB1).Quantitative polymerase chain reaction,western blotting,and enzyme-linked immunosorbent assay were conducted to assess the levels of some inflammation factors,such as HMGB1,interleukin 6,interleukin 1β,toll-like receptor 4,and tumor necrosis factorα.Brain water content,neural function deficit score,and Evans blue were used to measure the neural function of mice.RESULTS Our findings indicated that BMSC-exo can promote neuroinflammation and functional recovery.MicroRNA chip analysis of BMSC-exo identified miR-129-5p as the specific microRNA with a protective role in neuroinflammation.Overexpression of miR-129-5p in BMSC-exo reduced the inflammatory response and neurological impairment in comorbid diabetes and ICH cases.Furthermore,we found that miR-129-5p had a targeted binding relationship with HMGB1 mRNA.CONCLUSION We demonstrated that BMSC-exo can reduce the inflammatory response after ICH with diabetes,thereby improving the neurological function of the brain.展开更多
文摘目的探讨糖尿病肾病(diabetic nephropathy,DN)患者外周血单个核细胞中miR-92b-5p水平与高迁移率族蛋白Box1(high mobility group protein box1,HMGB1)/核因子κB(nuclear factor-κB,NF-κB)通路的相关性。方法选择2020年3月-2021年2月在河南省老干部康复医院就诊的197例2型糖尿病患者作为研究对象,合并DN患者96例作为DN组,无DN患者101例作为单纯糖尿病组,选择健康受检者100例作为对照组。采用实时定量PCR检测外周血单个核细胞中miR-92b-5p相对表达量,采用酶联免疫吸附法检测血清中HMGB1、NF-κB水平。采用受试者工作特征曲线分析miR-92b-5p对DN的诊断价值。结果DN组和单纯糖尿病组患者外周血单个核细胞中miR-92b-5p相对表达量显著低于对照组,DN组患者外周血单个核细胞中miR-92b-5p相对表达量显著低于单纯糖尿病组,差异有统计学意义(P<0.05)。DN组和单纯糖尿病组患者血清中HMGB1、NF-κB水平显著高于对照组,DN组患者血清中HMGB1、NF-κB水平显著高于单纯糖尿病组,差异有统计学意义(P<0.05)。受试者工作特征曲线结果显示,曲线下面积为0.935(95%CI 0.900~0.971,P<0.01)。DN患者miR-92-5p相对表达量与血清HMGB1、NF-κB水平均成负相关(r值分别为-0.376、-0.417,P<0.05)。结论miR-92-5p参与DN的疾病调控过程,且与HMGB1/NF-κB通路表达密切相关,可作为DN潜在的诊断靶标。
文摘Objective: Ethyl Pyruvate (EP) has been shown to be an effective anti-inflammatory agent in a variety of model systems. The aim of this study was to investigate the effects of EP on High Mobility Group Box1(HMGB1) genes expression and the possible mechanisms of EP protecting against acute lung injury induced by sepsis. Methods: Forty Wistar rats were randomly divided into normal controls,sham operation,acute lung injury,and EP treatment (40 mg/kg intra-peritoneally every 6 hrs) groups. At the time points of 24 hours the animals in each group were sacrificed, and the lungs were harvested. Wet/dry lung weight ratio, the protein in the bronchoalveolar lavage fluid(BALF),and pulmonary permeability index(PPI) were determined. The histological morphology of lung was observed under microscope. The expression of HMGB1 mRNA was measured using semi-quantitative RT-PCR. Results: EP treatment decreased wet/dry lung weight ratio, the protein in the BALF,and PPI (P<0.01). The histological morphology of lung injury was ameliorated. EP significantly inhibited the HMGB1 mRNA expression(P<0.01). HMGB1 mRNA expression in lungs positively correlation with wet/dry lung weight ratio, the protein in the BALF,and PPI. Conclusion: EP administered inhibits HMGB1 mRNA expression, and protects the lungs against acute injury induced by sepsis.
基金supported by a grant of the M.D.-Ph.D./Medical Scientist Training Program through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(to HK)+3 种基金supported by National Research Foundation of Korea(NRF)grants funded by the Korean government(MSITMinistry of Science and ICT)(NRF2019R1A5A2026045 and NRF-2021R1F1A1061819)a grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(HR21C1003)New Faculty Research Fund of Ajou University School of Medicine(to JYC)。
文摘High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.
基金Supported by the Major Project of Changzhou Science and Technology Bureau,No.CJ20220255.
文摘BACKGROUND Accumulating studies indicated that maintain nuclei homeostasis was deemed to the protective factors for the occurrence of cancer.Thus,high-mobility group box 1(HMGB1)might influence the risk and poorer prognoses of colorectal cancer(CRC).AIM This study was designed to investigate whether HMGB1 polymorphisms influence the risk and lymph node metastasis(LNM)of CRC.METHODS Firstly,we designed an investigation with 1003 CRC patients and 1303 cancer-free controls to observe whether HMGB1 rs1412125 T>C and rs1045411 C>T SNPs could influence the risk of cancer.Subsequently,we carried out a correlation-analysis to assess whether these SNPs could alter the risk of LNM.RESULTS The current investigation suggested a relationship of HMGB1 rs1412125 SNP with the increased susceptibility of CRC.In a subgroup analysis,our findings suggested that this SNP could enhance an occurrence of CRC in≥61 years,non-drinker and body mass index<24 kg/m2 subgroups.However,we found that there was null association between HMGB1 rs1412125 SNP and LNM,even in different CRC region.These observations were confirmed by calculating the power value(more than 0.8).The association of HMGB1 rs1045411 C>T SNP with CRC risk and LNM was not found in any compare.CONCLUSION This study highlights a possible association between HMGB1 rs1412125 polymorphism and the increased risk of CRC.In the future,more studies should be conducted to explore HMGB1 rs1412125 polymorphism in relation to CRC development.
基金supported by the National Natural Science Foundation of China(82001281 and 82371195)Hubei Provincial Natural Science Foundation of China for Distinguished Young Scholars(2022CFA104)the Research Fund of Jianghan University(2022XKZX28).
文摘High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
基金supported by the National Research Foundation of Korea(NRF)funded by the government of the Republic of Korea[2023R1A2C1004955]the Technology Innovation Program funded by the Ministry of Trade,Industry&Energy(Korea)(20009707)+1 种基金the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(2020R1A6A3A01099056)the Korea Institute for Advancement of Technology funded by the Ministry of Trade,Industry and Energy(P0025489).
文摘Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model,experimental autoimmune encephalomyelitis(EAE).This study investigates the role of high mobility group box 1(HMGB1)in oligodendrocyte precursor cells(OPCs)in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier(BBB)by using OPC-specific HMGB1 knockout(KO)mice.We found that HMGB1 released from OPCs promotes BBB disruption,subsequently allowing increased immune cell infiltration.The migration of CD4+T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes(OLs).OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS,leading to less damage to the myelin sheath and mitigated EAE progression.CD4+T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs.Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.
基金Supported by Lingnan Medical Research Center of Guangzhou University of Chinese MedicineNational Natural Science Foundation of China:Mechanism of Chang’an Decoction in Intestinal Mucosal Immunity of Ulcerative Colitis on Exocrine Mediated Rab27(81903963)Natural Science Foundation of Guangdong Province:the Role of the Neuropeptide Spexin-associated Gycogen Synthase Kinase-3βSignaling Pathway in Regulating the Enteric Nervous-immune Network in Ulcerative Colitis and the Intervention Mechanism of Chang’an Formula(2018A030310614)。
文摘OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions and important signaling pathways of the Rab27-and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database,gene ontology database,Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis.Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results.Colon length,body weight,and disease activity index were measured.Hematoxylin and eosin staining was applied to validate the histopathology.Tight junction proteins were detected by immunohistochemistry.The proportions of T helper 17 cells(Th17)and regulatory T cells(Treg)in mesenteric lymph nodes were measured viaflow cytometry.Proinflammatory cytokines like interleukin(IL)17(IL-17),IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factorβand IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction,respectively.The expression levels of high mobility group box 1(HMGB1),P53 and phospho-P53(P-P53)in colonic tissues were detected by immunofluorescence and Western blotting.RESULTS:Bioinformatics analysis revealed that compared with normal tissues,the expression of Rab27 was significantly increased in UC tissues.Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity.Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport,nutrient metabolism,transmembrane transport and the downstream pathway of P53.According to animal experiments,the expression of Rab27 was increased in UC tissues,which aggravated the colonic pathological damage,activated the expression of HMGB1,and also leaded to the imbalance of Th17 and Treg cells.After CAD intervention,Rab27 overexpression,weight loss,colon shortening,and pathological damage were substantial reduced,the expression of tight junction proteins,zona occludens 1 and Occludin were increased.The effect of CAD at high-dose was more obvious.In addition,CAD upgraded the number of Treg cells and the production of TGF-βand IL-10,while decreasing the number of Th17 cells and the expression of inflammatory cytokines(IL-17,IL-21,and IL-22).Moreover,colon inflammation was alleviated by CAD,as indicated by the regulation of HMGB1 and P-P53 expression.CONCLUSION:The expression of Rab27,HMGB1 and P-P53 could be decreased by CAD,and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.
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 Hubei Provincial Natural Science Foundation of China(grants 2023AFB208)the Chinese Primary Health Care Foundation(Grant No.cphcf-2022-222)+2 种基金2025 Hubei Provincial Natural Science Foundation Innovation and Development Joint Fund Project:(JCZRLH202500457)Shanghai Foundation for Anti-Cancer&Cancer Prevention Development Phase II Exploration Oncology Research Fund Project:“Study on the Mechanism of ANO9-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma”(No Grant Number)Qingdao Sheci Public Welfare Relief Center Pan-Cancer Treatment Research Fund Project:(QD-HN30008).
文摘Objective:The World Health Organization(WHO)grading based on histopathology cannot always accurately predict tumor behavior of meningiomas.To overcome the limitations of the WHO grading,the study aims to propose a novel oxidative stress-based molecular classification for WHO grade 2/3 meningiomas.Methods:Differentially expressed oxidative stress-related genes were analyzed between 86 WHO grade 1(low grade)meningiomas and 99 grade 2/3(high grade)meningiomas.An oxidative stress-based molecular classification was developed in high-grade meningiomas through consensus clustering analysis.Immune microenvironment features,responses to immunotherapy and chemotherapy,and targeted drugs were evaluated.Three machine learning models:logistic regression,support vector machine,and random forest,were built for differentiating the classification.Key oxidative stress-related geneswere verified in humanmeningeal cells(HMC)and two meningioma cells(CH-157MN and IOMMLee)via reverse transcription quantitative polymerase chain reaction(RT-qPCR)and western blot.After knockdown of Forkhead Box M1(FOXM1)or Prion Protein(PRNP),cell growth,migration,and reactive oxygen species(ROS)levels were measured through cell counting kit-8(CCK-8),transwell,and immunofluorescence,respectively.Results:We classified high-grade meningiomas into two oxidative stress-based clusters,termed cluster 1 and cluster 2.Cluster 1 exhibited higher infiltrations of immune and stromal cells and higher expression of classic immune checkpoints:Cluster of Differentiation 86(CD86),Programmed Cell Death 1(PDCD1),and Leukocyte-Associated Immunoglobulin-Like Receptor 1(LAIR1),indicating that cluster 1 meningiomas might respond to immunotherapy.Drug sensitivity was heterogeneous between the two clusters.Three classifiers were established,which could accurately differentiate this molecular classification.FOXM1 and PRNP were experimentally evidenced to be highly expressed inmeningioma cells,and their knockdown hindered cell growth and migration and triggered ROS accumulation.Conclusion:In summary,our findings established a novel oxidative stress-based molecular classification and identified potential treatment vulnerabilities in high-grade meningiomas,which might assist personalized clinical management.
基金Supported by the Natural Science Foundation of China,No.81471081the Natural Science Foundation of Fujian Province,No.2023D009+1 种基金the Natural Science Foundation of Xiamen City,No.3502Z202373104 and No.3502Z20227162Scientific Research Foundation for Advanced Talents,Xiang’an Hospital of Xiamen University,No.PM201809170005。
文摘BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but the detailed mechanism is still unclear.Most studies ofβ-cell dedifferentiation rely on rodent models and human pathological specimens.The development of in vitro systems can facilitate the exploration ofβ-cell dedifferentiation.AIM To investigate the molecular mechanism ofβ-cell dedifferentiation.Hence,an in vitro model ofβ-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1832/13 cell line.METHODS The study was further analyzed using RNA-sequencing,transmission electron microscopy,quantitative real-time polymerase chain reaction and Western blot.RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulatedβ-cell forbidden genes and endocrine precursor cell marker genes,and down-regulated the expression ofβ-cell specific markers.Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum(ER)stressrelated genes.Moreover,the results also showed that forkhead box O1(Foxo1)inhibition potentiated genetic changes inβ-cell dedifferentiation induced by palmitic acid and high glucose.CONCLUSION ER stress is sufficient to triggerβ-cell dedifferentiation and is necessary for palmitic acid and high glucose-inducedβ-cell dedifferentiation.Foxo1 inhibition can further enhance these phenomena.
基金Supported by Guangzhou Basic and Applied Basic Research Foundation,No.202201010121Medical Joint Fund of Jinan University,No.YXZY2024014 and No.YXJC2022001+2 种基金Hospital Achievement Transformation and Cultivation Project,No.ZH201911the Key Discipline Project of Guangdong Province,No.2019-GDXK-0016and the Medical Science and Technology Research Foundation of Guangdong Province,No.B2021145.
文摘BACKGROUND Cervical cancer(CC)stem cell-like cells(CCSLCs),defined by the capacity of differentiation and self-renewal and proliferation,play a significant role in the progression of CC.However,the molecular mechanisms regulating their self-renewal are poorly understood.Therefore,elucidation of the epigenetic mechanisms that drive cancer stem cell self-renewal will enhance our ability to improve the effectiveness of targeted therapies for cancer stem cells.AIM To explore how DNA methyltransferase 1(DNMT1)/miR-342-3p/Forkhead box M1(FoxM1),which have been shown to have abnormal expression in CCSLCs,and their signaling pathways could stimulate self-renewal-related stemness in CCSLCs.METHODS Sphere-forming cells derived from CC cell lines HeLa,SiHa and CaSki served as CCSLCs.Self-renewal-related stemness was identified by determining sphere and colony formation efficiency,CD133 and CD49f protein level,and SRY-box transcription factor 2 and octamer-binding transcription factor 4 mRNA level.The microRNA expression profiles between HeLa cells and HeLa-derived CCSLCs or mRNA expression profiles that HeLaderived CCSLCs were transfected with or without miR-342-3p mimic were compared using quantitative PCR analysis.The expression levels of DNMT1 mRNA,miR-342-3p,and FoxM1 protein were examined by quantitative real-time PCR and western blotting.In vivo carcinogenicity was assessed using a mouse xenograft model.The functional effects of the DNMT1/miR-342-3p/FoxM1 axis were examined by in vivo and in vitro gain-of-activity and loss-of-activity assessments.Interplay among DNMT1,miR-342-3p,and FoxM1 was tested by methylationspecific PCR and a respective luciferase reporter assay.RESULTS CCSLCs derived from the established HeLa cell lines displayed higher self-renewal-related stemness,including enhanced sphere and colony formation efficiency,increased CD133 and CD49f protein level,and heightened transcriptional quantity of stemness-related factors SRY-box transcription factor 2 and octamer-binding transcription factor 4 in vitro as well as a stronger tumorigenic potential in vivo compared to their parental cells.Moreover,quantitative PCR showed that the miR-342-3p level was downregulated in HeLa-derived CCSLCs compared to HeLa cells.Its mimic significantly decreased DNMT1 and FoxM1 mRNA expression levels in CCSLCs.Knockdown of DNMT1 or miR-342-3p mimic transfection suppressed DNMT1 expression,increased miR-342-3p quantity by promoter demethylation,and inhibited CCSLC self-renewal.Inhibition of FoxM1 by shRNA transfection also resulted in the attenuation of CCSLC self-renewal but had little effect on the DNMT1 activity and miR-342-3p expression.Furthermore,the loss of CCSLC self-renewal exerted by miR-342-3p mimic was inverted by the overexpression of DNMT1 or FoxM1.Furthermore,DNMT1 and FoxM1 were recognized as straight targets by miR-342-3p in HeLa-derived CCSLCs.CONCLUSION Our findings suggested that a novel DNMT1/miR-342-3p/FoxM1 signal axis promotes CCSLC self-renewal and presented a potential target for the treatment of CC through suppression of CCSLC self-renewal.However,this pathway has been previously implicated in CC,as evidenced by prior studies showing miR-342-3p-mediated downregulation of FoxM1 in cervical cancer cells.Additionally,research on liver cancer further supports the involvement of miR-342-3p in suppressing FoxM1 expression.While our study contributed to this body of knowledge,we did not present a completely novel axis but reinforced the therapeutic potential of targeting the DNMT1/miR-342-3p/FoxM1 axis to suppress CCSLC self-renewal in CC treatment.
文摘目的:探究宫腔粘连(Intrauterine adhesion,IUA)患者子宫内膜组织中高迁移率族蛋白B1(High mobility group box1,HMGB1)、高迁移率族蛋白A2(High mobility group protein A2,HMGA2)和表皮生长因子受体(Epidermal growth factor receptor,EGFR)表达与病情及预后关系。方法:选取2021年8月-2023年8月本院收治的68例IUA患者(IUA组)和60例正常宫腔患者(对照组),采用免疫组化法检测HMGB1、HMGA2和EGFR表达,分析其与病情严重程度及预后不良的关系。结果:IUA组HMGB1阳性表达率低于对照组,HMGA2和EGFR阳性表达率显著升高(P<0.05)。随着病情加重,IUA患者子宫内膜组织中HMGB1阳性表达率依次降低,HMGA2和EGFR阳性表达率依次升高(P<0.05)。单因素分析显示,患者预后不良与流产史、术前月经量、粘连范围、粘连性质、HMGB1、HMGA2及EGFR表达情况有关(P<0.05),与年龄和病程无关(P>0.05)。多因素Logistic回归分析显示,流产史>3次、术前闭经、粘连范围>2/3、粘连性质肌性、HMGB1阴性表达、HMGA2及EGFR阳性表达是患者术后复发的危险因素(P<0.05)。结论:IUA患者子宫内膜组织中HMGB1低表达及HMGA2和EGFR高表达与患者病情程度及预后有关,可作为患者患病程度及不良预后的评估指标。
基金funded by the Suqian Science and Technology Program Project(No.K202008).
文摘Objective Non-small cell lung cancer(NSCLC)is a leading cause of cancer-associated mortality.This study aimed to investigate the role of checkpoint kinase 1(CHEK1)in NSCLC progression and its regulatory relationship with forkhead box protein M1(FOXM1).Methods Transwell assays were used to evaluate the migration and invasion capabilities of NSCLC cells with either CHEK1 overexpression or knockdown.The expression of epithelial−mesenchymal transition(EMT)markers in NSCLC cells under CHEK1 overexpression or knockdown conditions was analyzed via Western blotting.Proliferative capacity was assessed using CCK-8 assays in NSCLC cells with modulated CHEK1 expression.Additionally,real-time quantitative PCR was employed to measure CHEK1 and FOXM1 expression levels in NSCLC tissues.The effects of CHEK1 knockdown on tumor growth were further validated in animal models.The binding of FOXM1 to the CHEK1 promoter region was examined using dual-luciferase reporter assays and chromatin immunoprecipitation(ChIP)assays.Results FOXM1 and CHEK1 were upregulated in NSCLC tissues.CHEK1 overexpression promoted NSCLC cell proliferation,while its knockdown suppressed proliferation,inhibited EMT,and reduced tumor growth in vivo.FOXM1 was shown to directly bind to CHEK1 promoter,thereby upregulating CHEK1 expression.Conclusion CHEK1 promotes NSCLC cell proliferation and tumor growth,and its expression is regulated by FOXM1.These findings suggest CHEK1 and FOXM1 are potential therapeutic targets for NSCLC treatment.
基金Supported by Kuwait Foundation for the Advancement of Sciences,No.RACB-2021-007.
文摘In this editorial,we highlight the study by Wang et al published in a recent issue of the World Journal of Diabetes.Type 2 diabetes is increasingly recognized as a β-cell dysfunction disorder,with apoptosis and dedifferentiation being key factors in insulin secretion loss.β-cell dedifferentiation is a regression from a mature insulin-secretory phenotype to a progenitor-like state,characterized by the loss of key transcription factors such as pancreatic and duodenal homeobox 1 and MAF bZIP transcription factor A,and the ectopic expression of developmental markers such as neurogenin 3 and aldehyde dehydrogenase 1 family member A3.This editorial discusses the key role of metabolic stress-saturated fatty acids and high glucose-in triggering dedifferentiation through endoplasmic reticulum(ER)stress and repression of the forkhead box protein O1(FoxO1)transcription factor.The study by Wang et al demonstrated how ER dysfunction and FoxO1 suppression collaborate to destabilizeβ-cell identity.Notably,evidence suggests that this process can be reversed under certain circumstances,with potential for therapies aiming to redifferentiateβ-cells or prevent identity loss.We also outline the therapeutic potential of modulating ER stress pathways,controlling FoxO1 activity,and developing biomarkers to trackβ-cell plasticity in patients.Overall,β-cell dedifferentiation knowledge and manipulation offer new avenues for the treatment of diabetes by restoring functionalβ-cell mass.
基金supported by the National Key Research and Development Program of China(Nos.2018YFC1002804 and 2016YFC1000600)the National Natural Science Foundation of China(Nos.81771618 and 81971356)the Fundamental Research Funds for the Central Universities(No.2042023kf0028).
文摘Objective Innate lymphoid cells(ILCs)are a class of newly discovered immunocytes.Group 1 ILCs(ILC1s)are identified in the decidua of humans and mice.High mobility group box 1(HMGB1)is predicted to be one of the target genes of miR-142-3p,which is closely related to pregnancy-related diseases.Furthermore,miR-142-3p and HMGB1 are involved in regulating the NF-κB signaling pathway.This study aimed to examine the regulatory effect of miR-142-3p on ILC1s and the underlying mechanism involving HMGB1 and the NF-κB signaling pathway.Methods Mouse models of normal pregnancy and abortion were constructed,and the alterations of ILC1s,miR-142-3p,ILC1 transcription factor(T-bet),and pro-inflammatory cytokines of ILC1s(TNF-α,IFN-γand IL-2)were detected in mice from different groups.The targeting regulation of HMGB1 by miR-142-3p in ILC1s,and the expression of HMGB1 in normal pregnant mice and abortive mice were investigated.In addition,the regulatory effects of miR-142-3p and HMGB1 on ILC1s were detected in vitro by CCK-8,Annexin-V/PI,ELISA,and RT-PCR,respectively.Furthermore,changes of the NF-κB signaling pathway in ILC1s were examined in the different groups.For the in vivo studies,miR-142-3p-Agomir was injected in the uterus of abortive mice to evaluate the abortion rate and alterations of ILC1s at the maternal-fetal interface,and further detect the expression of HMGB1,pro-inflammatory cytokines,and the NF-κB signaling pathway.Results The number of ILC1s was significantly increased,the level of HMGB1 was significantly upregulated,and that of miR-142-3p was considerably downregulated in the abortive mice as compared with the normal pregnant mice(all P<0.05).In addition,miR-142-3p was found to drastically inhibit the activation of the NF-κB signaling pathway(P<0.05).The number of ILC1s and the levels of pro-inflammatory cytokines were significantly downregulated and the activation of the NF-κB signaling pathway was inhibited in the miR-142-3p Agomir group(all P<0.05).Conclusion miR-142-3p can regulate ILC1s by targeting HMGB1 via the NF-κB signaling pathway,and attenuate the inflammation at the maternal-fetal interface in abortive mice.
基金Supported by the National Natural Science Foundation of China,No.81900743Heilongjiang Province Outstanding Young Medical Talents Training Grant Project,China,No.HYD2020YQ0007.
文摘BACKGROUND Diabetic intracerebral hemorrhage(ICH)is a serious complication of diabetes.The role and mechanism of bone marrow mesenchymal stem cell(BMSC)-derived exosomes(BMSC-exo)in neuroinflammation post-ICH in patients with diabetes are unknown.In this study,we investigated the regulation of BMSC-exo on hyperglycemia-induced neuroinflammation.AIM To study the mechanism of BMSC-exo on nerve function damage after diabetes complicated with cerebral hemorrhage.METHODS BMSC-exo were isolated from mouse BMSC media.This was followed by transfection with microRNA-129-5p(miR-129-5p).BMSC-exo or miR-129-5poverexpressing BMSC-exo were intravitreally injected into a diabetes mouse model with ICH for in vivo analyses and were cocultured with high glucoseaffected BV2 cells for in vitro analyses.The dual luciferase test and RNA immunoprecipitation test verified the targeted binding relationship between miR-129-5p and high-mobility group box 1(HMGB1).Quantitative polymerase chain reaction,western blotting,and enzyme-linked immunosorbent assay were conducted to assess the levels of some inflammation factors,such as HMGB1,interleukin 6,interleukin 1β,toll-like receptor 4,and tumor necrosis factorα.Brain water content,neural function deficit score,and Evans blue were used to measure the neural function of mice.RESULTS Our findings indicated that BMSC-exo can promote neuroinflammation and functional recovery.MicroRNA chip analysis of BMSC-exo identified miR-129-5p as the specific microRNA with a protective role in neuroinflammation.Overexpression of miR-129-5p in BMSC-exo reduced the inflammatory response and neurological impairment in comorbid diabetes and ICH cases.Furthermore,we found that miR-129-5p had a targeted binding relationship with HMGB1 mRNA.CONCLUSION We demonstrated that BMSC-exo can reduce the inflammatory response after ICH with diabetes,thereby improving the neurological function of the brain.
