Pharmacology & Therapeutics最新文献_第4页

Suppressor tRNAs as personalized therapy for nonsense mutation-associated pathologies 抑制trna作为无义突变相关病理的个性化治疗

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-22 DOI: 10.1016/j.pharmthera.2025.108919

Zoya Ignatova, Suki Albers

引用次数: 0

Macrophages at the crossroads of cellular senescence and cancer development and progression: Therapeutic opportunities and challenges 巨噬细胞在细胞衰老和癌症发展和进展的十字路口：治疗的机遇和挑战。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-07 DOI: 10.1016/j.pharmthera.2025.108906

Shi-Long Jiang , Dong Wang , Chan Zou , Ze-Wu Zhu , Chao Luo , Zhi-Bin Wang

{"title":"Macrophages at the crossroads of cellular senescence and cancer development and progression: Therapeutic opportunities and challenges","authors":"Shi-Long Jiang , Dong Wang , Chan Zou , Ze-Wu Zhu , Chao Luo , Zhi-Bin Wang","doi":"10.1016/j.pharmthera.2025.108906","DOIUrl":"10.1016/j.pharmthera.2025.108906","url":null,"abstract":"<div><div>Macrophages are pleiotropic immune cells essential for maintaining tissue homeostasis and modulating immune responses. Their inherent plasticity enables polarization into distinct functional phenotypes: M1 (pro-inflammatory) and M2 (anti-inflammatory), which critically influence the progression of various diseases, including cancer. Cellular senescence, a state characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory factors (SASP), substantially contributes to aging and disease pathogenesis. The interaction between macrophages and senescent cells is complex: macrophages contribute to tissue integrity by clearing senescent cells to prevent tissue dysfunction, while senescent cells can alter macrophage function, influencing inflammation and cancer development. This review examines the dual roles of macrophages in cellular senescence and cancer, focusing on their capacity to both protect against and promote tumor progression. It examines how macrophages recognize and phagocytose senescent cells, the impact of macrophage dysfunction on senescence-associated pathologies, and the role of tumor-associated macrophages (TAMs) in shaping the tumor microenvironment. Key concepts to be addressed include macrophage plasticity, SASP-mediated modulation of macrophage function, and the dual role of macrophages in cancer, where they can either suppress tumor growth or promote progression via angiogenesis, immune evasion, and metastasis. The mutual interplay between macrophages and senescent cells highlights the therapeutic potential of targeting this interaction for managing age-related diseases and cancer.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"274 ","pages":"Article 108906"},"PeriodicalIF":12.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of lysine acetylation in metabolic sensing and proteostasis 赖氨酸乙酰化在代谢感知和蛋白质静止中的作用。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-07 DOI: 10.1016/j.pharmthera.2025.108908

Aziz Eftekhari , Usman Sabir , Takhar Kasumov

{"title":"The role of lysine acetylation in metabolic sensing and proteostasis","authors":"Aziz Eftekhari , Usman Sabir , Takhar Kasumov","doi":"10.1016/j.pharmthera.2025.108908","DOIUrl":"10.1016/j.pharmthera.2025.108908","url":null,"abstract":"<div><div>Post-translational acetylation of lysine residues is a dynamic and reversible modification that plays a pivotal role in regulating protein structure, function, and interactions. This modification is mediated by central metabolite acetyl-CoA and is tightly controlled by the opposing actions of lysine acetyltransferases (<strong>KAT</strong>s) and lysine deacetylases (<strong>KDAC</strong>s), including the NAD<sup>+</sup>-dependent sirtuins. As a nutrient-sensing post-translational modification (<strong>PTM</strong>), acetylation is essential for maintaining cellular homeostasis, particularly by modulating proteostasis and metabolic flexibility—the ability of cells to rewire metabolic pathways in response to fluctuating energy demands and nutrient availability.</div><div>Dysregulation of acetylation has been implicated in the pathogenesis of metabolic disorders, neurodegenerative diseases, and cancer. Emerging evidence suggests that targeting acetylation-regulating enzymes with small-molecule inhibitors or activators hold promise for elucidating the role of acetylation in metabolic sensing and protein homeostasis. This review examines the regulation of acetylation across various metabolic states, its impact on metabolic adaptability, and its intricate interplay with proteostasis mechanisms. Additionally, it highlights the role of site-specific acetylation dynamics and sirtuin biology shaping metabolic regulation, providing key insights into the mechanisms underlying metabolic disorders and their progression. Understanding the regulatory mechanisms governing acetylation-dependent metabolic sensing could facilitate the development of precision therapeutics to restore metabolic homeostasis.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"274 ","pages":"Article 108908"},"PeriodicalIF":12.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of G protein-coupled receptor conformation on signaling bias: Integrating simulations and biophysical experiments G蛋白偶联受体构象对信号偏倚的影响：整合模拟和生物物理实验。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-07 DOI: 10.1016/j.pharmthera.2025.108905

Gian Marco Elisi , Giovanni Bottegoni

{"title":"Impact of G protein-coupled receptor conformation on signaling bias: Integrating simulations and biophysical experiments","authors":"Gian Marco Elisi , Giovanni Bottegoni","doi":"10.1016/j.pharmthera.2025.108905","DOIUrl":"10.1016/j.pharmthera.2025.108905","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are a ubiquitous family of transmembrane proteins essential for signal transduction and serve as key targets for numerous drug classes. A single GPCR often mediates multiple, largely independent pathways, which can sometimes be selectively modulated by biased ligands that preferentially activate specific signaling routes. These molecules stabilize distinct receptor conformations, with even subtle structural variations capable of driving different cellular responses. Capturing the conformations responsible for biased signaling, however, often proves challenging with traditional experimental techniques. Recent advances in experimental methods, coupled with computational modeling, have shed new light on the structural mechanisms underlying biased signaling. This review highlights therapeutically relevant examples, focusing on mechanisms such as (i) partial occupation of the orthosteric pocket, resulting in submaximal activation, and (ii) binding to alternative sites via bitopic or allosteric compounds. Emphasis is placed on studies that integrate biophysical and computational approaches, demonstrating their synergistic potential to unravel the complexities of GPCR signaling. This combined strategy paves the way for the rational design of innovative drugs with greater precision and therapeutic efficacy.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"274 ","pages":"Article 108905"},"PeriodicalIF":12.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human PSC-derived liver cells and their applications for disease models and drug discovery 人psc来源的肝细胞及其在疾病模型和药物发现中的应用。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-07 DOI: 10.1016/j.pharmthera.2025.108907

Yuta Koui , Minoru Tanaka , Taketomo Kido

{"title":"Human PSC-derived liver cells and their applications for disease models and drug discovery","authors":"Yuta Koui , Minoru Tanaka , Taketomo Kido","doi":"10.1016/j.pharmthera.2025.108907","DOIUrl":"10.1016/j.pharmthera.2025.108907","url":null,"abstract":"<div><div>The liver comprises hepatic parenchymal cells, primarily hepatocytes, and non-parenchymal cells such as liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and cholangiocytes. These cell types interact with each other to maintain homeostasis through metabolism, detoxification, and protein synthesis. Such cellular interactions also play crucial roles in regulating the onset and progression of liver diseases. Consequently, the development of <em>in vitro</em> multicellular liver models is vital for elucidating the mechanisms underlying liver diseases and for evaluating the efficacy and toxicity of novel therapeutic drugs. Given their ability to proliferate and differentiate into diverse cell types <em>in vitro</em>, human pluripotent stem cells (hPSCs), including embryonic stem cells and induced PSCs, offer valuable potential for generating various liver cell types and constructing liver disease models for drug discovery research. Furthermore, patient-derived or gene-edited iPSCs can be employed to model genetic liver disorders. This review summarizes the development of differentiation protocols for hPSC-derived hepatocytes, LSECs, HSCs, and cholangiocytes, as well as their applications in drug discovery research.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"274 ","pages":"Article 108907"},"PeriodicalIF":12.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neutrophil Extracellular Traps (NETs) as drivers of atherosclerosis: Pathogenic mechanisms and therapeutic opportunities 中性粒细胞胞外陷阱（NETs）作为动脉粥样硬化的驱动因素：致病机制和治疗机会

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-20 DOI: 10.1016/j.pharmthera.2025.108917

Shravya Shetty , Manikandan Subramanian

{"title":"Neutrophil Extracellular Traps (NETs) as drivers of atherosclerosis: Pathogenic mechanisms and therapeutic opportunities","authors":"Shravya Shetty , Manikandan Subramanian","doi":"10.1016/j.pharmthera.2025.108917","DOIUrl":"10.1016/j.pharmthera.2025.108917","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) are the leading cause of death globally. The primary pathological process underlying CVDs is atherosclerosis, a chronic lipid-driven inflammatory condition that results in the narrowing of medium- and large-arteries due to a build-up of fibrofatty, leukocyte-rich plaques. Adverse clinical outcomes are usually a result of plaque erosion or rupture which result in acute luminal thrombosis with ensuing tissue ischaemia. Immune cell infiltration and the associated inflammation are recognized as key drivers of the development of unstable plaques. Whilst the role of macrophages, dendritic cells, T- and B-lymphocytes are extensively documented in the progression of atherosclerosis, the role of neutrophils, which are the dominant leukocyte subset in humans, is relatively understudied. Interestingly, studies in the last decade have shed light on the critical role of neutrophil extracellular traps (NETs) in mediating inflammasome activation, plaque progression, and adverse clinical outcomes. NETs are complex extracellular DNA structures released by neutrophils undergoing death by a specialized process of NETosis. This review will comprehensively examine the key drivers of NETosis in atherosclerosis, mechanisms of NET clearance, the pathogenic role of NETs in plaque progression, and finally novel pharmacological approaches to target NETs to prevent atherothrombosis and its associated clinical complications.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"274 ","pages":"Article 108917"},"PeriodicalIF":12.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic exploration of biased ligands at class A G protein-coupled receptors over the past 20 years 在过去的20年中，对A类G蛋白偶联受体的偏配体的治疗探索

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-21 DOI: 10.1016/j.pharmthera.2025.108918

Jixia Wang , Fangfang Xu , Yanfang Liu , Han Zhou , Wenjie Yuan , Fan Liu , Ye Fang , Xinmiao Liang

{"title":"Therapeutic exploration of biased ligands at class A G protein-coupled receptors over the past 20 years","authors":"Jixia Wang , Fangfang Xu , Yanfang Liu , Han Zhou , Wenjie Yuan , Fan Liu , Ye Fang , Xinmiao Liang","doi":"10.1016/j.pharmthera.2025.108918","DOIUrl":"10.1016/j.pharmthera.2025.108918","url":null,"abstract":"<div><div>Recent decades have witnessed significant advances in the development of biased ligands for G protein-coupled receptors (GPCRs) as potential therapeutic agents with enhanced efficacy and reduced on-target side effects. This is largely attributed to the unique capability of biased ligands to activate pathway-selective signaling, which can effectively modulate in vivo pharmacology. This review presents a comprehensive analysis of biased ligands targeting class A GPCRs over the past 20 years, encompassing discovery strategies, assays, biological effects and therapeutic applications. The analysis covers approximately 383 biased ligands acting on 60 different GPCRs, among which opioid, 5-hydroxytryptamine, dopamine, adrenergic and cannabinoid receptors are the five subfamilies with the highest number of reported biased ligands. The biological effects of these biased ligands are primarily investigated in the area of pain, cardiovascular, neurological, respiratory, metabolic and inflammatory diseases. The regulatory approval of the opioid biased agonist TRV130 for pain management, along with the growing number of biased drugs tested in clinical trials, heralds a new era in GPCR drug development. Additionally, various natural product biased ligands have been identified. A deeper understanding of the biological functions and pharmacological effects of biased ligands will support future advancements in GPCR drug development.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"274 ","pages":"Article 108918"},"PeriodicalIF":12.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hydroxyl carboxylic acid receptor-2 (HCAR2) as a potential target in neurometabolic diseases 羟基羧酸受体2 （HCAR2）作为神经代谢性疾病的潜在靶点。

IF 12.5 1区医学

Pharmacology & Therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-07 DOI: 10.1016/j.pharmthera.2025.108909

Lara Testai , Francesca Guida , Silvia Salerno , Simone Brogi , Andrea Maria Morace , Leonardo Carbonetti , Federica Ricciardi , Michela Perrone , Enza Palazzo , Vincenzo Calderone , Sabatino Maione , Livio Luongo

{"title":"Hydroxyl carboxylic acid receptor-2 (HCAR2) as a potential target in neurometabolic diseases","authors":"Lara Testai , Francesca Guida , Silvia Salerno , Simone Brogi , Andrea Maria Morace , Leonardo Carbonetti , Federica Ricciardi , Michela Perrone , Enza Palazzo , Vincenzo Calderone , Sabatino Maione , Livio Luongo","doi":"10.1016/j.pharmthera.2025.108909","DOIUrl":"10.1016/j.pharmthera.2025.108909","url":null,"abstract":"<div><div>Hydroxycarboxylic acid receptor 2 (HCAR2) is a G-protein-coupled receptor initially identified for its role in lipid metabolism. Beyond its classical metabolic functions, HCAR2 plays a pivotal role in chronic inflammatory diseases, neurometabolic disorders, and pain modulation. Evidence from preclinical studies suggest that when endogenously activated by β-hydroxybutyrate and pharmacologically by niacin and its derivatives, HCAR2 attenuates microglial reactivity, suppress pro-inflammatory cytokine release, and modulate neuronal excitability, by offering neuroprotective benefits in neurological disorders and chronic pain. Additionally, emerging data highlight its involvement in gut-brain axis regulation, linking dietary interventions and microbiota-derived metabolites to Central Nervous System function. The development of selective HCAR2 agonists with improved pharmacokinetic and safety profiles holds promise for treatments targeting both peripheral and central pathologies. This review explores the structural and functional aspects of HCAR2, and describe novel synthetic HCAR2 agonists, by emphasizing its therapeutic potential across a spectrum of metabolic and neuroinflammatory disorders.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"274 ","pages":"Article 108909"},"PeriodicalIF":12.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antiviral drug repurposing: different approaches and the case of antifungal drugs 抗病毒药物的再利用：不同的方法和抗真菌药物的案例。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-06-23 DOI: 10.1016/j.pharmthera.2025.108903

Sara Tuci , Beatrice Mercorelli , Arianna Loregian

{"title":"Antiviral drug repurposing: different approaches and the case of antifungal drugs","authors":"Sara Tuci , Beatrice Mercorelli , Arianna Loregian","doi":"10.1016/j.pharmthera.2025.108903","DOIUrl":"10.1016/j.pharmthera.2025.108903","url":null,"abstract":"<div><div>In recent years, the emergence of new viruses and the re-emergence of old ones have posed a significant challenge to global Public Health. Viruses characterised by high morbidity and mortality rates have the potential to spread rapidly, causing large epidemic outbreaks and even pandemics. In this context, viral infections still lacking effective treatments represent a serious threat to human health. For this reason, sustained development and implementation of countermeasures are urgently needed against these infections, as they are for diseases for which the emergence of drug resistance is rapidly increasing. In this regard, compared to <em>de novo</em> drug discovery, drug repurposing could represent a highly efficient, faster, and more affordable strategy to develop new drugs. Here, we provide a comprehensive review of the different experimental and computational approaches used for drug repurposing and discuss their advantages and limitations in comparison with other drug discovery strategies. In addition, as an example of the successful application of drug repurposing, we present the case of approved antifungal drugs that could be repurposed to counteract viral infections.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108903"},"PeriodicalIF":12.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retinoid dynamics in vision: from visual cycle biology to retina disease treatments 视觉中的类维甲酸动力学：从视觉周期生物学到视网膜疾病治疗。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-09-01 Epub Date: 2025-06-21 DOI: 10.1016/j.pharmthera.2025.108902

Jaclyn Swigris , Made Airanthi K. Widjaja-Adhi , Marcin Golczak

{"title":"Retinoid dynamics in vision: from visual cycle biology to retina disease treatments","authors":"Jaclyn Swigris , Made Airanthi K. Widjaja-Adhi , Marcin Golczak","doi":"10.1016/j.pharmthera.2025.108902","DOIUrl":"10.1016/j.pharmthera.2025.108902","url":null,"abstract":"<div><div>Light perception is a biological process that facilitates a profound interaction between the external world and the internal functions of living organisms. It begins with the absorption of photons with specialized visual pigments that contain vitamin A-derived chromophores. The light energy triggers the photoisomerization of the visual chromophore, initiating a cascade of signaling events that ultimately convert light into electrical signals interpreted as vision. However, the sustainability of vision relies on the continuous supply of the visual chromophore, which is maintained through light-dependent and light-independent processes. The importance of these processes is underscored by numerous blinding retinal diseases linked to impaired regeneration of the chromophore. Thus, research into the molecular mechanisms of visual chromophore biosynthesis has not only deepened our understanding of the organization of visual systems but also uncovered the etiologies of these debilitating diseases. In this review, we synthesize recent progress in understanding the mechanisms responsible for visual chromophore biosynthesis. We examine biological targets, therapeutic strategies, and drug discovery efforts aimed at restoring or bypassing metabolic blockades in visual chromophore regeneration, and assess the progress of clinical trials evaluating the effectiveness of therapies for degenerative retinal diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108902"},"PeriodicalIF":12.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0