Current pharmaceutical design最新文献

{"title":"Untargeted Metabolomics Analysis of Vaginal Secretion Reveals Potential Pathogenesis of Atrophic Vaginitis.","authors":"Chenyun Zhang, Yali Ren, Jiaxiong Li, Guanghua Wang, Jiehua Ma, Jin Qiu","doi":"10.2174/0113816128362600250203051056","DOIUrl":"https://doi.org/10.2174/0113816128362600250203051056","url":null,"abstract":"<p><strong>Introduction: </strong>Atrophic vaginitis (AV) is a common and frequently occurring disease, lacking effective curative measures. Exploring the mechanism of vaginal mucosal homeostasis from the perspective of metabolites has great research prospects.</p><p><strong>Methods: </strong>We compared the metabolic profiles of vaginal secretions between AV patients and healthy individuals via liquid chromatography-tandem mass spectrometry (LC-MS/MS). We further explored effective and sensitive metabolites and metabolic pathways for senile vaginitis through bioinformatics analysis and experimental verification. Through untargeted metabolomics analysis, we screened 561 differential metabolites in two groups of vaginal secretion samples. These differential metabolites were mainly concentrated in fatty acids/carboxylic acids, glycerophospholipids, organic oxides, steroids, and their derivatives. They were mainly enriched in purine metabolism, diabetic cardiomyopathy generation, and choline metabolism pathways.</p><p><strong>Results: </strong>The receiver operating characteristic analysis showed the metabolites (e.g., guggulsterone, umbelliprenin, and inosinic acid) to have good discrimination ability for the AV group. In addition, we also explored the potential mechanism of action of umbelliprenin at the cellular level.</p><p><strong>Conclusion: </strong>This study is expected to provide a new perspective for understanding the relationship between metabolites and the pathogenesis of AV.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential New Treatments for Chronic Kidney Diseases: A Concise Review.","authors":"Rami A Al-Horani","doi":"10.2174/0113816128360091250117040009","DOIUrl":"https://doi.org/10.2174/0113816128360091250117040009","url":null,"abstract":"<p><p>Chronic Kidney Disease (CKD) affects about 37 million Americans. Approximately 20% of patients with high blood pressure and 33% of patients with diabetes have kidney disease. CKD is most common among people aged 65 or older and is slightly more common in women. It substantially impacts certain ethnic groups more than others and is associated with a huge financial burden. End-Stage Kidney Disease (ESKD) is treated with dialysis or a kidney transplantation. CKD and ESKD are very detrimental and expensive illnesses, demanding creative therapeutic interventions to enable better management and enhanced clinical outcomes. Toward this goal, agents from various novel drug classes showed promising safety and efficacy in patients with varying severity of CKD in several phase 2 studies. This concise review will shed light on the clinical trials of runcaciguat, cotadutide, osocimab, and Endothelin Receptor Antagonists (ERAs) in patients with CKD and/or ESKD. These drugs were retrieved following surveying the Clinical Trial database as well as the Pubmed database, both maintained by the US National Library of Medicine.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inorganic Nanoparticles-based Drug Delivery Systems for Neurodegenerative Diseases Therapy.","authors":"Iman Bagherpour, M R Mozafari, Seyed Morteza Naghib","doi":"10.2174/0113816128352935250116064725","DOIUrl":"https://doi.org/10.2174/0113816128352935250116064725","url":null,"abstract":"<p><p>Neurodegenerative disorders (NDs) are highly prevalent among the aging population. It primarily affects the central nervous system (CNS), but the effects are also observed in the peripheral nervous system. Neural degeneration is a progressive loss of structure and function of neurons, which may ultimately involve cell death. The blood-brain barrier (BBB), which separates peripheral blood circulation from the central nervous system, is essential for maintaining intracerebral homeostasis. Drug delivery systems based on nanomaterials (NDDSs) employ nanoparticles (NPs) as their drug transport vehicles. Moreover, nanotechnologybased methods usually involve numerous nanosized carrier platforms, which potentiate the effect of the therapeutic agents in the therapy of NDs, especially in diagnosis and drug delivery, with negligible side effects. In addition, nanotechnology-based techniques have offered several strategies to cross BBB to intensify the bioavailability of drug moieties in the brain. In the last few years, diverse kinds of nanoparticles (NPs) have been developed by incorporating various biocompatible components (e.g., polysaccharide-based NPs, polymeric NPs, selenium NPs, AuNPs, protein-based NPs, gadolinium NPs, etc.), that showed great therapeutic benefits against NDs. The discussion concluded with a look at the opportunities and problems that come with NDDSs in modern basic and clinical research.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological Evaluation and Computational Modelling Studies on N-acyl Hydrazone and 2,5-Substituted 1,3,4-Oxadiazole Derivatives as Non-toxic Antimicrobial Agents.","authors":"Betül Giray, Nil Kaya, Martina Fiabane, Ayse Seyma Buyuk, Hatice Başpinar Küçük, Semra Sardas, Mattia Mori","doi":"10.2174/0113816128361524250131110036","DOIUrl":"https://doi.org/10.2174/0113816128361524250131110036","url":null,"abstract":"<p><strong>Introduction: </strong>The increasing use of antibiotics coupled with the lack of innovative and effective antimicrobial agents has increased the development of antimicrobial resistance (AMR) worldwide. To overcome the AMR-associated prolonged disease duration and increased mortality rates, new antimicrobial agents are in high demand. In this context, hydrazone and oxadiazole derivatives are endowed with remarkable biocidal activity, becoming profitable scaffolds in the design of antimicrobial candidates.</p><p><strong>Method: </strong>In this study, the antimicrobial effects of N-acyl hydrazones 1-15 and 2,5-substituted 1,3,4- oxadiazoles 16-27 against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213, Bacillus subtilis ATCC 6633, and clinically isolated Shigella sonnei, Klebsiella pneumoniae, and Candida albicans were evaluated. For this purpose, Kirby-Bauer disc diffusion and MIC tests were carried out, indicating that most of these compounds were active against tested microorganisms. Particularly, several compounds proved active against E. coli, whereas S. aureus showed higher resistance. The genotoxic potential of most active compounds was determined by in vitro alkaline comet assay, and they were found to be non-toxic at studied concentrations.</p><p><strong>Results: </strong>Finally, molecular docking and dynamics (MD) studies identified four compounds as potential inhibitors of bacterial DNA gyrase B (GyrB).</p><p><strong>Conclusion: </strong>Further exploration of molecular determinants revealed favourable drug-like properties, highlighting the potential of these molecules for subsequent hit-to-lead optimization studies.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skin Aging: Insights into the Role of Fatty Acids.","authors":"Snehal Kshirsagar, Asha Thomas, Sanjeevani Deshkar, Lata Kothapalli, Trupti Borhade, Sohan Chitlange, Avinash Sanap, Ramesh Bhonde","doi":"10.2174/0113816128357677250116115754","DOIUrl":"https://doi.org/10.2174/0113816128357677250116115754","url":null,"abstract":"<p><p>The human skin, being the largest organ, provides defense against bacteria, toxins, and ultraviolet radiation. The skin may experience changes like dryness, photodamage, oxidative damage, and inflammation. This review explores sources of fatty acids and how they can prevent skin damage, with the goal of determining their potential for preventing skin aging. The role and significance of various mechanistic pathways and molecular targets involved in skin aging are highlighted. By using current research findings, this review contributes to a comprehensive understanding of how fatty acids may serve as a proactive approach to promoting youthful skin and mitigating the signs of skin aging. In addition to treating specific skin conditions, nutraceuticals offer immense potential to minimize, postpone, or prevent premature skin aging. The substances that are most frequently employed include carotenoids, polyunsaturated fatty acids, plant polyphenols, bioactive peptides, oligosaccharides, and vitamins. Numerous human trials have demonstrated the impact of supplementing with these items on indicators of aging. The most pertinent clinical and non-clinical investigations are assessed in this review. Based on the comprehensive understanding of the significant role of fatty acids in addressing skin aging, this review may open doors and offer avenues for future explorations.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of Roxadustat in Anemia with Chronic Kidney Disease.","authors":"Yongda Lin, Chunlin Liao, Lingqian Zheng, Wenmin Chen, Tianbiao Zhou, Tianyu Li","doi":"10.2174/0113816128354065250114154721","DOIUrl":"https://doi.org/10.2174/0113816128354065250114154721","url":null,"abstract":"<p><strong>Introduction: </strong>Anemia is one of the complications of chronic kidney disease (CKD), and its incidence gradually increases as the disease progresses. A major cause of such anemia is the severe erythropoietin deficiency in CKD. Therefore, improvement in red blood cell production is a choice of treatment. Erythropoiesis- stimulating agents (ESAs) have been used for the therapy of anemia induced in CKD. Roxadustat is a novel drug for improving such anemia. This study aimed to compare the efficacy of roxadustat and ESAs in patients with CKD.</p><p><strong>Material and methods: </strong>A retrospective analysis of CKD patients with anemia who regularly use roxadustat and ESAs in the Nephrology Department of the Second Affiliated Hospital of Shantou University School of Medicine was carried out. Baseline clinical data and clinical indicators during the medication period were collected and analyzed in both groups.</p><p><strong>Results: </strong>In this retrospective study, we found that roxadustat was effective in improving anemia. The anemia rate, Hb<11g/dL, before treatment in patients with CKD was 94.55%. The standard rate of patients with CKD anemia was 25.45% after one month of treatment, 54.54% after three months of treatment, and 65.45% after six months of treatment. In the clinical observations of the medication, roxadustat did not differ from ESAs in the treatment of anemia in CKD. However, roxadustat did not improve micro-inflammatory status or increase serum potassium.</p><p><strong>Conclusion: </strong>Roxadustat did not differ from ESAs in the treatment of anemia in CKD patients. However, it has the potential to lower blood lipids and improve iron deficiency.</p><p><strong>Clinical trial registration number: </strong>ChiCTR2300071087.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Latest Expansions in Solid Lipid-based Nanoparticle Technology for Treatment of Cancer.","authors":"Smita Devendra Lilhare, Kalyani Sakure, Anjali Patel, Kushagra Nagori, Savitri Uttam Pathode, Ajazuddin, Hemant Badwaik","doi":"10.2174/0113816128334022241211033220","DOIUrl":"https://doi.org/10.2174/0113816128334022241211033220","url":null,"abstract":"<p><p>The field of cancer therapy has witnessed significant strides with the emergence of innovative drug delivery systems and one such promising avenue is solid lipid-based nanoparticle (SLN) technology. This abstract provides a complete overview of current advances in developing SLNs for effective cancer treatment solid lipid nanoparticles (NPs) represent a novel drug delivery platform characterized by their unique composition which includes biocompatible lipids as the main carrier material. This technology addresses challenges related to standard chemotherapy such as low bioavailability limited medicine stability and non-specific targeting. The incorporation of lipids in SLNs ensures enhanced drug encapsulation, protection of therapeutic agents from degradation-controlled release profiles. Recent breakthroughs in SLN technology have focused on optimizing formulation parameters to achieve superior drug loading capacities stability and sustained release kinetics. Advanced fabrication techniques including high-pressure homogenization and microemulsion methods have been pivotal in tailoring SLN properties for specific cancer types and therapeutic agents. Furthermore, SLNs' capacity to passively build up in tumor tissues using increased penetration and retention effects has been harnessed for targeted drug transport. Surface modifications using ligands or antibodies to facilitate active targeting, enhancing medication delivery's selectivity to tumor cells decreasing unwanted effects on normal tissues. This abstract highlights recent preclinical and clinical studies demonstrating the efficacy of SLN-based formulations in enhancing the therapeutic outcomes of various anticancer agents. The versatile nature of SLN technology makes it a viable option for the advancement of personalized and precision cancer therapies, marking a significant stride toward overcoming the limitations of conventional cancer treatments. As research in this domain progresses, the integration of SLNs holds immense potential for revolutionizing tumor treatment strategies.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crippled Hepatocarcinogenesis Inhibition of Quercetin in Glycolysis Pathway with Hepatic Farnesoid X Receptor Deficiency.","authors":"Wusheng Zhong, Tao Chen, Ling Chen, Yaqi Xing, Haorui Lin, Shuli Xie, Mateen Nawaz, Danmei Huang, Zhanqin Huang, Jun Lu, Zhiming Chen, Yongdong Niu","doi":"10.2174/0113816128342642250111055339","DOIUrl":"https://doi.org/10.2174/0113816128342642250111055339","url":null,"abstract":"<p><strong>Aim: </strong>Quercetin, a bioactive flavonoid extracted from traditional Chinese medicine, has antihepatocellular carcinoma effects. Farnesoid X receptor (FXR), a nuclear receptor highly expressed in the liver, plays important roles in maintaining hepatic glucose homeostasis, anti-inflammation, liver regeneration, and anti-cancer properties. Whether quercetin regulates the glycolysis/glycolysis pathway through FXR signaling remains unknown.</p><p><strong>Methods: </strong>KEGG Enrichment, GO Enrichment, Protein-Protein Interaction (PPI) Network, Molecular Docking, and RNA-Seq Analysis (Swiss Target Prediction, GeneCard databases, Kaplan-Meier Plotter, etc). Cell activity, cell proliferation, and cell cycles were separately analyzed by CCK-8 assay, clone formation assay, and flow cytometry. QRT-PCR determined the mRNA levels of related genes in response to quercetin. HPLCMS/ MSHPLC-MS/MS determined the metabolite profiles. FXR deficiency Hep3B cells were used for discriminating the quercetin's effects with or without FXR.</p><p><strong>Results: </strong>Quercetin-related genes were significantly correlated with FXR in hepatocarcinogenesis, especially in glycolysis. The top 30 related genes between FXR, quercetin, and glycolysis were enriched and chosen to further study. Furthermore, the strongest binding energy determined by the molecular docking model of between quercetin and FXR was -6.55 kcal/mol. Quercetin inhibited cell proliferation by the accumulation of Hep3B cells in the S-phase. The differential expressed genes (C-MYC, PCNA, CYCLIN-D1, and P21) associated with glycolysis were observed. Furthermore, quercetin also inhibited the expression of HK2, GAPDH, and LDHA. Meanwhile, the levels of glycolysis/gluconeogenesis-related metabolites were regulated by quercetin.</p><p><strong>Conclusion: </strong>Quercetin makes an essential anti-HCC effect by crippling the glycolysis/gluconeogenesis process via FXR signaling.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting the Role of Long Non-coding RNA PSMA3-AS1 in Human Cancers: Current Evidence and Future Directions.","authors":"Jingjie Yang, Kexing Liu, Lihan Chen, Haodong He, Tongtong Li, Li Li, Xiaolan Li, Chengfu Yuan","doi":"10.2174/0113816128350406241223053744","DOIUrl":"https://doi.org/10.2174/0113816128350406241223053744","url":null,"abstract":"<p><p>Long non-coding RNAs (lncRNAs) refer to RNA molecules that exceed 200 nucleotides in length. While lncRNAs do not possess the capacity to encode proteins, they play crucial roles in gene expression, chromatin remodeling, and protein relocation. PSMA3 antisense RNA 1 (PSMA3-AS1) is a newly discovered lncRNA located on human chromosome 14q23.1. Convincing evidence shows that it acts as a tumor-promoting factor in several forms of human cancers. Moreover, high expression of PSMA3-AS1 is linked to poor clinical and pathological features and adverse prognosis in eight types of cancer. The molecular mechanisms of PSMA3- AS1 are diverse and complex. Existing evidence demonstrates that PSMA3-AS1 is activated by two transcription factors, PAX5 and YY-1, and influences cancer cell growth, metastasis, apoptosis, drug resistance, oxidative stress, and autophagy by acting as a competing endogenous RNA, activating signaling pathways, directly interacting with RNA or proteins, as well as participating in the epithelial-mesenchymal transition process. Therefore, PSMA3-AS1 holds promise as a biomarker for cancer detection and prediction, as well as a novel therapeutic target. This review explores the expression features, biological roles, potential mechanisms, and clinical significance of PSMA3-AS1 in various human cancers and provides directions for future research.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Review Unveiling the Ferroptosis-Regulated Cell Signalling Pathways in Breast Cancer to Elucidate Potent Targets for Cancer Management.","authors":"Pratibha Pandey, Shivam Pandey, Seema Ramniwas, Suhas Ballal, Sanjay Kumar, Mahakshit Bhat, Shilpa Sharma, M Ravi Kumar, Fahad Khan","doi":"10.2174/0113816128343266241230045019","DOIUrl":"https://doi.org/10.2174/0113816128343266241230045019","url":null,"abstract":"<p><p>Recent research suggests that targeting ferroptosis exhibits promise as a potent treatment approach for breast carcinoma. Specific subtypes of tumor cells exhibit heightened vulnerability to ferroptosis-inducing chemicals, which selectively trigger tumor stem cells' demise, enhance tumor cells' sensitivity to chemotherapeutic drugs, and eliminate cancerous cells. Ferroptosis plays a dual role in breast cancer progression, emerging as both a stimulating and inhibitory component. Ferroptosis is effective in treating cancer cells (mesenchymal breast), identified by their ability to undergo Epithelial-mesenchymal Transition (EMT) and their resistance to conventional therapies. Pharmaceutical drugs that hinder the activity of enzymes known as kinases, which are involved in the AKT/mTOR/PI3K signaling pathway, have shown significant potential in the treatment of breast carcinoma. This review investigates the molecular mechanisms of different signaling pathways implicated in ferroptosis in breast carcinoma, with specific emphasis on metastasis, invasion, and proliferation. Our study contributes to understanding a potentially important target that could be used in developing therapeutic strategies for breast cancer treatment.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}