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
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
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
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
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
Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.Ho...Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.展开更多
Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of ant...Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular infection.Herein,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.展开更多
In this review research,the full bio-medical potential and application of the severe acute respiratory syndrome(SARS)-CoV-2 viruses are discussed in detail with the aim of discovering innovative treatment strategies i...In this review research,the full bio-medical potential and application of the severe acute respiratory syndrome(SARS)-CoV-2 viruses are discussed in detail with the aim of discovering innovative treatment strategies in virology and medicine.The SARS-CoV-2 which caused an international health crisis also unraveled an opportunity to gain from its pathogenic effects to treat the affected people.The study aims at testing whether the newly discovered SARS-CoV-2 can be used for therapeutic and clinical purposes.With in-depth analytics,this investigation issue endeavors to unearth new ways of fighting infectious diseases and to improve existing medical interventions.Beside scientific and practical significance the role of this work is vital.By learning the biologic and molecular mysteries of SARS-CoV-2,the researchers can create precise medicines and vaccines not only against COVID-19 but also the other infectious diseases as well.Furthermore,this recommendation may open the door to the future development of gene therapy and vaccine technology.In this sense,it combines multiple approaches,such as viral studies,immunology,and molecular biology.Laboratory experiments,computer program modeling and clinical trials are applied to detection of the SARS-COV-2 in therapeutic implementation.The principal conclusion and analysis of this research put forth the fact that SARS-CoV-2 can be utilized in anti-viral treatment,cancer therapy,and vaccine programs.The study results confirm the inherent adaptability of viruses like SARS-CoV-2 and emphasis on the development of specific therapeutic measures.It is valuable because of its potential to add to virology and medication,showing new ways for virus-based treatment.In addition,the impact of these results on treatments would be revolutionary,with potential to invent superior and flexible interventions against infectious disease.In short,the therapeutic use of SARS-CoV-2 can be regarded as a bold innovation with tremendous consequences for general health,and ultimately for medical science.展开更多
Over 950 billion(about 3.8 million tons)masks have been consumed in the last four years around the world to protect human beings from COVID-19 and air pollution.However,very few of these used masks are being recycled,...Over 950 billion(about 3.8 million tons)masks have been consumed in the last four years around the world to protect human beings from COVID-19 and air pollution.However,very few of these used masks are being recycled,with the majority of them being landfilled or incinerated.To address this issue,we propose a repurposing upcycling strategy by converting these polypropylene(PP)-based waste masks to highperformance thermally conductive nanocomposites(PP@G,where G refers to graphene)with exceptional electromagnetic interference shielding property.The PP@G is fabricated by loading tannic acid onto PP fibers via electrostatic self-assembling,followed by mixing with graphene nanoplatelets(GNPs).Because this strategy enables the GNPs to form efficient thermal and electrical conduction pathways along the PP fiber surface,the PP@G shows a high thermal conductivity of 87 W m^(-1)K^(-1)and exhibits an electromagnetic interference shielding effectiveness of 88 dB(1100 dB cm^(−1)),making it potentially applicable for heat dissipation and electromagnetic shielding in advanced electronic devices.Life cycle assessment and techno-economic assessment results show that our repurposing strategy has significant advantages over existing methods in reducing environmental impacts and economic benefits.This strategy offers a facile and promising approach to upcycling/repurposing of fibrous waste plastics.展开更多
Objective:Prostate cancer(PCA)is the second most widespread cancer among men globally,with a rising mortality rate.Enzyme-responsive lipid nanoparticles(ERLNs)are promising vectors for the selective delivery of antica...Objective:Prostate cancer(PCA)is the second most widespread cancer among men globally,with a rising mortality rate.Enzyme-responsive lipid nanoparticles(ERLNs)are promising vectors for the selective delivery of anticancer agents to tumor cells.The goal of this study is to fabricate ERLNs for dual delivery of gefitinib(GF)and simvastatin(SV)to PCA cells.Methods:ERLNs loaded with GF and SV(ERLNGFSV)were assembled using bottomup and top-down techniques.Subsequently,these ERLN cargoes were coated with triacylglycerol,and phospholipids and capped with chitosan(CS).The ERLNGFSV,and CS engineered ERLNGFSV(CERLNGFSV)formulations were characterized for particle size(PS),zeta potential(ZP),and polydispersity index(PDI).The biocompatibility,and cytotoxicity of the plain and GF plus SV-loaded ERLN cargoes were assessed using erythrocytes and PC-3 cell line.Additionally,molecular docking simulations(MDS)were conducted to examine the influence of GF and SV on succinate dehydrogenase(SDH),glutathione peroxidase-4(GPX-4),and 5α-reductase(5α-RD).Results:These results showed that plain,ERLNGFSV,and CERLNGFSV cargoes have a nanoscale size and homogeneous appearance.Moreover,ERLNGFSV and CERLNGFSV were biocompatible,with no detrimental effects on erythrocytes.Treatment with GF,SV,GF plus SV,ERLNGFSV,and CERLNGFSV significantly reduced the viability of PC-3 cells compared to control cells.Particularly,the blend of GF and SV,as well as ERLNGFSV and CERLNGFSV augmented PC-3 cell death.Also,treating PC-3 cells with free drugs,their combination,ERLNGFSV,and CERLNGFSV formulations elevated the percentage of apoptotic cells.MDS studies demonstrated that GF and SV interact with the active sites of SDH,GPX-4,and 5α-reductase.Conclusions:This study concludes that SVGF combination and ERLNs loading induce particular delivery,and synergism on PC-3 death through action on multiple pathways involved in cell proliferation,and apoptosis,besides the interaction with SDH,GPX-4,and 5α-RD.Therefore,GFSV-loaded ERLN cargoes are a promising strategy for PCA treatment.In vivo studies are necessary to confirm these findings for clinical applications.展开更多
AMP-activated protein kinase(AMPK)is a highly conserved serine/threonine kinase that functions as a central regulator of cellular energy status.In cancer,where metabolic reprogramming enables rapid proliferation and s...AMP-activated protein kinase(AMPK)is a highly conserved serine/threonine kinase that functions as a central regulator of cellular energy status.In cancer,where metabolic reprogramming enables rapid proliferation and survival under stress,AMPK functions as a metabolic checkpoint that restrains tumor growth by inhibiting biosynthetic pathways and promoting catabolic processes,such as autophagy and fatty acid oxidation.Given its role in opposing many hallmarks of cancer metabolism,AMPK has attracted significant interest as a therapeutic target.This review examines the molecular mechanisms by which AMPK influences tumor progression and evaluates the preclinical and clinical evidence for pharmacological AMPK activation using agents such as metformin,phenformin,and canagliflozin.While promising anti-tumor effects have been reported in specific contexts—such as HER2-positive breast cancer,colorectal cancer,and metabolically distinct lung cancer subtypes—clinical efficacy remains variable.Limitations include indirect activation mechanisms,low tissue penetrance,tumor heterogeneity,and lack of reliable biomarkers for patient selection.We discuss emerging strategies to overcome these challenges,including combination therapies,metabolic stratification,and the development of direct AMPK activators or mRNA-based delivery platforms.Together,these insights support a renewed focus on AMPK as a modifiable node in cancermetabolismand a candidate for integration into precision oncology frameworks.展开更多
Objectives:Ovarian cancer,a leading cause of gynecological malignancy-related mortality,is charac-terized by limited therapeutic options and a poor prognosis.Although pyrimethamine has emerged as a promising candidate...Objectives:Ovarian cancer,a leading cause of gynecological malignancy-related mortality,is charac-terized by limited therapeutic options and a poor prognosis.Although pyrimethamine has emerged as a promising candidate demonstrating efficacy in treating various tumors,the precise mechanisms of its antitumor effects remain obscure.This study was specifically designed to investigate the mode of action underlying the antitumor effects of pyrimethamine in preclinical settings.Methods:The effects of pyrimethamine on cellular proliferation were meticulously assessed using both the cell counting kit 8(CCK-8)assay and the colony formation assay,with the effects further confirmed in a murine model.A confocal microscope was utilized to monitor the dynamic alterations in mitochondria within ovarian cancer cells.Additionally,adenosine triphosphate(ATP)and reactive oxygen species(ROS)assays were conducted to measure mitochondrial damage induced by pyrimethamine in ovarian cancer cell lines.The mitochondrial membrane potential was assessed using fluorescent dyes as an indicator of mitochondrial functional status.Furthermore,transcriptome analysis and immunohistochemical techniques were employed to detect the impact of pyrimethamine on ovarian cancer cells.Results:Our results demonstrated that pyrimethamine induced ovarian cancer cell death through mitochondrial dysfunction and lethal mitophagy.Transcriptome profiling analysis and Western blot demonstrated that activation of the p38/JNK/ERK signaling pathway was implicated in the process of pyrimethamine-induced mitophagy in ovarian cancer cells.Importantly,combination treatment with pyrimethamine and paclitaxel in vitro and in vivo showed a synergistic antitumor effect.Conclusions:Altogether,these findings indicate that the antitumor effects of pyrimethamine result from the induction of lethal mitophagy via regulation of the p38/JNK/ERK pathway in ovarian cancer.Considering the low toxicity and high tolerance associated with pyrimethamine,it is suggested that pyrimethamine be evaluated in the treatment of ovarian cancer,either as a monotherapy or in combination with paclitaxel.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
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.
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.
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funded by the National Natural Science Foundation of China(32270161,32100117,32100118)the Natural Science Foundation of Jiangsu Province of China(BK20210899,BK20210900,BK20210901)+1 种基金Research Grant of Jiangsu Commission of Health,China(ZD2021036)the Starting Grant for Talents of Xuzhou Medical University(D2021007,D2021008).
文摘Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.
基金supported by the National Key Research and Development Program of China(2021YFD1801000)the Natural Science Foundation of China(32373066)+1 种基金the Natural Science Foundation of Jilin Province(20230101142JC)the Fundamental Research Funds for the Central Universities.
文摘Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular infection.Herein,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.
文摘In this review research,the full bio-medical potential and application of the severe acute respiratory syndrome(SARS)-CoV-2 viruses are discussed in detail with the aim of discovering innovative treatment strategies in virology and medicine.The SARS-CoV-2 which caused an international health crisis also unraveled an opportunity to gain from its pathogenic effects to treat the affected people.The study aims at testing whether the newly discovered SARS-CoV-2 can be used for therapeutic and clinical purposes.With in-depth analytics,this investigation issue endeavors to unearth new ways of fighting infectious diseases and to improve existing medical interventions.Beside scientific and practical significance the role of this work is vital.By learning the biologic and molecular mysteries of SARS-CoV-2,the researchers can create precise medicines and vaccines not only against COVID-19 but also the other infectious diseases as well.Furthermore,this recommendation may open the door to the future development of gene therapy and vaccine technology.In this sense,it combines multiple approaches,such as viral studies,immunology,and molecular biology.Laboratory experiments,computer program modeling and clinical trials are applied to detection of the SARS-COV-2 in therapeutic implementation.The principal conclusion and analysis of this research put forth the fact that SARS-CoV-2 can be utilized in anti-viral treatment,cancer therapy,and vaccine programs.The study results confirm the inherent adaptability of viruses like SARS-CoV-2 and emphasis on the development of specific therapeutic measures.It is valuable because of its potential to add to virology and medication,showing new ways for virus-based treatment.In addition,the impact of these results on treatments would be revolutionary,with potential to invent superior and flexible interventions against infectious disease.In short,the therapeutic use of SARS-CoV-2 can be regarded as a bold innovation with tremendous consequences for general health,and ultimately for medical science.
基金the National Key Research and Development Program of China(2023YFD2201404)the National Natural Science Foundation of China Youth Fund(No.52103072)+2 种基金Beijing Natural Science Foundation(No.2222068)5·5 Engineering Research&Innovation Team Project of Beijing Forestry University(No:BLRC2023A02)the Regional Research Collaboration(RRC)Program-“Sustainable Industry Manufacturing Planning for Long‑term Ecosystems(SIMPLE)Hub”.
文摘Over 950 billion(about 3.8 million tons)masks have been consumed in the last four years around the world to protect human beings from COVID-19 and air pollution.However,very few of these used masks are being recycled,with the majority of them being landfilled or incinerated.To address this issue,we propose a repurposing upcycling strategy by converting these polypropylene(PP)-based waste masks to highperformance thermally conductive nanocomposites(PP@G,where G refers to graphene)with exceptional electromagnetic interference shielding property.The PP@G is fabricated by loading tannic acid onto PP fibers via electrostatic self-assembling,followed by mixing with graphene nanoplatelets(GNPs).Because this strategy enables the GNPs to form efficient thermal and electrical conduction pathways along the PP fiber surface,the PP@G shows a high thermal conductivity of 87 W m^(-1)K^(-1)and exhibits an electromagnetic interference shielding effectiveness of 88 dB(1100 dB cm^(−1)),making it potentially applicable for heat dissipation and electromagnetic shielding in advanced electronic devices.Life cycle assessment and techno-economic assessment results show that our repurposing strategy has significant advantages over existing methods in reducing environmental impacts and economic benefits.This strategy offers a facile and promising approach to upcycling/repurposing of fibrous waste plastics.
文摘Objective:Prostate cancer(PCA)is the second most widespread cancer among men globally,with a rising mortality rate.Enzyme-responsive lipid nanoparticles(ERLNs)are promising vectors for the selective delivery of anticancer agents to tumor cells.The goal of this study is to fabricate ERLNs for dual delivery of gefitinib(GF)and simvastatin(SV)to PCA cells.Methods:ERLNs loaded with GF and SV(ERLNGFSV)were assembled using bottomup and top-down techniques.Subsequently,these ERLN cargoes were coated with triacylglycerol,and phospholipids and capped with chitosan(CS).The ERLNGFSV,and CS engineered ERLNGFSV(CERLNGFSV)formulations were characterized for particle size(PS),zeta potential(ZP),and polydispersity index(PDI).The biocompatibility,and cytotoxicity of the plain and GF plus SV-loaded ERLN cargoes were assessed using erythrocytes and PC-3 cell line.Additionally,molecular docking simulations(MDS)were conducted to examine the influence of GF and SV on succinate dehydrogenase(SDH),glutathione peroxidase-4(GPX-4),and 5α-reductase(5α-RD).Results:These results showed that plain,ERLNGFSV,and CERLNGFSV cargoes have a nanoscale size and homogeneous appearance.Moreover,ERLNGFSV and CERLNGFSV were biocompatible,with no detrimental effects on erythrocytes.Treatment with GF,SV,GF plus SV,ERLNGFSV,and CERLNGFSV significantly reduced the viability of PC-3 cells compared to control cells.Particularly,the blend of GF and SV,as well as ERLNGFSV and CERLNGFSV augmented PC-3 cell death.Also,treating PC-3 cells with free drugs,their combination,ERLNGFSV,and CERLNGFSV formulations elevated the percentage of apoptotic cells.MDS studies demonstrated that GF and SV interact with the active sites of SDH,GPX-4,and 5α-reductase.Conclusions:This study concludes that SVGF combination and ERLNs loading induce particular delivery,and synergism on PC-3 death through action on multiple pathways involved in cell proliferation,and apoptosis,besides the interaction with SDH,GPX-4,and 5α-RD.Therefore,GFSV-loaded ERLN cargoes are a promising strategy for PCA treatment.In vivo studies are necessary to confirm these findings for clinical applications.
基金supported by the National Research Foundation of Korea(NRF)through the Ministry of Education(2021R1I1A3059820)(to Jea-Hyun Baek).
文摘AMP-activated protein kinase(AMPK)is a highly conserved serine/threonine kinase that functions as a central regulator of cellular energy status.In cancer,where metabolic reprogramming enables rapid proliferation and survival under stress,AMPK functions as a metabolic checkpoint that restrains tumor growth by inhibiting biosynthetic pathways and promoting catabolic processes,such as autophagy and fatty acid oxidation.Given its role in opposing many hallmarks of cancer metabolism,AMPK has attracted significant interest as a therapeutic target.This review examines the molecular mechanisms by which AMPK influences tumor progression and evaluates the preclinical and clinical evidence for pharmacological AMPK activation using agents such as metformin,phenformin,and canagliflozin.While promising anti-tumor effects have been reported in specific contexts—such as HER2-positive breast cancer,colorectal cancer,and metabolically distinct lung cancer subtypes—clinical efficacy remains variable.Limitations include indirect activation mechanisms,low tissue penetrance,tumor heterogeneity,and lack of reliable biomarkers for patient selection.We discuss emerging strategies to overcome these challenges,including combination therapies,metabolic stratification,and the development of direct AMPK activators or mRNA-based delivery platforms.Together,these insights support a renewed focus on AMPK as a modifiable node in cancermetabolismand a candidate for integration into precision oncology frameworks.
基金supported by the Natural Science Foundation of Sichuan Province,China,grant number:2021YJ0011.
文摘Objectives:Ovarian cancer,a leading cause of gynecological malignancy-related mortality,is charac-terized by limited therapeutic options and a poor prognosis.Although pyrimethamine has emerged as a promising candidate demonstrating efficacy in treating various tumors,the precise mechanisms of its antitumor effects remain obscure.This study was specifically designed to investigate the mode of action underlying the antitumor effects of pyrimethamine in preclinical settings.Methods:The effects of pyrimethamine on cellular proliferation were meticulously assessed using both the cell counting kit 8(CCK-8)assay and the colony formation assay,with the effects further confirmed in a murine model.A confocal microscope was utilized to monitor the dynamic alterations in mitochondria within ovarian cancer cells.Additionally,adenosine triphosphate(ATP)and reactive oxygen species(ROS)assays were conducted to measure mitochondrial damage induced by pyrimethamine in ovarian cancer cell lines.The mitochondrial membrane potential was assessed using fluorescent dyes as an indicator of mitochondrial functional status.Furthermore,transcriptome analysis and immunohistochemical techniques were employed to detect the impact of pyrimethamine on ovarian cancer cells.Results:Our results demonstrated that pyrimethamine induced ovarian cancer cell death through mitochondrial dysfunction and lethal mitophagy.Transcriptome profiling analysis and Western blot demonstrated that activation of the p38/JNK/ERK signaling pathway was implicated in the process of pyrimethamine-induced mitophagy in ovarian cancer cells.Importantly,combination treatment with pyrimethamine and paclitaxel in vitro and in vivo showed a synergistic antitumor effect.Conclusions:Altogether,these findings indicate that the antitumor effects of pyrimethamine result from the induction of lethal mitophagy via regulation of the p38/JNK/ERK pathway in ovarian cancer.Considering the low toxicity and high tolerance associated with pyrimethamine,it is suggested that pyrimethamine be evaluated in the treatment of ovarian cancer,either as a monotherapy or in combination with paclitaxel.
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.
