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Annual review of pharmacology and toxicology最新文献

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Toluene Toxicity in the Brain: From Cellular Targets to Molecular Mechanisms. 脑中的甲苯毒性：从细胞靶点到分子机制。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 DOI: 10.1146/annurev-pharmtox-012924-010532
Andrew A Shaw, Jeffery D Steketee, Anna N Bukiya, Alex M Dopico
{"title":"Toluene Toxicity in the Brain: From Cellular Targets to Molecular Mechanisms.","authors":"Andrew A Shaw, Jeffery D Steketee, Anna N Bukiya, Alex M Dopico","doi":"10.1146/annurev-pharmtox-012924-010532","DOIUrl":"10.1146/annurev-pharmtox-012924-010532","url":null,"abstract":"<p><p>Toluene intoxication constitutes a persistent public health problem worldwide. While most organs can be damaged, the brain is a primary target whether exposure is accidental, occupational, or recreational. Interventions to prevent/revert brain damage by toluene are curtailed by the scarce information on the molecular targets and mechanisms mediating toluene's brain toxicity and the common exposure to other neurotoxins and/or coexistence of neurological/psychiatric disorders. We examine (<i>a</i>) the physicochemical properties of toluene that allow this inhalant to primarily target the lipid-rich brain; (<i>b</i>) the cell types targeted by toluene (neurons, different types of glia), while considering a cerebrovascular component; and (<i>c</i>) putative molecular mechanisms by which toluene may modify receptor function while analyzing structural features that allow toluene to directly interact with membrane lipids or specific proteins. This information constitutes a stepping stone to design pharmacotherapies that counteract toluene brain intoxication.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"65 1","pages":"487-506"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027693","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
Pharma[e]cology: How the Gut Microbiome Contributes to Variations in Drug Response. 制药学：肠道微生物组如何导致药物反应的变化。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1146/annurev-pharmtox-022724-100847
Kai R Trepka, Christine A Olson, Vaibhav Upadhyay, Chen Zhang, Peter J Turnbaugh
{"title":"Pharma[e]cology: How the Gut Microbiome Contributes to Variations in Drug Response.","authors":"Kai R Trepka, Christine A Olson, Vaibhav Upadhyay, Chen Zhang, Peter J Turnbaugh","doi":"10.1146/annurev-pharmtox-022724-100847","DOIUrl":"10.1146/annurev-pharmtox-022724-100847","url":null,"abstract":"<p><p>Drugs represent our first, and sometimes last, line of defense for many diseases, yet despite decades of research we still do not fully understand why a given drug works in one patient and fails in the next. The human gut microbiome is one of the missing puzzle pieces, due to its ability to parallel and extend host pathways for drug metabolism, along with more complex host-microbiome interactions. Herein, we focus on the well-established links between the gut microbiome and drugs for heart disease and cancer, plus emerging data on neurological disease. We highlight the interdisciplinary methods that are available and how they can be used to address major remaining knowledge gaps, including the consequences of microbial drug metabolism for treatment outcomes. Continued progress in this area promises fundamental biological insights into humans and their associated microbial communities and strategies for leveraging the microbiome to improve the practice of medicine.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"355-373"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer. PROTACs 作为阉割耐药前列腺癌药物发现的治疗模式。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1146/annurev-pharmtox-030624-110238
Ling-Yu Wang, Chiu-Lien Hung, Tsan-Chun Wang, Hung-Chih Hsu, Hsing-Jien Kung, Kwang-Huei Lin
{"title":"PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer.","authors":"Ling-Yu Wang, Chiu-Lien Hung, Tsan-Chun Wang, Hung-Chih Hsu, Hsing-Jien Kung, Kwang-Huei Lin","doi":"10.1146/annurev-pharmtox-030624-110238","DOIUrl":"10.1146/annurev-pharmtox-030624-110238","url":null,"abstract":"<p><p>Castration-resistant prostate cancer (CRPC) presents significant challenges in clinical management due to its resistance to conventional androgen receptor (AR)-targeting therapies. The advent of proteolysis targeting chimeras (PROTACs) has revolutionized cancer therapy by enabling the targeted degradation of key molecular players implicated in CRPC progression. In this review we discuss the developments of PROTACs for CRPC treatment, focusing on AR and other CRPC-associated regulators. We provide an overview of the strategic trends in AR PROTAC development from the aspect of targeting site selection and preclinical antitumor evaluation, as well as updates on AR degraders in clinical applications. Additionally, we briefly address the current status of selective AR degrader development. Furthermore, we review new developments in PROTACs as potential CRPC treatment paradigms, highlighting those targeting chromatin modulators BRD4, EZH2, and SWI/SNF; transcription regulator SMAD3; and kinases CDK9 and PIM1. Given the molecular targets shared between CRPC and neuroendocrine prostate cancer (NEPC), we also discuss the potential of PROTACs in addressing NEPC.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"375-396"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905651","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
Progress and Challenges in the Field of Snakebite Envenoming Therapeutics. 蛇咬致病疗法领域的进展与挑战。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1146/annurev-pharmtox-022024-033544
José María Gutiérrez, Nicholas R Casewell, Andreas H Laustsen
{"title":"Progress and Challenges in the Field of Snakebite Envenoming Therapeutics.","authors":"José María Gutiérrez, Nicholas R Casewell, Andreas H Laustsen","doi":"10.1146/annurev-pharmtox-022024-033544","DOIUrl":"10.1146/annurev-pharmtox-022024-033544","url":null,"abstract":"<p><p>Snakebite envenoming kills and maims hundreds of thousands of people every year, especially in the rural settings of tropical regions. Envenomings are still treated with animal-derived antivenoms, which have prevented many lives from being lost but which are also medicines in need of innovation. Strides are being made to improve envenoming therapies, with promising efforts made toward optimizing manufacturing and quality aspects of existing antivenoms, accelerating research and development of recombinant antivenoms based on monoclonal antibodies, and repurposing of small-molecule inhibitors that block key toxins. Here, we review the most recent advances in these fields and discuss therapeutic opportunities and limitations for different snakebite treatment modalities. Finally, we discuss challenges related to preclinical and clinical evaluation, regulatory pathways, large-scale manufacture, and distribution and access that need to be addressed to fulfill the goals of the World Health Organization's global strategy to prevent and control snakebite envenoming.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"465-485"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873984","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
Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases. 细胞内 RyR2 钙释放通道抑制剂作为心律失常性心脏病的治疗药物。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1146/annurev-pharmtox-061724-080739
Tri Q Do, Björn C Knollmann
{"title":"Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases.","authors":"Tri Q Do, Björn C Knollmann","doi":"10.1146/annurev-pharmtox-061724-080739","DOIUrl":"10.1146/annurev-pharmtox-061724-080739","url":null,"abstract":"<p><p>Ryanodine receptor type 2 (RyR2) is the principal intracellular calcium release channel in the cardiac sarcoplasmic reticulum (SR). Pathological RyR2 hyperactivity generates arrhythmia risk in genetic and structural heart diseases. <i>RYR2</i> gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia. In structural heart diseases (i.e., heart failure), posttranslation modifications render RyR2 channels leaky, resulting in pathologic calcium release during diastole, contributing to arrhythmogenesis and contractile dysfunction. Hence, RyR2 represents a therapeutic target in arrhythmogenic heart diseases. We provide an overview of the structure and function of RyR2, and then review US Food and Drug Administration-approved and investigational RyR2 inhibitors. A therapeutic classification of RyR2 inhibitors is proposed based on their mechanism of action. Class I RyR2 inhibitors (e.g., flecainide) do not change SR calcium content and are primarily antiarrhythmic. Class II RyR2 inhibitors (e.g., dantrolene) increase SR calcium content, making them less effective as antiarrhythmics but preferable in conditions with reduced SR calcium content such as heart failure.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"443-463"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387448","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
GPCR Biosensors to Study Conformational Dynamics and Signaling in Drug Discovery. 研究药物发现中构象动力学和信号传导的 GPCR 生物传感器。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1146/annurev-pharmtox-061724-080836
Victoria R Saca, Colin Burdette, Thomas P Sakmar
{"title":"GPCR Biosensors to Study Conformational Dynamics and Signaling in Drug Discovery.","authors":"Victoria R Saca, Colin Burdette, Thomas P Sakmar","doi":"10.1146/annurev-pharmtox-061724-080836","DOIUrl":"10.1146/annurev-pharmtox-061724-080836","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are a superfamily of transmembrane signal transducers that facilitate the flow of chemical signals across membranes. GPCRs are a desirable class of drug targets, and the activation and deactivation dynamics of these receptors are widely studied. Multidisciplinary approaches for studying GPCRs, such as downstream biochemical signaling assays, cryo-electron microscopy structural determinations, and molecular dynamics simulations, have provided insights concerning conformational dynamics and signaling mechanisms. However, new approaches including biosensors that use luminescence- and fluorescence-based readouts have been developed to investigate GPCR-related protein interactions and dynamics directly in cellular environments. Luminescence- and fluorescence-based readout approaches have also included the development of GPCR biosensor platforms that utilize enabling technologies to facilitate multiplexing and miniaturization. General principles underlying the biosensor platforms and technologies include scalability, orthogonality, and kinetic resolution. Further application and development of GPCR biosensors could facilitate hit identification in drug discovery campaigns. The goals of this review are to summarize developments in the field of GPCR-related biosensors and to discuss the current available technologies.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"7-28"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279685","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
Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics. 磷酸二酯酶：不断演变的概念和对人类治疗的影响。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1146/annurev-pharmtox-031524-025239
Evan D Kelly, Mark J Ranek, Manling Zhang, David A Kass, Grace K Muller
{"title":"Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.","authors":"Evan D Kelly, Mark J Ranek, Manling Zhang, David A Kass, Grace K Muller","doi":"10.1146/annurev-pharmtox-031524-025239","DOIUrl":"10.1146/annurev-pharmtox-031524-025239","url":null,"abstract":"<p><p>Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides. While the 11 PDE subfamilies share common features, key differences confer signaling specificity. The differences include substrate selectivity, enzymatic activity regulation, tissue expression, and subcellular localization. Selective inhibitors of each subfamily have elucidated the protean role of PDEs in normal cell function. PDEs are also linked to diseases, some of which affect the immune, cardiac, and vascular systems. Selective PDE inhibitors are clinically used to treat these specific disorders. Ongoing preclinical studies and clinical trials are likely to lead to the approval of additional PDE-targeting drugs for therapy in human disease. In this review, we discuss the structure and function of PDEs and examine current and evolving therapeutic uses of PDE inhibitors, highlighting their mechanisms and innovative applications that could further leverage this crucial family of enzymes in clinical settings.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"415-441"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339829","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
Decoding the Therapeutic Target SVEP1: Harnessing Molecular Trait GWASs to Unravel Mechanisms of Human Disease. 解码治疗靶点SVEP1：利用分子特征GWASs揭示人类疾病机制
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 DOI: 10.1146/annurev-pharmtox-061724-080905
Jared S Elenbaas, Paul C Lee, Ved Patel, Nathan O Stitziel
{"title":"Decoding the Therapeutic Target SVEP1: Harnessing Molecular Trait GWASs to Unravel Mechanisms of Human Disease.","authors":"Jared S Elenbaas, Paul C Lee, Ved Patel, Nathan O Stitziel","doi":"10.1146/annurev-pharmtox-061724-080905","DOIUrl":"10.1146/annurev-pharmtox-061724-080905","url":null,"abstract":"<p><p>Although human genetics has substantial potential to illuminate novel disease pathways and facilitate drug development, identifying causal variants and deciphering their mechanisms remain challenging. We believe these challenges can be addressed, in part, by creatively repurposing the results of molecular trait genome-wide association studies (GWASs). In this review, we introduce techniques related to molecular GWASs and unconventionally apply them to understanding <i>SVEP1</i>, a human coronary artery disease risk locus. Our analyses highlight SVEP1's causal link to cardiometabolic disease and glaucoma, as well as the surprising discovery of SVEP1 as the first known physiologic ligand for PEAR1, a critical receptor governing platelet reactivity. We further employ these techniques to dissect the interactions between SVEP1, PEAR1, and the Ang/Tie pathway, with therapeutic implications for a constellation of diseases. This review underscores the potential of molecular GWASs to guide drug discovery and unravel the complexities of human health and disease by demonstrating an integrative approach that grounds mechanistic research in human biology.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"65 1","pages":"131-148"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027565","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
Pollution of Soil by Pharmaceuticals: Implications for Metazoan and Environmental Health. 药物对土壤的污染：对元虫和环境健康的影响。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1146/annurev-pharmtox-030124-111214
Chubin Zhang, Leon P Barron, Stephen R Stürzenbaum
{"title":"Pollution of Soil by Pharmaceuticals: Implications for Metazoan and Environmental Health.","authors":"Chubin Zhang, Leon P Barron, Stephen R Stürzenbaum","doi":"10.1146/annurev-pharmtox-030124-111214","DOIUrl":"10.1146/annurev-pharmtox-030124-111214","url":null,"abstract":"<p><p>The use of pharmaceuticals has grown substantially and their consequential release via wastewaters poses a potential threat to aquatic and terrestrial environments. While transportation prediction models for aquatic environments are well established, they cannot be universally extrapolated to terrestrial systems. Pharmaceuticals and their metabolites are, for example, readily detected in the excreta of terrestrial organisms (including humans). Furthermore, the trophic transfer of pharmaceuticals to and from food webs is often overlooked, which in turn highlights a public health concern and emphasizes the pressing need to elucidate how today's potpourri of pharmaceuticals affect the terrestrial system, their biophysical behaviors, and their interactions with soil metazoans. This review explores the existing knowledge base of pharmaceutical exposure sources, mobility, persistence, (bio)availability, (bio)accumulation, (bio)magnification, and trophic transfer of pharmaceuticals through the soil and terrestrial food chains.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"547-565"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124646","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
G Protein-Coupled Receptor Heteromers in Brain: Functional and Therapeutic Importance in Neuropsychiatric Disorders. 脑内G蛋白偶联受体异构体：在神经精神疾病中的功能和治疗重要性。
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2025-01-01 DOI: 10.1146/annurev-pharmtox-061724-080727
Yalin Sun, Ahmed Hasbi, Susan R George
{"title":"G Protein-Coupled Receptor Heteromers in Brain: Functional and Therapeutic Importance in Neuropsychiatric Disorders.","authors":"Yalin Sun, Ahmed Hasbi, Susan R George","doi":"10.1146/annurev-pharmtox-061724-080727","DOIUrl":"10.1146/annurev-pharmtox-061724-080727","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) represent the largest family of plasma membrane proteins targeted for therapeutic development. For decades, GPCRs were investigated as monomeric entities during analysis of their pharmacology or signaling and during drug development. However, a considerable body of evidence now indicates that GPCRs function as dimers or higher-order oligomers. Greater acceptance of oligomerization occurred with the recognition that GPCR interactions form heteromeric receptor complexes, which was validated in vivo, often with pharmacologic, signaling, and functional properties distinct from the constituent protomers. GPCR heteromerization is reviewed in the context of brain disorders, with examples illustrating their functional implication in diverse neuropsychiatric and neurodegenerative disorders, making them an enormous unexploited resource for selective pharmacotherapy target identification. The strategies for development of heteromer-selective ligands are discussed as a new opportunity to precisely target the function of a receptor complex with greater specificity, in contrast to the classical ligands targeting individual receptors.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"65 1","pages":"215-236"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027670","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
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