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 IC50 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
Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)causes the compli-cated disease COVID-19.Clinicians are continuously facing huge problems in the treatment of patients,as COVID-19-specific drugs are not avai...Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)causes the compli-cated disease COVID-19.Clinicians are continuously facing huge problems in the treatment of patients,as COVID-19-specific drugs are not available,hence the principle of drug repurpos-ing serves as a one-and-only hope.Globally,the repurposing of many drugs is underway;few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials.Here in this review,our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs,the potential mechanism of actions,and the current clinical trial status of various drugs which are under repurposing since early 2020.At last,we briefly proposed the probable phar-macological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.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
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
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
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 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
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
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
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
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
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
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
Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly atte...Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway,leading to phosphorylation and inactivation of yes-associated protein 1.This discovery links Gprotein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis.The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease.With its established safety and affordability,levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models.Here,we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation,discuss translational opportunities for levodopa in liver fibrosis,and propose future directions to validate this pathway across disease models and clinical settings.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
Pharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines(TCMs)for the treatment of diseases.TCMs,in“multi-component,multi-t...Pharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines(TCMs)for the treatment of diseases.TCMs,in“multi-component,multi-target,multi-pathway”paradigm,show satisfactory clinical results in complex diseases.New ideas and methods are urgently needed to explain the complex interactions between TCMs and diseases.Network pharmacology(NP)provides a novel paradigm to uncover and visualize the underlying interaction networks of TCMs against multifactorial diseases.The development and application of NP has promoted the safety,efficacy,and mechanism investigations of TCMs,which then reinforces the credibility and popularity of TCMs.The current organcentricity of medicine and the“one disease-one target-one drug”dogma obstruct the understanding of complex diseases and the development of effective drugs.Therefore,more attentions should be paid to shift from“phenotype and symptom”to“endotype and cause”in understanding and redefining current diseases.In the past two decades,with the advent of advanced and intelligent technologies(such as metabolomics,proteomics,transcriptomics,single-cell omics,and artificial intelligence),NP has been improved and deeply implemented,and presented its great value and potential as the next drug-discovery paradigm.NP is developed to cure causal mechanisms instead of treating symptoms.This review briefly summarizes the recent research progress on NP application in TCMs for efficacy research,mechanism elucidation,target prediction,safety evaluation,drug repurposing,and drug design.展开更多
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 IC50 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.
基金supported by the Department of Science and Technology India[NanoMission:DST/NM/NT/2018/105(G)SERB:EMR/2017/000992]and Focused Basic Research(FBR)(No.MLP-142),HCP-40(Pan-Cancer Mission),Council of Scientific and Industrial Research(CSIR),Govt.of India.
文摘Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)causes the compli-cated disease COVID-19.Clinicians are continuously facing huge problems in the treatment of patients,as COVID-19-specific drugs are not available,hence the principle of drug repurpos-ing serves as a one-and-only hope.Globally,the repurposing of many drugs is underway;few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials.Here in this review,our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs,the potential mechanism of actions,and the current clinical trial status of various drugs which are under repurposing since early 2020.At last,we briefly proposed the probable phar-macological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.
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.
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 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.
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.
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 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 Open Project Fund of Henan Provincial Research Center for Precision Diagnosis and Treatment of Pulmonary Diseases Based on Multi-omics,No.DZXGCZXKF04.
文摘Liver fibrosis remains a major global health challenge with limited therapeutic options.In their recent study,Wang et al report that levodopa,a dopamine precursor widely used in Parkinson’s disease,significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway,leading to phosphorylation and inactivation of yes-associated protein 1.This discovery links Gprotein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis.The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease.With its established safety and affordability,levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models.Here,we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation,discuss translational opportunities for levodopa in liver fibrosis,and propose future directions to validate this pathway across disease models and clinical settings.
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the Natural Science Foundation of Zhejiang Province(No.LZ20H290002)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202002)+2 种基金the Fundamental Research Funds for the Central Universities(No.226-2022-00226)the Science and Technological Innovation Project for College Students in Zhejiang Province(Xinmiao Talent Plan 2022R424A005)Zhejiang Provincial Administration of Traditional Chinese Medicine(Nos.2022ZQ022,2023ZF083).
文摘Pharmacodynamics material basis and effective mechanisms are the two main issues to decipher the mechnisms of action of Traditional Chinese medicines(TCMs)for the treatment of diseases.TCMs,in“multi-component,multi-target,multi-pathway”paradigm,show satisfactory clinical results in complex diseases.New ideas and methods are urgently needed to explain the complex interactions between TCMs and diseases.Network pharmacology(NP)provides a novel paradigm to uncover and visualize the underlying interaction networks of TCMs against multifactorial diseases.The development and application of NP has promoted the safety,efficacy,and mechanism investigations of TCMs,which then reinforces the credibility and popularity of TCMs.The current organcentricity of medicine and the“one disease-one target-one drug”dogma obstruct the understanding of complex diseases and the development of effective drugs.Therefore,more attentions should be paid to shift from“phenotype and symptom”to“endotype and cause”in understanding and redefining current diseases.In the past two decades,with the advent of advanced and intelligent technologies(such as metabolomics,proteomics,transcriptomics,single-cell omics,and artificial intelligence),NP has been improved and deeply implemented,and presented its great value and potential as the next drug-discovery paradigm.NP is developed to cure causal mechanisms instead of treating symptoms.This review briefly summarizes the recent research progress on NP application in TCMs for efficacy research,mechanism elucidation,target prediction,safety evaluation,drug repurposing,and drug design.
