Current Protocols in Pharmacology最新文献_第3页

Cerebral Open Flow Microperfusion to Monitor Drug Transport Across the Blood-Brain Barrier 脑开放血流微灌注监测药物通过血脑屏障的转运

Current Protocols in Pharmacology Pub Date : 2019-05-30 DOI: 10.1002/cpph.60

Joanna Hummer, Thomas Altendorfer-Kroath, Thomas Birngruber

引用次数: 7

Investigating the Mitochondrial Permeability Transition Pore in Disease Phenotypes and Drug Screening 线粒体通透性过渡孔在疾病表型和药物筛选中的研究

Current Protocols in Pharmacology Pub Date : 2019-05-13 DOI: 10.1002/cpph.59

Gauri Bhosale, Michael R. Duchen

{"title":"Investigating the Mitochondrial Permeability Transition Pore in Disease Phenotypes and Drug Screening","authors":"Gauri Bhosale, Michael R. Duchen","doi":"10.1002/cpph.59","DOIUrl":"10.1002/cpph.59","url":null,"abstract":"Mitochondria act as ‘sinks’ for Ca2+ signaling, with mitochondrial Ca2+ uptake linking physiological stimuli to increased ATP production. However, mitochondrial Ca2+ overload can induce a cellular catastrophe by opening of the mitochondrial permeability transition pore (mPTP). This pore is a large conductance pathway in the inner mitochondrial membrane that causes bioenergetic collapse and appears to represent a final common path to cell death in many diseases. The role of the mPTP as a determinant of disease outcome is best established in ischemia/reperfusion injury in the heart, brain, and kidney, and it is also implicated in neurodegenerative disorders and muscular dystrophies. As the probability of pore opening can be modulated by drugs, it represents a useful pharmacological target for translational research in drug discovery. Described in this unit is a protocol utilizing isolated mitochondria to quantify this phenomenon and to develop a high-throughput platform for phenotypic screens for Ca2+ dyshomeostasis. © 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.59","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37236872","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}

引用次数: 12

Determination of Dermal Pharmacokinetics by Microdialysis Sampling in Rats 微透析取样法测定大鼠皮肤药代动力学

Current Protocols in Pharmacology Pub Date : 2019-04-26 DOI: 10.1002/cpph.58

Nivea M. F. Voelkner, Alexander Voelkner, Hartmut Derendorf

引用次数: 4

Evaluation of Compound Activity in Primary Human Intestinal Organoids Using Gene Expression and Histology 用基因表达和组织学评价化合物在原代人肠道类器官中的活性

Current Protocols in Pharmacology Pub Date : 2019-03-28 DOI: 10.1002/cpph.54

Ronald Marchelletta, Jingxue Yu, Clara Moon, Mihee M. Kim

{"title":"Evaluation of Compound Activity in Primary Human Intestinal Organoids Using Gene Expression and Histology","authors":"Ronald Marchelletta, Jingxue Yu, Clara Moon, Mihee M. Kim","doi":"10.1002/cpph.54","DOIUrl":"10.1002/cpph.54","url":null,"abstract":"Human intestinal organoids have enabled performance of functional epithelial studies and modeling of human diseases of the intestine. This unit describes 1) a method to isolate and culture crypts from human intestinal tissue, 2) use of combinatorial methods to expand stem cell–enriched spheroids and differentiate them into organoids composed of various intestinal epithelial cell types, and 3) methods to stimulate these organoids with and measure their responsiveness to external stimuli. To validate the differentiation, organoids can be stained to qualitatively evaluate the presence of colonic crypt morphology and specialized epithelial cell markers. These organoids are responsive to challenge with tumor necrosis factor α (TNFα), resulting in cytokine-induced apoptosis. TNFα-driven apoptosis can be blocked by a small-molecule inhibitor of Ire1α (4μ8C), an endoplasmic-reticulum stress sensor. This is one example of how the human intestinal organoid model can be a powerful tool to elucidate important biological pathways involved in human disease in intestinal epithelial cells. © 2019 by John Wiley & Sons, Inc.","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.54","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37273083","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}

引用次数: 1

Translational Use of a Standardized Full Human Skin Organ Culture Model in Autoimmune Blistering Diseases 标准化全人体皮肤器官培养模型在自身免疫性水疱疾病中的转化应用

Current Protocols in Pharmacology Pub Date : 2019-03-08 DOI: 10.1002/cpph.56

Imke A. K. Burmester, Shirin Emtenani, Jan-Gerrit Johns, Ralf J. Ludwig, Christoph M. Hammers, Jennifer E. Hundt

引用次数: 11

Issue Information TOC 发布信息TOC

Current Protocols in Pharmacology Pub Date : 2019-03-05 DOI: 10.1002/cpph.50

引用次数: 0

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity 阿尔茨海默病的临床前模型:相关性和转化有效性

Current Protocols in Pharmacology Pub Date : 2019-02-25 DOI: 10.1002/cpph.57

Kevin Mullane, Michael Williams

{"title":"Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity","authors":"Kevin Mullane, Michael Williams","doi":"10.1002/cpph.57","DOIUrl":"10.1002/cpph.57","url":null,"abstract":"The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40-year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease-associated mechanisms. This indicates that the preclinical data generated from current AD targets to support the selection, optimization, and translation of new chemical entities (NCEs) and biologics to clinical trials is seriously compromised. While many of these failures reflect flawed hypotheses or a lack of adequate characterization of the preclinical pharmacodynamic and pharmacokinetic (PD/PK) properties of lead NCEs—including their bioavailability and toxicity—the conceptualization, validation, and interrogation of the current animal models of AD represent key limitations. The overwhelming majority of these AD models are transgenic, based on aspects of the amyloid hypothesis and the genetics of the familial form of the disease. As a result, these generally lack construct and predictive validity for the sporadic form of the human disease. The 170 or so transgenic models, perhaps the largest number ever focused on a single disease, use rodents, mainly mice, and in addition to amyloid also address aspects of tau causality with more complex multigene models including other presumed causative factors together with amyloid. This overview discusses the current animal models of AD in the context of both the controversies surrounding the causative role of amyloid in the disease and the need to develop validated models of cognitive function/dysfunction that more appropriately reflect the phenotype(s) of human aged-related dementias. © 2019 by John Wiley & Sons, Inc.","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"84 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.57","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36997173","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}

引用次数: 89

Drug Discovery for Pemphigoid Diseases 类天疱疮疾病的药物发现

Current Protocols in Pharmacology Pub Date : 2019-02-20 DOI: 10.1002/cpph.55

Anika Kasprick, Katja Bieber, Ralf J. Ludwig

{"title":"Drug Discovery for Pemphigoid Diseases","authors":"Anika Kasprick, Katja Bieber, Ralf J. Ludwig","doi":"10.1002/cpph.55","DOIUrl":"10.1002/cpph.55","url":null,"abstract":"Pemphigoid diseases (PDs) are a group of autoimmune bullous diseases characterized and caused by autoantibodies targeting structural proteins of the skin and mucous membranes. Chronic inflammation, subepidermal blistering, and often scaring are the clinical characteristics of PDs. Itching and, in severe cases, disabilities resulting from scaring (i.e., blindness, esophageal strictures) are the leading subjective symptoms. Treatment of PDs, which is based on nonspecific immunosuppression, is challenging because of frequent relapses, lack of efficacy, and numerous adverse events. In addition, the incidence of PDs is increasing. Given the high morbidity, limited therapeutic options, and increasing incidence, there is a growing urgency for drug discovery to help treat this condition. The recent development of PD model systems has added to the understanding of PD pathogenesis and, based on these insights, new clinical trials will soon be launched. The (auto-)antibody transfer PD models allow for investigations into autoantibody-mediated tissue pathology, while immunization-induced PD models more closely resemble the clinical situation. The latter duplicate all aspects of the human disease and are useful for investigating PD pathogenesis and testing therapeutic interventions. This article describes antibody transfer and immunization-induced PD mouse models currently employed for translational PD research. © 2019 by John Wiley & Sons, Inc.","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"84 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.55","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36983029","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}

引用次数: 23

Murine Models of Pancreatitis Leading to the Development of Pancreatic Cancer. 小鼠胰腺炎模型导致胰腺癌的发展。

Current Protocols in Pharmacology Pub Date : 2018-12-01 Epub Date: 2018-10-16 DOI: 10.1002/cpph.48

Ana S Leal, Karen T Liby

{"title":"Murine Models of Pancreatitis Leading to the Development of Pancreatic Cancer.","authors":"Ana S Leal, Karen T Liby","doi":"10.1002/cpph.48","DOIUrl":"https://doi.org/10.1002/cpph.48","url":null,"abstract":"Chronic or repeated episodes of acute pancreatic inflammation, or pancreatitis, are risk factors for the development of pancreatic cancer. Pancreatic cancer is characterized by a strong fibro-inflammatory tumor microenvironment. In pancreatitis, the same fibro-inflammatory reaction is observed concurrently with a loss of normal pancreatic cells. Mouse models are commonly employed to study the progression of pancreatitis and pancreatic cancer, with genetic and pharmacological tools used to elucidate cellular and acellular interactions within pancreatic tumors. Described in this article is a protocol for using KrasG12D ; Pdx1-Cre (KC) mice stimulated with caerulein, a small oligopeptide that increases secretion of digestive enzymes, as a model for pancreatitis. KRAS is mutated in 90-95% of the tumors in patients with pancreatic cancer. The combination of this mutation with an inflammatory stimulus accelerates the development of pancreatic cancer. The protocol detailed in this report follows the progression of disease in KC mice from pancreatic intraepithelial neoplasias to invasive pancreatic adenocarcinoma. © 2018 by John Wiley & Sons, Inc.","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"83 1","pages":"e48"},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.48","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36633492","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}

引用次数: 6

The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents. Irwin试验和功能观察电池(FOB)用于评估化合物对啮齿动物行为、生理和安全药理学的影响。

Current Protocols in Pharmacology Pub Date : 2018-12-01 Epub Date: 2018-09-04 DOI: 10.1002/cpph.43

Joanne R Mathiasen, Virginia C Moser

引用次数: 37