Thuy Le Lam Nguyen, Dung Van Nguyen, Kyung-Sun Heo
{"title":"Potential biological functions and future perspectives of sialylated milk oligosaccharides.","authors":"Thuy Le Lam Nguyen, Dung Van Nguyen, Kyung-Sun Heo","doi":"10.1007/s12272-024-01492-3","DOIUrl":"10.1007/s12272-024-01492-3","url":null,"abstract":"<p><p>Sialyllactoses (SLs) primarily include sialylated human milk oligosaccharides (HMOs) and bovine milk oligosaccharides (BMOs). First, the safety assessment of 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL) revealed low toxicity in various animal models and human participants. SLs constitute a unique milk component, highlighting the essential nutrients and bioactive components crucial for infant development, along with numerous associated health benefits for various diseases. This review explores the safety, biosynthesis, and potential biological effects of SLs, with a specific focus on their influence across various physiological systems, including the gastrointestinal system, immune disorders, rare genetic disorders (such as GNE myopathy), cancers, neurological disorders, cardiovascular diseases, diverse cancers, and viral infections, thus indicating their therapeutic potential.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Young-Jung Kim, Wun-A Kook, Shi-Xun Ma, Bo-Ram Lee, Yong-Hyun Ko, Seon-Kyung Kim, Youyoung Lee, Jae-Gyeong Lee, Sooyeun Lee, Kyeong-Man Kim, Seok-Yong Lee, Choon-Gon Jang
{"title":"The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents","authors":"Young-Jung Kim, Wun-A Kook, Shi-Xun Ma, Bo-Ram Lee, Yong-Hyun Ko, Seon-Kyung Kim, Youyoung Lee, Jae-Gyeong Lee, Sooyeun Lee, Kyeong-Man Kim, Seok-Yong Lee, Choon-Gon Jang","doi":"10.1007/s12272-024-01491-4","DOIUrl":"https://doi.org/10.1007/s12272-024-01491-4","url":null,"abstract":"<p>Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140323811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenwen Ding, Xiaoxue Yang, Kaiyi Lai, Yu Jiang, Ying Liu
{"title":"The potential of therapeutic strategies targeting mitochondrial biogenesis for the treatment of insulin resistance and type 2 diabetes mellitus.","authors":"Wenwen Ding, Xiaoxue Yang, Kaiyi Lai, Yu Jiang, Ying Liu","doi":"10.1007/s12272-024-01490-5","DOIUrl":"10.1007/s12272-024-01490-5","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is a persistent metabolic disorder marked by deficiencies in insulin secretion and/or function, affecting various tissues and organs and leading to numerous complications. Mitochondrial biogenesis, the process by which cells generate new mitochondria utilizing existing ones plays a crucial role in energy homeostasis, glucose metabolism, and lipid handling. Recent evidence suggests that promoting mitochondrial biogenesis can alleviate insulin resistance in the liver, adipose tissue, and skeletal muscle while improving pancreatic β-cell function. Moreover, enhanced mitochondrial biogenesis has been shown to ameliorate T2DM symptoms and may contribute to therapeutic effects for the treatment of diabetic nephropathy, cardiomyopathy, retinopathy, and neuropathy. This review summarizes the intricate connection between mitochondrial biogenesis and T2DM, highlighting the potential of novel therapeutic strategies targeting mitochondrial biogenesis for T2DM treatment and its associated complications. It also discusses several natural products that exhibit beneficial effects on T2DM by promoting mitochondrial biogenesis.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Seulah Lee, Mina Jang, Rhim Ryoo, Jongtae Roh, Sung-Kyun Ko, Ki Hyun Kim
{"title":"New autophagy-modulating lanostane-type triterpenoids from a hallucinogenic poisonous mushroom Gymnopilus orientispectabilis.","authors":"Seulah Lee, Mina Jang, Rhim Ryoo, Jongtae Roh, Sung-Kyun Ko, Ki Hyun Kim","doi":"10.1007/s12272-024-01486-1","DOIUrl":"10.1007/s12272-024-01486-1","url":null,"abstract":"<p><p>Gymnopilus orientispectabilis, also known as \"big laughter mushroom,\" is a hallucinogenic poisonous mushroom that causes excessive laughter upon ingestion. From the fruiting bodies of G. orientispectabilis, eight lanostane-type triterpenoids (1-8), including seven novel compounds: gymnojunols A-G (2-8), were isolated. The chemical structures of these new compounds (2-8) were determined by analyzing their 1D and 2D NMR spectra and HR-EISMS, and their absolute configurations were unambiguously assigned by quantum chemical ECD calculations and a computational method coupled with a statistical procedure (DP4+). Upon evaluating autophagic activity, compounds 2, 6, and 7 increased LC3B-II levels in HeLa cells to a similar extent as bafilomycin, an autophagy inhibitor. In contrast, compound 8 decreased the levels of both LC3B-I and LC3B-II, and a similar effect was observed following treatment with rapamycin, an autophagy inducer. Our findings provide experimental evidence for new potential autophagy modulators in the hallucinogenic poisonous mushroom G. orientispectabilis.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ya-Xiao Liu, Xiao-Mei Song, Lin-Wei Dan, Jia-Mei Tang, Yi Jiang, Chong Deng, Dong-Dong Zhang, Yu-Ze Li, Wei Wang
{"title":"Astragali Radix: comprehensive review of its botany, phytochemistry, pharmacology and clinical application.","authors":"Ya-Xiao Liu, Xiao-Mei Song, Lin-Wei Dan, Jia-Mei Tang, Yi Jiang, Chong Deng, Dong-Dong Zhang, Yu-Ze Li, Wei Wang","doi":"10.1007/s12272-024-01489-y","DOIUrl":"10.1007/s12272-024-01489-y","url":null,"abstract":"<p><p>Astragali Radix (A. Radix) is the dried root of Astragalus membranaceus var. mongholicus (Bge) Hsiao or Astragalus membranaceus (Fisch.) Bge., belonging to the family Leguminosae, which is mainly distributed in China. A. Radix has been consumed as a tonic in China for more than 2000 years because of its medicinal effects of invigorating the spleen and replenishing qi. Currently, more than 400 natural compounds have been isolated and identified from A. Radix, mainly including saponins, flavonoids, phenylpropanoids, alkaloids, and others. Modern pharmacological studies have shown that A. Radix has anti-tumor, anti-inflammatory, immunomodulatory, anti-atherosclerotic, cardioprotective, anti-hypertensive, and anti-aging effects. It has been clinically used in the treatment of tumors, cardiovascular diseases, and cerebrovascular complications associated with diabetes with few side effects and high safety. This paper reviewed the progress of research on its chemical constituents, pharmacological effects, clinical applications, developing applications, and toxicology, which provides a basis for the better development and utilization of A. Radix.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140139874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Arsenic trioxide: applications, mechanisms of action, toxicity and rescue strategies to date.","authors":"Meng Yan, Hao Wang, Rui Wei, Wenwen Li","doi":"10.1007/s12272-023-01481-y","DOIUrl":"10.1007/s12272-023-01481-y","url":null,"abstract":"<p><p>Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000 years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity. This review presents a comprehensive overview of arsenic trioxide from preclinical and clinical efficacy, potential mechanisms of action, toxicities, and rescue strategies for toxicities to provide guidance or assistance for the clinical application of arsenic trioxide.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139037358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xinyan Qu, Yingying Song, Qingjun Li, Qi Xu, Yanru Li, Huimin Zhang, Xuemei Cheng, Charles R Mackay, Quanbo Wang, Wei Liu
{"title":"Indole-3-acetic acid ameliorates dextran sulfate sodium-induced colitis via the ERK signaling pathway.","authors":"Xinyan Qu, Yingying Song, Qingjun Li, Qi Xu, Yanru Li, Huimin Zhang, Xuemei Cheng, Charles R Mackay, Quanbo Wang, Wei Liu","doi":"10.1007/s12272-024-01488-z","DOIUrl":"10.1007/s12272-024-01488-z","url":null,"abstract":"<p><p>Microbiota-derived catabolism of nutrients is closely related to ulcerative colitis (UC). The level of indole-3-acetic acid (IAA), a microbiota-dependent metabolite of tryptophan, was decreased significantly in the feces of UC patients. Thus supplementation with IAA could be a potential therapeutic method for ameliorating colitis. In this work, the protective effect of supplementation with IAA on dextran sulfate sodium (DSS)-induced colitis was evaluated, and the underlying mechanism was elucidated. The results indicated that the administration of IAA significantly relieved DSS-induced weight loss, reduced the disease activity index (DAI), restored colon length, alleviated intestinal injury, and improved the intestinal tight junction barrier. Furthermore, IAA inhibited intestinal inflammation by reducing the expression of proinflammatory cytokines and promoting the production of IL-10 and TGF-β1. In addition, the ERK signaling pathway is an important mediator of various physiological processes including inflammatory responses and is closely associated with the expression of IL-10. Notably, IAA treatment induced the activation of extracellular signal-regulated kinase (ERK), which is involved in the progression of colitis, while the ERK inhibitor U0126 attenuated the beneficial effects of IAA. In summary, IAA could attenuate the clinical symptoms of colitis, and the ERK signaling pathway was involved in the underlying mechanism. Supplementation with IAA could be a potential option for preventing or ameliorating UC.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yueyue Guan, Guohua Tang, Lei Li, Jianzhong Shu, Yuhua Zhao, Li Huang, Jun Tang
{"title":"Herbal medicine and gut microbiota: exploring untapped therapeutic potential in neurodegenerative disease management.","authors":"Yueyue Guan, Guohua Tang, Lei Li, Jianzhong Shu, Yuhua Zhao, Li Huang, Jun Tang","doi":"10.1007/s12272-023-01484-9","DOIUrl":"10.1007/s12272-023-01484-9","url":null,"abstract":"<p><p>The gut microbiota that exists in the human gastrointestinal tract is incredibly important for the maintenance of general health as it contributes to multiple aspects of host physiology. Recent research has revealed a dynamic connection between the gut microbiota and the central nervous system, that can influence neurodegenerative diseases (NDs). Indeed, imbalances in the gut microbiota, or dysbiosis, play a vital role in the pathogenesis and progression of human diseases, particularly NDs. Herbal medicine has been used for centuries to treat human diseases, including NDs. These compounds help to relieve symptoms and delay the progression of NDs by improving intestinal barrier function, reducing neuroinflammation, and modulating neurotransmitter production. Notably, herbal medicine can mitigate the progression of NDs by regulating the gut microbiota. Therefore, an in-depth understanding of the potential mechanisms by which herbal medicine regulates the gut microbiota in the treatment of NDs can help explain the pathogenesis of NDs from a novel perspective and propose novel therapeutic strategies for NDs. In this review, we investigate the potential neuroprotective effects of herbal medicine, focusing on its ability to regulate the gut microbiota and restore homeostasis. We also highlight the challenges and future research priorities of the integration of herbal medicine and modern medicine. As the global population ages, access to this information is becoming increasingly important for developing effective treatments for these diseases.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10830735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Min Seo Lee, Hyun Joo Shim, Yong-Yeon Cho, Joo Young Lee, Han Chang Kang, Im-Sook Song, Hye Suk Lee
{"title":"Comparative metabolism of aschantin in human and animal hepatocytes.","authors":"Min Seo Lee, Hyun Joo Shim, Yong-Yeon Cho, Joo Young Lee, Han Chang Kang, Im-Sook Song, Hye Suk Lee","doi":"10.1007/s12272-023-01483-w","DOIUrl":"10.1007/s12272-023-01483-w","url":null,"abstract":"<p><p>Aschantin, a tetrahydrofurofuran lignan with a 1,3-benzodioxole group derived from Flos Magnoliae, exhibits antioxidant, anti-inflammatory, cytotoxic, and antimicrobial activities. This study compared the metabolic profiles of aschantin in human, dog, mouse, and rat hepatocytes using liquid chromatography-high-resolution mass spectrometry. The hepatic extraction ratio of aschantin among the four species was 0.46-0.77, suggesting that it undergoes a moderate-to-extensive degree of hepatic metabolism. Hepatocyte incubation of aschantin produced 4 phase 1 metabolites, including aschantin catechol (M1), O-desmethylaschantin (M2 and M3), and hydroxyaschantin (M4), and 14 phase 2 metabolites, including O-methyl-M1 (M5 and M6) via catechol O-methyltransferase (COMT), six glucuronides of M1, M2, M3, M5, and M6, and six sulfates of M1, M2, M3, M5, and M6. Enzyme kinetic studies using aschantin revealed that the production of M1, a major metabolite, via O-demethylenation is catalyzed by cytochrome 2C8 (CYP2C8), CYP2C9, CYP2C19, CYP3A4, and CYP3A5 enzymes; the formation of M2 (O-desmethylaschantin) is catalyzed by CYP2C9 and CYP2C19; and the formation of M4 is catalyzed by CYP3A4 enzyme. Two glutathione (GSH) conjugates of M1 were identified after incubation of aschantin with human and animal liver microsomes in the presence of nicotinamide adenine dinucleotide phosphate and GSH, but they were not detected in the hepatocytes of all species. In conclusion, aschantin is extensively metabolized, producing 18 metabolites in human and animal hepatocytes catalyzed by CYP, COMT, UDP-glucuronosyltransferase, and sulfotransferase. These results can help in clarifying the involvement of metabolizing enzymes in the pharmacokinetics and drug interactions of aschantin and in elucidating GSH conjugation associated with the reactive intermediate formed from M1 (aschantin catechol).</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139105711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Prenylated flavonoid fractions from Glycyrrhiza glabra alleviate insulin resistance in HepG2 cells by regulating the ERK/IRS-1 and PI3K/Akt signaling pathways.","authors":"Defeng Li, Jinling Fan, Lin Du, Guoyan Ren","doi":"10.1007/s12272-024-01485-2","DOIUrl":"10.1007/s12272-024-01485-2","url":null,"abstract":"<p><p>Insulin resistance (IR) is a key factor in the pathogenesis of disrupted glucose metabolism. Although the extract of Glycyrrhiza glabra has shown significant hypoglycemic activity, its bioactive components remain to be identified, and their mechanisms of action, especially on hepatocyte glucose metabolism, are yet to be explored. In the present study, the primary compounds from Glycyrrhiza glabra [named prenylated flavonoid fractions (PFFs)] have been identified and their chemical structures have been elucidated. The therapeutic effects of PFFs extracted from G. glabra on glucose metabolism disorders and IR in high insulin-induced insulin-resistant HepG2 (IR-HepG2) cells have been determined. Glabridin (GLD) was used as a control. The results indicated that, similar to GLD, PFFs increased glucose consumption, glucose uptake, and translocation of glucose transporter 4 to the plasma membrane in IR-HepG2 cells. In addition, they enhanced the activities of glycogen synthase, glucokinase, and pyruvate kinase, while reducing the activities of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Furthermore, they activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway and suppressed the extracellular signal-regulated kinase/insulin receptor substrate-1 (ERK/IRS-1) pathway. These findings suggest that, similar to GLD, PFFs can alleviate impaired glucose metabolism and alleviate IR in IR-HepG2 cells.Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.The authors and their affiliations have been confirmed as correct.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}