Phytotherapy Research最新文献

{"title":"Isopimpinellin: A Promising Treatment for Colitis-Related Colorectal Cancer That Targets ALOX5-Mediated Macrophage Polarization.","authors":"Min Zhan, Qin Yi, Liang Yu, Qiankun Li, Murong Jiang, Dongsheng Wu, Mintao Jian, Hui Cao, Donghua Bin","doi":"10.1002/ptr.70065","DOIUrl":"https://doi.org/10.1002/ptr.70065","url":null,"abstract":"<p><p>Colitis-associated colon cancer (CAC) is a malignant tumor caused by long-term inflammation. Isopimpinellin, known for its anti-inflammatory and anti-tumor properties in areas beyond CAC, may target arachidonate 5-lipoxygenase (ALOX5). This study aims to investigate the regulation of the isopimpinellin/ALOX5 axis in CAC. CAC mouse model was induced through intraperitoneal injection of 10 mg/kg azoxymethane and administration of 2% dextran sulfate sodium salt in drinking water. Oral isopimpinellin (50 or 100 mg/kg) was administered. ALOX5 expression was upregulated via adenovirus delivery. Non-targeted metabolomics was employed to analyze the influence of isopimpinellin on metabolic profiles. The 100 mg/kg isopimpinellin demonstrated promising therapeutic effects, as evidenced by protected colon tissue and the inhibition of inflammation and tumor. Pro-inflammatory factors were elevated in para-carcinoma tissues, while anti-inflammatory cytokines were upregulated in cancer tissues. M2 macrophages were increased in cancer tissues, whereas M1 macrophages were elevated in para-carcinoma tissues. Oral administration of isopimpinellin suppressed M2 polarization and M1 polarization in macrophages of cancer and para-carcinoma tissues, respectively. The overexpression of ALOX5, which was expressed in macrophages in the colon, abolished the effects of isopimpinellin. Finally, isopimpinellin altered metabolism in CAC mice, involving cancer-related metabolic processes and signaling pathways in cancer tissues, and amino acid metabolic pathways in para-carcinoma tissues. Isopimpinellin inhibits macrophage M1 polarization in cancer tissues and M2 polarization in para-carcinoma tissues by targeting ALOX5, thereby inhibiting tumor growth and inflammatory response in CAC mice. This study provides strategies for the treatment of CAC.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Antiinflammatory Effects and Chemical Constituents of Veronicastrum axillare\".","authors":"","doi":"10.1002/ptr.70101","DOIUrl":"https://doi.org/10.1002/ptr.70101","url":null,"abstract":"","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Diversity of Flavonoids and Their Clinical Application Prospects in Neurological Disorders.","authors":"Shuai Cheng, Hongwei Gao, Yaxing Yang, Mengxue Zhang, Jing Wang, Na Li, Yonghua Ji, Hongjie Wang, You Zhou","doi":"10.1002/ptr.70097","DOIUrl":"https://doi.org/10.1002/ptr.70097","url":null,"abstract":"<p><p>Flavonoids are a diverse group of polyphenolic compounds found in plant-based foods and herbs, characterized by their varied hydroxylation and glycosylation patterns. Their complex molecular structures confer a wide range of pharmacological activities, including antioxidant effects through reactive oxygen species (ROS) scavenging and Nrf2 activation, anti-inflammatory properties via NF-κB inhibition, anti-apoptotic effects, and modulation of ion channel activities. These mechanisms make flavonoids promising candidates for therapeutic applications across various conditions, including neurological disorders, cardiovascular diseases, cancer, and metabolic disorders. Specifically, inflammation and ion channel dysfunction are common underlying factors in many diseases, positioning flavonoids as potential multi-target interventions. For instance, apigenin and vitexin are natural, safe alternatives for treating neuroinflammatory conditions such as multiple sclerosis, offering efficacy with minimal side effects. This review categorizes flavonoids based on their structural characteristics and explores their advancements in addressing inflammation, oxidative stress, apoptosis, ion channel regulation, pain relief, and neurological disorders, including epilepsy, Alzheimer's disease, Parkinson's disease, and anti-stroke. Ultimately, the review underscores the need for further high-quality studies to firmly establish the clinical efficacy of these plant-derived compounds, alongside research into optimal dosing and formulation strategies, highlighting their potential as multi-faceted therapeutic agents for neurological disorders.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotective Effect of Licorice Extract Against Myocardial Ischemia and Ischemia/Reperfusion Injury via Blocking Cardiac Inflammation by Sirt3/NLRP3.","authors":"Anpei Wang, Yi Li, Fei Zhao, Hai Fang, Chengxue Pan, Bo Wei","doi":"10.1002/ptr.70104","DOIUrl":"https://doi.org/10.1002/ptr.70104","url":null,"abstract":"<p><p>Cardioprotective formulations in traditional Chinese medicine often combine cold and hot herbs, with licorice frequently included to balance their properties and reduce adverse effects. However, the independent cardioprotective mechanisms of licorice in ischemic heart disease remain unclear. This study aimed to investigate the effects of licorice extract (GC) on myocardial ischemia (MI) and ischemia/reperfusion (MI/R) injury. Myocardial injury models were established using H₂O₂-induced H9c2 cardiomyocytes and left anterior descending coronary artery ligation in rats. Cardioprotective effects were evaluated through electrocardiography, echocardiography, and pharmacodynamic assessments. Network pharmacology and PCR were used to explore the anti-inflammatory mechanism, followed by investigation of the upstream inflammatory pathways using Western blotting, co-immunoprecipitation, immunofluorescence, and molecular docking. Metabolomics confirmed GC's impact on terminal metabolic disturbances. Pharmacodynamic evaluations demonstrated that GC exerted significant cardioprotective effects both in vitro and in vivo. Network pharmacology suggested anti-inflammatory potential, which was confirmed by PCR showing reduced levels of IL-1β, IL-6, and TNF-α. Expression analysis of seven Sirtuin and four NOD-like receptor family members revealed that GC's anti-inflammatory effect was mediated by upregulation of Sirt3, leading to inhibition of NLRP3 inflammasome activation, decreased Caspase-1 activity, and reduced secretion of IL-1β and IL-18. Additionally, GC modulated ischemia-induced metabolic disturbances, notably restoring disrupted amino acid and unsaturated fatty acid metabolism. In conclusion, GC exerted cardioprotective effects by suppressing inflammation through the Sirt3/NLRP3 axis and restoring metabolic homeostasis. These findings supported its traditional use and suggested its potential application in cardiovascular health.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hesperidin Inhibits Oxidative Stress and Apoptosis of Granulosa Cells in Polycystic Ovarian Syndrome Through the JAK2/STAT3 and PI3K/AKT Pathways.","authors":"Qixuan Zhang, Zhe Yang, Xiangyang Ou, Mengying Zhang, Rui Ji, Gengxiang Wu","doi":"10.1002/ptr.70100","DOIUrl":"https://doi.org/10.1002/ptr.70100","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder syndrome in women of childbearing age. Hesperidin (HES), a phytoflavonoid glycoside found in citrus fruits such as oranges and lemons, has a variety of pharmacological effects. HES has been extensively studied to protect a variety of tissues from oxidative damage. However, it is not known whether HES may have a therapeutic effect on PCOS. In this study, potential therapeutic targets for HES treatment of PCOS were identified through network pharmacology, altered phosphorylation modification of JAK2 and PI3K was verified in granular cells of PCOS patients, and the mechanism of HES treatment of PCOS was revealed through in vivo and in vitro experiments. Based on network-based pharmacological studies, PI3K/Akt and JAK2/STAT3 pathways are potential pathways for HES treatment of PCOS, and molecular docking results show that JAK2 has the best binding activity with HES. Western blotting results showed that the phosphorylation modification of JAK2 and PI3K in granular cells of PCOS patients was changed. Experiments in KGN cell lines have shown that HES can reduce DHT-induced oxidative stress and apoptotic damage. Activating JAK2 or inhibiting PI3K can both reverse this therapeutic effect. In vivo experiments have shown similar results. HES affects oxidative stress and apoptosis in PCOS through signaling crosstalk between JAK2/STAT3 and PI3K/AKT pathways.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Icariside II Ameliorates Depression Induced by High-Fat Diet via the Microbiota-Gut-Brain Axis in Mice.","authors":"Yun-Mei Luo, Lan Dong, Ye-Li Li, Mu Lin, Dian-You Xie, Jian-Mei Gao, Yuan-Dong Zhang, Yi Zhun Zhu, Qi-Hai Gong","doi":"10.1002/ptr.70103","DOIUrl":"https://doi.org/10.1002/ptr.70103","url":null,"abstract":"<p><p>Obesity can lead to depression via the microbiota-gut-brain axis. Icariside II (ICS II), a flavonoid compound derived from the traditional Chinese medicine Herbal Epimedium, exerts excellent neuroprotective effects. However, the pharmacological effects and underlying mechanisms of ICS II in obesity-induced depression remain unexplored. The present study aims to investigate whether ICS II can mitigate depression induced by a high-fat diet (HFD) in mice through modulating the microbiota-gut-brain axis. Metabolic parameters were reflected through changes in body weight and blood lipids, while depressive phenotypes were evaluated through behavioral tests and neurotransmitter analysis. The microbiota composition was analyzed by 16S ribosomal RNA gene sequencing, and short chain fatty acids (SCFAs) were detected by liquid chromatography-tandem mass spectrometry. The gut barrier and brain blood barrier (BBB) functions were observed by pathological methods. Fecal microbiota transplantation was used to demonstrate the causality of microbiota-mediated effects. The results showed that ICS II alleviated obesity status and depressive-like behaviors. ICS II reshaped gut microbiota and increased SCFAs. Meanwhile, ICS II relieved gut barrier impairment and systemic inflammation. In the brain, ICS II alleviated neuroinflammation and BBB injury. Intriguingly, fecal microbiota from ICS II-treated HFD mice improved depressive-like behaviors, intestinal barrier dysfunction, and BBB damage compared with those receiving microbiota from HFD mice. Our findings reveal for the first time that ICS II improves the obesity-related metabolic dysregulation and alleviates HFD-induced depression via the microbiota-gut-brain axis. Overall, this study indicates that ICS II is a potential candidate compound for treating obesity-related mental diseases.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catalpol: An Iridoid Glycoside With Potential in Combating Cancer Development and Progression-A Comprehensive Review.","authors":"Lucas Fornari Laurindo, Victória Dogani Rodrigues, Elen Landgraf Guiguer, Lívia Fornari Laurindo, Debora Aparecida Pires de Campos Zuccari, Claudia Rucco Penteado Detregiachi, Adriano Cressoni Araújo, Jéssica da Silva Camarinha Oliveira, Durvanei Augusto Maria, Jefferson Aparecido Dias, Rose Eli Grassi Rici, Caroline Barbalho Lamas, Rosa Direito, Sandra Maria Barbalho","doi":"10.1002/ptr.70057","DOIUrl":"https://doi.org/10.1002/ptr.70057","url":null,"abstract":"<p><p>Catalpol, a natural iridoid glycoside known for its anti-proliferative effects, has been proposed as an anticancer compound. Catalpol targets critical processes involved in cancer cell progression, like malignant proliferation, apoptosis, and metastasis. Additionally, catalpol presents potent anti-inflammatory and antioxidant properties crucial for cancer prevention and intervention. Due to the absence of clinical trials, this review investigates twelve studies, encompassing in vitro and animal trials from reputable databases, such as PubMed, with no time restrictions. Therefore, we covered evidence from catalpol's effects against several types of cancer, including breast, liver, colorectal, lung, gastric, bladder, and ovarian cancer, as well as osteosarcoma, and assessed various outcomes related to cell viability, apoptosis, migration, and modulation of molecular mechanisms by catalpol. Notably, catalpol induced cancer cell death via induction of mitochondrial apoptosis pathways, regulation of the expression of specific microRNAs, modulation of Sirt1, Kras, RACK1, PARP, PI3K/Akt, Bcl-2, and STAT3/JAK2/Src signaling pathways, and inactivation of NF-kB and Smad 2/3 signaling pathways. Furthermore, catalpol limits cancer metastasis due to modulation of critical metalloproteinases associated with cancer migration. Catalpol also synergizes with chemotherapeutic and adjuvant agents to induce cancer control, including regorafenib in liver cancer and chloroquine in gastric cancer, promoting increased anticancer action via upregulated cancer cell apoptosis, decreased proliferation, and inhibited angiogenesis via PI3K/p-Akt/mTOR/NF-κB, VEGF/VEGFR2, and Bax signaling pathways modulation. Catalpol derivatives also gained attention. Pyrazole-, imidazole-, and hydrolyzed-based catalpol derivatives increase cancer cell apoptosis and death and decrease tumor angiogenesis through similar pathways. This review seeks to provide understanding of catalpol's anticancer effects, its mechanisms of action, and its potential as a therapeutic anticancer agent while advocating for future research conductance.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Ginkgo biloba Extract Promotes Treg Differentiation to Ameliorate Ischemic Stroke via Inhibition of HIF-1α/HK2 Pathway\".","authors":"","doi":"10.1002/ptr.70093","DOIUrl":"https://doi.org/10.1002/ptr.70093","url":null,"abstract":"","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scutellarin Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting M1 Macrophage Polarization via the GBP2/JAK2/STAT3 Signaling Pathway.","authors":"Jiajia Tang, Yiwei Ding, Wei Chen, Jun Shi, Chunyang Zhang, Xiaoyu Zhao, Jiao Li, Zhihai Han, Xuxin Chen","doi":"10.1002/ptr.70099","DOIUrl":"https://doi.org/10.1002/ptr.70099","url":null,"abstract":"<p><p>Uncontrolled inflammation and excessive M1 macrophage polarization are key drivers of acute lung injury (ALI). Scutellarin (SCU), a natural flavonoid compound, possesses anti-inflammatory activity, but its precise mechanism remains unclear. This study aimed to investigate whether SCU alleviates ALI by targeting guanine nucleotide-binding protein 2 (GBP2) and regulating alveolar macrophage polarization. A lipopolysaccharide (LPS)-induced ALI mouse model was used to evaluate the therapeutic effects of SCU. Macrophage polarization and lung injury severity were assessed histologically and by cytokine analysis. Transcriptomic profiling (RNA-seq) identified GBP2 as a candidate target. GBP2 was knocked down or overexpressed in MH-S cells to evaluate its role in LPS-induced polarization. Co-immunoprecipitation, molecular docking, and immunofluorescence were performed to confirm the interaction between GBP2 and STAT3. SCU pre-treatment significantly alleviated lung injury, reduced inflammatory cytokine levels, and improved the wet-to-dry lung weight ratio. It modulated macrophage polarization by downregulating LPS-induced M1 polarization in alveolar macrophages. Mechanistically, SCU downregulated GBP2 expression and suppressed activation of the JAK2/STAT3 signaling pathway in LPS-stimulated models. SCU ameliorates LPS-induced ALI by modulating alveolar macrophage polarization through inhibition of the GBP2/JAK2/STAT3 pathway. These findings suggest that SCU may serve as a potential therapeutic agent for ALI.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sepsis-Induced Liver Injury Mitigated by Isoferulic Acid Through Inhibition of Hepatic Ferroptosis via the SIRT1 Signaling Pathway.","authors":"Jian Gan, Tong Xu, Jiayi Zhang, Can Huang, Yue Hua, Honglin Xu, Guoyong Zhang, Changlei Hu, Mingjie Pang, Bin Liu, Yingchun Zhou","doi":"10.1002/ptr.70098","DOIUrl":"https://doi.org/10.1002/ptr.70098","url":null,"abstract":"<p><p>The liver plays a crucial role in the progression of sepsis in patients. Notably, it is the center of metabolism and detoxification, and is important for immune regulation and inflammatory response. Isoferulic acid (IFA), as a phenolic acid compound naturally found in Cimicifuga plants, is recognized for its anti-inflammatory, antioxidant, and free radical-scavenging properties. However, its protective mechanism underlying sepsis-induced acute liver injury remains unknown. The present work focused on examining the effect of IFA on treating sepsis-mediated liver injury and exploring its potential protective mechanism. In the in vivo experiments, the cecal ligation and puncture (CLP) model was used to induce sepsis in mice. EX-527 was administered through intraperitoneal injection, while IFA was given via intragastric administration. Thereafter, hepatic pathological damage was assessed through hematoxylin-eosin staining. Lipid peroxidation levels were determined by measuring MDA, SOD, GSH, and ferrous iron contents. Meanwhile, relevant gene and target protein levels were analyzed using qPCR, immunohistochemistry, and Western blotting. For the in vitro experiments, ferroptosis was induced in AML12 cells with erastin, followed by transfection with SIRT1-siRNA and treatment with IFA. Subsequently, ROS levels were systematically assessed, the extent of mitochondrial membrane potential (MMP) damage was quantified, and Nrf2 immunofluorescence staining analysis was performed in AML12 cells. Finally, molecular docking and surface plasmon resonance (SPR) technologies were applied in confirming the SIRT1-IFA interaction. From the in vivo experiments, sepsis induced by CLP triggered hepatic ferroptosis. While intragastric administration of IFA reduced liver ferroptosis, the intraperitoneal injection of EX-527 combined with intragastric administration of IFA reversed the protective effect of IFA. As revealed by the in vitro experiments, IFA mitigated the erastin-induced ferroptosis of AML12 cells. After transfection with SIRT1-siRNA, the protective effect of IFA was reversed. IFA alleviated the sepsis-induced acute liver injury through the SIRT1 signaling pathway.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}