International journal of drug discovery and pharmacology最新文献

{"title":"Cardiac β-Adrenoceptor Signaling: The New Insight on An Old Target in the Therapy of Cardiovascular Disease","authors":"Ying Song, A. Woo, Yan Zhang, Ruiping Xiao","doi":"10.53941/ijddp.v1i1.177","DOIUrl":"https://doi.org/10.53941/ijddp.v1i1.177","url":null,"abstract":"Review\u0000Cardiac β-Adrenoceptor Signaling: The New Insight on An Old Target in the Therapy of Cardiovascular Disease\u0000\u0000Ying Song 1, Anthony Yiu-Ho Woo 2,*, Yan Zhang 3,4,*, and Ruiping Xiao 5,6,7,8\u0000\u0000\u00001 Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China.\u00002 School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.\u00003 Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.\u00004 Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China.\u00005 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China.\u00006 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.\u00007 Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China.\u00008 PKU-Nanjing Joint Institute of Translational Medicine, Nanjing, 210000, China.\u0000* Correspondence: yiuhowoo@syphu.edu.cn (Anthony Yiu-Ho Woo), Tel.: +86-24-23986375; zhangyan9876@pku.edu.cn (Yan Zhang), Tel.: +86-10-82805945.\u0000 \u0000 \u0000Received: 19 October 2022\u0000Accepted: 28 October 2022\u0000Published: 21 December 2022\u0000 \u0000\u0000Abstract: A variety of G protein-coupled receptors (GPCRs) are involved in the regulation of cardiovascular function. The β-adrenoceptors (β-ARs), with three subtypes, are the dominant receptor species in the heart, in which the β1-AR and the β2-AR are considered functional. Stimulation of the β-ARs produces myocardial inotropy via activation of the Gs-cAMP-PKA signaling cascade. Prolonged stimulation of the β1-AR is cardiac harmful because the stimulated β1-AR couples only to Gs proteins and it mediates a cardiotoxic signal. On the other hand, the β2-AR couples dually to both Gs and Gi proteins and the β2-AR-Gi pathway is antiapoptotic. The activated Gi signal also counteracts the β-AR-Gs-promoted positive inotropic effect. Other key players in cardiac β-AR signaling include Ca2+/calmodulin-dependent protein kinases (CaMKs), GPCR kinases (GRKs), β-arrestins and phosphodiesterases. During heart failure, excessive sympathetic stimulation results in the activation of the cardiotoxic β1-AR-CaMKIIδ pathway and the upregulation of GRK2 and Gi in the heart. GRK2 promotes the desensitization of β-ARs and enhances a β2-AR-mediated Gi signaling. These signal transduction processes accompanying the downregulation of the β1-AR are involved in cardiac dysfunction, maladaptive cardiac remodeling, and the progression of chronic heart failure. β-Blockers are widely used in the treatment of cardiovascular disease. They have established their position as one of the “four pillars of heart failure” thirty years ago. In the present review, we provide an overview of the ","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90613163","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":"Current Progress in Drug Target Identification and Drug Delivery","authors":"X. Wang","doi":"10.53941/ijddp.v1i1.214","DOIUrl":"https://doi.org/10.53941/ijddp.v1i1.214","url":null,"abstract":"Editorial\u0000Current Progress in Drug Target Identification and Drug Delivery\u0000\u0000Xin Wang\u0000\u0000\u0000Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, M13 9PT Manchester, UK.\u0000* Correspondence: xin.wang@manchester.ac.uk\u0000","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74107210","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":"Progress of 3D Organoid Technology for Preclinical Investigations: Towards Human In Vitro Models","authors":"Yingjuan Liu, Honglin Xu, S. Abraham, X. Wang, B. Keavney","doi":"10.53941/ijddp.v1i1.188","DOIUrl":"https://doi.org/10.53941/ijddp.v1i1.188","url":null,"abstract":"Review\u0000Progress of 3D Organoid Technology for Preclinical Investigations: Towards Human In Vitro Models\u0000\u0000Yingjuan Liu *, Honglin Xu, Sabu Abraham, Xin Wang, and Bernard D. Keavney*\u0000\u0000\u0000Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, M13 9PT, UK.\u0000* Correspondence: yingjuan.liu@manchester.ac.uk (Yingjuan Liu);\u0000bernard.keavney@manchester.ac.uk (Bernard D. Keavney)\u0000 \u0000 \u0000Received: 1 November 2022\u0000Accepted: 24 November 2022\u0000Published: 21 December 2022\u0000 \u0000\u0000Abstract: Currently, with an increased requirement for new therapeutic strategies, preclinical drug testing or screening platforms have rapidly evolved in recent years. In comparison to traditional 2D cell cultures, 3D organoids or spheroids with or without scaffolds improve the microenvironment of in vitro cultures, advancing the in vitro biological observation and enabling mechanistic studies of drug reactions in the human tissue-like environment. 3D organoids and spheroids are straightforward to produce, and relatively uniform in size and shape. This helps to facilitate high throughput screening requirements. Spheroids and organoids have been applied in anti-cancer drug testing, toxicity evaluations, as well as mechanism studies for variable organ systems, including the intestine, liver, pancreas, brain, and heart. Among 3D cultures of spheroids and organoids, ‘tumour spheroids’ formed by dissociated tumour tissues or cancer cell lines are relatively simple in composition and commonly applied to anticancer drug screening. The ‘healthy organoids’ differentiated from hiPSCs/hESCs are more complex in cell composition, distribution, structure and function with higher similarity to in vivo organs, and have found applications in toxicity tests, personalised medicine, and therapeutic and mechanistic studies. In most cases, the multicellular 3D organoids are more resistant and stable in reaction to stimulations or chemicals in vitro , suggesting more accurate modelling of in vivo responses. Here, we review recent progress in human-origin organoid/spheroid systems and their applications in preclinical studies.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83743757","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":"Advances of the Target-Based and Phenotypic Screenings and Strategies in Drug Discovery","authors":"Shou-bao Wang, Zihan Wang, Lianhua Fang, Yang Lv, G. Du","doi":"10.53941/ijddp.v1i1.199","DOIUrl":"https://doi.org/10.53941/ijddp.v1i1.199","url":null,"abstract":"Review\u0000Advances of the Target-Based and Phenotypic Screenings and Strategies in Drug Discovery\u0000\u0000Shoubao Wang 1,*, Zihan Wang1, Lianhua Fang1, Yang Lv2, and Guanhua Du1,*\u0000\u0000\u00001 Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.\u00002 Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.\u0000* Correspondence: shoubaowang@imm.ac.cn (Shoubao Wang); dugh@imm.ac.cn (Guanhua Du).\u0000 \u0000 \u0000Received: 8 November 2022\u0000Accepted: 15 November 2022\u0000Published: 21 December 2022\u0000 \u0000\u0000Abstract: Drug discovery and development is a complex and expensive process. There are two approaches, phenotypic and target-based approaches, each holding different advantages for screening novel drug candidates when pursuing successful marketing authorization. However, the attrition rates of drug candidates continue to increase. In this review, we discuss recent successes and ongoing advances in phenotypic screening and target-based screening for drug discovery. We also explore how strategic and technological innovations may fuel new approaches in drug discovery. There are two approaches in drug discovery.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82225834","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":"From Bench to Bedside: Current Developments in RNA-Based Therapies for Treatment of Hyperlipidemia","authors":"Yufei Zhou, Chen Chen","doi":"10.53941/ijddp.v1i1.141","DOIUrl":"https://doi.org/10.53941/ijddp.v1i1.141","url":null,"abstract":"Review\u0000From Bench to Bedside: Current Developments in RNA-Based Therapies for Treatment of Hyperlipidemia\u0000\u0000Yufei Zhou and Chen Chen *\u0000\u0000\u0000Division of Cardiology and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.\u0000* Correspondence: chenchen@tjh.tjmu.edu.cn; Tel. & Fax: 86-27-6937-8422.\u0000 \u0000 \u0000Received: 7 October 2022\u0000Accepted: 1 November 2022\u0000Published: 21 December 2022\u0000 \u0000\u0000Abstract: Hyperlipidemia is one of the conditions that constitute metabolic disorder and it is a common public health problem. The condition is characterized by increased levels of cholesterol, triglycerides and/or lipoproteins; it is a recognized as a risk factor for the onset of many diseases such as type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. Up to now, the primary drugs for treating hyperlipidemia are statins and monoclonal antibody drugs against proprotein convertase subtilisin/kexin type 9 (PCSK9). The main limitation of statins for long-term use is intolerable side effects. Evolocumab and Alirocumab, two monoclonal antibodies against PCSK9, can effectively decrease the level of low-density lipoprotein cholesterol (LDL-C) in patients with statin intolerance and familial hypercholesterolemia, while causing fewer side effects. However, due to its short half-life and high costs, these monoclonal antibody treatments might result in patients’ non-compliance with medication and considerable economic burden on patients. Given that RNA plays a key role in gene regulation, RNA-based therapeutics have become powerful blueprints for designing new anti-hyperlipidemia drugs. Here, we summarized RNA-based therapeutic strategies and the current clinical trials for RNA drugs in hyperlipidemia treatment.","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81076074","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 Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy.","authors":"Paulina Langa, Beata M Wolska, R John Solaro","doi":"10.53941/ijddp.v1i1.189","DOIUrl":"10.53941/ijddp.v1i1.189","url":null,"abstract":"<p><p>We focus here on the Hippo pathway in the hierarchical sensing and modulation of the mechanical state of the adult heart in health and disease. The Hippo pathway interrogates the micro-environment of cardiac myocytes providing surveillance of the mechanical state with engagement of signaling pathways critical to homeostasis of cardiac development, remodeling, and function and vulnerable to pathologies. Our discussion centers on Hippo signaling in the altered mechanical state instigated by variants of genes expressing mutant sarcomere proteins that trigger a progression to dilated cardiomyopathy (familial DCM). There is an unmet need for therapies in DCM. Recent progress in the discovery of small molecules that target Hippo signaling and are intended for use in cardiac disorders provides leads for modifying Hippo in DCM. As we emphasize, identifying useful targets in DCM requires in depth understanding of cell specific Hippo signaling in the cardiac micro-environment.</p>","PeriodicalId":94047,"journal":{"name":"International journal of drug discovery and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73878630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}