Pub Date : 2022-07-01DOI: 10.1124/pharmrev.121.000527
Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters, Vivian Hook
Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated CTSB gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the CTSB gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double CTSB and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that CTSB KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no CTSB KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that CTSB gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders. SIGNIFICANCE STATEMENT: This review provides a comprehensive compilation of the extensive data on the effects of deleting the cathepsin B (CTSB) gene in neurological and aging mouse models of brain disorders. Mice lacking the CTSB gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a drug target for discovery of CTSB inhibitors as potential therapeutics for treating numerous neurological diseases.
Cathepsin B(CTSB)是一种强大的溶酶体蛋白酶。本综述评估了 CTSB 基因敲除(KO)在改善神经系统疾病和衰老动物模型大脑功能障碍方面的效果。12项研究显示,删除CTSB基因可显著改善脑外伤、脑缺血、炎性疼痛、阿片耐受性、癫痫、衰老、转基因阿尔茨海默病(AD)和牙周炎AD模型的行为缺陷、神经病理学和/或生物标志物。一项研究发现,在多发性硬化症模型中,双 CTSB 和 cathepsin S KO 小鼠具有有益作用。在三项研究中,使用淀粉样前体蛋白(APP)模拟常见散发性 AD 的转基因 AD 模型显示,CTSB KO 可改善记忆、神经病理学和生物标志物;两项研究使用了代表罕见家族性 AD 的 APP,但未发现 CTSB KO 的效果;两项研究使用了高度工程化的 APP 构建,并报告称生物标志物略有增加。在临床研究中,所有报告都发现 CTSB 酶在多种神经系统疾病中上调,包括 AD,其中 CTSB 升高与认知功能障碍呈正相关。在多种神经系统动物模型中,CTSB 也是上调而非下调。此外,人类基因突变数据也提供了 CTSB 上调导致疾病的先例。因此,这些数据一致表明,通过阻断导致人类神经系统疾病表型的 CTSB 酶上调,CTSB 基因 KO 可改善大脑功能障碍并减少病理变化。总体研究结果为将 CTSB 作为合理的药物靶点以及将 CTSB 抑制剂作为治疗各种神经系统疾病的候选药物提供了有力支持。意义声明:这篇综述全面汇集了有关在神经和衰老小鼠脑部疾病模型中删除 cathepsin B (CTSB) 基因的影响的大量数据。缺失 CTSB 基因的小鼠神经行为缺陷得到改善,神经病理变化减少,神经元细胞死亡和炎症生物标志物得到改善。令人信服的 CTSB 证据的意义在于,这些数据的一致性验证了 CTSB 是一种药物靶点,可用于发现 CTSB 抑制剂,作为治疗多种神经系统疾病的潜在疗法。
{"title":"Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders.","authors":"Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters, Vivian Hook","doi":"10.1124/pharmrev.121.000527","DOIUrl":"10.1124/pharmrev.121.000527","url":null,"abstract":"<p><p>Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated <i>CTSB</i> gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the <i>CTSB</i> gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double <i>CTSB</i> and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that <i>CTSB</i> KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no <i>CTSB</i> KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that <i>CTSB</i> gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders. SIGNIFICANCE STATEMENT: This review provides a comprehensive compilation of the extensive data on the effects of deleting the cathepsin B (<i>CTSB</i>) gene in neurological and aging mouse models of brain disorders. Mice lacking the <i>CTSB</i> gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a drug target for discovery of CTSB inhibitors as potential therapeutics for treating numerous neurological diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553114/pdf/pharmrev.121.000527.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9217353","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}
A reliable translation of in vitro and preclinical data on drug absorption, distribution, metabolism, and excretion (ADME) to humans is important for safe and effective drug development. Precision medicine that is expected to provide the right clinical dose for the right patient at the right time requires a comprehensive understanding of population factors affecting drug disposition and response. Characterization of drug-metabolizing enzymes and transporters for the protein abundance and their interindividual as well as differential tissue and cross-species variabilities is important for translational ADME and precision medicine. This review first provides a brief overview of quantitative proteomics principles including liquid chromatography-tandem mass spectrometry tools, data acquisition approaches, proteomics sample preparation techniques, and quality controls for ensuring rigor and reproducibility in protein quantification data. Then, potential applications of quantitative proteomics in the translation of in vitro and preclinical data as well as prediction of interindividual variability are discussed in detail with tabulated examples. The applications of quantitative proteomics data in physiologically based pharmacokinetic modeling for ADME prediction are discussed with representative case examples. Finally, various considerations for reliable quantitative proteomics analysis for translational ADME and precision medicine and the future directions are discussed. SIGNIFICANCE STATEMENT: Quantitative proteomics analysis of drug-metabolizing enzymes and transporters in humans and preclinical species provides key physiological information that assists in the translation of in vitro and preclinical data to humans. This review provides the principles and applications of quantitative proteomics in characterizing in vitro, ex vivo, and preclinical models for translational research and interindividual variability prediction. Integration of these data into physiologically based pharmacokinetic modeling is proving to be critical for safe, effective, timely, and cost-effective drug development.
{"title":"Quantitative Proteomics in Translational Absorption, Distribution, Metabolism, and Excretion and Precision Medicine.","authors":"Deepak Ahire, Laken Kruger, Sheena Sharma, Vijaya Saradhi Mettu, Abdul Basit, Bhagwat Prasad","doi":"10.1124/pharmrev.121.000449","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000449","url":null,"abstract":"<p><p>A reliable translation of in vitro and preclinical data on drug absorption, distribution, metabolism, and excretion (ADME) to humans is important for safe and effective drug development. Precision medicine that is expected to provide the right clinical dose for the right patient at the right time requires a comprehensive understanding of population factors affecting drug disposition and response. Characterization of drug-metabolizing enzymes and transporters for the protein abundance and their interindividual as well as differential tissue and cross-species variabilities is important for translational ADME and precision medicine. This review first provides a brief overview of quantitative proteomics principles including liquid chromatography-tandem mass spectrometry tools, data acquisition approaches, proteomics sample preparation techniques, and quality controls for ensuring rigor and reproducibility in protein quantification data. Then, potential applications of quantitative proteomics in the translation of in vitro and preclinical data as well as prediction of interindividual variability are discussed in detail with tabulated examples. The applications of quantitative proteomics data in physiologically based pharmacokinetic modeling for ADME prediction are discussed with representative case examples. Finally, various considerations for reliable quantitative proteomics analysis for translational ADME and precision medicine and the future directions are discussed. SIGNIFICANCE STATEMENT: Quantitative proteomics analysis of drug-metabolizing enzymes and transporters in humans and preclinical species provides key physiological information that assists in the translation of in vitro and preclinical data to humans. This review provides the principles and applications of quantitative proteomics in characterizing in vitro, ex vivo, and preclinical models for translational research and interindividual variability prediction. Integration of these data into physiologically based pharmacokinetic modeling is proving to be critical for safe, effective, timely, and cost-effective drug development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553121/pdf/pharmrev.121.000449.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786781","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}
Pub Date : 2022-07-01DOI: 10.1124/pharmrev.121.000564
Zhengnan Yuan, Ladie Kimberly De La Cruz, Xiaoxiao Yang, Binghe Wang
Carbon monoxide (CO) has been firmly established as an endogenous signaling molecule with a variety of pathophysiological and pharmacological functions, including immunomodulation, organ protection, and circadian clock regulation, among many others. In terms of its molecular mechanism(s) of action, CO is known to bind to a large number of hemoproteins with at least 25 identified targets, including hemoglobin, myoglobin, neuroglobin, cytochrome c oxidase, cytochrome P450, soluble guanylyl cyclase, myeloperoxidase, and some ion channels with dissociation constant values spanning the range of sub-nM to high μM. Although CO's binding affinity with a large number of targets has been extensively studied and firmly established, there is a pressing need to incorporate such binding information into the analysis of CO's biologic response in the context of affinity and dosage. Especially important is to understand the reservoir role of hemoglobin in CO storage, transport, distribution, and transfer. We critically review the literature and inject a sense of quantitative assessment into our analyses of the various relationships among binding affinity, CO concentration, target occupancy level, and anticipated pharmacological actions. We hope that this review presents a picture of the overall landscape of CO's engagement with various targets, stimulates additional research, and helps to move the CO field in the direction of examining individual targets in the context of all of the targets and the concentration of available CO. We believe that such work will help the further understanding of the relationship of CO concentration and its pathophysiological functions and the eventual development of CO-based therapeutics. SIGNIFICANCE STATEMENT: The further development of carbon monoxide (CO) as a therapeutic agent will significantly rely on the understanding of CO's engagement with therapeutically relevant targets of varying affinity. This review critically examines the literature by quantitatively analyzing the intricate relationships among targets, target affinity for CO, CO level, and the affinity state of carboxyhemoglobin and provide a holistic approach to examining the molecular mechanism(s) of action for CO.
{"title":"Carbon Monoxide Signaling: Examining Its Engagement with Various Molecular Targets in the Context of Binding Affinity, Concentration, and Biologic Response.","authors":"Zhengnan Yuan, Ladie Kimberly De La Cruz, Xiaoxiao Yang, Binghe Wang","doi":"10.1124/pharmrev.121.000564","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000564","url":null,"abstract":"<p><p>Carbon monoxide (CO) has been firmly established as an endogenous signaling molecule with a variety of pathophysiological and pharmacological functions, including immunomodulation, organ protection, and circadian clock regulation, among many others. In terms of its molecular mechanism(s) of action, CO is known to bind to a large number of hemoproteins with at least 25 identified targets, including hemoglobin, myoglobin, neuroglobin, cytochrome c oxidase, cytochrome P450, soluble guanylyl cyclase, myeloperoxidase, and some ion channels with dissociation constant values spanning the range of sub-nM to high <i>μ</i>M. Although CO's binding affinity with a large number of targets has been extensively studied and firmly established, there is a pressing need to incorporate such binding information into the analysis of CO's biologic response in the context of affinity and dosage. Especially important is to understand the reservoir role of hemoglobin in CO storage, transport, distribution, and transfer. We critically review the literature and inject a sense of quantitative assessment into our analyses of the various relationships among binding affinity, CO concentration, target occupancy level, and anticipated pharmacological actions. We hope that this review presents a picture of the overall landscape of CO's engagement with various targets, stimulates additional research, and helps to move the CO field in the direction of examining individual targets in the context of all of the targets and the concentration of available CO. We believe that such work will help the further understanding of the relationship of CO concentration and its pathophysiological functions and the eventual development of CO-based therapeutics. SIGNIFICANCE STATEMENT: The further development of carbon monoxide (CO) as a therapeutic agent will significantly rely on the understanding of CO's engagement with therapeutically relevant targets of varying affinity. This review critically examines the literature by quantitatively analyzing the intricate relationships among targets, target affinity for CO, CO level, and the affinity state of carboxyhemoglobin and provide a holistic approach to examining the molecular mechanism(s) of action for CO.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553107/pdf/pharmrev.121.000564.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722272","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}
Pub Date : 2022-07-01DOI: 10.1124/pharmrev.121.000349
Luiz G N de Almeida, Hayley Thode, Yekta Eslambolchi, Sameeksha Chopra, Daniel Young, Sean Gill, Laurent Devel, Antoine Dufour
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
{"title":"Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology.","authors":"Luiz G N de Almeida, Hayley Thode, Yekta Eslambolchi, Sameeksha Chopra, Daniel Young, Sean Gill, Laurent Devel, Antoine Dufour","doi":"10.1124/pharmrev.121.000349","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000349","url":null,"abstract":"<p><p>The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40332540","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}
Pub Date : 2022-07-01DOI: 10.1124/pharmrev.121.000499
Yiming Jin, Shahab Edalatian Zakeri, Raman Bahal, Andrew J Wiemer
Drug conjugates, including antibody-drug conjugates, are a step toward realizing Paul Ehrlich's idea from over 100 years ago of a "magic bullet" for cancer treatment. Through balancing selective targeting molecules with highly potent payloads, drug conjugates can target specific tumor microenvironments and kill tumor cells. A drug conjugate consists of three parts: a targeting agent, a linker, and a payload. In some conjugates, monoclonal antibodies act as the targeting agent, but new strategies for targeting include antibody derivatives, peptides, and even small molecules. Linkers are responsible for connecting the payload to the targeting agent. Payloads impact vital cellular processes to kill tumor cells. At present, there are 12 antibody-drug conjugates on the market for different types of cancers. Research on drug conjugates is increasing year by year to solve problems encountered in conjugate design, such as tumor heterogeneity, poor circulation, low drug loading, low tumor uptake, and heterogenous expression of target antigens. This review highlights some important preclinical research on drug conjugates in recent years. We focus on three significant areas: improvement of antibody-drug conjugates, identification of new conjugate targets, and development of new types of drug conjugates, including nanotechnology. We close by highlighting the critical barriers to clinical translation and the open questions going forward. SIGNIFICANCE STATEMENT: The development of anticancer drug conjugates is now focused in three broad areas: improvements to existing antibody drug conjugates, identification of new targets, and development of new conjugate forms. This article focuses on the exciting preclinical studies in these three areas and advances in the technology that improves preclinical development.
{"title":"New Technologies Bloom Together for Bettering Cancer Drug Conjugates.","authors":"Yiming Jin, Shahab Edalatian Zakeri, Raman Bahal, Andrew J Wiemer","doi":"10.1124/pharmrev.121.000499","DOIUrl":"10.1124/pharmrev.121.000499","url":null,"abstract":"<p><p>Drug conjugates, including antibody-drug conjugates, are a step toward realizing Paul Ehrlich's idea from over 100 years ago of a \"magic bullet\" for cancer treatment. Through balancing selective targeting molecules with highly potent payloads, drug conjugates can target specific tumor microenvironments and kill tumor cells. A drug conjugate consists of three parts: a targeting agent, a linker, and a payload. In some conjugates, monoclonal antibodies act as the targeting agent, but new strategies for targeting include antibody derivatives, peptides, and even small molecules. Linkers are responsible for connecting the payload to the targeting agent. Payloads impact vital cellular processes to kill tumor cells. At present, there are 12 antibody-drug conjugates on the market for different types of cancers. Research on drug conjugates is increasing year by year to solve problems encountered in conjugate design, such as tumor heterogeneity, poor circulation, low drug loading, low tumor uptake, and heterogenous expression of target antigens. This review highlights some important preclinical research on drug conjugates in recent years. We focus on three significant areas: improvement of antibody-drug conjugates, identification of new conjugate targets, and development of new types of drug conjugates, including nanotechnology. We close by highlighting the critical barriers to clinical translation and the open questions going forward. SIGNIFICANCE STATEMENT: The development of anticancer drug conjugates is now focused in three broad areas: improvements to existing antibody drug conjugates, identification of new targets, and development of new conjugate forms. This article focuses on the exciting preclinical studies in these three areas and advances in the technology that improves preclinical development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cf/24/pharmrev.121.000499.PMC9553120.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786759","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}
Pub Date : 2022-06-16DOI: 10.1124/pharmrev.121.000408
M. Dambrova, M. Makrecka-Kuka, J. Kuka, R. Vilskersts, Didi O. T. Nordberg, M. Attwood, S. Smesny, Z. Sen, Anchi Guo, Eponine Oler, Siyang Tian, Jiamin Zheng, D. Wishart, E. Liepinsh, H. Schiöth
Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal β-oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. Significance Statement This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.
{"title":"Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials","authors":"M. Dambrova, M. Makrecka-Kuka, J. Kuka, R. Vilskersts, Didi O. T. Nordberg, M. Attwood, S. Smesny, Z. Sen, Anchi Guo, Eponine Oler, Siyang Tian, Jiamin Zheng, D. Wishart, E. Liepinsh, H. Schiöth","doi":"10.1124/pharmrev.121.000408","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000408","url":null,"abstract":"Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal β-oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. Significance Statement This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48006213","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}
Pub Date : 2022-06-16DOI: 10.1124/pharmrev.121.000540
D. Luessen, P. Conn
Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders. Significance Statement Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.
{"title":"Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease","authors":"D. Luessen, P. Conn","doi":"10.1124/pharmrev.121.000540","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000540","url":null,"abstract":"Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders. Significance Statement Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43333612","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}
Pub Date : 2022-04-01DOI: 10.1124/pharmrev.120.000256
Eléonore Beurel, Eva M Medina-Rodriguez, Richard S Jope
There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, "immunosuppressed" T cells, and alterations in the relative abundance of T cell subtypes. T helper (Th) cells have the capacity to differentiate to various lineages depending on the cytokine environment, antigen stimulation, and costimulation. Regulatory T cells are decreased, and the Th1/Th2 ratio and the Th17 cells are increased in patients with depression. Evidence for changes in each Th lineage has been reported to some extent in patients with depression. However, the evidence is strongest for the association of depression with changes in Th17 cells. Th17 cells produce the inflammatory cytokine interleukin (IL)-17A, and the discovery of Th17 cell involvement in depression evolved from the well established link that IL-6, which is required for Th17 cell differentiation, contributes to the onset, and possibly maintenance, of depression. One intriguing action of Th17 cells is their participation in the gut-brain axis to mediate stress responses. Although the mechanisms of action of Th17 cells in depression remain unclear, neutralization of IL-17A by anti-IL-17A antibodies, blocking stress-induced production, or release of gut Th17 cells represent feasible therapeutic approaches and might provide a new avenue to improve depression symptoms. SIGNIFICANCE STATEMENT: Th17 cells appear as a promising therapeutic target for depression, for which efficacious therapeutic options are limited. The use of neutralizing antibodies targeting Th17 cells has provided encouraging results in depressed patients with comorbid autoimmune diseases.
目前有 11% 的美国人患有抑郁症,我们亟需了解导致抑郁症易感性的机制,以改进治疗方法。由 T 细胞和 B 细胞组成的适应性免疫系统已成为抑郁症的潜在诱因,这一点已在淋巴细胞小鼠中得到证实。总体而言,抑郁症患者的循环 T 细胞和调节性 B 细胞减少,T 细胞受到 "免疫抑制",T 细胞亚型的相对丰度也发生了变化。T 辅助(Th)细胞有能力根据细胞因子环境、抗原刺激和成本刺激分化成不同的系。抑郁症患者的调节性 T 细胞减少,Th1/Th2 比率和 Th17 细胞增加。有证据表明,抑郁症患者的 Th 系发生了一定程度的变化。然而,最有力的证据是抑郁症与 Th17 细胞的变化有关。Th17 细胞会产生炎性细胞因子白细胞介素(IL)-17A,Th17 细胞参与抑郁症的发现源于一种公认的联系,即 Th17 细胞分化所需的 IL-6 会导致抑郁症的发生,甚至可能维持抑郁症。Th17 细胞的一个引人入胜的作用是参与肠道-大脑轴介导应激反应。尽管 Th17 细胞在抑郁症中的作用机制仍不清楚,但通过抗 IL-17A 抗体中和 IL-17A、阻断压力诱导的产生或释放肠道 Th17 细胞是可行的治疗方法,并可能为改善抑郁症状提供一条新途径。意义声明:Th17细胞似乎是治疗抑郁症的一个很有前景的靶点,但对抑郁症的有效治疗方案却很有限。使用针对 Th17 细胞的中和抗体治疗合并自身免疫性疾病的抑郁症患者取得了令人鼓舞的效果。
{"title":"Targeting the Adaptive Immune System in Depression: Focus on T Helper 17 Cells.","authors":"Eléonore Beurel, Eva M Medina-Rodriguez, Richard S Jope","doi":"10.1124/pharmrev.120.000256","DOIUrl":"10.1124/pharmrev.120.000256","url":null,"abstract":"<p><p>There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, \"immunosuppressed\" T cells, and alterations in the relative abundance of T cell subtypes. T helper (Th) cells have the capacity to differentiate to various lineages depending on the cytokine environment, antigen stimulation, and costimulation. Regulatory T cells are decreased, and the Th1/Th2 ratio and the Th17 cells are increased in patients with depression. Evidence for changes in each Th lineage has been reported to some extent in patients with depression. However, the evidence is strongest for the association of depression with changes in Th17 cells. Th17 cells produce the inflammatory cytokine interleukin (IL)-17A, and the discovery of Th17 cell involvement in depression evolved from the well established link that IL-6, which is required for Th17 cell differentiation, contributes to the onset, and possibly maintenance, of depression. One intriguing action of Th17 cells is their participation in the gut-brain axis to mediate stress responses. Although the mechanisms of action of Th17 cells in depression remain unclear, neutralization of IL-17A by anti-IL-17A antibodies, blocking stress-induced production, or release of gut Th17 cells represent feasible therapeutic approaches and might provide a new avenue to improve depression symptoms. SIGNIFICANCE STATEMENT: Th17 cells appear as a promising therapeutic target for depression, for which efficacious therapeutic options are limited. The use of neutralizing antibodies targeting Th17 cells has provided encouraging results in depressed patients with comorbid autoimmune diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973514/pdf/pharmrev.120.000256.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9596052","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}
Pub Date : 2022-04-01DOI: 10.1124/pharmrev.121.000445
Adriaan P IJzerman, Kenneth A Jacobson, Christa E Müller, Bruce N Cronstein, Rodrigo A Cunha
Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. SIGNIFICANCE STATEMENT: Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists ("biased" or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A2A- and A2BAR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A2AAR antagonist (istradefylline) has been approved as an anti-Parkinson agent.
国际基础与临床药理学联合会(International Union of Basic and Clinical Pharmacology)上一份关于腺苷受体命名与分类的报告(2011 年)包含了有关这一 G 蛋白偶联受体亚家族的一系列新进展,包括蛋白质结构、蛋白质寡聚化、蛋白质多样性以及小分子的异位调节。从那时起,大量新数据和新成果不断涌现,让我们得以探索腺苷受体的目标结合动力学和偏倚信号传导等新概念,研究多种受体结构和新型配体,评估新药理学,并对腺苷受体配体的临床试验进行评估。因此,本综述应被视为 2001 年和 2011 年报告的进一步更新。意义声明:腺苷受体(ARs)是未来治疗慢性和急性疾病(包括炎症性疾病、神经退行性疾病和癌症)的持续关注点。目前,由于腺苷受体结构生物学的巨大进步,腺苷受体激动剂(无论是否 "偏向")和拮抗剂的设计主要基于结构。A2A- 和 A2BAR 似乎可以调节肿瘤生物学中的免疫反应。许多针对这一适应症的临床试验正在进行中,而一种 A2AAR 拮抗剂(istradefylline)已被批准作为抗帕金森病药物。
{"title":"International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update.","authors":"Adriaan P IJzerman, Kenneth A Jacobson, Christa E Müller, Bruce N Cronstein, Rodrigo A Cunha","doi":"10.1124/pharmrev.121.000445","DOIUrl":"10.1124/pharmrev.121.000445","url":null,"abstract":"<p><p>Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. SIGNIFICANCE STATEMENT: Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists (\"biased\" or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A<sub>2A</sub>- and A<sub>2B</sub>AR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A<sub>2A</sub>AR antagonist (istradefylline) has been approved as an anti-Parkinson agent.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908723","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}
Pub Date : 2022-03-17DOI: 10.1124/pharmrev.121.000418
Idoia Gallego, Ilia Villate-Beitia, L. Saenz-del-Burgo, G. Puras, J. Pedraz
Central nervous system (CNS) diseases, especially acute ischemic events and neurodegenerative disorders, constitute a public health problem with no effective treatments to allow a persistent solution. Failed therapies targeting neuronal recovery have revealed the multifactorial and intricate pathophysiology underlying such CNS disorders as ischemic stroke, Alzheimeŕs disease, amyotrophic lateral sclerosis, vascular Parkisonism, vascular dementia, and aging, in which cerebral microvasculature impairment seems to play a key role. In fact, a reduction in vessel density and cerebral blood flow occurs in these scenarios, contributing to neuronal dysfunction and leading to loss of cognitive function. In this review, we provide an overview of healthy brain microvasculature structure and function in health and the effect of the aforementioned cerebral CNS diseases. We discuss the emerging new therapeutic opportunities, and their delivery approaches, aimed at recovering brain vascularization in this context. Significance Statement The lack of effective treatments, mainly focused on neuron recovery, has prompted the search of other therapies to treat cerebral central nervous system diseases. The disruption and degeneration of cerebral microvasculature has been evidenced in neurodegenerative diseases, stroke, and aging, constituting a potential target for restoring vascularization, neuronal functioning, and cognitive capacities by the development of therapeutic pro-angiogenic strategies.
{"title":"Therapeutic Opportunities and Delivery Strategies for Brain Revascularization in Stroke, Neurodegeneration, and Aging","authors":"Idoia Gallego, Ilia Villate-Beitia, L. Saenz-del-Burgo, G. Puras, J. Pedraz","doi":"10.1124/pharmrev.121.000418","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000418","url":null,"abstract":"Central nervous system (CNS) diseases, especially acute ischemic events and neurodegenerative disorders, constitute a public health problem with no effective treatments to allow a persistent solution. Failed therapies targeting neuronal recovery have revealed the multifactorial and intricate pathophysiology underlying such CNS disorders as ischemic stroke, Alzheimeŕs disease, amyotrophic lateral sclerosis, vascular Parkisonism, vascular dementia, and aging, in which cerebral microvasculature impairment seems to play a key role. In fact, a reduction in vessel density and cerebral blood flow occurs in these scenarios, contributing to neuronal dysfunction and leading to loss of cognitive function. In this review, we provide an overview of healthy brain microvasculature structure and function in health and the effect of the aforementioned cerebral CNS diseases. We discuss the emerging new therapeutic opportunities, and their delivery approaches, aimed at recovering brain vascularization in this context. Significance Statement The lack of effective treatments, mainly focused on neuron recovery, has prompted the search of other therapies to treat cerebral central nervous system diseases. The disruption and degeneration of cerebral microvasculature has been evidenced in neurodegenerative diseases, stroke, and aging, constituting a potential target for restoring vascularization, neuronal functioning, and cognitive capacities by the development of therapeutic pro-angiogenic strategies.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46366496","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}