{"title":"Design, synthesis and biological evaluation of novel urolithin derivatives targeting liver cancer cells.","authors":"Mi Tian, Lirong Zhao, Yu Lan, Chen Li, Yipeng Ling, Benhong Zhou","doi":"10.1080/14756366.2025.2490707","DOIUrl":"10.1080/14756366.2025.2490707","url":null,"abstract":"<p><p>We designed and synthesised 22 new urolithin derivatives (UDs) based on methyl-urolithin A (mUA) to identify anti-cancer drugs with high efficacy and low toxicity and evaluated their anti-cancer activities <i>in vitro</i>. Cytotoxicity tests were performed on three cell lines (DU145, T24, and HepG2) and a human normal cell line (HK-2). The half-inhibitory concentration (IC<sub>50</sub>) of derivative UD-4c to hepatoma HepG2 cells (IC<sub>50</sub> = 4.66 ± 0.12 μM) was significantly lower than that of sorafenib (IC<sub>50</sub> =7.76 ± 0.12 μM), and exhibited less toxicity to HK-2 cells. Preliminary studies on the mechanism revealed that the derivative UD-4c could significantly inhibit the HepG2 cell growth and colony formation, block the HepG2 cell cycle in the G2/M phase, and induce apoptosis of HepG2 cells dose-dependently. The derivative UD-4c can be used as a potential lead compound to further develop new drugs for hepatocellular carcinoma treatment based on the evaluation of anti-cancer activity.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2490707"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advances in ERK1/2 inhibition: a medicinal chemistry perspective on structure and regulation.","authors":"Vimlendu Kumar Sah, Ankit Kumar Singh, Adarsh Kumar, Vineet Prajapati, Amandeep Singh Kalsi, Habibullah Khalilullah, Mariusz Jaremko, Abdul-Hamid Emwas, Amita Verma, Pradeep Kumar","doi":"10.1080/14756366.2025.2555510","DOIUrl":"10.1080/14756366.2025.2555510","url":null,"abstract":"<p><p>The mitogen-activated protein kinase (MAPK) pathway-also known as the RAS/RAF/MEK/ERK pathway-is a critical signalling cascade involved in regulating cell growth, proliferation, and survival. First discovered in the early 1980s, the pathway's extracellular signal-regulated kinase (ERK) subfamily was identified in the 1990s. The ERK family includes several isoforms-ERK1, ERK2, ERK3, ERK5, and ERK6-with ERK1 (MAPK3) and ERK2 (MAPK1) being the most well-characterised and playing central roles in MAPK signalling. Deregulation of ERK signalling (commonly referred to as the ERK pathway or ERKp) has been implicated in approximately 40% of human cancers. This review focuses on the structural insights of ERK1/2 and their critical role in the MAPK signalling cascade. Despite their clinical significance, no ERK inhibitors have yet been approved by the FDA. Several molecules-such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204-are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2555510"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qing-Qing Xun, Jing Zhang, Lei Feng, Yu-Ying Ma, Ying Li, Xiao-Long Shi
{"title":"Identification of a novel pyrrolo[2,3-<i>b</i>]pyridine compound as a potent glycogen synthase kinase 3β inhibitor for treating Alzheimer's disease.","authors":"Qing-Qing Xun, Jing Zhang, Lei Feng, Yu-Ying Ma, Ying Li, Xiao-Long Shi","doi":"10.1080/14756366.2025.2466846","DOIUrl":"10.1080/14756366.2025.2466846","url":null,"abstract":"<p><p>Herein, a novel pyrrolo[2,3-<i>b</i>]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, <b>S01</b>, was rationally designed and synthesised to target Alzheimer's disease (AD). <b>S01</b> inhibited GSK-3β, with an IC<sub>50</sub> of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that <b>S01</b> efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, <b>S01</b> showed low cytotoxicity to SH-SY5Y cells, significantly upregulated the expression of β-catenin and neurogenesis-related biomarkers, and effectively promoted the outgrowth of differentiated neuronal neurites. Moreover, <b>S01</b> substantially ameliorated dyskinesia in AlCl<sub>3</sub>-induced zebrafish AD models at a concentration of 0.12 μM, which was more potent than Donepezil (8 μM) under identical conditions. Acute toxicity experiments further confirmed the safety of <b>S01</b> in vivo. Our findings suggested that <b>S01</b> is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2466846"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Chemical composition, antioxidant activities, and enzyme inhibitory effects of <i>Lespedeza bicolour</i> Turcz. essential oil.","authors":"Jiadong Zhu, Ziyue Xu, Xu Liu","doi":"10.1080/14756366.2025.2460053","DOIUrl":"10.1080/14756366.2025.2460053","url":null,"abstract":"<p><p><i>Lespedeza bicolour</i> Turcz. is a traditional medicinal plant with a wide range of ethnomedicinal values. The main components of <i>L. bicolour</i> essential oil (EO) were β-pinene (15.41%), β-phellandrene (12.43%), and caryophyllene (7.79%). The EO of <i>L. bicolour</i> showed antioxidant activity against ABTS radical and DPPH radical with an IC<sub>50</sub> value of 0.69 ± 0.03 mg/mL and 10.44 ± 2.09 mg/mL, respectively. The FRAP antioxidant value was 81.96 ± 6.17 μmol/g. The EO had activities against acetylcholinesterase, α-glucosidase, and β-lactamase with IC<sub>50</sub> values of 309.30 ± 11.16 μg/mL, 360.47 ± 35.67 μg/mL, and 27.54 ± 1.21 μg/mL, respectively. Molecular docking showed methyl dehydroabietate docked well with all tested enzymes. Sclareol and (+)-borneol acetate showed the strongest binding affinity to α-glucosidase and β-lactamase, respectively. The present study provides a direction for searching enzyme inhibitors for three tested enzymes and shows <i>L. bicolour</i> EO possesses the potential to treat a series of diseases.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2460053"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jie Mu, Si-Si Chen, Shi-Qing Li, Qiang Jin, Jin Geng, Li-Wei Zou
{"title":"Discovery of lignans as the effective inhibitors of CES1A alleviate lipid droplets formation.","authors":"Jie Mu, Si-Si Chen, Shi-Qing Li, Qiang Jin, Jin Geng, Li-Wei Zou","doi":"10.1080/14756366.2025.2472817","DOIUrl":"https://doi.org/10.1080/14756366.2025.2472817","url":null,"abstract":"<p><p>ER carboxylesterase 1A (CES1A) is an important metabolic enzyme involved in lipid metabolism. Targeting the CES1A is a promising approach for diseases associated with disorders of lipid metabolism therapy. In this study, screening of 26 natural lignans, three of them were found displaying potent inhibition on CES1A and high specificity over other serine hydrolases. Inhibition kinetic analyses demonstrated that Schisandrin C and Anwuligan were mixed-type inhibitors, while Magnolol acts as a competitive inhibitor. Further investigation showed that they were cell permeable and exhibited minimal cytotoxicity and mitochondrial toxicity, as well as capable of inhibiting intracellular CES1A in living cells. Further investigation found that three Schisandras decreased the number of lipid droplets (LDs) in free fatty acid (FFA)-treated HepG2 cells. Collectively, our findings suggest that Schisandrin C is a potent and highly selective inhibitor of CES1A, which can be served as a promising lead compound.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2472817"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11986867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Changhao Zhao, Hanying Wu, Huajing Liu, Hui Dong, Miao-Miao Niu, Kun Shi, Fengzhen Wang
{"title":"Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation.","authors":"Changhao Zhao, Hanying Wu, Huajing Liu, Hui Dong, Miao-Miao Niu, Kun Shi, Fengzhen Wang","doi":"10.1080/14756366.2025.2522810","DOIUrl":"10.1080/14756366.2025.2522810","url":null,"abstract":"<p><p>Aberrant expression of PLK1 and PLK4 is closely associated with tumourigenesis, and their simultaneous inhibition can effectively suppress tumour proliferation. In this study, we successfully identified peptide inhibitors (Peptides <b>1-5</b>) capable of simultaneously targeting PLK1-PBD and PLK4-PB3 via pharmacophore-based virtual screening. Binding affinity analyses demonstrated that all candidate peptides exhibited nanomolar binding affinity for both targets. <i>In vitro</i> cancer cell growth inhibition assays revealed that these peptides could suppress the growth of cervical cancer cells. Among them, Peptide-<b>2</b> showed the optimal binding affinity and anticancer cell proliferative activity (PLK1-PBD: <i>K</i><sub>d</sub> = 8.02 ± 0.16 nM; PLK4-PB3: <i>K</i><sub>d</sub> = 11.32 ± 0.19 nM; IC<sub>50</sub> = 0.44 ± 0.03). Molecular dynamics (MD) simulations further predicted that Peptide-2 could stably bind to the binding sites of both PLK1-PBD and PLK4-PB3. This study reported a novel peptide inhibitor Peptide-2 with potent dual-target inhibitory activity against PLK1-PBD/PLK4-PB3, providing a novel strategy for cancer therapy.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2522810"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nguyen Viet Phong, Hyo-Sung Kim, Yan Zhao, Eunbyul Yeom, Seo Young Yang
{"title":"Indirubin-3'-oxime as a dual-action agent: mitigating heat-induced male infertility in <i>Drosophila melanogaster</i> and inhibiting soluble epoxide hydrolase.","authors":"Nguyen Viet Phong, Hyo-Sung Kim, Yan Zhao, Eunbyul Yeom, Seo Young Yang","doi":"10.1080/14756366.2024.2447719","DOIUrl":"10.1080/14756366.2024.2447719","url":null,"abstract":"<p><p>This study investigated the potential of the indirubin-3'-oxime (I3O) compound to mitigate temperature-induced male infertility in <i>Drosophila melanogaster</i>. Elevated temperatures significantly reduced egg-hatching rates, but I3O supplementation improved these rates, suggesting it can partially restore fertility under heat stress. Additionally, I3O was found to inhibit soluble epoxide hydrolase (sEH), an enzyme involved in the metabolism of epoxyeicosatrienoic acids, which are vital for reproductive health. I3O exhibited sEH inhibitions with an IC<sub>50</sub> value of 59.74 ± 0.41 µM. Enzyme kinetics revealed that I3O acts as a non-competitive inhibitor of sEH with a <i>K<sub>i</sub></i> value of 78.88 µM. Molecular docking showed strong interactions between I3O and key residues in the allosteric regions within the sEH enzyme, with a binding affinity of -9.2 kcal/mol. These interactions were supported by 100 ns molecular dynamics simulations, which confirmed the stability of the sEH-I3O complex.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2447719"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marwa H El-Wakil, Rasha A Ghazala, Hadeel A El-Dershaby, Danuta Drozdowska, Agnieszka Wróbel-Tałałaj, Cezary Parzych, Artur Ratkiewicz, Beata Kolesińska, Heba A Abd El-Razik, Farid S G Soliman
{"title":"Rational design, synthesis, and molecular modelling insights of dual DNA binders/DHFR inhibitors bearing arylidene-hydrazinyl-1,3-thiazole scaffold with apoptotic and anti-migratory potential in breast MCF-7 cancer cells.","authors":"Marwa H El-Wakil, Rasha A Ghazala, Hadeel A El-Dershaby, Danuta Drozdowska, Agnieszka Wróbel-Tałałaj, Cezary Parzych, Artur Ratkiewicz, Beata Kolesińska, Heba A Abd El-Razik, Farid S G Soliman","doi":"10.1080/14756366.2025.2468353","DOIUrl":"10.1080/14756366.2025.2468353","url":null,"abstract":"<p><p>In light of searching for new breast cancer therapies, DNA-targeted small molecules were rationally designed to simultaneously bind DNA and inhibit human dihydrofolate reductase (<i>h</i>DHFR). Fourteen new arylidene-hydrazinyl-1,3-thiazoles (<b>5-18</b>) were synthesised and their dual DNA groove binding potential and <i>in vitro h</i>DHFR inhibition were performed. Two compounds, <b>5</b> and <b>11</b>, proved their dual efficacy. Molecular docking and molecular dynamics simulations were performed for those active derivatives to explore their mode of binding and stability of interactions inside DHFR active site. Anti-breast cancer activity was assessed for <b>5</b> and <b>11</b> on MCF-7 cells using <b>MTX</b> as reference. IC<sub>50</sub> measurements revealed that both compounds were more potent and selective than <b>MTX</b>. Cytotoxicity was examined against normal skin fibroblasts to examine safety and selectivity Moreover, mechanistic studies including apoptosis induction and wound healing were performed. Further <i>in silico</i> ADMET assessment was conducted to determine their eligibility as drug leads suitable for future optimisation and development.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2468353"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhen Xu, Lixia Guan, Yuting Wang, Miao-Miao Niu, Yashi Ruan, Cen Xu, Li Yang
{"title":"Discovery of a novel PLK1 inhibitor with high inhibitory potency using a combined virtual screening strategy.","authors":"Zhen Xu, Lixia Guan, Yuting Wang, Miao-Miao Niu, Yashi Ruan, Cen Xu, Li Yang","doi":"10.1080/14756366.2025.2467798","DOIUrl":"10.1080/14756366.2025.2467798","url":null,"abstract":"<p><p>PLK1 is essential for cell cycle regulation and proliferation, and its elevated expression in prostate cancer is associated with high tumour grade. Therefore, PLK1 inhibition is considered a promising strategy for the treatment of prostate cancer. Here, we identified five compounds (Hits 1-5) targeting the kinase domain (KD) of PLK1 using a combined virtual screening approach. Hits 1-5 all had picomolar (pM) inhibitory potency against PLK1. Notably, Hit-4 showed the strongest inhibitory activity against PLK1 (IC<sub>50</sub> = 22.61 ± 1.12 pM) and displayed high selectivity for PLK1. Meanwhile, molecular dynamics (MD) simulations revealed that the complex formed by Hit-4 and PLK1 remained stable. Importantly, Hit-4 exhibited potent inhibitory effects on the proliferation of DU-145 prostate cancer cells (IC<sub>50</sub> = 0.09 ± 0.01 nM). In conclusion, Hit-4 is a potent and highly selective antitumor candidate with therapeutic potential for prostate cancer.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2467798"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Production and functional characteristics of a novel hirudin variant with better anticoagulant activities than bivalirudin.","authors":"Peijuan Ge, Min Jin, Zimo Li, Licheng Zhu","doi":"10.1080/14756366.2025.2554899","DOIUrl":"10.1080/14756366.2025.2554899","url":null,"abstract":"<p><p>Current antithrombotic therapies face dual constraints of bleeding complications and monitoring requirements. Although natural hirudin provides targeted thrombin inhibition, its clinical adoption is hindered by sourcing limitations. This study developed a recombinant hirudin variant HMg (rHMg) with enhanced anticoagulant activity through genetic engineering and established cost-effective large-scale production methods. The synthesised <i>HMg</i> gene was expressed in <i>E. coli</i> BL21 via a pET vector plasmid, followed by nickel-affinity purification. Systematic evaluations demonstrated rHMg's antithrombin activity of 9573 ATU/mg, dose-dependent prolongation of APTT/PT/TT. It has superior thrombin inhibition with the IC<sub>50</sub> and K<sub>i</sub> values were 2.8 and 0.323 nM respectively compared to FDA approved drug bivalirudin (p < 0.001). The high-yield prokaryotic expression of rHMg with enhanced anticoagulant efficacy provides a novel strategy for developing affordable antithrombotic drugs, showing significant potential for cardiovascular disease management.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2554899"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}