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CaMKII as a Therapeutic Target in Cardiovascular Disease. 作为心血管疾病治疗靶点的 CaMKII。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2023-01-20 Epub Date: 2022-08-16 DOI: 10.1146/annurev-pharmtox-051421-111814
Oscar E Reyes Gaido, Lubika J Nkashama, Kate L Schole, Qinchuan Wang, Priya Umapathi, Olurotimi O Mesubi, Klitos Konstantinidis, Elizabeth D Luczak, Mark E Anderson
{"title":"CaMKII as a Therapeutic Target in Cardiovascular Disease.","authors":"Oscar E Reyes Gaido, Lubika J Nkashama, Kate L Schole, Qinchuan Wang, Priya Umapathi, Olurotimi O Mesubi, Klitos Konstantinidis, Elizabeth D Luczak, Mark E Anderson","doi":"10.1146/annurev-pharmtox-051421-111814","DOIUrl":"10.1146/annurev-pharmtox-051421-111814","url":null,"abstract":"<p><p>CaMKII (the multifunctional Ca<sup>2+</sup> and calmodulin-dependent protein kinase II) is a highly validated signal for promoting a variety of common diseases, particularly in the cardiovascular system. Despite substantial amounts of convincing preclinical data, CaMKII inhibitors have yet to emerge in clinical practice. Therapeutic inhibition is challenged by the diversity of CaMKII isoforms and splice variants and by physiological CaMKII activity that contributes to learning and memory. Thus, uncoupling the harmful and beneficial aspects of CaMKII will be paramount to developing effective therapies. In the last decade, several targeting strategies have emerged, including small molecules, peptides, and nucleotides, which hold promise in discriminating pathological from physiological CaMKII activity. Here we review the cellular and molecular biology of CaMKII, discuss its role in physiological and pathological signaling, and consider new findings and approaches for developing CaMKII therapeutics.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"63 ","pages":"249-272"},"PeriodicalIF":12.5,"publicationDate":"2023-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9120748","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
Neuropathic Pain: Mechanisms, Sex Differences, and Potential Therapies for a Global Problem. 神经性疼痛：机理、性别差异和解决全球性问题的潜在疗法。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2023-01-20 DOI: 10.1146/annurev-pharmtox-051421-112259
Shahrzad Ghazisaeidi, Milind M Muley, Michael W Salter
{"title":"Neuropathic Pain: Mechanisms, Sex Differences, and Potential Therapies for a Global Problem.","authors":"Shahrzad Ghazisaeidi, Milind M Muley, Michael W Salter","doi":"10.1146/annurev-pharmtox-051421-112259","DOIUrl":"10.1146/annurev-pharmtox-051421-112259","url":null,"abstract":"<p><p>The study of chronic pain continues to generate ever-increasing numbers of publications, but safe and efficacious treatments for chronic pain remain elusive. Recognition of sex-specific mechanisms underlying chronic pain has resulted in a surge of studies that include both sexes. A predominant focus has been on identifying sex differences, yet many newly identified cellular mechanisms and alterations in gene expression are conserved between the sexes. Here we review sex differences and similarities in cellular and molecular signals that drive the generation and resolution of neuropathic pain. The mix of differences and similarities reflects degeneracy in peripheral and central signaling processes by which neurons, immune cells, and glia codependently drive pain hypersensitivity. Recent findings identifying critical signaling nodes foreshadow the development of rationally designed, broadly applicable analgesic strategies. However, the paucity of effective, safe pain treatments compels targeted therapies as well to increase therapeutic options that help reduce the global burden of suffering.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"63 ","pages":"565-583"},"PeriodicalIF":12.5,"publicationDate":"2023-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9126126","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: 20
KCNQ Potassium Channels as Targets of Botanical Folk Medicines. 作为民间植物药靶点的 KCNQ 钾通道
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2022-01-06 Epub Date: 2021-09-13 DOI: 10.1146/annurev-pharmtox-052120-104249
Kaitlyn E Redford, Geoffrey W Abbott
{"title":"KCNQ Potassium Channels as Targets of Botanical Folk Medicines.","authors":"Kaitlyn E Redford, Geoffrey W Abbott","doi":"10.1146/annurev-pharmtox-052120-104249","DOIUrl":"10.1146/annurev-pharmtox-052120-104249","url":null,"abstract":"<p><p>Since prehistory, human species have depended on plants for both food and medicine. Even in countries with ready access to modern medicines, alternative treatments are still highly regarded and commonly used. Unlike modern pharmaceuticals, many botanical medicines are in widespread use despite a lack of safety and efficacy data derived from controlled clinical trials and often unclear mechanisms of action. Contributing to this are the complex and undefined composition and likely multifactorial mechanisms of action and multiple targets of many botanical medicines. Here, we review the newfound importance of the ubiquitous KCNQ subfamily of voltage-gated potassium channels as targets for botanical medicines, including basil, capers, cilantro, lavender, fennel, chamomile, ginger, and <i>Camellia</i>, <i>Sophora</i>, and <i>Mallotus</i> species. We discuss the implications for the traditional use of these plants for disorders such as seizures, hypertension, and diabetes and the molecular mechanisms of plant secondary metabolite effects on KCNQ channels.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"62 ","pages":"447-464"},"PeriodicalIF":11.2,"publicationDate":"2022-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809153/pdf/nihms-1857008.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10491528","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
Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes? 中枢神经系统对葡萄糖稳态的控制：2 型糖尿病的治疗目标？
IF 11.2 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2022-01-06 DOI: 10.1146/annurev-pharmtox-052220-010446
Zaman Mirzadeh, Chelsea L Faber, Michael W Schwartz
{"title":"Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?","authors":"Zaman Mirzadeh, Chelsea L Faber, Michael W Schwartz","doi":"10.1146/annurev-pharmtox-052220-010446","DOIUrl":"10.1146/annurev-pharmtox-052220-010446","url":null,"abstract":"<p><p>Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"62 ","pages":"55-84"},"PeriodicalIF":11.2,"publicationDate":"2022-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8900291/pdf/nihms-1781368.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9463880","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
Pharmacology of TRPC Channels and Its Potential in Cardiovascular and Metabolic Medicine. TRPC通道的药理作用及其在心血管和代谢医学中的潜力。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2022-01-06 DOI: 10.1146/annurev-pharmtox-030121-122314
Robin S Bon, David J Wright, David J Beech, Piruthivi Sukumar
{"title":"Pharmacology of TRPC Channels and Its Potential in Cardiovascular and Metabolic Medicine.","authors":"Robin S Bon,&nbsp;David J Wright,&nbsp;David J Beech,&nbsp;Piruthivi Sukumar","doi":"10.1146/annurev-pharmtox-030121-122314","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-030121-122314","url":null,"abstract":"<p><p>Transient receptor potential canonical (TRPC) proteins assemble to form homo- or heterotetrameric, nonselective cation channels permeable to K<sup>+</sup>, Na<sup>+</sup>, and Ca<sup>2+</sup>. TRPC channels are thought to act as complex integrators of physical and chemical environmental stimuli. Although the understanding of essential physiological roles of TRPC channels is incomplete, their implication in various pathological mechanisms and conditions of the nervous system, kidneys, and cardiovascular system in combination with the lack of major adverse effects of TRPC knockout or TRPC channel inhibition is driving the search of TRPC channel modulators as potential therapeutics. Here, we review the most promising small-molecule TRPC channel modulators, the understanding of their mode of action, and their potential in the study and treatment of cardiovascular and metabolic disease.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"62 ","pages":"427-446"},"PeriodicalIF":12.5,"publicationDate":"2022-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9161015","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: 10
Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders. 唐氏综合症的产前和产后药物治疗:预防或改善神经发育和神经退行性疾病的研究。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2022-01-06 DOI: 10.1146/annurev-pharmtox-041521-103641
Renata Bartesaghi, Stefano Vicari, William C Mobley
{"title":"Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders.","authors":"Renata Bartesaghi,&nbsp;Stefano Vicari,&nbsp;William C Mobley","doi":"10.1146/annurev-pharmtox-041521-103641","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-041521-103641","url":null,"abstract":"<p><p>Those with Down syndrome (DS)-trisomy for chromosome 21-are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"62 ","pages":"211-233"},"PeriodicalIF":12.5,"publicationDate":"2022-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9632639/pdf/nihms-1845638.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10841686","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: 4
Synthetic Retinoids Beyond Cancer Therapy. 合成类维生素a超越癌症治疗。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2022-01-06 DOI: 10.1146/annurev-pharmtox-052120-104428
Lorraine J Gudas
{"title":"Synthetic Retinoids Beyond Cancer Therapy.","authors":"Lorraine J Gudas","doi":"10.1146/annurev-pharmtox-052120-104428","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-052120-104428","url":null,"abstract":"<p><p>While the uses of retinoids for cancer treatment continue to evolve, this review focuses on other therapeutic areas in which retinoids [retinol (vitamin A), all-<i>trans</i> retinoic acid (RA), and synthetic retinoic acid receptor (RAR)α-, β-, and γ-selective agonists] are being used and on promising new research that suggests additional uses for retinoids for the treatment of disorders of the kidneys, skeletal muscles, heart, pancreas, liver, nervous system, skin, and other organs. The most mature area, in terms of US Food and Drug Administration-approved, RAR-selective agonists, is for treatment of various skin diseases. Synthetic retinoid agonists have major advantages over endogenous RAR agonists such as RA. Because they act through a specific RAR, side effects may be minimized, and synthetic retinoids often have better pharmaceutical properties than does RA. Based on our increasing knowledge of the multiple roles of retinoids in development, epigenetic regulation, and tissue repair, other exciting therapeutic areas are emerging.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"62 ","pages":"155-175"},"PeriodicalIF":12.5,"publicationDate":"2022-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10264058/pdf/nihms-1904578.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9978007","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: 7
Epigenetic Neuropharmacology: Drugs Affecting the Epigenome in the Brain. 表观遗传神经药理学:影响大脑表观基因组的药物。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2021-01-06 DOI: 10.1146/annurev-pharmtox-030220-022920
Miklos Toth
{"title":"Epigenetic Neuropharmacology: Drugs Affecting the Epigenome in the Brain.","authors":"Miklos Toth","doi":"10.1146/annurev-pharmtox-030220-022920","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-030220-022920","url":null,"abstract":"<p><p>This review explores how different classes of drugs, including those with therapeutic and abuse potential, alter brain functions and behavior via the epigenome. Epigenetics, in its simplest interpretation, is the study of the regulation of a genes' transcriptional potential. The epigenome is established during development but is malleable throughout life by a wide variety of drugs, with both clinical utility and abuse potential. An epigenetic effect can be central to the drug's therapeutic or abuse potential, or it can be independent from the main effect but nevertheless produce beneficial or adverse side effects. Here, I discuss the various epigenetic effects of main pharmacological drug classes, including antidepressants, antiepileptics, and drugs of abuse.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"61 ","pages":"181-201"},"PeriodicalIF":12.5,"publicationDate":"2021-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-pharmtox-030220-022920","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9242962","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: 8
Inhibin. 抑制素。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2020-02-07 DOI: 10.32388/5bw2ar
C. Li, K. Ramasharma
{"title":"Inhibin.","authors":"C. Li, K. Ramasharma","doi":"10.32388/5bw2ar","DOIUrl":"https://doi.org/10.32388/5bw2ar","url":null,"abstract":"Inhibin is a glycoprotein which specifically inhibits FSH secretion. In follicular fluid, several forms of inhibin have been identified with mol. wts between 120 and 32 kd. The smallest active form is a glycosylated 32-kd protein with an 18-kd A chain and a 13-kd B chain. The secretion of inhibin by granulosa cells of the follicle is stimulated by FSH and testosterone, but not LH, and treatment of women with clomiphene and HMG/FSH results in an increase in the plasma concentration of inhibin. However, during the follicular phase of the normal menstrual cycle, FSH is inhibited mainly by oestradiol and inhibin levels remain constant or decline in parallel with those of FSH. It is probable that inhibin and oestradiol act together to cause the suppression of FSH. During the luteal phase, the human corpus luteum under the influence of LH secretes inhibin as well as oestradiol and progesterone. This combined negative feedback signal from the corpus luteum accounts for the suppression of FSH release and thus the failure of follicular growth during the luteal phase.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"58 10","pages":"1-21"},"PeriodicalIF":12.5,"publicationDate":"2020-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41271901","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 Pharmacology at the Single-Molecule Level. 单分子水平的G蛋白偶联受体药理学。
IF 12.5 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2020-01-08 DOI: 10.1146/annurev-pharmtox-010919-023348
D. Calebiro, J. Grimes
{"title":"G Protein-Coupled Receptor Pharmacology at the Single-Molecule Level.","authors":"D. Calebiro, J. Grimes","doi":"10.1146/annurev-pharmtox-010919-023348","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-010919-023348","url":null,"abstract":"G protein-coupled receptors (GPCRs) mediate the effects of numerous hormones and neurotransmitters and are major pharmacological targets. Classical studies with crude cell lysates or membrane preparations have identified the main biochemical steps involved in GPCR signaling. Moreover, recent studies on purified proteins have provided astounding details at the atomic level of the 3-D structures of receptors in multiple conformations, including in complex with G proteins and β-arrestins. However, several fundamental questions remain regarding the highly specific effects and rapid nature of GPCR signaling. Recent developments in single-molecule microscopy are providing important contributions to answering these questions. Overall, single-molecule studies have revealed unexpected levels of complexity, with receptors existing in different conformations and dynamically interacting among themselves, their signaling partners, and structural elements of the plasma membrane to produce highly localized signals in space and time. These findings may provide a new basis to develop innovative strategies to modulate GPCR function for pharmacological purposes. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2020-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-pharmtox-010919-023348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42506705","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: 14
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