The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integrat...The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies.Human epidermal growth factor receptor,hormone receptors,and angiogenesis factors are among the established therapies in tumor reduction and managing side effects.Novel targeted therapies like KRAS G12C,Claudin-18 isoform 2(CLDN18.2),Trophoblast cell-surface antigen 2(TROP2),and epigenetic regulators emphasize their promise in advancing precision medicine.However,in many cases,the resistance mechanisms associated with these interventions render them ineffective in carrying out their functions.The purpose of this review is to provide a comprehensive and up-to-date examination of both established and emerging drug targets and mechanisms of treatment resistance in oncology.This review seeks to elucidate recent advancements,address persisting challenges,and explore opportunities for innovative developments in cancer target research.Additionally,it explores the growing role of artificial intelligence in reshaping cancer drug discovery and development frameworks as potential avenues for future research.In conclusion,innovative approaches in oncology,supported by pharmacological research,ongoing clinical trials,molecular biosciences,and artificial intelligence,are poised to significantly transform cancer treatment.展开更多
Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms...Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms are often overlooked.Recent evidence suggests that monocyte phenotypic plasticity plays a central role in PAD development,affecting atherogenesis,plaque progression,ischemia-reperfusion injury,and chronic ischemic remodeling.This narrative review aims to summarize the latest advances(2023-2025)in understanding monocyte diversity,functional states,and their changes throughout different stages of PAD.We discuss both established and emerging biomarkers,such as circulating monocyte subset proportions,functional assays,immune checkpoint expression,and multi-omics signatures,highlighting their potential for prognosis and the challenges in translating them to clinical practice.We also present a stage-specific approach to mapping out potential therapies,linking monocyte phenotypes to molecular targets and possible interventions.Additionally,we address regulatory,economic,and implementation considerations for applying these findings in a clinical setting.The goal of this review is to facilitate the development of targeted immunomodulatory strategies to improve limb and cardiovascular outcomes in PAD by combining mechanistic understanding with therapeutic innovation.展开更多
MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have sugge...MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer's disease,including the modulation and accumulation of amyloid-beta and tau proteins.Moreover,miRNAs have been implicated in the regulation of neuroinflammation thro ugh various inflammatory pathways,notably the nuclear factor kappa B signaling cascade.Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation,and they perform promising roles in regulating neuronal death and development.miRNAs also offer a novel avenue for direct reprogramming of neurons,representing a promising strategy for Alzheimer's disease treatment.The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer's disease pathology,influencing miRNA activity and disease progression.In this review,we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer's disease,focusing primarily on four representative miRNAs:miR-9,miR-29,miR-126,and miR-146a for further exploration.We also discuss the influence of miRNA biogenesis on Alzheimer's disease,emphasizing how dysregulation of miRNA processing may contribute to the disease.Additionally,we highlight the potential of miRNAs as both diagnostic biomarke rs and therapeutic targets in Alzheimer's disease,along with promising vector delive ry strategies aimed at improving clinical outcomes.Finally,we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer's disease.By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents,we aim to provide insights that will inform future research and development in this promising field.展开更多
Background:Giant cell arteritis(GCA),the most common systemic vasculitis affecting elderly individuals,currently lacks specific therapies.This study aimed to systematically identify therapeutic targets for GCA through...Background:Giant cell arteritis(GCA),the most common systemic vasculitis affecting elderly individuals,currently lacks specific therapies.This study aimed to systematically identify therapeutic targets for GCA through integration of large-scale multi-omics datasets.Methods:We constructed a multi-stage analytical framework encompassing 32 proteomic datasets(covering 2914 unique plasma proteins)and 6 transcriptomic datasets.Multi-omics integration strategies,including two-sample Mendelian randomization,colocalization analysis,and functional enrichment analysis,were employed to identify and validate causal relationships between candidate targets and GCA risk across 4 independent European-ancestry GCA cohorts.Single-cell RNA sequencing analysis of peripheral blood mononuclear cells from untreated GCA patients was performed to characterize hub gene-immune cell relationships.Results:We identified 43 plasma proteins causally associated with GCA[false discovery rate(FDR)<0.05],with 17 representing novel therapeutic targets.Through dual validation using proteome-wide association studies and transcriptome-wide association studies,we identified 13 high-confidence candidate targets with distinct tissue-specific expression patterns.Unc-51 like kinase 3(ULK3)emerged as the strongest protective factor(odds ratio=0.47,95%confidence interval:0.37–0.71)through autophagy regulation,while SLAMF7 represents an immediate drug repositioning opportunity as the target of food and drug administration-approved elotuzumab.Five targets have existing approved drugs(SLAMF7,ICAM1,IL18,IL6ST,CTSS).Single-cell analysis revealed profound disruption of hub gene-immune cell relationships in untreated GCA patients,with cell-type-specific alterations in inflammatory gene expression,and TYMP as the most critical hub gene.Conclusions:This study provides a clinically-actionable atlas of 43 potential therapeutic targets in GCA,identifying novel mechanisms including autophagy modulation and metabolic reprogramming,with immediate drug repositioning opportunities and precision medicine strategies based on tissue-specific and cell-type-specific expression patterns.These findings require experimental validation before clinical translation.展开更多
Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains c...Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.展开更多
We investigate the spatial and temporal correlations of hot-electron generation in high-intensity laser interaction with massive and thin copper targets under conditions relevant to inertial confinement fusion.Using K...We investigate the spatial and temporal correlations of hot-electron generation in high-intensity laser interaction with massive and thin copper targets under conditions relevant to inertial confinement fusion.Using Ka time-resolved imaging,it is found that in the case of massive targets,the hot-electron generation follows the laser pulse intensity with a short delay needed for favorable plasma formation.Conversely,a significant delay in the x-ray emission compared with the laser pulse intensity profile is observed in the case of thin targets.Theoretical analysis and numerical simulations suggest that this is related to radiation preheating of the foil and the increase in hot-electron lifetime in a hot expanding plasma.展开更多
Computing electrostatic interaction on non-cooperative targets with unknown meshes is crucial for electrostatic-based space on-orbit services.Although meshes for electrostatic interaction computations can be reconstru...Computing electrostatic interaction on non-cooperative targets with unknown meshes is crucial for electrostatic-based space on-orbit services.Although meshes for electrostatic interaction computations can be reconstructed from point clouds,they are usually too dense,leading to high computational costs.This paper presents an optimization method for converting dense meshes into optimal meshes,enabling fast and accurate computation of the electrostatic interaction by point clouds.First,the dense mesh reconstructed from point clouds is simplified into a coarse mesh using local operators.Second,the simplified mesh is refined by an iterative strategy that integrates a lightweight method of moments and an impedance matrix inheritance technique,ultimately yielding an optimal mesh for computing the electrostatic interaction.Simulation results show that our method effectively optimizes dense meshes,making electrostatic interaction computations using point clouds approximately 63.4 times more efficient than the previous method.展开更多
This paper addresses the three-dimensional(3-D)approach angle constrained cooperative guidance problem for speed-varying missiles against maneuvering targets.First,the guidance problem is formulated in a relative refe...This paper addresses the three-dimensional(3-D)approach angle constrained cooperative guidance problem for speed-varying missiles against maneuvering targets.First,the guidance problem is formulated in a relative reference frame and a virtual control input is selected.Then,the cooperative guidance law is designed on the basis of a prediction-correction framework.The time-to-go under the baseline command is estimated by an efficient prediction method with a realistic aerodynamic model and a biased command is developed by utilizing the time-to-go predictions for synchronizing different missiles'impact times.The design of the biased command is decoupled into the individual design of its direction and magnitude.It is proved that the designed cooperative guidance law can make the time-to-go consensus error converge to zero before interception.Finally,the designed guidance law is validated through a series of numerical simulations.展开更多
Background:Breast cancer(BC)remains one of the most prevalent and complex malignancies worldwide,necessitating advanced approaches for its study and treatment.Therefore,we conducted a comprehensive analysis merging pl...Background:Breast cancer(BC)remains one of the most prevalent and complex malignancies worldwide,necessitating advanced approaches for its study and treatment.Therefore,we conducted a comprehensive analysis merging plasma proteomics and transcriptomics to discover the potential druggable targets in BC.Methods:Our analytical framework encompassed following approaches:two-sample Mendelian randomization(MR)for protein analysis,summary-based MR(SMR)for transcript evaluation,along with colocalization studies of coding genes.This multi-omics strategy,coupled with protein-protein interaction(PPI)network and Gene Ontology(GO)analyses,revealed candidate biomarkers and their biological significance in BC.Results:We discovered 46 proteins showing significant associations with BC through analysis of pQTLs encompassing 3,707 plasma proteins derived from three extensive large-scale genome-wide association studies(GWAS),combined with blood-and tissue-specific expression QTLs.The previously identified 11 proteins through MR were annexin IV(ANX4),snurportin 1(SPN1),fibroblast growth factor receptor 2(FGFR2),rab GDP dissociation inhibitor beta,alpha-1,4-galactosyltransferase(A4GALT),toll like receptor1(TLR1),Unc-51 like kinase 3(ULK3),parkinsonism associated deglycase(PARK7),TNF receptor superfamily member 9(TNFRSF9),immunoglobulin superfamily containing leucine rich repeat(ISLR2),cathepsin F(CTSF).Importantly,our study provides novel causal genetic evidence for 34 additional proteins whose roles in BC had not previously been established through transcriptome-or proteome-wide MR analyses,even though some had been discussed in observational or mechanistic contexts.From these findings,five newly identified proteins SUGP1(OR 1.12,95%CI 1.06-1.18),PKD2(OR 1.38,95%CI 1.20-1.59),KAT3(OR 1.06,95%CI 1.03-1.09),HPLN4(OR 1.24,95%CI 1.12-1.38),GST M1-1(OR 0.96,95%CI 0.94-0.98),and SEM4A(OR 1.17,95%CI 1.09-1.26)demonstrated significance across MR,SMR,and colocalization studies.The remaining 27 proteins,including Coagulation Factor V,PTN9,TS101(TSG101),RSPO3,CGA,CEBPB,CASP8,RALB,SCAMP3,EIF2AK3,Sialoadhesin(SIGLEC1),NSF,CD68,sL-Selectin(SELL),F177A(FAM177A1),PEAR1,BY55,NIT2,ATX3,TFPI-2,NAG,Layilin,RCL,PDCD6,CILP2,DAG1 and CATF,emerged as potential therapeutic candidates as well.Conclusion:The multi-omics examination incorporating plasma proteins and gene transcripts revealed 46 promising drug candidates for BC,suggesting new treatments in future.展开更多
In recent years,multidisciplinary treatment strategies have profoundly improved drug responses and survival outcomes of breast cancer(BC)patients.However,there is an urgent need for novel therapies for BC patients who...In recent years,multidisciplinary treatment strategies have profoundly improved drug responses and survival outcomes of breast cancer(BC)patients.However,there is an urgent need for novel therapies for BC patients who are heavily treated or develop resistance to conventional treatment regimens.Radionuclide therapy(RT)and targeted radionuclide therapy(TRT)have emerged as paradigm-shifting therapeutic approaches for BC,which enable functions of both imaging and localised treatment.They utilise radionuclides that can selectively bind to biomarkers overexpressing on BC cells,allowing precise delivery and localised tumour irradiation.Moreover,several types of radionuclides possess‘cross-fire’effects that result in the eradication of neighbouring tumour cells lacking the biomarker expression.In the current review,we summarise the potential biomarkers for the development of RT and TRT that can be employed in the treatment of BC,including receptor markers of ER,PR and HER2,together with other markers of Trop2,PD-1,EGFR,GRPR and PSMA.展开更多
Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and...Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.展开更多
Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal lin...Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+cytotoxic T cell-related genes and ALS risk.Methods Single-cell RNA sequencing(scRNA-seq)of peripheral blood mononuclear cells(PBMCs)from patients with ALS and healthy controls(HC)was used to identify differentially expressed genes(DEGs)in CD4+cytotoxic T cells.Comprehensive analyses of CD4+cytotoxic T cells,including pseudotemporal trajectory,intercellular communication,and metabolic pathway analysis,were performed.Mendelian randomization(MR)analysis evaluated the causal effects of DEGs on ALS risk,with validation using independent genome-wide association study(GWAS)data.Expression patterns of the causal genes were further verified using scRNA-seq,bulk-seq,and clinical samples.Results CD4+cytotoxic T cells were significantly expanded in patients with ALS.The upregulated genes S100A6,SERPINB6,SMAD7,and TPST2 were positively correlated with ALS susceptibility,whereas DIP2A showed a protective association.Conclusion S100A6,SERPINB6,SMAD7,TPST2,and DIP2A were identified as causal genes and potential therapeutic targets in ALS,implicating CD4+cytotoxic T cells in the disease mechanisms.Further studies targeting these genes and neuroinflammatory pathways are warranted.展开更多
Elucidation of ligand-protein interactions provides new insights into the physiological functions and mechanisms of ligand molecules,enabling new ideas for the treatment of diseases,and drug discovery and development....Elucidation of ligand-protein interactions provides new insights into the physiological functions and mechanisms of ligand molecules,enabling new ideas for the treatment of diseases,and drug discovery and development.Most ligand-protein binding occurs only in specific regions of proteins.The identification of protein targets and binding regions is crucial for drug discovery and development,as well as for the in-depth study of drug-protein conformational relationships[1].展开更多
Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are ne...Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.展开更多
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neuro...Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neurological disease in humans.The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation ofβ-amyloid(Aβ)peptides is the main cause of the disease.Although this hypothesis has been found to be convincing,a growing body of evidence suggests that it does not fully explain the pathogenesis of AD.Neuroinflammation is a crucial element in the pathogenesis of AD,as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function.This paper will first summarize the impact of microglia-mediated neuroinflammation on AD,exploring the phenotypic changes that follow microglia activation.Secondly,the interactions between microglia,Aβ,microtubule-associated protein,apolipoprotein E and neurons are thoroughly investigated,with particular focus on the interactive mechanisms.Furthermore,the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed.A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD.This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD,with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.展开更多
Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical r...Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical research and,until recently,a series of disappointing clinical trials,no specific disease mod-ifying pharmacological treatment has yet been approved for this condition.Recent novel approaches to understanding the molecular pathogenesis of AP provide us with renewed optimism for translational drug discovery.Although digestive enzyme activation is the hallmark of AP,a critical mechanism that initiates AP is intracellular calcium(Ca2+)overload in pancreatic parenchymal cells,which triggers mitochondrial dysfunction,endoplasmic reticulum(ER)stress,and impairs autophagic flux.These processes are piv-otal to the disease and present a range of drug targets,associated with the inflammatory responses that drive local and systemic inflammation in AP.Progress in translation has now been made,targeting the ORAI channel with the inhibitor zegocractin(Auxora)to reduce pancreatic injury and inflammatory re-sponses in human AP.Herein we evaluated potential drug targets for the early treatment of AP,focused on intra-acinar mechanisms of injury central to the onset and severity of AP.Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies.展开更多
Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiolo...Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.展开更多
This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical...This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical regulators of mRNA stability,splicing,transport,translation,and degradation,directly influencing gene expression through sequence-and structure-specific binding.In the nervous system,RBPs sustain synaptic plasticity,neural development,and neuronal homeostasis.Emerging evidence shows that exercise modulates the expression and activity of RBPs,thereby influencing mRNA translation and neurotransmitter signaling,which may underlie its beneficial effects on brain function.Dysregulation of specific RBPs has been identified in SZ,implicating them in disrupted synaptic transmission,impaired plasticity,and neuroinflammation.RBPs involved in memory and emotional regulation show marked dysfunction in SZ patients.Some RBPs have been proposed as potential biomarkers for early diagnosis and treatment monitoring.Moreover,therapeutic modulation of RBPs,through pharmacological or behavioral interventions such as exercise,may restore neuronal function by targeting post-transcriptional gene regulation.Exercise,as a non-invasive modulator of RBP expression,holds promise as an adjunctive strategy in SZ treatment,particularly in early stages.Further research into RBP-mediated pathways may offer novel insights into SZ pathophysiology and inform the development of targeted interventions.展开更多
BACKGROUND Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS...BACKGROUND Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS A comprehensive analytical framework was developed to identify multi-omics biomarkers of DN.Protein-protein interaction network and Gene Ontology analyses were performed to explore the biological functions of biomarkers.Tier 1 target proteins were further analyzed.Candidate drug prediction and molecular docking studies were conducted to identify potential treatments while assessing the side effects of key target proteins.The mediation of immune cells in the association between proteins and DN was examined through two-step network Mendelian randomization(MR)analysis.RESULTS Nine DN-associated proteins were identified by analyzing protein quantitative trait loci from extensive genome-wide association study data.BTN3A1 and MICB were confirmed using MR,summary data-based MR,and colocalization analyses.Of the nine,HSPA1B,PSMB9,BTN3A1,SCGN,NOTUM,and MICB showed negative associations with DN,whereas WARS,BRD2,and CSNK2B were positive.Gene Ontology analysis indicated enrichment in inflammatory response and neuronal injury pathways.BTN3A1 and MICB were identified as Tier 1 targets.Drug prediction and molecular docking analyses indicated cyclosporin A as a potential therapeutic candidate.Two-step network MR analysis showed that MICB mediated DN through human leukocyte antigen-DR++monocytes.These integrated findings point to an immune-mediated mechanism with translational potential and nominate BTN3A1 and MICB for focused functional validation.CONCLUSION Our integrated multi-omics approach identified two promising therapeutic targets for DN,laying the groundwork for new treatment strategies and enhancing our understanding of MICB’s role in DN.展开更多
文摘The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies.Human epidermal growth factor receptor,hormone receptors,and angiogenesis factors are among the established therapies in tumor reduction and managing side effects.Novel targeted therapies like KRAS G12C,Claudin-18 isoform 2(CLDN18.2),Trophoblast cell-surface antigen 2(TROP2),and epigenetic regulators emphasize their promise in advancing precision medicine.However,in many cases,the resistance mechanisms associated with these interventions render them ineffective in carrying out their functions.The purpose of this review is to provide a comprehensive and up-to-date examination of both established and emerging drug targets and mechanisms of treatment resistance in oncology.This review seeks to elucidate recent advancements,address persisting challenges,and explore opportunities for innovative developments in cancer target research.Additionally,it explores the growing role of artificial intelligence in reshaping cancer drug discovery and development frameworks as potential avenues for future research.In conclusion,innovative approaches in oncology,supported by pharmacological research,ongoing clinical trials,molecular biosciences,and artificial intelligence,are poised to significantly transform cancer treatment.
文摘Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms are often overlooked.Recent evidence suggests that monocyte phenotypic plasticity plays a central role in PAD development,affecting atherogenesis,plaque progression,ischemia-reperfusion injury,and chronic ischemic remodeling.This narrative review aims to summarize the latest advances(2023-2025)in understanding monocyte diversity,functional states,and their changes throughout different stages of PAD.We discuss both established and emerging biomarkers,such as circulating monocyte subset proportions,functional assays,immune checkpoint expression,and multi-omics signatures,highlighting their potential for prognosis and the challenges in translating them to clinical practice.We also present a stage-specific approach to mapping out potential therapies,linking monocyte phenotypes to molecular targets and possible interventions.Additionally,we address regulatory,economic,and implementation considerations for applying these findings in a clinical setting.The goal of this review is to facilitate the development of targeted immunomodulatory strategies to improve limb and cardiovascular outcomes in PAD by combining mechanistic understanding with therapeutic innovation.
基金National Natural Science Foundation of China,No.82405067(to YW)。
文摘MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer's disease,including the modulation and accumulation of amyloid-beta and tau proteins.Moreover,miRNAs have been implicated in the regulation of neuroinflammation thro ugh various inflammatory pathways,notably the nuclear factor kappa B signaling cascade.Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation,and they perform promising roles in regulating neuronal death and development.miRNAs also offer a novel avenue for direct reprogramming of neurons,representing a promising strategy for Alzheimer's disease treatment.The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer's disease pathology,influencing miRNA activity and disease progression.In this review,we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer's disease,focusing primarily on four representative miRNAs:miR-9,miR-29,miR-126,and miR-146a for further exploration.We also discuss the influence of miRNA biogenesis on Alzheimer's disease,emphasizing how dysregulation of miRNA processing may contribute to the disease.Additionally,we highlight the potential of miRNAs as both diagnostic biomarke rs and therapeutic targets in Alzheimer's disease,along with promising vector delive ry strategies aimed at improving clinical outcomes.Finally,we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer's disease.By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents,we aim to provide insights that will inform future research and development in this promising field.
基金supported by grants from the Fundamental Research Funds for the Central Universities(No.2025ZFJH03)the Central Guidance Fund for Local Science and Technology Development(No.2024ZY01054)the CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5-045).
文摘Background:Giant cell arteritis(GCA),the most common systemic vasculitis affecting elderly individuals,currently lacks specific therapies.This study aimed to systematically identify therapeutic targets for GCA through integration of large-scale multi-omics datasets.Methods:We constructed a multi-stage analytical framework encompassing 32 proteomic datasets(covering 2914 unique plasma proteins)and 6 transcriptomic datasets.Multi-omics integration strategies,including two-sample Mendelian randomization,colocalization analysis,and functional enrichment analysis,were employed to identify and validate causal relationships between candidate targets and GCA risk across 4 independent European-ancestry GCA cohorts.Single-cell RNA sequencing analysis of peripheral blood mononuclear cells from untreated GCA patients was performed to characterize hub gene-immune cell relationships.Results:We identified 43 plasma proteins causally associated with GCA[false discovery rate(FDR)<0.05],with 17 representing novel therapeutic targets.Through dual validation using proteome-wide association studies and transcriptome-wide association studies,we identified 13 high-confidence candidate targets with distinct tissue-specific expression patterns.Unc-51 like kinase 3(ULK3)emerged as the strongest protective factor(odds ratio=0.47,95%confidence interval:0.37–0.71)through autophagy regulation,while SLAMF7 represents an immediate drug repositioning opportunity as the target of food and drug administration-approved elotuzumab.Five targets have existing approved drugs(SLAMF7,ICAM1,IL18,IL6ST,CTSS).Single-cell analysis revealed profound disruption of hub gene-immune cell relationships in untreated GCA patients,with cell-type-specific alterations in inflammatory gene expression,and TYMP as the most critical hub gene.Conclusions:This study provides a clinically-actionable atlas of 43 potential therapeutic targets in GCA,identifying novel mechanisms including autophagy modulation and metabolic reprogramming,with immediate drug repositioning opportunities and precision medicine strategies based on tissue-specific and cell-type-specific expression patterns.These findings require experimental validation before clinical translation.
基金support from the National Natural Science Foundation of China(Grant Nos.:U21A20407 and 81973467).
文摘Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.
基金funding via EUROfusion Enabling research Project No.AWP21-ENR-01-CEA-02“Advancing Shock Ignition for Direct-Drive Inertial Fusion,”the framework of the EUROfusion Consortium,funded by the European Union via the Euratom Research and Training Programme (Grant Agreement No.101052200-EUROfusion)+2 种基金the Czech Ministry of Education,Youth and Sports (CMEYS) for funding the operation of the PALS facility (Grant No.LM2023068)the EuroHPC Joint Undertaking for awarding access to Karolina at IT4Innovations (VSB-TU),Czechia under Project No.EHPC-REG-2023R02-006(DD-23-157)the Ministry of Education,Youth and Sports of the Czech Republic through e-INFRA CZ (Grant No.ID:90140)
文摘We investigate the spatial and temporal correlations of hot-electron generation in high-intensity laser interaction with massive and thin copper targets under conditions relevant to inertial confinement fusion.Using Ka time-resolved imaging,it is found that in the case of massive targets,the hot-electron generation follows the laser pulse intensity with a short delay needed for favorable plasma formation.Conversely,a significant delay in the x-ray emission compared with the laser pulse intensity profile is observed in the case of thin targets.Theoretical analysis and numerical simulations suggest that this is related to radiation preheating of the foil and the increase in hot-electron lifetime in a hot expanding plasma.
基金supported by the National Natural Science Foundation of China(No.62003269).
文摘Computing electrostatic interaction on non-cooperative targets with unknown meshes is crucial for electrostatic-based space on-orbit services.Although meshes for electrostatic interaction computations can be reconstructed from point clouds,they are usually too dense,leading to high computational costs.This paper presents an optimization method for converting dense meshes into optimal meshes,enabling fast and accurate computation of the electrostatic interaction by point clouds.First,the dense mesh reconstructed from point clouds is simplified into a coarse mesh using local operators.Second,the simplified mesh is refined by an iterative strategy that integrates a lightweight method of moments and an impedance matrix inheritance technique,ultimately yielding an optimal mesh for computing the electrostatic interaction.Simulation results show that our method effectively optimizes dense meshes,making electrostatic interaction computations using point clouds approximately 63.4 times more efficient than the previous method.
基金supported by Key R&D Program(Soft Science Project)of Shandong Province,China(No.2020CXGC011502)National Natural Science Foundation of China(Nos.62273043 and 62103049).
文摘This paper addresses the three-dimensional(3-D)approach angle constrained cooperative guidance problem for speed-varying missiles against maneuvering targets.First,the guidance problem is formulated in a relative reference frame and a virtual control input is selected.Then,the cooperative guidance law is designed on the basis of a prediction-correction framework.The time-to-go under the baseline command is estimated by an efficient prediction method with a realistic aerodynamic model and a biased command is developed by utilizing the time-to-go predictions for synchronizing different missiles'impact times.The design of the biased command is decoupled into the individual design of its direction and magnitude.It is proved that the designed cooperative guidance law can make the time-to-go consensus error converge to zero before interception.Finally,the designed guidance law is validated through a series of numerical simulations.
基金supported by grants from the Natural Science Foundation of Gansu Province(24JRRA937 and 25JRRA1234)grants from the National Natural Science Foundation of China(82360469)+2 种基金The Fundamental Research Funds for the Central Universities(lzujbky-2024-ou19)Scientific research projects in the health industry of Gansu Province(GSWSKY2024-78 and GSWSKY2025-23)Research Project for Introduced Talents of Northwest Minzu University(xbmuyjrc2023020).
文摘Background:Breast cancer(BC)remains one of the most prevalent and complex malignancies worldwide,necessitating advanced approaches for its study and treatment.Therefore,we conducted a comprehensive analysis merging plasma proteomics and transcriptomics to discover the potential druggable targets in BC.Methods:Our analytical framework encompassed following approaches:two-sample Mendelian randomization(MR)for protein analysis,summary-based MR(SMR)for transcript evaluation,along with colocalization studies of coding genes.This multi-omics strategy,coupled with protein-protein interaction(PPI)network and Gene Ontology(GO)analyses,revealed candidate biomarkers and their biological significance in BC.Results:We discovered 46 proteins showing significant associations with BC through analysis of pQTLs encompassing 3,707 plasma proteins derived from three extensive large-scale genome-wide association studies(GWAS),combined with blood-and tissue-specific expression QTLs.The previously identified 11 proteins through MR were annexin IV(ANX4),snurportin 1(SPN1),fibroblast growth factor receptor 2(FGFR2),rab GDP dissociation inhibitor beta,alpha-1,4-galactosyltransferase(A4GALT),toll like receptor1(TLR1),Unc-51 like kinase 3(ULK3),parkinsonism associated deglycase(PARK7),TNF receptor superfamily member 9(TNFRSF9),immunoglobulin superfamily containing leucine rich repeat(ISLR2),cathepsin F(CTSF).Importantly,our study provides novel causal genetic evidence for 34 additional proteins whose roles in BC had not previously been established through transcriptome-or proteome-wide MR analyses,even though some had been discussed in observational or mechanistic contexts.From these findings,five newly identified proteins SUGP1(OR 1.12,95%CI 1.06-1.18),PKD2(OR 1.38,95%CI 1.20-1.59),KAT3(OR 1.06,95%CI 1.03-1.09),HPLN4(OR 1.24,95%CI 1.12-1.38),GST M1-1(OR 0.96,95%CI 0.94-0.98),and SEM4A(OR 1.17,95%CI 1.09-1.26)demonstrated significance across MR,SMR,and colocalization studies.The remaining 27 proteins,including Coagulation Factor V,PTN9,TS101(TSG101),RSPO3,CGA,CEBPB,CASP8,RALB,SCAMP3,EIF2AK3,Sialoadhesin(SIGLEC1),NSF,CD68,sL-Selectin(SELL),F177A(FAM177A1),PEAR1,BY55,NIT2,ATX3,TFPI-2,NAG,Layilin,RCL,PDCD6,CILP2,DAG1 and CATF,emerged as potential therapeutic candidates as well.Conclusion:The multi-omics examination incorporating plasma proteins and gene transcripts revealed 46 promising drug candidates for BC,suggesting new treatments in future.
基金Noncommunicable Chronic Diseases-National Science and Technology Major Project,Grant/Award Number:2023ZD0502200National Natural Science Foundation of China,Grant/Award Number:82103010+2 种基金Cultivation Project of Medical Oncology Key Foundation of Cancer HospitalChinese Academy of Medical Sciences,Grant/Award Number:CICAMS-MOCP2022004Joint Innovative Fund of Beijing Natural Science Foundation and Changping District,Grant/Award Number:L234004。
文摘In recent years,multidisciplinary treatment strategies have profoundly improved drug responses and survival outcomes of breast cancer(BC)patients.However,there is an urgent need for novel therapies for BC patients who are heavily treated or develop resistance to conventional treatment regimens.Radionuclide therapy(RT)and targeted radionuclide therapy(TRT)have emerged as paradigm-shifting therapeutic approaches for BC,which enable functions of both imaging and localised treatment.They utilise radionuclides that can selectively bind to biomarkers overexpressing on BC cells,allowing precise delivery and localised tumour irradiation.Moreover,several types of radionuclides possess‘cross-fire’effects that result in the eradication of neighbouring tumour cells lacking the biomarker expression.In the current review,we summarise the potential biomarkers for the development of RT and TRT that can be employed in the treatment of BC,including receptor markers of ER,PR and HER2,together with other markers of Trop2,PD-1,EGFR,GRPR and PSMA.
基金support from the Sichuan Science and Technology Program(2024JDHJ0043 and 2025YFHZ0121).
文摘Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.
文摘Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+cytotoxic T cell-related genes and ALS risk.Methods Single-cell RNA sequencing(scRNA-seq)of peripheral blood mononuclear cells(PBMCs)from patients with ALS and healthy controls(HC)was used to identify differentially expressed genes(DEGs)in CD4+cytotoxic T cells.Comprehensive analyses of CD4+cytotoxic T cells,including pseudotemporal trajectory,intercellular communication,and metabolic pathway analysis,were performed.Mendelian randomization(MR)analysis evaluated the causal effects of DEGs on ALS risk,with validation using independent genome-wide association study(GWAS)data.Expression patterns of the causal genes were further verified using scRNA-seq,bulk-seq,and clinical samples.Results CD4+cytotoxic T cells were significantly expanded in patients with ALS.The upregulated genes S100A6,SERPINB6,SMAD7,and TPST2 were positively correlated with ALS susceptibility,whereas DIP2A showed a protective association.Conclusion S100A6,SERPINB6,SMAD7,TPST2,and DIP2A were identified as causal genes and potential therapeutic targets in ALS,implicating CD4+cytotoxic T cells in the disease mechanisms.Further studies targeting these genes and neuroinflammatory pathways are warranted.
文摘Elucidation of ligand-protein interactions provides new insights into the physiological functions and mechanisms of ligand molecules,enabling new ideas for the treatment of diseases,and drug discovery and development.Most ligand-protein binding occurs only in specific regions of proteins.The identification of protein targets and binding regions is crucial for drug discovery and development,as well as for the in-depth study of drug-protein conformational relationships[1].
基金supported by the Natural Science Foundation of Fujian Province,No.2021J02035(to WX).
文摘Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
文摘Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neurological disease in humans.The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation ofβ-amyloid(Aβ)peptides is the main cause of the disease.Although this hypothesis has been found to be convincing,a growing body of evidence suggests that it does not fully explain the pathogenesis of AD.Neuroinflammation is a crucial element in the pathogenesis of AD,as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function.This paper will first summarize the impact of microglia-mediated neuroinflammation on AD,exploring the phenotypic changes that follow microglia activation.Secondly,the interactions between microglia,Aβ,microtubule-associated protein,apolipoprotein E and neurons are thoroughly investigated,with particular focus on the interactive mechanisms.Furthermore,the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed.A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD.This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD,with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.
基金supported by grants from the National Nat-ural Science Foundation of China(82122010 and 82070659)the National High Level Hospital Clinical Research Funding(2022-PUMCH-E-003)+1 种基金the CAMS Innovation Fund for Medical Science(2022-I2M-1-004)an NIHR Senior Investigator Award。
文摘Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical research and,until recently,a series of disappointing clinical trials,no specific disease mod-ifying pharmacological treatment has yet been approved for this condition.Recent novel approaches to understanding the molecular pathogenesis of AP provide us with renewed optimism for translational drug discovery.Although digestive enzyme activation is the hallmark of AP,a critical mechanism that initiates AP is intracellular calcium(Ca2+)overload in pancreatic parenchymal cells,which triggers mitochondrial dysfunction,endoplasmic reticulum(ER)stress,and impairs autophagic flux.These processes are piv-otal to the disease and present a range of drug targets,associated with the inflammatory responses that drive local and systemic inflammation in AP.Progress in translation has now been made,targeting the ORAI channel with the inhibitor zegocractin(Auxora)to reduce pancreatic injury and inflammatory re-sponses in human AP.Herein we evaluated potential drug targets for the early treatment of AP,focused on intra-acinar mechanisms of injury central to the onset and severity of AP.Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies.
文摘Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.
文摘This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical regulators of mRNA stability,splicing,transport,translation,and degradation,directly influencing gene expression through sequence-and structure-specific binding.In the nervous system,RBPs sustain synaptic plasticity,neural development,and neuronal homeostasis.Emerging evidence shows that exercise modulates the expression and activity of RBPs,thereby influencing mRNA translation and neurotransmitter signaling,which may underlie its beneficial effects on brain function.Dysregulation of specific RBPs has been identified in SZ,implicating them in disrupted synaptic transmission,impaired plasticity,and neuroinflammation.RBPs involved in memory and emotional regulation show marked dysfunction in SZ patients.Some RBPs have been proposed as potential biomarkers for early diagnosis and treatment monitoring.Moreover,therapeutic modulation of RBPs,through pharmacological or behavioral interventions such as exercise,may restore neuronal function by targeting post-transcriptional gene regulation.Exercise,as a non-invasive modulator of RBP expression,holds promise as an adjunctive strategy in SZ treatment,particularly in early stages.Further research into RBP-mediated pathways may offer novel insights into SZ pathophysiology and inform the development of targeted interventions.
基金Supported by the Key Project of the Affiliated Hospital of North Sichuan Medical College,No.2023ZD008the Project of the Doctoral Initiation Fund,No.2023GC002+3 种基金Scientific Research and Development Program Project,No.2024PTZK008Sichuan Province Clinical Key Specialty Construction Project,No.2023GZZKP002Science and Technology Project of Nanchong,No.22SXQT0364Research Development Plan Project of Affiliated Hospital of North Sichuan Medical College,No.2024MPZK003.
文摘BACKGROUND Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS A comprehensive analytical framework was developed to identify multi-omics biomarkers of DN.Protein-protein interaction network and Gene Ontology analyses were performed to explore the biological functions of biomarkers.Tier 1 target proteins were further analyzed.Candidate drug prediction and molecular docking studies were conducted to identify potential treatments while assessing the side effects of key target proteins.The mediation of immune cells in the association between proteins and DN was examined through two-step network Mendelian randomization(MR)analysis.RESULTS Nine DN-associated proteins were identified by analyzing protein quantitative trait loci from extensive genome-wide association study data.BTN3A1 and MICB were confirmed using MR,summary data-based MR,and colocalization analyses.Of the nine,HSPA1B,PSMB9,BTN3A1,SCGN,NOTUM,and MICB showed negative associations with DN,whereas WARS,BRD2,and CSNK2B were positive.Gene Ontology analysis indicated enrichment in inflammatory response and neuronal injury pathways.BTN3A1 and MICB were identified as Tier 1 targets.Drug prediction and molecular docking analyses indicated cyclosporin A as a potential therapeutic candidate.Two-step network MR analysis showed that MICB mediated DN through human leukocyte antigen-DR++monocytes.These integrated findings point to an immune-mediated mechanism with translational potential and nominate BTN3A1 and MICB for focused functional validation.CONCLUSION Our integrated multi-omics approach identified two promising therapeutic targets for DN,laying the groundwork for new treatment strategies and enhancing our understanding of MICB’s role in DN.
