Alzheimer s disease is a neurodegenerative disorder that leads to progressive memory loss,cognitive decline,and behavioral changes.Des pite ongoing research,its exa ct causes and effective treatments remain elusive.Tr...Alzheimer s disease is a neurodegenerative disorder that leads to progressive memory loss,cognitive decline,and behavioral changes.Des pite ongoing research,its exa ct causes and effective treatments remain elusive.Traditional approaches have focused on symptom management,but breakthroughs in bioinformatics and high-thro ughput drug screening are offering new pathways to potential therapies.This review highlights our recent effo rts to identify novel drug candidates for Alzheimer's disease by leve raging computational methods and la rge-scale biological datasets.Our work introduces two key innovations in Alzheimer's disease research:addressing sex-specific diffe rences and leve raging drug repurposing for accelerated treatment discove ry.By combining sex-stratified preclinical data with machine learning and in vivo validation,we improve translational relevance and support precision medicine.Using the TgF344-AD rat model,which mimics human Alzheimer's disease spatial memory deficits and pathology,we explored the efficacy of various US Food and Drug Administrationapproved and investigational drugs.These included ibudilast,timapiprant,RG2833,diazoxide/dibenzoylmethane(combined),and BT-11,which targeted key Alzheimer's disease-related molecular pathways such as amyloid-beta plaques,Ta u tangles,and neuroinflammation.These drugs,at various stages of development,offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer's disease.This review underscores the need for a multifaceted approach to Alzheimer's disease treatment,combining symptom relief with disease modification.展开更多
Carbamazepine is an antiepileptic drug also used for neuropathic pain and mood stabilization.It is a strong enzyme inducer and autoinducer with multiple well-documented drug–drug interactions and adverse drug reactio...Carbamazepine is an antiepileptic drug also used for neuropathic pain and mood stabilization.It is a strong enzyme inducer and autoinducer with multiple well-documented drug–drug interactions and adverse drug reactions.Widely licensed and in use since the 1960s,carbamazepine has well-characterized pharmacological,pharmacogenetic,and safety profiles,and remains extensively used in neurology and psychiatry.In 2024,carbamazepine was recommended for inclusion in the World Health Organization list of essential medicines.Carbamazepine has a complex mode of action that includes neuronal stabilization,neuroprotection,neurotransmitter modulation,enhancement of autophagy,and anti-inflammatory effects.These make carbamazepine a good candidate for drug repurposing in oncology,genetic diseases,neurodegeneration,and systemic inflammation.Recent advances in precision medicine,genomics,and on/off-target drug repositioning have enabled the identification of new carbamazepinemolecular targets for novel applications in different therapeuticmodalities.This review highlights carbamazepine repurposing studies in cancers such as breast and colorectal,based on its mode of action.In addition,repurposing studies in genetic diseases such asmetaphyseal achondroplasia and Fragile-X,as well as in neurodegenerative conditions such as amyotrophic lateral sclerosis and Alzheimer's dementia,are discussed.The pharmacological mechanisms and drug repurposing pathways are critically summarized in order to provide insights into their therapeutic potential and proposed future directions.展开更多
Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the devel...Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols(P),targeted drugs(T),and metal ions(M),collectively referred to as PTM regimens.The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.Methods:The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h,respectively,using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)assay and optical density at 600 nm(OD600).The synergistic effects of drug combinations were evaluated by combination index(CI),where CI<1 indicates synergism,CI=1 indicates addition,and CI>1 indicates antagonism.Efficacy index(EI)was also calculated.Assays of efflux pump ATPase activities were conducted using a colorimetric method.Results:This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols(specifically curcumin(C)and green tea polyphenols(G)),repurposed drugs(memantine(Mem),thioridazine(TRZ),cisplatin(Cis),and 5-fluorouracil(5FU)),and ZnSO_(4)(Zn)across three cultured cancer cell lines and four cultured pathogens.The most effective regimens,GC·Mem·Zn and GC·TRZ·Zn,significantly enhanced the anticancer efficacy(EI)of cisplatin across the three cancer lines(OECM-1,A549 and DLD-1)by 7,11 and 21;7,9,and 17 fold,respectively,while the enhancements for 5-fluorouracil were 5,6 and 12;5,5 and 9 fold,respectively.Furthermore,these PTM regimens demonstrated substantial synergistic inhibition of Na^(+)-K^(+)-Mg^(2+)-ATPase and Mg^(2+)-ATPase in the cultured cancer cells,as well as a reduction in biofilm formation by the four cultured pathogens,suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.Conclusion:Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy,particularly regarding their synergistic selective anticancer efficacy,inhibition of efflux pump ATPase,and antibiofilm formation of pathogens,these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents.Further preclinical and clinical investigations are warranted.展开更多
Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challengin...Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.展开更多
Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Vir...Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Virus superfamily 1 helicase could resolve hydrogen bonds between base pairs and participate in nucleic acid replication and has emerged as a potential target for managing virus infection.Nonetheless,current drug exploitation targeting viral helicases is still in infancy.This work establishes an intelligent multi-computational screening programme to screen potential inhibitors targeting tobacco mosaic virus(TMV)helicase using Food and Drug Administration(FDA)-approved commercially available molecule library.The ranked top 6 hits were further validated by root mean square deviations/fluctuations(RMSD/F),molecular mechanics Poisson Boltzmann surface area(MM-PBSA),density functional theory(DFT)calculations,and bioactivity evaluation.Encouragingly,lumacaftor(ΔE_(total)=-29.0kcal/mol,K_(d)=0.22μmol/L,half maximal inhibitory concentration(IC_(50))=162.5μmol/L)displayed superior binding strength and enzyme inhibition against TMV helicase compared to ningnanmycin(K_(d)=9.35μmol/L,IC_(50)>200μmol/L).Therefore,lumacaftor may be able to inhibit TMV replication by binding to helicase and interfering with its biofunctionability.Besides,the lumacaftor-helicase binding mode changes from H-bonding/electrostatic interactions to hydrophobic interactions in trajectory analysis.Overall,current findings suggest this state-of-the-art stratagem is fruitful and has the potential to be engaged in rapid mining of other target inhibitors for disease treatment.展开更多
Colorectal cancer(CRC)ranks as the third most common cancer globally and the second leading cause of cancer-related deaths,representing a significant health burden.Despite advancements in traditional treatments such a...Colorectal cancer(CRC)ranks as the third most common cancer globally and the second leading cause of cancer-related deaths,representing a significant health burden.Despite advancements in traditional treatments such as surgery,chemotherapy,targeted therapy,and immunotherapy,these approaches still face challenges,including high costs,limited efficacy,and drug resistance.Drug repurposing has emerged as a promising strategy for CRC treatment,offering advantages with reduced development timelines,lower costs,and improved drug accessibility.This review explores drug repurposing strategies for CRC,supported by multidisciplinary technologies,and discusses the current challenges in the field.展开更多
Drug repurposing offers a promising alternative to traditional drug development and significantly re-duces costs and timelines by identifying new therapeutic uses for existing drugs.However,the current approaches ofte...Drug repurposing offers a promising alternative to traditional drug development and significantly re-duces costs and timelines by identifying new therapeutic uses for existing drugs.However,the current approaches often rely on limited data sources and simplistic hypotheses,which restrict their ability to capture the multi-faceted nature of biological systems.This study introduces adaptive multi-view learning(AMVL),a novel methodology that integrates chemical-induced transcriptional profiles(CTPs),knowledge graph(KG)embeddings,and large language model(LLM)representations,to enhance drug repurposing predictions.AMVL incorporates an innovative similarity matrix expansion strategy and leverages multi-view learning(MVL),matrix factorization,and ensemble optimization techniques to integrate heterogeneous multi-source data.Comprehensive evaluations on benchmark datasets(Fdata-set,Cdataset,and Ydataset)and the large-scale iDrug dataset demonstrate that AMVL outperforms state-of-the-art(SOTA)methods,achieving superior accuracy in predicting drug-disease associations across multiple metrics.Literature-based validation further confirmed the model's predictive capabilities,with seven out of the top ten predictions corroborated by post-2011 evidence.To promote transparency and reproducibility,all data and codes used in this study were open-sourced,providing resources for pro-cessing CTPs,KG,and LLM-based similarity calculations,along with the complete AMVL algorithm and benchmarking procedures.By unifying diverse data modalities,AMVL offers a robust and scalable so-lution for accelerating drug discovery,fostering advancements in translational medicine and integrating multi-omics data.We aim to inspire further innovations in multi-source data integration and support the development of more precise and efficient strategies for advancing drug discovery and translational medicine.展开更多
Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagn...Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagnosed at advanced stages.This means that only approximately 60%of patients are eligible for curative treat-ment,and overall,GC patients have a 5-year survival rate of only 28.3%,under-scoring the importance of developing new treatment strategies.Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment because of its lower cost and faster development time.A variety of targetable pathways are involved in GC progression,including the mitogen-activated protein kinase,phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,p53,Janus kinase 2/signal transducer and activator of transcription 3,hypoxia-inducible factor-1α,wingless-type mouse mammary tumor virus integration site family/beta-catenin(Wnt/β-catenin),nuclear factor kappa B,and Hippo pathways.Therefore,the repurposing of drugs targeting these pathways represents an interesting option in the search for new treatments for GC.In this review,we explore some relevant pathways involved in the development of GC and the possibilities of repurposing drugs that target them.展开更多
The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough establ...The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough established a novel framework for site-specific gene delivery through repurposing ancient viral tools.展开更多
Protozoan infections(e.g.,malaria,trypanosomiasis,and toxoplasmosis)pose a considerable global burden on public health and socioeconomic problems,leading to high rates of morbidity and mortality.Due to the limited ars...Protozoan infections(e.g.,malaria,trypanosomiasis,and toxoplasmosis)pose a considerable global burden on public health and socioeconomic problems,leading to high rates of morbidity and mortality.Due to the limited arsenal of effective drugs for these diseases,which are associated with devastating side effects and escalating drug resistance,there is an urgent need for innovative antiprotozoal drugs.The emergence of drug repurposing offers a low-cost approach to discovering new therapies for protozoan diseases.In this review,we summarize recent advances in drug repurposing for various human protozoan diseases and explore cost-effective strategies to identify viable new treatments.We highlight the cross-applicability of repurposed drugs across diverse diseases and harness common chemical motifs to provide new insights into drug design,facilitating the discovery of new antiprotozoal drugs.Challenges and opportunities in the field are discussed,delineating novel directions for ongoing and future research.展开更多
Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA...Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychiatric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC_(50))values of 0.753μM,0.542μM,and 1.210μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.展开更多
Objective To improve the system of accelerated review and approval,and to speed up the development and marketing of repurposing drugs for rare diseases in China.Methods The relevant concepts of rare diseases and the d...Objective To improve the system of accelerated review and approval,and to speed up the development and marketing of repurposing drugs for rare diseases in China.Methods The relevant concepts of rare diseases and the definition of drug repurposing were introduced so as to sort out the advantages and disadvantages of the research and development of drug repurposing for rare diseases.Then,the incentive mechanisms of the research and development of drug repurposing for rare diseases in China and abroad were compared.Results and Conclusion Some suggestions on improving the incentive mechanism of repurposing drugs for rare diseases such as policy support for talents introduction,capital investment,and innovation capabilities are proposed.Besides,the government should further improve policies for the research and development of repurposing drugs for rare diseases,which can gradually narrow the gap between the research and innovation of drug repurposing in developed countries,thus benefiting the patients of rare diseases.展开更多
BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast ...BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.展开更多
Breast cancer(BC)remains the most frequently diagnosed malignancy worldwide,with an estimated 2.3 million new cases and approximately 685,000 deaths reported in 2020.Forecasts suggest a substantial rise in global inci...Breast cancer(BC)remains the most frequently diagnosed malignancy worldwide,with an estimated 2.3 million new cases and approximately 685,000 deaths reported in 2020.Forecasts suggest a substantial rise in global incidence,with new annual cases projected to reach 3.2 million by 2050,representing a 39%increase.Additionally,BC is expected to account for approximately 7.7%of the anticipated$25.2 trillion global economic burden associated with cancer by 2050.These trends underscore an urgent need for affordable,widely accessible and effective therapeutic strategies,particularly in low-and middle-income countries.Statins,commonly prescribed for the treatment of hypercholesterolaemia via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA)reductase,have garnered increasing interest for their potential anticancer properties.This review focuses on the mechanistic underpinnings and therapeutic implications of statin use,particularly simvastatin,in the context of BC.Statins exert their primary effect through inhibition of the mevalonate pathway,which is crucial for cholesterol and isoprenoid biosynthesis.Disruption of this pathway impairs the prenylation of key signalling proteins,including members of the Ras and Rho GTPase families,which are essential for cancer cell proliferation,survival and metastasis.Preclinical evidence has demonstrated that simvastatin can induce tumour cell apoptosis,arrest cell-cycle progression and inhibit oncogenic signalling pathways.These effects have been particularly pronounced in hormone receptor-negative and triple-negative breast cancer(TNBC)subtypes,which are often associated with poor prognosis and limited treatment options.Epidemiological and observational studies further support a potential association between statin use and reduced BC recurrence and mortality.Nevertheless,robust evidence from randomised controlled trials remains limited,and further investigation is required to establish causality and define optimal therapeutic regimens.Given their well-established safety profile,global accessibility and pleiotropic effects,statins,especially simvastatin,represent a promising class of repurposed drugs in the adjuvant treatment of BC.This review synthesises evidence from the past two decades,highlighting the need for continued clinical research to validate and optimise the use of statins as adjunctive agents in BC therapy.展开更多
Despite having multiple treatment options,the overall outcomes,including the survival rates of non-small cell lung cancer(NSCLC)patients,remain relatively low,indicating the need to explore new approaches to achieve i...Despite having multiple treatment options,the overall outcomes,including the survival rates of non-small cell lung cancer(NSCLC)patients,remain relatively low,indicating the need to explore new approaches to achieve improved therapeutic responses.To that end,repurposed drugs such as metformin have been evaluated against many cancer types,including NSCLC.Metformin,a widely used oral hypoglycemic drug for type 2 diabetes,exhibits anticancer properties and synergy with several standards of care agents.In this review,we provide a comprehensive overview of the role and anticancer mechanisms of metformin-based combination approaches for the treatment of NSCLC.We logically discussed the experimental evidence from the in vitro and in vivo studies utilizing metformin alone,and then its combination with chemotherapeutic agents,targeted therapy,and immunotherapy.We also present clinical trials that underscore the beneficial and adverse outcomes of metformin use in combination with targeted therapy and chemotherapeutic agents,and emphasize the limitations and challenges for the treatment of diabetic and nondiabetic NSCLC patients.It appears that,regardless of the diverse anticancer mechanisms of this biguanide,the benefits may be confined to a specific patient subgroup,which opens new avenues to be explored for NSCLC treatment.展开更多
Objective:Glioblastoma(GB)therapy is challenged by tumor heterogeneity and multidrug resistance(MDR),highlighting the need for effective therapies.This study aimed to explore the combined anticancer effects of Sunitin...Objective:Glioblastoma(GB)therapy is challenged by tumor heterogeneity and multidrug resistance(MDR),highlighting the need for effective therapies.This study aimed to explore the combined anticancer effects of Sunitinib(SNB)and Fenofibrate(FEN)on U87 cells.Methods:U87 cells were exposed to SNB,FEN,or their combination for 24 h,followed by evaluations of cell viability,migration,and clonogenic survival using MTT,scratch,and colony formation assays.Intracellular reactive oxygen species(ROS)were quantified via the 2′,7′-dichlorofluorescein assay,while mitochondrial membrane potential(MMP)was assessed using JC-1 red/green fluorescence.Molecular docking was performed to investigate SNB and FEN interactions with multiple molecular targets,including topoisomerase II(TOP-II),c-Jun N-terminal kinase(JNK),histone deacetylase 2(HDAC2),cyclooxygenase-2(COX-2),matrix metalloproteinase-9(MMP-9),cytochrome P4503A4(CYP3A4),glutathione peroxidase 4(GPX4),glutathione Stransferase(GST),heme oxygenase-1(HO-1),and 5-lipoxygenase(5-LOX).Results:The results demonstrated that both SNB and FEN significantly reduced U87 cell viability,migration,and clonogenic potential,with the combination treatment exhibiting synergistic cytotoxicity.SNB alone markedly increased ROS levels,while FEN,individually or in combination,reduced oxidative stress.Although SNB diminished mitochondrial membrane potential,cotreatment with FEN restored MMP values close to control levels.Docking analyses revealed that SNB displayed strong affinities for TOP-II,JNK,and HDAC2,whereas FEN preferentially interacted with MMP-9,COX-2,CYP3A4,and GPX4,suggesting complementary mechanisms targeting oxidative stress,inflammation,and programmed cell death regulation.Conclusion:The combination of SNB and FEN represents a promising multi-targeted therapeutic approach against GB.SNB and FEN combination capable of modulating and reprogramming key molecular pathways involved in GB progression and MDR.展开更多
Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CR...Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC_(50) values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.展开更多
Over the course of the past 70 years, the objectives of CA （cellular automata） research shifted from speculative and illustrative purposes without immediate goals outside of given implementations to the more utilita...Over the course of the past 70 years, the objectives of CA （cellular automata） research shifted from speculative and illustrative purposes without immediate goals outside of given implementations to the more utilitarian scientific and engineering objectives of simulating, controlling and predicting other phenomena. Looking back at our own 10-year history of CA related work, however, we recognize a generally inverse tendency from utilitarian objectives to finding more illustrative and speculative value. In this paper, we present a reflection on our own body of CA work, and we discuss the qualities of the various outcomes and insights we gained from a second-order cybernetic perspective. We argue that much of our own CA work may best be understood as creating machines for showing and for repurposing that allow their observers to gain new （second-order cybernetic） ways of seeing from interacting with them.展开更多
基金National Institutes of Health,No.R01AG057555(to PI,L.Xie,co-l,MEFP,PAS,PR)。
文摘Alzheimer s disease is a neurodegenerative disorder that leads to progressive memory loss,cognitive decline,and behavioral changes.Des pite ongoing research,its exa ct causes and effective treatments remain elusive.Traditional approaches have focused on symptom management,but breakthroughs in bioinformatics and high-thro ughput drug screening are offering new pathways to potential therapies.This review highlights our recent effo rts to identify novel drug candidates for Alzheimer's disease by leve raging computational methods and la rge-scale biological datasets.Our work introduces two key innovations in Alzheimer's disease research:addressing sex-specific diffe rences and leve raging drug repurposing for accelerated treatment discove ry.By combining sex-stratified preclinical data with machine learning and in vivo validation,we improve translational relevance and support precision medicine.Using the TgF344-AD rat model,which mimics human Alzheimer's disease spatial memory deficits and pathology,we explored the efficacy of various US Food and Drug Administrationapproved and investigational drugs.These included ibudilast,timapiprant,RG2833,diazoxide/dibenzoylmethane(combined),and BT-11,which targeted key Alzheimer's disease-related molecular pathways such as amyloid-beta plaques,Ta u tangles,and neuroinflammation.These drugs,at various stages of development,offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer's disease.This review underscores the need for a multifaceted approach to Alzheimer's disease treatment,combining symptom relief with disease modification.
文摘Carbamazepine is an antiepileptic drug also used for neuropathic pain and mood stabilization.It is a strong enzyme inducer and autoinducer with multiple well-documented drug–drug interactions and adverse drug reactions.Widely licensed and in use since the 1960s,carbamazepine has well-characterized pharmacological,pharmacogenetic,and safety profiles,and remains extensively used in neurology and psychiatry.In 2024,carbamazepine was recommended for inclusion in the World Health Organization list of essential medicines.Carbamazepine has a complex mode of action that includes neuronal stabilization,neuroprotection,neurotransmitter modulation,enhancement of autophagy,and anti-inflammatory effects.These make carbamazepine a good candidate for drug repurposing in oncology,genetic diseases,neurodegeneration,and systemic inflammation.Recent advances in precision medicine,genomics,and on/off-target drug repositioning have enabled the identification of new carbamazepinemolecular targets for novel applications in different therapeuticmodalities.This review highlights carbamazepine repurposing studies in cancers such as breast and colorectal,based on its mode of action.In addition,repurposing studies in genetic diseases such asmetaphyseal achondroplasia and Fragile-X,as well as in neurodegenerative conditions such as amyotrophic lateral sclerosis and Alzheimer's dementia,are discussed.The pharmacological mechanisms and drug repurposing pathways are critically summarized in order to provide insights into their therapeutic potential and proposed future directions.
文摘Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols(P),targeted drugs(T),and metal ions(M),collectively referred to as PTM regimens.The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.Methods:The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h,respectively,using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)assay and optical density at 600 nm(OD600).The synergistic effects of drug combinations were evaluated by combination index(CI),where CI<1 indicates synergism,CI=1 indicates addition,and CI>1 indicates antagonism.Efficacy index(EI)was also calculated.Assays of efflux pump ATPase activities were conducted using a colorimetric method.Results:This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols(specifically curcumin(C)and green tea polyphenols(G)),repurposed drugs(memantine(Mem),thioridazine(TRZ),cisplatin(Cis),and 5-fluorouracil(5FU)),and ZnSO_(4)(Zn)across three cultured cancer cell lines and four cultured pathogens.The most effective regimens,GC·Mem·Zn and GC·TRZ·Zn,significantly enhanced the anticancer efficacy(EI)of cisplatin across the three cancer lines(OECM-1,A549 and DLD-1)by 7,11 and 21;7,9,and 17 fold,respectively,while the enhancements for 5-fluorouracil were 5,6 and 12;5,5 and 9 fold,respectively.Furthermore,these PTM regimens demonstrated substantial synergistic inhibition of Na^(+)-K^(+)-Mg^(2+)-ATPase and Mg^(2+)-ATPase in the cultured cancer cells,as well as a reduction in biofilm formation by the four cultured pathogens,suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.Conclusion:Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy,particularly regarding their synergistic selective anticancer efficacy,inhibition of efflux pump ATPase,and antibiofilm formation of pathogens,these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents.Further preclinical and clinical investigations are warranted.
基金supported by the Science and Technology Development Fund,Macao SAR,China(Grant Nos.:FDCT 0001/2020/AKP and 006/2023/SKL)Guangxi Science and Technology Major Program,China(Program No.:Guike AA22096022).
文摘Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.
基金financially supported by National Natural Science Foundation of China(Nos.32372610,U23A20201,32160661,32202359)National Key Research and Development Program of China(No.2022YFD1700300)the Central Government Guides Local Science and Technology Development Fund Projects(Nos.[Qiankehezhongyindi(2023)001]and[Qiankehezhongyindi[2024]007])。
文摘Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Virus superfamily 1 helicase could resolve hydrogen bonds between base pairs and participate in nucleic acid replication and has emerged as a potential target for managing virus infection.Nonetheless,current drug exploitation targeting viral helicases is still in infancy.This work establishes an intelligent multi-computational screening programme to screen potential inhibitors targeting tobacco mosaic virus(TMV)helicase using Food and Drug Administration(FDA)-approved commercially available molecule library.The ranked top 6 hits were further validated by root mean square deviations/fluctuations(RMSD/F),molecular mechanics Poisson Boltzmann surface area(MM-PBSA),density functional theory(DFT)calculations,and bioactivity evaluation.Encouragingly,lumacaftor(ΔE_(total)=-29.0kcal/mol,K_(d)=0.22μmol/L,half maximal inhibitory concentration(IC_(50))=162.5μmol/L)displayed superior binding strength and enzyme inhibition against TMV helicase compared to ningnanmycin(K_(d)=9.35μmol/L,IC_(50)>200μmol/L).Therefore,lumacaftor may be able to inhibit TMV replication by binding to helicase and interfering with its biofunctionability.Besides,the lumacaftor-helicase binding mode changes from H-bonding/electrostatic interactions to hydrophobic interactions in trajectory analysis.Overall,current findings suggest this state-of-the-art stratagem is fruitful and has the potential to be engaged in rapid mining of other target inhibitors for disease treatment.
基金Supported by the National Natural Science Foundation of China,No.82273457the Natural Science Foundation of Guangdong Province,No.2023A1515012762Science and Technology Special Project of Guangdong Province,No.210715216902829.
文摘Colorectal cancer(CRC)ranks as the third most common cancer globally and the second leading cause of cancer-related deaths,representing a significant health burden.Despite advancements in traditional treatments such as surgery,chemotherapy,targeted therapy,and immunotherapy,these approaches still face challenges,including high costs,limited efficacy,and drug resistance.Drug repurposing has emerged as a promising strategy for CRC treatment,offering advantages with reduced development timelines,lower costs,and improved drug accessibility.This review explores drug repurposing strategies for CRC,supported by multidisciplinary technologies,and discusses the current challenges in the field.
基金supported by the National Natural Science Foundation of China(Grant No.:62101087)the China Postdoctoral Science Foundation(Grant No.:2021MD703942)+2 种基金the Chongqing Postdoctoral Research Project Special Funding,China(Grant No.:2021XM2016)the Science Foundation of Chongqing Municipal Commission of Education,China(Grant No.:KJQN202100642)the Chongqing Natural Science Foundation,China(Grant No.:cstc2021jcyj-msxmX0834).
文摘Drug repurposing offers a promising alternative to traditional drug development and significantly re-duces costs and timelines by identifying new therapeutic uses for existing drugs.However,the current approaches often rely on limited data sources and simplistic hypotheses,which restrict their ability to capture the multi-faceted nature of biological systems.This study introduces adaptive multi-view learning(AMVL),a novel methodology that integrates chemical-induced transcriptional profiles(CTPs),knowledge graph(KG)embeddings,and large language model(LLM)representations,to enhance drug repurposing predictions.AMVL incorporates an innovative similarity matrix expansion strategy and leverages multi-view learning(MVL),matrix factorization,and ensemble optimization techniques to integrate heterogeneous multi-source data.Comprehensive evaluations on benchmark datasets(Fdata-set,Cdataset,and Ydataset)and the large-scale iDrug dataset demonstrate that AMVL outperforms state-of-the-art(SOTA)methods,achieving superior accuracy in predicting drug-disease associations across multiple metrics.Literature-based validation further confirmed the model's predictive capabilities,with seven out of the top ten predictions corroborated by post-2011 evidence.To promote transparency and reproducibility,all data and codes used in this study were open-sourced,providing resources for pro-cessing CTPs,KG,and LLM-based similarity calculations,along with the complete AMVL algorithm and benchmarking procedures.By unifying diverse data modalities,AMVL offers a robust and scalable so-lution for accelerating drug discovery,fostering advancements in translational medicine and integrating multi-omics data.We aim to inspire further innovations in multi-source data integration and support the development of more precise and efficient strategies for advancing drug discovery and translational medicine.
基金Supported by the Instituto de Salud Carlos III,No.PI24/00784,No.PI24/00737,No.PI21/01181,No.PI21/00333 and No.INT22/00112Departamento de Universidad,Innovación y Transformación Digital Gobierno de Navarra,No.0011-1408-2024-000011,No.0011-1408-2022-000010.
文摘Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagnosed at advanced stages.This means that only approximately 60%of patients are eligible for curative treat-ment,and overall,GC patients have a 5-year survival rate of only 28.3%,under-scoring the importance of developing new treatment strategies.Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment because of its lower cost and faster development time.A variety of targetable pathways are involved in GC progression,including the mitogen-activated protein kinase,phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,p53,Janus kinase 2/signal transducer and activator of transcription 3,hypoxia-inducible factor-1α,wingless-type mouse mammary tumor virus integration site family/beta-catenin(Wnt/β-catenin),nuclear factor kappa B,and Hippo pathways.Therefore,the repurposing of drugs targeting these pathways represents an interesting option in the search for new treatments for GC.In this review,we explore some relevant pathways involved in the development of GC and the possibilities of repurposing drugs that target them.
文摘The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough established a novel framework for site-specific gene delivery through repurposing ancient viral tools.
基金financially supported by the National Natural Science Foundation of China(Grant Nos.:32270690 and 32070671)the Postdoctor Research Fund of West China Hospital,Sichuan University,China(Grant No.:2024HXBH059)。
文摘Protozoan infections(e.g.,malaria,trypanosomiasis,and toxoplasmosis)pose a considerable global burden on public health and socioeconomic problems,leading to high rates of morbidity and mortality.Due to the limited arsenal of effective drugs for these diseases,which are associated with devastating side effects and escalating drug resistance,there is an urgent need for innovative antiprotozoal drugs.The emergence of drug repurposing offers a low-cost approach to discovering new therapies for protozoan diseases.In this review,we summarize recent advances in drug repurposing for various human protozoan diseases and explore cost-effective strategies to identify viable new treatments.We highlight the cross-applicability of repurposed drugs across diverse diseases and harness common chemical motifs to provide new insights into drug design,facilitating the discovery of new antiprotozoal drugs.Challenges and opportunities in the field are discussed,delineating novel directions for ongoing and future research.
基金supported by the Natural Science Foundation of China(Grant No.:21505009)the Natural Science Foundation of Chongqing,China(Grant No.:2023NSCQ-MSX0140)the Open Project of Central Nervous System Drug Key Laboratory of Sichuan Province,China(Grant No.:230012-01SZ).
文摘Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychiatric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC_(50))values of 0.753μM,0.542μM,and 1.210μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.
文摘Objective To improve the system of accelerated review and approval,and to speed up the development and marketing of repurposing drugs for rare diseases in China.Methods The relevant concepts of rare diseases and the definition of drug repurposing were introduced so as to sort out the advantages and disadvantages of the research and development of drug repurposing for rare diseases.Then,the incentive mechanisms of the research and development of drug repurposing for rare diseases in China and abroad were compared.Results and Conclusion Some suggestions on improving the incentive mechanism of repurposing drugs for rare diseases such as policy support for talents introduction,capital investment,and innovation capabilities are proposed.Besides,the government should further improve policies for the research and development of repurposing drugs for rare diseases,which can gradually narrow the gap between the research and innovation of drug repurposing in developed countries,thus benefiting the patients of rare diseases.
文摘BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.
基金supported by Rural Health Research Institute,Charles Sturt University.
文摘Breast cancer(BC)remains the most frequently diagnosed malignancy worldwide,with an estimated 2.3 million new cases and approximately 685,000 deaths reported in 2020.Forecasts suggest a substantial rise in global incidence,with new annual cases projected to reach 3.2 million by 2050,representing a 39%increase.Additionally,BC is expected to account for approximately 7.7%of the anticipated$25.2 trillion global economic burden associated with cancer by 2050.These trends underscore an urgent need for affordable,widely accessible and effective therapeutic strategies,particularly in low-and middle-income countries.Statins,commonly prescribed for the treatment of hypercholesterolaemia via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA)reductase,have garnered increasing interest for their potential anticancer properties.This review focuses on the mechanistic underpinnings and therapeutic implications of statin use,particularly simvastatin,in the context of BC.Statins exert their primary effect through inhibition of the mevalonate pathway,which is crucial for cholesterol and isoprenoid biosynthesis.Disruption of this pathway impairs the prenylation of key signalling proteins,including members of the Ras and Rho GTPase families,which are essential for cancer cell proliferation,survival and metastasis.Preclinical evidence has demonstrated that simvastatin can induce tumour cell apoptosis,arrest cell-cycle progression and inhibit oncogenic signalling pathways.These effects have been particularly pronounced in hormone receptor-negative and triple-negative breast cancer(TNBC)subtypes,which are often associated with poor prognosis and limited treatment options.Epidemiological and observational studies further support a potential association between statin use and reduced BC recurrence and mortality.Nevertheless,robust evidence from randomised controlled trials remains limited,and further investigation is required to establish causality and define optimal therapeutic regimens.Given their well-established safety profile,global accessibility and pleiotropic effects,statins,especially simvastatin,represent a promising class of repurposed drugs in the adjuvant treatment of BC.This review synthesises evidence from the past two decades,highlighting the need for continued clinical research to validate and optimise the use of statins as adjunctive agents in BC therapy.
基金supported by the National Institutes of Health(RPS,R21 ES033806).
文摘Despite having multiple treatment options,the overall outcomes,including the survival rates of non-small cell lung cancer(NSCLC)patients,remain relatively low,indicating the need to explore new approaches to achieve improved therapeutic responses.To that end,repurposed drugs such as metformin have been evaluated against many cancer types,including NSCLC.Metformin,a widely used oral hypoglycemic drug for type 2 diabetes,exhibits anticancer properties and synergy with several standards of care agents.In this review,we provide a comprehensive overview of the role and anticancer mechanisms of metformin-based combination approaches for the treatment of NSCLC.We logically discussed the experimental evidence from the in vitro and in vivo studies utilizing metformin alone,and then its combination with chemotherapeutic agents,targeted therapy,and immunotherapy.We also present clinical trials that underscore the beneficial and adverse outcomes of metformin use in combination with targeted therapy and chemotherapeutic agents,and emphasize the limitations and challenges for the treatment of diabetic and nondiabetic NSCLC patients.It appears that,regardless of the diverse anticancer mechanisms of this biguanide,the benefits may be confined to a specific patient subgroup,which opens new avenues to be explored for NSCLC treatment.
基金funding program(ORF-2025-1037)at King Saud University,Riyadh,Saudi Arabia.
文摘Objective:Glioblastoma(GB)therapy is challenged by tumor heterogeneity and multidrug resistance(MDR),highlighting the need for effective therapies.This study aimed to explore the combined anticancer effects of Sunitinib(SNB)and Fenofibrate(FEN)on U87 cells.Methods:U87 cells were exposed to SNB,FEN,or their combination for 24 h,followed by evaluations of cell viability,migration,and clonogenic survival using MTT,scratch,and colony formation assays.Intracellular reactive oxygen species(ROS)were quantified via the 2′,7′-dichlorofluorescein assay,while mitochondrial membrane potential(MMP)was assessed using JC-1 red/green fluorescence.Molecular docking was performed to investigate SNB and FEN interactions with multiple molecular targets,including topoisomerase II(TOP-II),c-Jun N-terminal kinase(JNK),histone deacetylase 2(HDAC2),cyclooxygenase-2(COX-2),matrix metalloproteinase-9(MMP-9),cytochrome P4503A4(CYP3A4),glutathione peroxidase 4(GPX4),glutathione Stransferase(GST),heme oxygenase-1(HO-1),and 5-lipoxygenase(5-LOX).Results:The results demonstrated that both SNB and FEN significantly reduced U87 cell viability,migration,and clonogenic potential,with the combination treatment exhibiting synergistic cytotoxicity.SNB alone markedly increased ROS levels,while FEN,individually or in combination,reduced oxidative stress.Although SNB diminished mitochondrial membrane potential,cotreatment with FEN restored MMP values close to control levels.Docking analyses revealed that SNB displayed strong affinities for TOP-II,JNK,and HDAC2,whereas FEN preferentially interacted with MMP-9,COX-2,CYP3A4,and GPX4,suggesting complementary mechanisms targeting oxidative stress,inflammation,and programmed cell death regulation.Conclusion:The combination of SNB and FEN represents a promising multi-targeted therapeutic approach against GB.SNB and FEN combination capable of modulating and reprogramming key molecular pathways involved in GB progression and MDR.
基金supported by the National Natural Science Foundation of China(82441036)Ganzhou Municipal Science and Technology Project(2022-RC1342)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515130004)Key-Area Research and Development Program of Guangdong Province(2019B020234003)Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer(2020B121201004)Open Project Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202210).
文摘Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC_(50) values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.
文摘Over the course of the past 70 years, the objectives of CA （cellular automata） research shifted from speculative and illustrative purposes without immediate goals outside of given implementations to the more utilitarian scientific and engineering objectives of simulating, controlling and predicting other phenomena. Looking back at our own 10-year history of CA related work, however, we recognize a generally inverse tendency from utilitarian objectives to finding more illustrative and speculative value. In this paper, we present a reflection on our own body of CA work, and we discuss the qualities of the various outcomes and insights we gained from a second-order cybernetic perspective. We argue that much of our own CA work may best be understood as creating machines for showing and for repurposing that allow their observers to gain new （second-order cybernetic） ways of seeing from interacting with them.
