查看更多>>摘要：Malformations of cortical development(MCD)are a group of developmental disor-ders characterized by abnormal cortical structures caused by genetic or harmful environ-mental factors.Many kinds of MCD are caused by genetic variation.MCD is the common cause of intellectual disability and intractable epilepsy.With rapid advances in imaging and sequencing technologies,the diagnostic rate of MCD has been increasing,and many potential genes causing MCD have been successively identified.However,the high genetic heterogeneity of MCD makes it challenging to understand the molecular pathogenesis of MCD and to identify effective targeted drugs.Thus,in this review,we outline important events of cortical devel-opment.Then we illustrate the progress of molecular genetic studies about MCD focusing on the PI3K/PTEN/AKT/mTOR pathway.Finally,we briefly discuss the diagnostic methods,disease models,and therapeutic strategies for MCD.The information will facilitate further research on MCD.Understanding the role of the PI3K/PTEN/AKT/mTOR pathway in MCD could lead to a novel strategy for treating MCD-related diseases.
查看更多>>摘要：N6-methyladenosine(m6A)methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years.Cardiovascular diseases(CVDs)are a leading cause of death globally.Emerging evidence demonstrates that RNA modifications,such as the m6A modification,are associated with the development and progression of many diseases,including CVDs.An increasing body of studies has indicated that programmed cell death(PCD)plays a vital role in CVDs.However,the mo-lecular mechanisms underlying m6A modification and PCD in CVDs remain poorly understood.Herein,elaborating on the highly complex connections between the m6A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m6A modi-fication mediating PCD have significant meaning in developing new strategies for the preven-tion and therapy of CVDs.There is great potential for clinical application.
查看更多>>摘要：Nicotinamide adenine dinucleotide(NAD+)/reduced NAD+(NADH)and nicotin-amide adenine dinucleotide phosphate(NADP+)/reduced NADP+(NADPH)are essential metab-olites involved in multiple metabolic pathways and cellular processes.NAD+and NADH redox couple plays a vital role in catabolic redox reactions,while NADPH is crucial for cellular anab-olism and antioxidant responses.Maintaining NAD(H)and NADP(H)homeostasis is crucial for normal physiological activity and is tightly regulated through various mechanisms,such as biosynthesis,consumption,recycling,and conversion between NAD(H)and NADP(H).The con-versions between NAD(H)and NADP(H)are controlled by NAD kinases(NADKs)and NADP(H)phosphatases[specifically,metazoan SpoT homolog-1(MESH1)and nocturnin(NOCT)].NADKs facilitate the synthesis of NADP+from NAD+,while MESH1 and NOCT convert NADP(H)into NAD(H).In this review,we summarize the physiological roles of NAD(H)and NADP(H)and discuss the regulatory mechanisms governing NAD(H)and NADP(H)homeostasis in three key as-pects:the transcriptional and posttranslational regulation of NADKs,the role of MESH1 and NOCT in maintaining NAD(H)and NADP(H)homeostasis,and the influence of the circadian clock on NAD(H)and NADP(H)homeostasis.In conclusion,NADKs,MESH1,and NOCT are integral to various cellular processes,regulating NAD(H)and NADP(H)homeostasis.Dysregulation of these enzymes results in various human diseases,such as cancers and metabolic disorders.Hence,strategies aiming to restore NAD(H)and NADP(H)homeostasis hold promise as novel therapeu-tic approaches for these diseases.
查看更多>>摘要：Mutations or abnormal expression of oncogenes and tumor suppressor genes are known to cause cancer.Recent studies have shown that epigenetic modifications are key drivers of cancer development and progression.Nevertheless,the mechanistic role of epige-netic dysregulation in the tumor microenvironment is not fully understood.Here,we reviewed the role of epigenetic modifications of cancer cells and non-cancer cells in the tumor micro-environment and recent research advances in cancer epigenetic drugs.In addition,we dis-cussed the great potential of epigenetic combination therapies in the clinical treatment of cancer.However,there are still some challenges in the field of cancer epigenetics,such as epigenetic tumor heterogeneity,epigenetic drug heterogeneity,and crosstalk between epige-netics,proteomics,metabolomics,and other omics,which may be the focus and difficulty of cancer treatment in the future.In conclusion,epigenetic modifications in the tumor microen-vironment are essential for future epigenetic drug development and the comprehensive treat-ment of cancer.Epigenetic combination therapy may be a novel strategy for the future clinical treatment of cancer.
查看更多>>摘要：Hematopoiesis represents a meticulously regulated and dynamic biological process.Genetic aberrations affecting blood cells,induced by various factors,frequently give rise to hematological tumors.These instances are often accompanied by a multitude of abnormal post-transcriptional regulatory events,including RNA alternative splicing,RNA localization,RNA degradation,and storage.Notably,post-transcriptional regulation plays a pivotal role in preserving hematopoietic homeostasis.The DEAD-Box RNA helicase genes emerge as crucial post-transcriptional regulatory factors,intricately involved in sustaining normal hematopoiesis through diverse mechanisms such as RNA alternative splicing,RNA modification,and ribosome assembly.This review consolidates the existing knowledge on the role of DEAD-box RNA heli-cases in regulating normal hematopoiesis and underscores the pathogenicity of mutant DEAD-Box RNA helicases in malignant hematopoiesis.Emphasis is placed on elucidating both the pos-itive and negative contributions of DEAD-box RNA helicases within the hematopoietic system.
查看更多>>摘要：Vitamin D binding protein(VDBP)serves as a key transporter protein responsible for binding and delivering vitamin D and its metabolites to target organs.VDBP plays a crucial part in the inflammatory reaction following tissue damage and is engaged in actin degradation.Recent research has shed light on its potential role in various diseases,leading to a growing interest in understanding the implications of VDBP in psychiatric and neurological disorders.The purpose of this review was to provide a summary of the existing understanding regarding the involvement of VDBP in neurological and psychiatric disorders.By examining the intricate interplay between VDBP and these disorders,this review contributes to a deeper understand-ing of underlying mechanisms and potential therapeutic avenues.Insights gained from the study of VDBP could pave the way for novel strategies in the diagnosis,prognosis,and treat-ment of psychiatric and neurological disorders.
查看更多>>摘要：Developmental defects of enamel are common due to genetic and environmental factors before and after birth.Cdc42,a Rho family small GTPase,regulates prenatal tooth development in mice.However,its role in postnatal tooth development,especially enamel for-mation,remains elusive.Here,we investigated Cdc42 functions in mouse enamel development and tooth repair after birth.Cdc42 showed highly dynamic temporospatial patterns in the developing incisors,with robust expression in ameloblast and odontoblast layers.Strikingly,epithelium-specific Cdc42 deletion resulted in enamel defects in incisors.Ameloblast differen-tiation was inhibited,and hypomineralization of enamel was observed upon epithelial Cdc42 deletion.Proteomic analysis showed that abnormal mitochondrial components,phosphotrans-ferase activity,and ion channel regulator activity occurred in the Cdc42 mutant dental epithe-lium.Reactive oxygen species accumulation was detected in the mutant mice,suggesting that abnormal oxidative stress occurred after Cdc42 depletion.Moreover,Cdc42 mutant mice showed delayed tooth repair and generated less calcified enamel.Mitochondrial dysfunction and abnormal oxygen consumption were evidenced by reduced Apool and Timm8a1 expression,increased Atp5j2 levels,and reactive oxygen species overproduction in the mutant repair epithelium.Epithelium-specific Cdc42 deletion attenuated ERK1/2 signaling in the labial cer-vical loop.Aberrant Sox2 expression in the mutant labial cervical loop after clipping might lead to delayed tooth repair.These findings suggested that mitochondrial dysfunction,up-regulated oxidative stress,and abnormal ion channel activity may be among multiple factors responsible for the observed enamel defects in Cdc42 mutant incisors.Overall,Cdc42 exerts multidimen-sional and pivotal roles in enamel development and is particularly required for ameloblast dif-ferentiation and enamel matrix formation.
查看更多>>摘要：As a pathological hallmark of type 2 diabetes mellitus(T2DM),islet amyloid is formed by the aggregation of islet amyloid polypeptide(IAPP).Endoplasmic reticulum(ER)stress interacts with IAPP aggregates and has been implicated in the pathogenesis of T2DM.To examine the role of ER stress in T2DM,we cloned the hIAPP promoter and analyzed its pro-moter activity in human β-cells.We found that ER stress significantly enhanced hIAPP promoter activity and expression in human β-cells via triggering X-box binding protein 1(XBP1)splicing.We identified a binding site of XBP1 in the hIAPP promoter.Disruption of this binding site by substitution or deletion mutagenesis significantly diminished the effects of ER stress on hIAPP promoter activity.Blockade of XBP splicing by MKC3946 treatment inhibited ER stress-induced hIAPP up-regulation and improved human β-cell survival and function.Our study uncovers a link between ER stress and IAPP at the transcriptional level and may provide novel insights into the role of ER stress in IAPP cytotoxicity and the pathogenesis of T2DM.
查看更多>>摘要：Fibroblast activation and extracellular matnx(ECM)deposition play an important role in the tracheal abnormal repair process and fibrosis.As a transcription factor,SOX9 is involved in fibroblast activation and ECM deposition.However,the mechanism of how SOX9 regulates fibrosis after tracheal injury remains unclear.We investigated the role of SOX9 in TGF-β1-induced fibroblast activation and ECM deposition in rat tracheal fibroblast(RTF)cells.SOX9 overexpression adenovirus(Ad-SOX9)and siRNA were transfected into RTF cells.We found that SOX9 expression was up-regulated in RTF cells treated with TGF-β1.SOX9 overex-pression activated fibroblasts and promoted ECM deposition.Silencing SOX9 inhibited cell pro-liferation,migration,and ECM deposition,induced G2 arrest,and increased apoptosis in RTF cells.RNA-seq and chromatin immunoprecipitation sequencing(ChlP-seq)assays identified MMP10,a matrix metalloproteinase involved in ECM deposition,as a direct target of SOX9,which promotes ECM degradation by increasing MMP10 expression through the Wnt/β-catenin signaling pathway.Furthermore,in vivo,SOX9 knockdown ameliorated granulation prolifera-tion and tracheal fibrosis,as manifested by reduced tracheal stenosis.In conclusion,our find-ings indicate that SOX9 can drive fibroblast activation,cell proliferation,and apoptosis resistance in tracheal fibrosis via the Wnt/β-catenin signaling pathway.The SOX9-MMP10-ECM biosynthesis axis plays an important role in tracheal injury and repair.Targeting SOX9 and its downstream target MMP10 may represent a promising therapeutic approach for tracheal fibrosis.
查看更多>>摘要：T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malig-nancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease.In this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to iden-tify potential stage-specific druggable targets and repositioned drugs for this disease.This mul-ti-omics integration helped identify 29 potential pathological genes for T-ALL.These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling pathway.Of these,four known druggable tar-gets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL.The TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-pos-itive stage.CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naive to maturation stages.Furthermore,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in T-ALL.Collectively,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.
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