Current drug discovery technologies最新文献

{"title":"Molecular Modeling Studies and Synthesis of Isocryptolepine Derivatives as Antimalarial Using Docking, CoMFA, CoMSIA, and HQSAR.","authors":"Shourya Pratap, Abhilasha Mittal, Sambit Kumar Parida","doi":"10.2174/0115701638333384250117165601","DOIUrl":"https://doi.org/10.2174/0115701638333384250117165601","url":null,"abstract":"<p><strong>Background: </strong>Our research highlights the synthesis of newer antimalarial compounds using molecular modeling studies.</p><p><strong>Objective: </strong>The study investigates a series of isocryptolepine derivatives from previous literature, focusing on their biological activities as antimalarial agents.</p><p><strong>Methods: </strong>Computational methods such as molecular docking and QSAR were employed to gain insights into the interaction between the synthesized compounds and the target enzyme PfDHFR-TS.</p><p><strong>Results: </strong>Molecular docking studies helped to identify key binding interactions, supporting the design of more effective compounds. Using CoMFA and CoMSIA, the study explored steric, electrostatic, and hydrogen-bonding fields, providing a quantitative structure-activity relationship (QSAR) for 49 compounds.</p><p><strong>Conclusion: </strong>The CoMFA model yielded strong predictive r² values of 0.971, while the CoMSIA model highlighted the significance of hydrophobic and hydrogen bond interactions. These findings inform the design of novel isocryptolepine derivatives with improved antimalarial activity.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Review of the Antiviral Activity of Berberine.","authors":"Fatemeh Forouzanfar, Zahra Meshkat","doi":"10.2174/0115701638360834250113111936","DOIUrl":"https://doi.org/10.2174/0115701638360834250113111936","url":null,"abstract":"<p><p>Berberine is an isoquinoline alkaloid with strong pharmacological activity such as analgesic, antioxidant, neuroprotective, antivirus, anti-inflammatory, anti-seizure, anti-obesity, and hypolipidemic effects. Accumulated evidence indicates berberine plays an inhibitory role against infection of numerous viruses, including human immunodeficiency virus, respiratory syncytial virus, hepatitis C virus, human papillomavirus, human cytomegalovirus, and influenza virus. Berberine's antiviral action has shown promise, making it a viable option for synergistically enhancing the inhibitory effect of current antiviral medicines. This review provides an overview of prior berberine antiviral studies to prepare for its potential use as a natural antiviral agent in future research.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal Impairment Caused by Statins in Rats Can Be Restored by Thymoquinone.","authors":"Sherif S Hassan, Charity Thomann, Shaimaa Amin, Magdy Youakim, Ehab A A El-Shaarawy, Sara Shawky Ibrahim","doi":"10.2174/0115701638333036250106040617","DOIUrl":"https://doi.org/10.2174/0115701638333036250106040617","url":null,"abstract":"<p><strong>Background: </strong>Atorvastatin (ATO) is an HMG-CoA reductase inhibitor used to lower blood cholesterol, but it causes renal injury in high doses. Thymoquinone (TQ), is a natural antioxidant that has been shown to protect the kidney through its anti-inflammatory, antioxidant, & antiapoptotic, effects.</p><p><strong>Objective: </strong>The current study aimed to investigate whether posttreatment TQ could reverse ATOinduced renal injury, and the possible mechanism of action by which TQ produced such an effect.</p><p><strong>Methods: </strong>Forty adult male rats were divided into 4 groups: (control; TQ-treated; ATO-treated; ATO plus TQ-treated). Blood and kidney tissue samples were tested for kidney functions, oxidative stress and apoptosis markers, and morphometric analyses of the histopathological and ultrastructural evaluations. Statistical analyses were done using JASP, Shapiro-Wilk, and Levene's test. ANOVA and Kruskal-Wallis tests were done to determine differences between groups. The significance level was set at p<.05.</p><p><strong>Results: </strong>The ATO-treated group showed abnormal outcome measures including kidney functions, oxidative stress and apoptotic markers, and morphometric analyses of the histopathological and ultrastructural findings. Post-treatment TQ improved all outcome measures.</p><p><strong>Conclusion: </strong>Posttreatment TQ could reverse oxidative stress-induced renal injury produced by highdose ATO, suggesting a potential clinical application in patients with renal insufficiency with hypercholesterolemia.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptic Ulcer Disease: A Comprehensive Review on Conventional Therapy and Herbal Treatment.","authors":"Vijay Kumar, Vrinda Goel, Sakshi Bajaj, Kalpana Garg, Anurag Bhargava, Ashwani K Dhingra","doi":"10.2174/0115701638332791250109044742","DOIUrl":"https://doi.org/10.2174/0115701638332791250109044742","url":null,"abstract":"<p><p>Still today, peptic ulcer disease (PUD) is a major digestive illness that affects millions of people around the world every year. This study looks at both traditional and herbal ways of treating PUD, focusing on how they work, how well they work, and whether they can work together. Pharmaceuticals like antibiotics, proton pump inhibitors (PPIs), and H2-receptor antagonists are common ways to treat the condition. In more serious cases, surgery may also be an option. The use of medical plants in phytotherapy, an herbal treatment, has shown promise in helping people with PUD deal with their symptoms and speed up the healing of ulcers. Citrus maxima (Pomelo), a plant in the Rutaceae family, may be able to help treat PUD because it has functional and antioxidant properties. In addition, studies on how well different plants treat PUD have shown that they have anti-inflammatory and cytoprotective qualities. Also, the parts of photosynthesis that plants use contain many beneficial substances that might help with the treatment of PUD. This all-around method would deal with many pathogenic pathways at the same time. More study needs to be done to learn more about how herbal therapies can be used to treat PUD and how they can be combined with other common treatments.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential of Nanoparticle Based Antimicrobial Drug Repurposing to Efficiently Target Alzheimer's: A Concise Update on Evidence-based Research and Challenges Ahead.","authors":"Biswabhusan Biswal, Bhabani Sankar Satapathy, Abhishek Mishra, Laxmidhar Maharana, Snigdha Pattnaik","doi":"10.2174/0115701638329824241220055621","DOIUrl":"https://doi.org/10.2174/0115701638329824241220055621","url":null,"abstract":"<p><p>Repurposing of drugs through nanocarriers (NCs) based platforms has been a recent trend in drug delivery research. Various routine drugs are now being repurposed to treat challenging neurodegenerative disorders including Alzheimer disease (AD). AD, at present is one of the challenging neurodegenerative disorders characterized by extracellular accumulation of amyloid-β and intracellular accumulations of neurofibrillary tangles. In spite of catchy progress in drug development, effective treatment outcome in AD patients is far-fetched dream. Out of several proposed hypothesis in the development and progression of AD, potential role of microorganisms causing dementia and AD cannot be ruled out. Several recent researches have been documented a clear correlation in between microbial infection and neuronal damage leading to progression of AD. Thus, antimicrobial drugs repurposing has been emerged as alternate, potential, cost-effective strategy to check progression of AD. Further, for efficient delivery of antimicrobial drugs to brain tissue, novel NCs based platforms are the preferred option to bypass blood-brain barrier. Several polymeric and lipid NCs have been extensively studied over the past years to improve antimicrobial drug delivery to brain. The present review encompasses various repurposing strategy of antimicrobial drugs delivered through various NCs to target AD. Evidence-based research outcome compiled from authentic database like Scopus, PubMed, Web of science have been pooled to provide an updated review. Side by side some light has been thrown on the practical problems faced by nanodrug carriers during technology transfer.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Importance of Computer-Aided Drug Design in Modern Pharmaceutical Research.","authors":"Uma Agarwal, Rajiv Kumar Tonk, Swati Paliwal","doi":"10.2174/0115701638361318241230073123","DOIUrl":"https://doi.org/10.2174/0115701638361318241230073123","url":null,"abstract":"<p><strong>Background: </strong>Computer-Aided Drug Design (CADD) approaches are essential in the drug discovery and development process. Both academic institutions and pharmaceutical and biotechnology corporations utilize them to enhance the efficacy of bioactive compounds.</p><p><strong>Objective: </strong>This study aims to entice researchers by investigating the benefits of Computer-Aided Drug and Design (CADD) and its fundamental principles. The main focus is to speed up the drug discovery process, improve accuracy, and reduce the time and financial resources needed, ultimately making a positive impact on public health.</p><p><strong>Method: </strong>A comprehensive literature search was conducted using databases such as PubMed and Scopus, focusing on studies published till 2024. The selection of studies was based on their analysis of the connection between contemporary pharmaceutical research and computer-aided drug design, with a focus on both structure-based and ligand-based drug design strategies can include molecular docking, fragment-based drug discovery, de novo drug design, pharmacophore modelling, Quantitative structure-activity relationship, 3D-QSAR, homology modelling, in silico absorption-distribution- metabolism-excretion-toxicity, and machine learning/deep learning.</p><p><strong>Result: </strong>Computer-Aided Drug Design (CADD) approaches are mathematical tools used to modify and measure certain characteristics of possible drug candidates. These methods are implemented in various applications. These encompass a variety of software products that are accessible to the public and can be purchased for corporate use. The CADD method is used at several stages of the drug development process, including as a foundation for chemical synthesis and biological testing. It provides information for the development of future SAR (Structure-Activity Relationship), resulting in enhanced molecules in terms of their activity and ADME (Absorption, Distribution, Metabolism, and Excretion). CADD techniques are predominantly employed to analyze and assess the affinity of large molecules for specific biomolecules, such as DNA, RNA, proteins, and enzymes, which serve exclusively as receptors. CADD improves the selection of lead compounds by predicting various parameters, including drug-likeness, physicochemical properties, pharmacokinetics, and toxicity. The application of CADD in drug modelling is to tackle challenges such as cost and time constraints. Modern computer-assisted drug discovery necessitates conducting virtual screening and high-throughput screening (HTS).</p><p><strong>Conclusion: </strong>Computer-aided drug design plays a crucial role for academic institutions and leading pharmaceutical companies in the development of drugs that enhance potency with the significance of reducing both time and costs.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delineating CYP2C19-Mediated Interactions: Network Pharmacology Investigation of Ilaprazole and Clopidogrel versus Conventional Proton Pump Inhibitors.","authors":"Priyadharshini Ananthathandavan, Damodharan Narayanasamy","doi":"10.2174/0115701638334244241224062453","DOIUrl":"https://doi.org/10.2174/0115701638334244241224062453","url":null,"abstract":"<p><strong>Background: </strong>Clopidogrel, an antiplatelet drug commonly used in cardiovascular disease, is metabolized by the liver mainly through CYP2C19. Concomitant use of Proton pump inhibitors along with clopidogrel may affect the potency of clopidogrel by CYP2C19 inhibition. However, a novel PPI, ilaprazole is known to differ in its pharmacokinetic features, given the potential differences between ilaprazole's interactions and their metabolism with clopidogrel. Network pharmacology investigation could be a useful tool to evaluate the drug-drug interaction between them.</p><p><strong>Methodology: </strong>The molecular structures and targets were retrieved from PubChem and SwissTargetPrediction to establish the information related to the identified drugs. The possible shared targets between the clopidogrel and PPIs were explored by a Venn analysis. Subsequently, Protein-Protein Interaction networks were established using the STRING database. Hub genes were also determined using the Cytoscape cytoHubba plugin.</p><p><strong>Results & discussion: </strong>Ilaprazole (13.6%) and pantoprazole (13.6%) were characterized by fewer targets being shared with clopidogrel compared to conventional PPIs (14.9%). Moreover, CYP2C19 was not a hub gene in ilaprazole and pantoprazole interactions, which indicated no significant CYP2C19 involvement. On the other hand, CYP2C19 functioned as a hub gene in the interactions with rabeprazole, lansoprazole, dexlansoprazole, omeprazole, and esomeprazole. As a result, patients receiving pantoprazole and ilaprazole would be at a lower risk for developing adverse cardiovascular events by maintaining the clopidogrel therapeutic effect.</p><p><strong>Conclusion: </strong>The application of the network pharmacology technique allows us to consider the potential for different effects of PPIs on clopidogrel and its metabolism via CYP2C19. There is a lower chance of experiencing adverse effects from an interaction between ilaprazole and clopidogrel as ilaprazole has not been linked to CYP2C19. More research is necessary to confirm these results and provide clinical guidance for patients undergoing clopidogrel and PPI combination therapy.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Review on Immunoregulatory Effects of Phytochemicals.","authors":"Shikha Sharma, Utkarsh Sharma, Neha Dangi, Mukesh K Gupta, Anurag Agrawal, Suraj N Mali, Bimal Krishna Banik","doi":"10.2174/0115701638326442241118053543","DOIUrl":"https://doi.org/10.2174/0115701638326442241118053543","url":null,"abstract":"<p><p>An efficient immune system in the host body plays a crucial role in the preservation of normal biological and immune reactions and processes, as well as the intrinsic environment. This is because the immune system is responsible for fighting off foreign invaders. A healthy immune system strengthens the body's defense against infections, illnesses, and other unwelcome pathogens, thereby reducing the risk of allergic reactions and autoimmune diseases. Innate immune cells and acquired immune system components interact in a corrective fashion to produce optimal immune responses. In recent years, researchers have begun to focus on the immune system as a potential primary target of toxicity from chemical, pharmacological, and environmental exposure. Sex, age, stress, malnutrition, alcohol, genetic variability, lifestyles, environmental pollutants, and chemotherapy are just a few of the many elements that might modify the host's immunological responses. The production, amplification, attenuation, or suppression of immunological responses are all examples of immunomodulation. There are a wide variety of synthetic and traditional treatments available, and many of them cause major side effects and develop pathogenic resistance very quickly. Natural substances called phytochemicals play a crucial role in regulating the body's immune system. Risk factors for immune response changes are discussed, as is the immunomodulatory action of phytochemicals like glycosides, alkaloids, phenolic acids, flavonoids, saponins, tannins, sterols, and steroids.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Screening of Novel Nitroimidazole Candidates: Targeting Key Enzymes of Oral Anaerobes for Anti-Parasitic Potential.","authors":"Touhami Lanez, Maroua Lanez, Riad Lanez, Elhafnaoui Lanez, Badia Talbi-Lanez","doi":"10.2174/0115701638326365241029080310","DOIUrl":"10.2174/0115701638326365241029080310","url":null,"abstract":"<p><strong>Background: </strong>The study focuses on evaluating the parasitic potential of novel metronidazole analogs using computational methods. Specifically, it aims to target key enzymes of oral anaerobes, including UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) of Fusobacterium nucleatum and DNA topoisomerase (Topo) of Prevotella intermedia.</p><p><strong>Objective: </strong>The objective is to assess the pharmacokinetic and toxicity properties of 368 novel nitroimidazole candidates through virtual screening. Additionally, the study aims to determine the binding affinity of the most promising candidates with the target proteins through molecular docking analyses.</p><p><strong>Methods: </strong>A combinatorial library of nitroimidazole candidates was constructed, and virtual screening was performed. Molecular docking analyses were conducted to evaluate the binding affinity of selected compounds with MurA and Topo. Further investigation involved molecular dynamic simulation to assess the stability of the compounds within the active sites of MurA and Topo.</p><p><strong>Results: </strong>All selected compounds exhibited activity against both MurA and Topo. Among them, Mnz11, Mnz12, and Mnz15 demonstrated the lowest binding free energies and IC50 values. Molecular dynamic simulation indicated that these three compounds remained stable within the active sites of MurA and Topo, with RMSD values consistently below 2Å. Additionally, the antibacterial potential of the most potent compound, Mnz15, was evaluated against a series of oral microbes.</p><p><strong>Conclusion: </strong>The study concludes that the newly identified nitroimidazole candidates show promise as anti-parasitic agents, based on their activity against key enzymes of oral anaerobes and their pharmacokinetic properties evaluated through computational methods.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preliminary Characterization of the Vasorelaxant Effect of Thymus atlanticus (Ball) Roussine Using Optical Methods.","authors":"Hamza Elbouny, Nabil Bouchebchoub, Brahim Ouahzizi, Rania Hajjami, Younes Filali-Zegzouti, Mohamed Yassine Amarouch, Chakib Alem","doi":"10.2174/0115701638309612240726060844","DOIUrl":"https://doi.org/10.2174/0115701638309612240726060844","url":null,"abstract":"<p><strong>Background: </strong>Thymus atlanticus (Ball) Roussine is a Moroccan endemic thyme species that is traditionally used as an aromatic and medicinal plant. Several studies have demonstrated its pharmacological significance and therapeutic value.</p><p><strong>Objective: </strong>The current study aimed to assess the vasorelaxant effect of the aqueous extract of this species.</p><p><strong>Methods: </strong>The contractility of isolated rat aortas was investigated using the multi-well organ bath technique. This method was adapted and validated in our experimental conditions using epinephrine and hydralazine as vasoconstrictive and vasodilator agents, respectively. The application of 10 μM epinephrine induced a clear vasoconstriction of the aorta rings (Lumen reduction = 31.8±0.4%). However, hydralazine induced a dose-dependent relaxation with an EC50 value of 6.1±1.2 mM. For the aqueous extract of T. atlanticus, the aortic rings were precontracted with epinephrine, and then increasing concentrations (0.125-1 mg/mL) of this extract were added cumulatively.</p><p><strong>Results: </strong>The results have indicated T. atlanticus extract to have a significant vasodilatory effect in a dose-dependent manner (EC50 = 0.52±0.03 mg/mL).</p><p><strong>Conclusion: </strong>The findings provide preliminary evidence of the vasorelaxant effect of the aqueous extract of T. atlanticus using a low-cost optical approach. However, the cellular and molecular mechanisms underlying this effect have yet to be revealed.</p>","PeriodicalId":93962,"journal":{"name":"Current drug discovery technologies","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}