Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

{"title":"Corrigendum to \"Riluzole ameliorates learning and memory deficits in Aβ25-35-induced rat model of Alzheimer's disease and is independent of cholinoceptor activation\" [Biomedicine & Pharmacotherapy, Volume 87, March 2017, Pages 135-144].","authors":"Zahra Mokhtari, Tourandokht Baluchnejadmojarad, Farnaz Nikbakht, Monireh Mansouri, Mehrdad Roghani","doi":"10.1016/j.biopha.2024.117626","DOIUrl":"10.1016/j.biopha.2024.117626","url":null,"abstract":"","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":" ","pages":"117626"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559728","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":"Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss.","authors":"Sooyoon Bang, Dong-Eun Kim, Hee-Taik Kang, Jong Hun Lee","doi":"10.1016/j.biopha.2024.116981","DOIUrl":"https://doi.org/10.1016/j.biopha.2024.116981","url":null,"abstract":"<p><p>Sarcopenia, which refers to age-related muscle loss, presents a significant challenge for the aging population. Age-related changes that contribute to sarcopenia include cellular senescence, decreased muscle stem cell number and regenerative capacity, impaired autophagy, and mitochondrial dysfunction. Metformin, an anti-diabetic agent, activates AMP-activated protein kinase (AMPK) and affects various cellular processes in addition to reducing hepatic gluconeogenesis, lowering blood glucose levels, and improving insulin resistance. However, its effect on skeletal muscle cells remains unclear. This study aimed to investigate the effects of metformin on age-related muscle loss using a late passage C2C12 cell model. The results demonstrated that metformin alleviated hallmarks of cellular senescence, including SA-β-gal activity and p21 overexpression. Moreover, treatment with pharmacological concentrations of metformin restored the reduced differentiation capacity in late passage cells, evident through increased myotube formation ability and enhanced expression of myogenic differentiation markers such as MyoD, MyoG, and MHC. These effects of metformin were attributed to enhanced autophagic activity, normalization of mitochondrial membrane potential, and improved mitochondrial respiratory capacity. These results suggest that pharmacological concentrations of metformin alleviate the hallmarks of cellular senescence, restore differentiation capacity, and improve autophagic flux and mitochondrial function. These findings support the potential use of metformin for the treatment of sarcopenia.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"116981"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634460","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":"Farnesol ameliorates DSS-induced IBD by regulating inflammatory cytokines, repairing the intestinal barrier, reversing the gut microbiota imbalance, and influencing fecal metabolome in C57BL/6 mice.","authors":"Ya Yuan, Dazuo Wu, Heping Chen, Zheng Ma, Xinyue Peng, Xiaodie Li, Chuchu Zhao, Linping Jiang, Jinping Liang, Weiwei Zhang, Juan Dai","doi":"10.1016/j.biopha.2024.117518","DOIUrl":"10.1016/j.biopha.2024.117518","url":null,"abstract":"<p><p>The incidence of inflammatory bowel disease (IBD) is rising globally, increasing interest in food ingredients for its prevention and control. This study evaluated the effect of farnesol (FAR), a key component of pomelo flower volatile oil, on dextran sodium sulfate (DSS)-induced colitis in C57BL/6 mice. FAR significantly alleviated DSS-induced colitis and secondary liver injury, as shown by improved body weight, DAI, colon length, and pathology, as well as liver function and blood lipid indices. The mechanism involves FAR-mediated regulation of inflammatory cytokines, increased expression of tight junction protein genes, and decreased expression of lipid metabolism-related proteins. FAR also enhanced gut microbiota diversity, balancing harmful and probiotic bacteria. Fecal metabolome analysis indicated FAR's role in reversing metabolic disturbances related to inflammation and liver lipid metabolism. These findings support developing functional foods for IBD treatment using pomelo flower volatile oil.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117518"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482971","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":"Semaglutide ameliorates Alzheimer's disease and restores oxytocin in APP/PS1 mice and human brain organoid models.","authors":"Yinbing Zhang, Cheng Tang, Yao He, Yingqian Zhang, Qinxi Li, Ting Zhang, Bangcheng Zhao, Aiping Tong, Qixing Zhong, Zhihui Zhong","doi":"10.1016/j.biopha.2024.117540","DOIUrl":"10.1016/j.biopha.2024.117540","url":null,"abstract":"<p><strong>Aims: </strong>To investigate the therapeutic effects and mechanisms of Semaglutide in Alzheimer's disease (AD), and identify its potential targets.</p><p><strong>Methods: </strong>We systematically evaluated the effect of Semaglutide on Alzheimer's disease (AD), using both mice and human organoid models.</p><p><strong>Results: </strong>Behavioral analyses on APP/PS1 mice demonstrated that Semaglutide improved the cognitive capabilities, particularly in the learning and memory domains. Biochemical investigations further highlighted its role in reducing amyloid plaque deposition and down-regulating the expression of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) expression in the mouse brain tissues. Meanwhile, oxytocin (OXT) was up-regulated after Semaglutide treatment. Subsequent studies using human AD-brain organoids (BOs) models revealed that, upon Semaglutide treatment, these AD-BO models also exhibited reduced levels of amyloid-beta (Aβ), phosphorylated Tau (p-Tau) and GFAP expression as well as increased OXT level.</p><p><strong>Conclusions: </strong>Semaglutide can ameliorate Alzheimer's disease in pre-clinical models, suggesting the promising therapeutic potential in AD patients.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117540"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482999","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":"Synaptic vesicle protein 2-targeted doxorubicin-loaded liposome for effective neuroblastoma therapy.","authors":"Yang Liu, Dongya Zhang, Miaomiao Kong, Yibin Wang, Huiyuan Mei, Chunxu Shan, Jianghui Meng, Yan Zou, Jiafu Wang","doi":"10.1016/j.biopha.2024.117548","DOIUrl":"10.1016/j.biopha.2024.117548","url":null,"abstract":"<p><p>Neuroblastoma, a pediatric cancer originating from neural crest tissues of the sympathetic nervous system, poses significant treatment challenges due to its molecular diversity and restricted druggable targets. While chemotherapy is a common treatment, its drawbacks, including poor targeting of cancer cells and nonspecific cytotoxicity, highlight the urgent need for innovative and effective therapeutic strategies. Herein, we developed a novel drug by coupling the receptor binding domain of botulinum neurotoxin type A (Hc) fused with monomeric streptavidin (mSA) to biotin coated doxorubicin (Dox)-loaded liposome, via interaction between mSA and biotin. The resultant Hc-coated liposome (Hc-Lipo@Dox) actively targeted the recycling synaptic vesicle 2 protein (SV2) abundantly expressed on the surface of neuroblastoma cells. Our results revealed that Hc-Lipo@Dox more effectively entered the neuroblastoma SH-SY5Y cells, inducing apoptosis compared to non-targeted liposome and free Dox. Moreover, Hc-Lipo@Dox rapidly enriched Dox in the subcutaneously implanted neuroblastoma tumor in nude mice, resulting potent anti-neuroblastoma effect compared to non-targeted liposomes or free Dox. Importantly, Hc-Lipo@Dox significantly improved the survival rate of treated mice, while also exhibiting a favorable safety profile with no discernible impact on mobility or observable side effects. These findings highlight the potential of SV2-targeted Dox liposome as a promising and well-tolerated chemotherapy approach for neuroblastoma treatment. Moreover, the technology established here has broader applications for various cancer therapies by substituting the Hc moiety with other tumor-specific targeting moieties.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117548"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483002","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":"The beneficial effects of Akkermansia muciniphila and its derivatives on pulmonary fibrosis.","authors":"Shahrbanoo Keshavarz Aziziraftar, Romina Bahrami, Danial Hashemi, Arefeh Shahryari, Amitis Ramezani, Fatemeh Ashrafian, Seyed Davar Siadat","doi":"10.1016/j.biopha.2024.117571","DOIUrl":"10.1016/j.biopha.2024.117571","url":null,"abstract":"<p><p>Pulmonary fibrosis (PF) is a progressive and debilitating respiratory condition characterized by excessive deposition of extracellular matrix proteins and scarring within the lung parenchyma. Despite extensive research, the pathogenesis of PF remains incompletely understood, and effective therapeutic options are limited. Emerging evidence suggests a potential link between gut microbiota dysbiosis and the development of PF, highlighting the gut-lung axis as a promising therapeutic target. Akkermansia muciniphila (A. muciniphila), a mucin-degrading bacterium residing in the gut mucosal layer, has garnered considerable interest due to its immunomodulatory and anti-inflammatory properties. This study investigates the therapeutic potential of live and pasteurized A. muciniphila, as well as its extracellular vesicles (EVs), in mitigating inflammation and fibrosis in a murine model of carbon tetrachloride (CCl4)-induced PF exacerbated by a high-fat diet (HFD). Male C57BL/6 mice were divided into groups receiving either a normal diet or an HFD, with or without CCl4 administration. The mice were then treated with live or pasteurized A. muciniphila, or its EVs. Lung tissue was analyzed for the expression of inflammatory markers and fibrosis markers using real-time PCR and ELISA. Administration of live and pasteurized A. muciniphila, as well as its EVs, significantly downregulated the expression of inflammatory and fibrosis markers in the lung tissue of CCl4-induced PF mice. Furthermore, these treatments ameliorated the increased production of IL-6 and reduced IL-10 levels observed in the HFD and CCl4-treated groups. These findings suggest that A. muciniphila and its derivatives exert protective effects against pulmonary inflammation and fibrosis, potentially through modulation of the gut-lung axis. The study highlights the therapeutic potential of A. muciniphila and its derivatives as novel interventions for the management of PF, warranting further preclinical and clinical investigations.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117571"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483004","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":"Native corn (Zea mays L., cv. 'Elotes Occidentales') polyphenols extract reduced total cholesterol and triglycerides levels, and decreased lipid accumulation in mice fed a high-fat diet.","authors":"Sarah N Lee-Martínez, Ivan Luzardo-Ocampo, Haydé A Vergara-Castañeda, Jose F Vasco-Leal, Marcela Gaytán-Martínez, M Liceth Cuellar-Nuñez","doi":"10.1016/j.biopha.2024.117610","DOIUrl":"10.1016/j.biopha.2024.117610","url":null,"abstract":"<p><p>Obesity is a complex disease with numerous molecular and metabolic implications that could be prevented through proper diet and lifestyle. Native corn is a promissory underutilized plant species containing bioactive compounds that could reduce the impact of obesity. This research aimed to characterize and evaluate the anti-obesogenic effect of a polyphenols-rich extract of native corn ('Elotes Occidentales') in HFD-fed mice. The powdered extract was administered using gelatins to C57BL/6 J mice randomly divided into four groups (n:8/group) for 13 weeks: standard diet (SD) group, HFD group, HFD+200 mg extract/kg body weight (BW), and HFD+400 mg extract/kg BW/day. Ellagic acid, chlorogenic acid, rutin, and kaempferol were the most abundant phenolics (2022.44-4028.43 µg/g). Among the HFD groups, the highest dose of the extracts promoted the lowest BW gain, and fasting triglycerides and cholesterol levels. Moreover, the HFD+400 mg/kg BW group showed the lowest epididymal and subcutaneous adipose tissue weight and adipocytes' diameter and area between the HFD-treated animals. The extract administration prevented hepatic lipid accumulation. Rutin demonstrated the highest in silico binding affinity with proteins from the AMPK pathway (ACACA, SIRT1, and SREBP1) (-6.70 to -8.70 kcal/mol). Results indicated beneficial effects in alleviating obesity-associated parameters in vivo due to bioactive compounds from native maize extracts.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117610"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514593","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":"Antimigratory effects of a new NF-κB inhibitor, (S)-b-salicyloylamino-a-exo-methylene-ƴ-butyrolactone, in 2D and 3D breast cancer models.","authors":"Paola Poma, Salvatrice Rigogliuso, Manuela Labbozzetta, Francesco Carfì Pavia, Camilla Carbone, Jun Ma, Alessandra Cusimano, Monica Notarbartolo","doi":"10.1016/j.biopha.2024.117552","DOIUrl":"10.1016/j.biopha.2024.117552","url":null,"abstract":"<p><p>One of the pharmacological approaches to neoplastic disease aims to target the metastatic capacity of tumor cells to reduce their aggressive behavior. In this study, we analyzed the antimigratory capacity of the compound SEMBL, (S)-β-salicyloylamino-a-exo-methylene-ƴ-butyrolactone, a new analog of (-)-Dehydroxymethylepoxyquinomicin ((-)-DHMEQ), in three different breast cancer cell lines: MCF-7, MCF-7R and MDA-MB-231. This molecule is characterized by intense antiproliferative activity, evaluated by MTS assay, showing greater potency than DHMEQ. SEMBL was able to inhibit nuclear factor κappa B (NF-κB) activation observed through TransAM™ assay, while cell invasion and wound healing assays revealed a strong reduction in invasive capacity mediated by metalloproteinase 2 (MMP-2) and Vimentin decrease. These results, obtained in vitro, were corroborated on 3D systems made up of Poly-L-Lactic Acid (PLLA) scaffolds. In summary, SEMBL exerts interesting anti-tumor activities in preclinical breast cancer models and therefore it could be a promising new molecule to be studied also in other types of neoplastic disease.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117552"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482987","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":"Isoliquiritigenin alleviates SLC7A11-mediated efferocytosis inhibition to promote wounds healing in diabetes.","authors":"Xiaokang Gong, Jinhong Cai, Wenbiao Zheng, Jiehe Huang, Tao Chen, Weijie Chen, Xin Zheng","doi":"10.1016/j.biopha.2024.117578","DOIUrl":"10.1016/j.biopha.2024.117578","url":null,"abstract":"<p><p>The healing process of chronic wounds often progresses slowly and is fraught with challenges, imposing increasing economic burdens and physical suffering on patients. Managing persistent wound inflammation and stimulating angiogenesis are crucial elements in promoting wound healing. Plants have been playing a key role in traditional medicine, and their abundant bioactive components continually inspire the development and innovation of new drugs. Isoliquiritigenin (ISL), a flavonoid compound derived from licorice roots known as chalcone, has demonstrated multifaceted pharmacological potential. However, its effects on diabetic wounds and the detailed mechanisms remain to be investigated. Through in-depth exploration using network pharmacology, we successfully predicted potential therapeutic targets of ISL for ischemic diseases. The revealed mechanisms primarily focused on the critical pathway of efferocytosis. Subsequent in vivo experiments demonstrated that ISL significantly enhanced the efferocytosis of dendritic cells (DC), improving the functional behaviors of endothelial cells. Further research indicated that ISL promoted DC efferocytosis by regulating SLC7A11-mediated glycolysis. Notably, the overexpression of SLC7A11 diminished the positive effects of ISL, suggesting a potential antagonistic role of SLC7A11 in the regulatory process. In the wounds of diabetic mice, we observed that ISL accelerated DC efferocytosis and angiogenesis, resulting in faster wound closure and better tissue repair. In summary, this study not only demonstrates the broad potential of ISL in managing diabetic wounds but also delves deeply into its mechanisms, laying a solid theoretical foundation for future clinical applications.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117578"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482989","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":"Melittin treatment suppressed malignant NSCLC progression through enhancing CTSB-mediated hyperautophagy.","authors":"Yuhan Wang, Tailei Yuan, Longyue He, Jingjing Huang, Nodemsahajoel Wilfred, Wenhui Yang, Mingming Jin, Gang Huang, Changlian Lu","doi":"10.1016/j.biopha.2024.117573","DOIUrl":"10.1016/j.biopha.2024.117573","url":null,"abstract":"<p><p>Melittin is preclinically investigated as anticancer agent in multiple tumor types. But its regulation role and regulatory mechanism regarding NSCLC is unknown. In our investigation, Proteomic test was employed to identify proteins that expressed abnormally in cancer cells and that with Melittin treatmented. The results showed CTSB was one of the Top proteins with different expression levels in the lysosomes of Melittin-treatmented cancer cells and showed an up-regulation trend. CTSB expression was increased in NSCLC cancer tissues compared to adjacent normal tissues, as demonstrated in lung cancer tissue chips experiment. However, Melittin treatment increased the CTSB level in lysosomes, which inhibited the malignant progression of NSCLC. We hypothesized that the relative homeostasis of CTSB in cancer cells was destroyed, and CTSB exerts its hydrolytic effect excessively, resulting in excessive autophagy of cancer cells, thus inhibiting the malignant progression of cancer cells. The direct combination of Melittin and CTSB was proposed by molecular docking technique, LiP-SMap was used to analyze the target genes and active components extracted from high-throughput sequencing proteomic data, and successfully verified that melittin was successfully demonstrated to directly target CTSB-binding. In vivo and in vitro studies have shown that Melittin treatment inhibits the malignant progression of A549 and HCC1833 cells and animal tumors, namely non-small cell lung cancer, by promoting CTSB-mediated hyperautophagy. CTSB-specific inhibitor CA-074 Me and autophagy inhibitor 3-MA treatment reversed the inhibit effect of Melittin to the malignant progression of NSCLC. Taken together, Melittin treatment inhibited malignant progression regarding NSCLC through enhancing CTSB-mediated hyperautophagy.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117573"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482991","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}