Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways

Various therapeutic strategies have been developed to overcome ovarian cancer.However,the prognoses resulting from these strategies are still unclear.In the present work,we screened 54 small molecule compounds approved by the FDA to identify novel agents that could inhibit the viability of human epithelial ovarian cancer cells.Among these,we identified disulfiram(DSF),an old alcohol-abuse drug,as a potential inducer of cell death in ovarian cancer.Mechanistically,DSF treatment significantly reduced the expression of the anti-apoptosis marker Bcell lymphoma/leukemia-2(Bcl-2)and increase the expression of the apoptotic molecules Bcl2 associated X(Bax)and cleaved caspase-3 to promote human epithelial ovarian cancer cell apoptosis.Furthermore,DSF is a newly identified effective copper ionophore,thus the combination of DSF and copper was used to reduce ovarian cancer viability than DSF single treatment.Combination treatment with DSF and copper also led to the reduced expression of ferredoxin 1 and loss of Fe-S cluster proteins(biomarkers of cuproptosis).In vivo,DSF and copper gluconate significantly decreased the tumor volume and increased the survival rate in a murine ovarian cancer xenograft model.Thus,the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer.

Systems-level biomarkers identification and drug repositioning in colorectal cancer

Colorectal cancer(CRC)is the most commonly diagnosed fatal cancer in both women and men worldwide.CRC ranked second in mortality and third in incidence in 2020.It is difficult to diagnose CRC at an early stage as there are no clinical symptoms.Despite advances in molecular biology,only a limited number of biomarkers have been translated into routine clinical practice to predict risk,prognosis and response to treatment.In the last decades,systems biology approaches at the omics level have gained importance.Over the years,several biomarkers for CRC have been discovered in terms of disease diagnosis and prognosis.On the other hand,a few drugs are being developed and used in clinics for the treatment of CRC.However,the development of new drugs is very costly and time-consuming as the research and development takes about 10 years and more than$1 billion.Therefore,drug repositioning(DR)could save time and money by establishing new indications for existing drugs.In this review,we aim to provide an overview of biomarkers for the diagnosis and prognosis of CRC from the systems biology perspective and insights into DR approaches for the prevention or treatment of CRC.

Repositioning of clinically approved drug Bazi Bushen capsule for treatment of Alzheimer′s disease using network pharma⁃cology approach and in vitro experimental validation

OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.Subsequently,new indications for BZBS were predicted by disease ontology(DO)enrich⁃ment analysis and initially validated by GO and KEGG pathway enrichment analysis.Further⁃more,the therapeutic target of BZBS acting on AD signaling pathway were identified by intersec⁃tion analysis.Two Alzheimer′s disease(AD)cell models,BV-2 and SH-SY5Y,were used to pre⁃liminarily verify the anti-AD efficacy and mecha⁃nism of BZBS in vitro.RESULTS In total,1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula,and 1320 BZBS targets with high confidence were predicted.Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treat⁃ment of AD.In vitro experiments showed that BZ⁃BS could significantly reduce the release of TNF-αand IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells.BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells,significantly increased mitochon⁃drial membrane potential,reduced the expres⁃sion of Caspase3 active fragment and PSEN1,and increased the expression of IDE.CONCLU⁃SIONS BZBS formula has a potential use in the treatment of AD,which is achieved through regu⁃lation of ERK1/2,NF-κB signaling pathways,and GSK-3β/β-catenin signaling pathway.Further⁃more,the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action.The study lays a foun⁃dation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.

PIMD:An Integrative Approach for Drug Repositioning Using Multiple Characterization Fusion

The accumulation of various types of drug informatics data and computational approaches for drug repositioning can accelerate pharmaceutical research and development.However,the integration of multi-dimensional drug data for precision repositioning remains a pressing challenge.Here,we propose a systematic framework named PIMD to predict drug therapeutic properties by integrating multi-dimensional data for drug repositioning.In PIMD,drug similarity networks(DSNs)based on chemical,pharmacological,and clinical data are fused into an integrated DSN(iDSN)composed of many clusters.Rather than simple fusion,PIMD offers a systematic way to annotate clusters.Unexpected drugs within clusters and drug pairs with a high iDSN similarity score are therefore identified to predict novel therapeutic uses.PIMD provides new insights into the universality,individuality,and complementarity of different drug properties by evaluating the contribution of each property data.To test the performance of PIMD,we use chemical,pharmacological,and clinical properties to generate an iDSN.Analyses of the contributions of each drug property indicate that this iDSN was driven by all data types and performs better than other DSNs.Within the top 20 recommended drug pairs,7 drugs have been reported to be repurposed.The source code for PIMD is available at https://github.com/Sepstar/PIMD/.

Identification of anthelmintic parbendazole as a therapeutic molecule for HNSCC through connectivity map-based drug repositioning

Head and neck squamous cell carcinoma(HNSCC) is one of the most common human cancers;however, its outcome of pharmacotherapy is always very limited. Herein, we performed a batch query in the connectivity map(cMap) based on bioinformatics, queried out 35 compounds with therapeutic potential, and screened out parbendazole as a most promising compound, which had an excellent inhibitory effect on the proliferation of HNSCC cell lines. In addition, tubulin was identified as a primary target of parbendazole, and the direct binding between them was further verified. Parbendazole was further proved as an effective tubulin polymerization inhibitor, which can block the cell cycle, cause apoptosis and prevent cell migration, and it exhibited reasonable therapeutic effect and low toxicity in the in vivo and in vitro anti-tumor evaluation. Our study repositioned an anthelmintic parbendazole to treat HNSCC, which revealed a therapeutic utility and provided a new treatment option for human cancers.

NOGEA: A Network-oriented Gene Entropy Approach for Dissecting Disease Comorbidity and Drug Repositioning

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes(DAGs),which are important for understanding disease initiation and developing precision therapeutics.However,DAGs often contain large amounts of redundant or false positive information,leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases.In this study,a networkoriented gene entropy approach(NOGEA)is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks.In addition,we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk.Master genes may also be used to extract the underlying information of different diseases,thus revealing mechanisms of disease comorbidity.More importantly,approved therapeutic targets are topologically localized in a small neighborhood of master genes in the interactome network,which provides a new way for predicting drug-disease associations.Through this method,11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments.Collectively,the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence,thus providing a valuable strategy for drug efficacy screening and repositioning.NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.

Converging multi-modality datasets to build efficient drug repositioning pipelines against Alzheimer’s disease and related dementias

Alzheimer’s disease and related dementias(AD/ADRD)affects more than 50 million people worldwide but there is no clear therapeutic option affordable for the general patient population.Recently,drug repositioning studies featuring collaborations between academic institutes,medical centers,and hospitals are generating novel therapeutics candidates against these devastating diseases and filling in an important area for healthcare that is poorly represented by pharmaceutical companies.Such drug repositioning studies converge expertise from bioinformatics,chemical informatics,medical informatics,artificial intelligence,high throughput and high-content screening and systems biology.They also take advantage of multi-scale,multi-modality datasets,ranging from transcriptomic and proteomic data,electronical medical records,and medical imaging to social media information of patient behaviors and emotions and epidemiology profiles of disease populations,in order to gain comprehensive understanding of disease mechanisms and drug effects.We proposed a recursive drug repositioning paradigm involving the iteration of three processing steps of modeling,prediction,and validation to identify known drugs and bioactive compounds for AD/ADRD.This recursive paradigm has the potential of quickly obtaining a panel of robust novel drug candidates for AD/ADRD and gaining in-depth understanding of disease mechanisms from those repositioned drug candidates,subsequently improving the success rate of predicting novel hits.

Multi-omics integration reveals potential stage-specific druggable targets in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease.In this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to identify potential stage-specific druggable targets and repositioned drugs for this disease.This multi-omics integration helped identify 29 potential pathological genes for T-ALL.These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling pathway.Of these,four known druggable targets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL.The TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage.CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naıve to maturation stages.Furthermore,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in T-ALL.Collectively,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.

Six psychotropics for pre-symptomatic ＆ early Alzheimer＇s (MCI), Parkinson＇s, and Huntington＇s disease modification

The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases （NDDs）, including Alzheimer＇s disease （AD）, Parkinson＇s disease （PD）, and Huntington＇s disease （HD）, has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious findings follow. Mild cognitive impairment （MCI） phase of AD： salutary human randomized controlled trial findings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD： human epidemiological data indicate that lithium reduc- es AD risk. Animal model studies （AMS） reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD： valproate AMS findings show promise. Pre-symptomatic PD： lithium and valproate AMS findings are encouraging. Early HD： uncontrolled clinical data indicate non-progression with lithium, fluoxetine, donepezil, and memantine. Pre-symptomatic HD： lithium and valproate are auspicious in AMS. Many other promising findings awaiting replication （valproate in MCI; lithium, valproate, fluoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, fluoxetine in pre-symptomatic PD; donepezil in early HD; lithium, fluoxetine, memantine in pre-symptomatic HD） are reviewed. Dose- and stage-dependent effects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage.

Novel therapeutic strategies and common mechanisms of neurodegenerative diseases

Neuroprotection holds particular significance in neurodegenerative diseases characterized by the death of brain cells.Despite differences in timeframe,location,pathology,and clinical outcomes,common pathophysiological mechanisms may exist,including oxidative stress and excitotoxicity.So far,neuroprotective therapies have yet to demonstrate significant benefits in clinical trials.1 Reasons for past translational failures may involve low experimental study quality,more complex pathophysiology than expected,challenging drug delivery,late intervention,and safety issues.However,recent advances offer renewed hope and potential breakthroughs that could change the treatment landscape in the future.These novel therapeutic strategies will be discussed in this issueofNeuroprotection.

Structure-based protein-protein interaction networks and drug design

Proteins carry out their functions by interacting with other proteins and small molecules, forming a complex interaction network. In this review, we briefly introduce classical graph theory based protein-protein interaction networks. We also describe the commonly used experimental methods to construct these networks, and the insights that can be gained from these networks. We then discuss the recent transition from graph theory based networks to structure based protein-protein interaction networks and the advantages of the latter over the former, using two networks as examples. We further discuss the usefulness of structure based protein-protein interaction networks for drug discovery, with a special emphasis on drug repositioning.

SARS-CoV-2 spike protein and RNA dependent RNA polymerase as targets for drug and vaccine development: A review

The present pandemic has posed a crisis to the economy of the world and the health sector.Therefore,the race to expand research to understand some good molecular targets for vaccine and therapeutic development for SARS-CoV-2 is inevitable.The newly discovered coronavirus 2019(COVID-19)is a positive sense,single-stranded RNA,and enveloped virus,assigned to the beta CoV genus.The virus(SARS-CoV-2)is more infectious than the previously detected coronaviruses(MERS and SARS).Findings from many studies have revealed that S protein and RdRp are good targets for drug repositioning,novel therapeutic development(antibodies and small molecule drugs),and vaccine discovery.Therapeutics such as chloroquine,convalescent plasma,monoclonal antibodies,spike binding peptides,and small molecules could alter the ability of S protein to bind to the ACE-2 receptor,and drugs such as remdesivir(targeting SARS-CoV-2 RdRp),favipir,and emetine could prevent SASR-CoV-2 RNA synthesis.The novel vaccines such as mRNA1273(Moderna),3LNP-mRNAs(Pfizer/BioNTech),and ChAdOx1-S(University of Oxford/Astra Zeneca)targeting S protein have proven to be effective in combating the present pandemic.Further exploration of the potential of S protein and RdRp is crucial in fighting the present pandemic.

DrSim: Similarity Learning for Transcriptional Phenotypic Drug Discovery

Transcriptional phenotypic drug discovery has achieved great success,and various compound perturbation-based data resources,such as connectivity map(CMap)and library of integrated network-based cellular signatures(LINCS),have been presented.Computational strategies fully mining these resources for phenotypic drug discovery have been proposed.Among them,the fundamental issue is to define the proper similarity between transcriptional profiles.Traditionally,such similarity has been defined in an unsupervised way.However,due to the high dimensionality and the existence of high noise in high-throughput data,similarity defined in the traditional way lacks robustness and has limited performance.To this end,we present Dr Sim,which is a learning-based framework that automatically infers similarity rather than defining it.We evaluated Dr Sim on publicly available in vitro and in vivo datasets in drug annotation and repositioning.The results indicated that Dr Sim outperforms the existing methods.In conclusion,by learning transcriptional similarity,Dr Sim facilitates the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery.The source code and manual of Dr Sim are available at https://github.com/bm2-lab/Dr Sim/.

Metformin capped Cu_(2)(OH)_(3)Cl nanosheets for chemodynamic wound disinfection

Recently,the development of chemodynamic therapy(CDT)offers a potential approach for fighting bacteria and treating infectious diseases,in which those CDT nanoagents can catalyze the generation of hydroxyl radicals(·OH)to destroy bacteria.In this work,to improve the efficiency of CDT,we have designed a new kind of metformin(Met)-capped two-dimensional Cu_(2)(OH)_(3)Cl nanosheets(CuOHCl-Met NSs)with good monodispersity,highly positive charge,and good biocompatibility for improving antibacterial effect and accelerating wound healing.With the capped Met,CuOHCl-Met NSs can effectively kill bacteria under a low concentration(6μg·mL^(−1))and a short treatment time(in 15 min),showing great advantages over the counterpart without Met.In vivo results demonstrated that CuOHCl-Met NSs accelerated the tissue regeneration of staphylococcus aureus-infected dermal wounds.This study provides a new pathway for improving efficiency of CDT nanoagent through using old drug.

Controlling schistosomiasis with praziquantel:How much longer without a viable alternative?

The current approach of morbidity control of schistosomiasis,a helminth disease of poverty with considerable public health and socioeconomic impact,is based on preventive chemotherapy with praziquantel.There is a pressing need for new drugs against this disease whose control entirely depends on this single drug that has been widely used over the past 40 years.We argue that a broader anthelminthic approach supplementing praziquantel with new antischistosomals targeting different parasite development stages would not only increase efficacy but also reduce the risk for drug resistance.Repositioning drugs already approved for other diseases provides a shortcut to clinical trials,as it is expected that such drugs rapidly pass the regulatory authorities.The antischistosomal properties of antimalarial drugs(e.g.,semisynthetic artemisinins,synthetic trioxolanes,trioxaquines and mefloquine)and of drugs being developed or registered for other purposes(e.g.,moxidectin and miltefosin),administered alone or in combination with praziquantel,have been tested in the laboratory and clinical trials.Another avenue to follow is the continued search for new antischistosomal properties in plants.Here,we summarise recent progress made in schistosomiasis chemotherapy,placing particular emphasis on repositioning of existing drugs against schistosomiasis.

COVID-19: Antiviral Agents, Antibody Development and Traditional Chinese Medicine

The World Health Organization(WHO) has declared coronavirus disease 2019(COVID-19) is the first pandemic caused by coronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2). Currently, there is no effective anti-SARS-CoV-2 drug approved worldwide for treatment of patients with COVID-19. Therapeutic options in response to the COVID-19 outbreak are urgently needed. To facilitate the better and faster development of therapeutic COVID-19 drugs, we present an overview of the global promising therapeutic drugs, including repurposing existing antiviral agents,network-based pharmacology research, antibody development and traditional Chinese medicine. Among all these drugs,we focus on the most promising drugs(such as favipiravir, tocilizumab, SARS-CoV-2 convalescent plasma, hydroxychloroquine, Lianhua Qingwen, interferon beta-1 a, remdesivir, etc.) that have or will enter the final stage of human testing—phase Ⅲ–Ⅳ clinical trials.

Repurposing of berbamine hydrochloride to inhibit Ebola virus by targeting viral glycoprotein

Ebola virus(EBOV)infection leads to staggeringly high mortality rate.Effective and low-cost treatments are urgently needed to control frequent EBOV outbreaks in Africa.In this study,we report that a natural compound called berbamine hydrochloride strongly inhibits EBOV replication in vitro and in vivo.Our work further showed that berbamine hydrochloride acts by directly binding to the cleaved EBOV glycoprotein(GPcl),disrupting GPcl interaction with viral receptor Niemann-Pick C1,thus blocking the fusion of viral and cellular membranes.Our data support the probability of developing anti-EBOV small molecule drugs by targeting viral GPcl.More importantly,since berbamine hydrochloride has been used in clinic to treat leukopenia,it holds great promise of being quickly repurposed as an anti-EBOV drug.