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.

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.

An Overview of Anterior Repositioning Splint Therapy for Disc Displacement-related Temporomandibular Disorders

Anterior repositioning splint(ARS)therapy is considered one of the most effective therapies for treating disc displacement-related temporomandibular disorders(TMDs),which account for a large proportion of TMD cases.Owing to the wide application of this therapy,the exact mechanism of remission has increasingly drawn attention.Given that practitioners have different views on ARS therapy,its indications are broadened,and operating methods diverged.This review attempts to provide an overview of ARS therapy and helps practitioners establish indications and suitable operating methods.Representative views in the past 10 years were summarised,and conclusions were drawn as follows:The mechanism of ARS therapy is mainly attributed to internal derangement correction,improvement of stress distribution and recently reported joint remodeling.It has an evident effect in the short term,and the most prevalent operating methods are protruding the mandible to the edge-to-edge position and wearing the ARS for 24 hours daily for 3-6 months.However,long-term stability is not optimal,and thus indications should be selected carefully.Notably,most of the clinical studies in this field are case analyses with low-quality evidence.Well-designed RCTs are required to further validate relevant theories.

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 agonists as potential neuroprotective agents

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases' different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins(or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors' effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins(or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use(utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists' neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

Quick repositioning maneuver for horizontal semicircular canal benign paroxysmal positional vertigo

Objective:To investigate the efficacy of quick repositioning maneuver for horizontal semicircular canal benign paroxysmal positional vertigo (H-BPPV). Methods:Clinical data of 67 patients with H-BPPV who underwent quick repositioning maneuver in our hospital from July 2009 to November 2014 were retrospectively analyzed. The maneuver involved rotating the patient in the axial plane for 180? from the involved side towards contralateral side as quickly as possible. Results:Complete symptom resolution was achieved in 61 patients (91.0%) at one week and in 64 patients (95.5%) at 3 months post-treatment. During the repositioning maneuver process, there were no obvious untoward responses except transient nausea with or without vomiting in a few patients. Conclusion:The results indicate that the quick repositioning maneuver is an easy and effective alternative treatment in the management of H-BPPV. Copyright ? 2015 The Authors. Production & hosting by Elsevier (Singapore) Pte Ltd On behalf of PLA General Hospital Department of Otolaryngology Head and Neck Surgery. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Repositioning imatinib for spinal cord injury

Efforts to pharmacologically restore central nervous system（CNS）function after injury has historically focused on promoting nerve growth with nerve growth factors such as nerve growth factor（NGF）,neurotrophin 3（NT3）and brain-derived neurotrophic factor（BDNF）.

Role of subjective visual vertical in patients with posterior canal benign paroxysmal positional vertigo as a prognostic marker after canalith repositioning maneuver

Objective:To study the potential role of subjective visual vertical(SVV)as a prognostic marker for canalith repositioning maneuver(CRM)in patients with posterior canal benign paroxysmal positional vertigo(PC-BPPV)for the Indian population.Methods:SVV was examined in 30 patients with PC-BPPV before and after canalith repositioning maneuver and after complete resolution of PC-BPPV.Study parameters included the mean of 10 angular tilt readings and direction of deviation,which were compared before and after CRM and following complete resolution of PC-BPPV.Results:The angle of SVV tilt was greater and deviated towards the affected ear before CRM in all patients,which decreased significantly shortly after CRM and continued to decrease after complete resolution of PC-BPPV(p<0.0001).Conclusions:SVV can be used to test utricular dysfunction in PC-BPPV.The angle of tilt improves in response to CRM,which may be used as a prognostic marker in patients with PC-BPPV receiving CRM.

Genetic expression of Col-2A and Col-10A as a function of administration of IGF-1 &TGF-<i>β</i>with and without anterior mandibular repositioning appliance on the growth of mandibular condylar cartilage in young rabbit

New Zealand (NZ) young rabbits with the administration of insulin-like growth factor (IGF-1) and transforming growth factor-β (TGF-β) with and without mandibular anterior repositioning appliances are explored for the growth of the mandibular condylar cartilage (MCC). 32 growing NZ and rabbits were divided into 4 groups: the group with saline injection in TMJ, the group which received growth factor injection in TMJ, the group which received anterior positioning appliance and the group which received growth factors injection as well as mandibular repositioning appliance. Gene expression was studied by real-time RT-PCR and cartilage growth by histomorphometry. Administration of growth factors along with mandibular repositioning appliances has induced 1) 1.70-fold expression of Col-2Agene (p value < 0.0005) and 2) 1.47-fold expression of Col-10Agene (p value < 0.0005). In contrast, administration of only mandibular repositioning appliances induced 1) 1.28-fold expression of Col-2Agene (p value < 0.0005) and 2) merely 0.62-fold expression of Col-10Agene (p value < 0.0005), while administration of growth factors only induced 1) mere 0.56-fold expression of Col-2Agene (p value 10A gene (p value growth factors along with mandibular repositioning appliances causes an increase in genetic expressions which have been corroborated by histomorphometry and validated by statistical analysis, during an accelerated growth of mandibular condylar cartilage. Administration of growth factors in the TMJ could provide a synergistic role along with mandibular repositioning appliances for treatment of mandibular retrognathism as well as disorders on the MCC.

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.

Factors affecting repositioning policy compliance:an integrative review

Objective:To explore the factors affecting nurses’compliance with repositioning policy.Methods:An integrative review was conducted following the Whittemore and Knafl methodology to identify the problem related to repositioning policy compliance.We searched the following databases:Coherence Wounds Group Specialized Register(Jan 1997 to Jun 2019),Ovid MEDLINE(Jan 1997 to Jun 2019),EBSCO CINAHL(Jan 1997 to Jun 2019),and Clinical Key database(Jan 2014 to Oct 2018).Results:The review revealed three factors that influence repositioning compliance:nurse-related factors,patient-related factors,and Environment-related factors.Conclusions:These factors directly impact one another and,in turn,influence the compliance of nurses to the repositioning policy.However,there is no evidence currently available that explains the collective impact of these factors and how they interact to affect repositioning policy compliance.Never theless,all these factors are impor tant and should be considered to enhance and fur ther improve the quality of nursing care and adherence to the repositioning policy。

Comparison of the Effectiveness of TRV Chair and Canalith Repositioning Procedure (CRP) for the Treatment of Benign Paroxysmal Positional Vertigo (BPPV)

The primary goal of this research is to evaluate the efficacy of traditional manual canalith repositioning procedures (CRP) to that of automated multi-axial repositioning chair (TRV). A total of 37 BPPV positive patients were distributed into two groups. The first group consisted of 20 patients, 10 under 50 years old (young group) and 10 over 50 years old (old group), who received TRV chair treatment, whereas the remaining 17 patients, 7 under 50 years old (young group) and 10 over 50 years old (old group) received CRP treatment. The DHI and VAS questionnaires were given to the patients before and after treatment, and the results were compared. The average VAS score for TRV patients was 84.5% (young group) and 77.5% (old group). These patients’ DHI results were as follows: for young patients, 10% had a mild handicap, 80% had a moderate handicap, and 10% had a severe handicap, while for the elderly, 40% had a mild handicap, 40% had a moderate handicap, and 20% had a severe handicap. The results improved significantly after the first treatment session. Old patients had a VAS of 28%, 30% had a mild handicap and only 10% had a moderate handicap. However, only 43% of the young group and 30% of the old group who underwent standard CRP suffered from mild handicap and had a VAS of 20% and 34.3% successively. The third session revealed that all patients in the TRV chair group had no handicap, whereas the CRP patients indicated that they still had a mild handicap. Upon analyzing the results, both treatment methods revealed the same efficacy in treating single canal BPPV. However, TRV chair appeared to be superior to traditional CRP in treating multi-canal BPPV.

Toric Intraocular Lens Malposition Corrected by Lens Repositioning to Manifest Refractive Cylinder Axis in Patient with Irregular Astigmatism Due to Corneal Scar

A case is presented of a patient with an unexpected poor visual result and subsequent correction following cataract removal surgery via phacoemulsification and intraocular lens implantation using a toric intraocular lens implant (IOL). The initial operation resulted in an uncorrected vision of 20/100 (0.70 logMAR). Retrospective analysis of the patient’s corneal topography revealed irregular astigmatism secondary to remote trauma to the cornea. The cylinder axis on manifest refraction (MR) was significantly different from measured keratometry, so a second procedure was performed to align the cylinder axis of the IOL with the steep axis on MR. This repositioning procedure improved visual outcome to a final uncorrected vision of 20/25 (0.10 logMAR) and best corrected acuity of 20/20 (0.0 logMAR).

Repositioning of the complete prolapsed silicone tube with modified suture-probe and silk thread traction method

The whole lacrimal passage intubation is widely used in lacrimal surgery.However,one of the most typical complications is the prolapse of the silicone tube from the medial canthus.In case,the bicanalicular silicone tube after whole lacrimal duct intubation has completely prolapsed from the medial canthus before extubation,then cannot be found in the opening of the nasolacrimal duct,and it would be a challenge to reposition or removal.A novel approach to employ a modified suture-probe and silk thread traction technique has been developed,and it is not only safe and effective,but also cost-effective.

Centromere repositioning and shifts in wheat evolution

The centromere is the region of a chromosome that directs its separation and plays an important role in cell division and reproduction of organisms.Elucidating the dynamics of centromeres is an alternative strategy for exploring the evolution of wheat.Here,we comprehensively analyzed centromeres from the de novoassembled common wheat cultivar Aikang58(AK58),Chinese Spring(CS),and all sequenced diploid and tetraploid ancestors by chromatin immunoprecipitation sequencing,whole-genome bisulfite sequencing,RNA sequencing,assay for transposase-accessible chromatin using sequencing,and comparative genomics.We found that centromere-associated sequences were concentrated during tetraploidization and hexaploidization.Centromeric repeats of wheat(CRWs)have undergone expansion during wheat evolution,with strong interweaving between the A and B subgenomes post tetraploidization.We found that CENH3 prefers to bind with younger CRWs,as directly supported by immunocolocalization on two chromosomes(1A and 2A)of wild emmer wheat with dicentromeric regions,only one of which bound with CENH3.In a comparison of AK58 with CS,obvious centromere repositioning was detected on chromosomes 1B,3D,and 4D.The active centromeres showed a unique combination of lower CG but higher CHH and CHG methylation levels.We also found that centromeric chromatin was more open than pericentromeric chromatin,with higher levels of gene expression but lower gene density.Frequent introgression between tetraploid and hexaploid wheat also had a strong influence on centromere position on the same chromosome.This study also showed that active wheat centromeres were genetically and epigenetically determined.

Ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China

OBJECTIVE: To explore the unique ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China.METHODS: Based on the natural life concept of "integration of universe and man," osteopathy in traditional Mongolian medicine in China uses the modern principles and methods of physiology, psychol-ogy, and biomechanics. Against this background,we explored the unique ideas, properties, and standards of fracture repositioning in traditional Mongolian medicine.RESULTS: Fracture treatment with osteopathy in traditional Mongolian medicine in China is based on(a) the ideas of natural, sealed, self and dynamic repositioning of fractures;(b) the properties of structural continuity and functional completeness;(c) the standards of "integration of movement and stillness" and "force to force." CONCLUSION: The unique ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China have resulted in the widespread use of such techniques and represents the future direction of the development of fracture repositioning.

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.

Satisfactory clinical outcome following delayed repositioning of a traumatic post-LASIK flap with dislocation and shrinkage managed by irrigation,stretching,and debridement

Objective：To report surgical management and favorable outcome in a case with delayed repair of traumatic laser in situ keratomileusis（LASIK）flap dislocation with shrinkage and folds.Methods：A 30-year-old man with a five-year history of bilateral LASIK experienced blunt trauma to his right eye followed by decreased vision for 5 weeks.The surgical management included initially softening the flap by irrigation with balanced salt solution（BSS）.The shrinkage folds were carefully and gently stretched by scraping with a 26-gauge cannula accompanied by BSS irrigation.All of the epithelial ingrowth on the flap inner surface and on the bed was thoroughly debrided by scraping and irrigation.After the flap was repositioned to match its original margin,a soft bandage contact lens was placed.Results：At his initial visit,slit-lamp microscopy and optical coherence tomography（OCT）showed shrinkage of the LASIK flap with an elevated margin approximately 3 mm above the original position.The flap covered half of the pupil and had multiple horizontal folds.Two months after surgery,the flap remained well positioned with only faint streaks in the anterior stroma.The uncorrected visual acuity of the right eye was 20/20 with a manifest refraction of Plano.Conclusions：For delayed repair of traumatically dislocated LASIK flaps,sufficient softening by BSS,stretching the shrinkage folds,and thorough debridement of ingrowth epithelium enable resetting the flap and provide satisfactory results.

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.