Handbook of experimental pharmacology最新文献

{"title":"Therapeutics for Substance-Using Women: The Need to Elucidate Sex-Specific Targets for Better-Tailored Treatments.","authors":"Helen C Fox,&nbsp;Verica Milivojevic,&nbsp;Rajita Sinha","doi":"10.1007/164_2023_687","DOIUrl":"10.1007/164_2023_687","url":null,"abstract":"<p><p>In the last decade, alcohol consumption in the US has risen by 84% in women compared with 35% in men. Furthermore, research has shown that sex- and gender-related differences may disadvantage women in terms of developing a range of psychological, cognitive, and medical problems considerably earlier in their drinking history than men, and despite consuming a similar quantity of substances. While this \"telescoping\" process has been acknowledged in the literature, a concomitant understanding of the underlying biobehavioral mechanisms, and an increase in the development of specific treatments tailored to women, has not occurred. In the current chapter we focus on understanding why the need for personalized, sex-specific medications is imperative, and highlight some of the potential sex-specific gonadal and stress-related adaptations underpinning the accelerated progress from controlled to compulsive drug and alcohol seeking in women. We additionally discuss the efficacy of these mechanisms as novel targets for medications development, using exogenous progesterone and guanfacine as examples. Finally, we assess some of the challenges faced and progress made in terms of developing innovative medications in women. We suggest that agents such as exogenous progesterone and adrenergic medications, such as guanfacine, may provide some efficacy in terms of attenuating stress-induced craving for several substances, as well as improving the ability to emotionally regulate in the face of stress, preferentially in women. However, to fully leverage the potential of these therapeutics in substance-using women, greater focus needs to the placed on reducing barriers to treatment and research by encouraging women into clinical trials.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"127-161"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10012196","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":"Compound Identification Strategies in Mass Spectrometry-Based Metabolomics and Pharmacometabolomics.","authors":"Rylan Hissong,&nbsp;Kendra R Evans,&nbsp;Charles R Evans","doi":"10.1007/164_2022_617","DOIUrl":"10.1007/164_2022_617","url":null,"abstract":"<p><p>The metabolome is composed of a vast array of molecules, including endogenous metabolites and lipids, diet- and microbiome-derived substances, pharmaceuticals and supplements, and exposome chemicals. Correct identification of compounds from this diversity of classes is essential to derive biologically relevant insights from metabolomics data. In this chapter, we aim to provide a practical overview of compound identification strategies for mass spectrometry-based metabolomics, with a particular eye toward pharmacologically-relevant studies. First, we describe routine compound identification strategies applicable to targeted metabolomics. Next, we discuss both experimental (data acquisition-focused) and computational (software-focused) strategies used to identify unknown compounds in untargeted metabolomics data. We then discuss the importance of, and methods for, assessing and reporting the level of confidence of compound identifications. Throughout the chapter, we discuss how these steps can be implemented using today's technology, but also highlight research underway to further improve accuracy and certainty of compound identification. For readers interested in interpreting metabolomics data already collected, this chapter will supply important context regarding the origin of the metabolite names assigned to features in the data and help them assess the certainty of the identifications. For those planning new data acquisition, the chapter supplies guidance for designing experiments and selecting analysis methods to enable accurate compound identification, and it will point the reader toward best-practice data analysis and reporting strategies to allow sound biological and pharmacological interpretation.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"277 ","pages":"43-71"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9407039","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":"CACNA1D-Related Channelopathies: From Hypertension to Autism.","authors":"Nadine J Ortner","doi":"10.1007/164_2022_626","DOIUrl":"https://doi.org/10.1007/164_2022_626","url":null,"abstract":"<p><p>Tightly controlled Ca²⁺ influx through voltage-gated Ca²⁺ channels (Cavs) is indispensable for proper physiological function. Thus, it is not surprising that Cav loss and/or gain of function have been implicated in human pathology. Deficiency of Cav1.3 L-type Ca²⁺ channels (LTCCs) causes deafness and bradycardia, whereas several genetic variants of CACNA1D, the gene encoding the pore-forming α1 subunit of Cav1.3, have been linked to various disease phenotypes, such as hypertension, congenital hypoglycemia, or autism. These variants include not only common polymorphisms associated with an increased disease risk, but also rare de novo missense variants conferring high risk. This review provides a concise summary of disease-associated CACNA1D variants, whereas the main focus lies on de novo germline variants found in individuals with a neurodevelopmental disorder of variable severity. Electrophysiological recordings revealed activity-enhancing gating changes induced by these de novo variants, and tools to predict their pathogenicity and to study the resulting pathophysiological consequences will be discussed. Despite the low number of affected patients, potential phenotype-genotype correlations and factors that could impact the severity of symptoms will be covered. Since increased channel activity is assumed as the disease-underlying mechanism, pharmacological inhibition could be a treatment option. In the absence of Cav1.3-selective blockers, dihydropyridine LTCC inhibitors clinically approved for the treatment of hypertension may be used for personalized off-label trials. Findings from in vitro studies and treatment attempts in some of the patients seem promising as outlined. Taken together, due to advances in diagnostic sequencing techniques the number of reported CACNA1D variants in human diseases is constantly rising. Evidence from in silico, in vitro, and in vivo disease models can help to predict the pathogenic potential of such variants and to guide diagnosis and treatment in the clinical practice when confronted with patients harboring CACNA1D variants.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"279 ","pages":"183-225"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912524","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":"Ca_V1.1 Calcium Channel Signaling Complexes in Excitation-Contraction Coupling: Insights from Channelopathies.","authors":"Marta Campiglio, Agnieszka Dyrda, Wietske E Tuinte, Enikő Török","doi":"10.1007/164_2022_627","DOIUrl":"10.1007/164_2022_627","url":null,"abstract":"<p><p>In skeletal muscle, excitation-contraction (EC) coupling relies on the mechanical coupling between two ion channels: the L-type voltage-gated calcium channel (Ca_V1.1), located in the sarcolemma and functioning as the voltage sensor of EC coupling, and the ryanodine receptor 1 (RyR1), located on the sarcoplasmic reticulum serving as the calcium release channel. To this day, the molecular mechanism by which these two ion channels are linked remains elusive. However, recently, skeletal muscle EC coupling could be reconstituted in heterologous cells, revealing that only four proteins are essential for this process: Ca_V1.1, RyR1, and the cytosolic proteins Ca_Vβ_1a and STAC3. Due to the crucial role of these proteins in skeletal muscle EC coupling, any mutation that affects any one of these proteins can have devastating consequences, resulting in congenital myopathies and other pathologies.Here, we summarize the current knowledge concerning these four essential proteins and discuss the pathophysiology of the Ca_V1.1, RyR1, and STAC3-related skeletal muscle diseases with an emphasis on the molecular mechanisms. Being part of the same signalosome, mutations in different proteins often result in congenital myopathies with similar symptoms or even in the same disease.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"279 ","pages":"3-39"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912527","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":"Mechanisms of Vascular Ca_V1.2 Channel Regulation During Diabetic Hyperglycemia.","authors":"Miguel Martín-Aragón Baudel,&nbsp;Junyoung Hong,&nbsp;Johannes W Hell,&nbsp;Madeline Nieves-Cintrón,&nbsp;Manuel F Navedo","doi":"10.1007/164_2022_628","DOIUrl":"10.1007/164_2022_628","url":null,"abstract":"<p><p>Diabetes is a leading cause of disability and mortality worldwide. A major underlying factor in diabetes is the excessive glucose levels in the bloodstream (e.g., hyperglycemia). Vascular complications directly result from this metabolic abnormality, leading to disabling and life-threatening conditions. Dysfunction of vascular smooth muscle cells is a well-recognized factor mediating vascular complications during diabetic hyperglycemia. The function of vascular smooth muscle cells is exquisitely controlled by different ion channels. Among the ion channels, the L-type Ca_V1.2 channel plays a key role as it is the main Ca²⁺ entry pathway regulating vascular smooth muscle contractile state. The activity of Ca_V1.2 channels in vascular smooth muscle is altered by diabetic hyperglycemia, which may contribute to vascular complications. In this chapter, we summarize the current understanding of the regulation of Ca_V1.2 channels in vascular smooth muscle by different signaling pathways. We place special attention on the regulation of Ca_V1.2 channel activity in vascular smooth muscle by a newly uncovered AKAP5/P2Y₁₁/AC5/PKA/Ca_V1.2 axis that is engaged during diabetic hyperglycemia. We further describe the pathophysiological implications of activation of this axis as it relates to myogenic tone and vascular reactivity and propose that this complex may be targeted for developing therapies to treat diabetic vascular complications.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"279 ","pages":"41-58"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9899627","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":"Challenges Related to the Use of Next-Generation Sequencing for the Optimization of Drug Therapy.","authors":"Yitian Zhou,&nbsp;Volker M Lauschke","doi":"10.1007/164_2022_596","DOIUrl":"https://doi.org/10.1007/164_2022_596","url":null,"abstract":"<p><p>Over the last decade, next-generation sequencing (NGS) methods have become increasingly used in various areas of human genomics. In routine clinical care, their use is already implemented in oncology to profile the mutational landscape of a tumor, as well as in rare disease diagnostics. However, its utilization in pharmacogenomics is largely lacking behind. Recent population-scale genome data has revealed that human pharmacogenes carry a plethora of rare genetic variations that are not interrogated by conventional array-based profiling methods and it is estimated that these variants could explain around 30% of the genetically encoded functional pharmacogenetic variability.To interpret the impact of such variants on drug response a multitude of computational tools have been developed, but, while there have been major advancements, it remains to be shown whether their accuracy is sufficient to improve personalized pharmacogenetic recommendations in robust trials. In addition, conventional short-read sequencing methods face difficulties in the interrogation of complex pharmacogenes and high NGS test costs require stringent evaluations of cost-effectiveness to decide about reimbursement by national healthcare programs. Here, we illustrate current challenges and discuss future directions toward the clinical implementation of NGS to inform genotype-guided decision-making.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"280 ","pages":"237-260"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10138521","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 Implementation of Pharmacogenetics in the United Kingdom.","authors":"John H McDermott,&nbsp;Videha Sharma,&nbsp;Jessica Keen,&nbsp;William G Newman,&nbsp;Munir Pirmohamed","doi":"10.1007/164_2023_658","DOIUrl":"https://doi.org/10.1007/164_2023_658","url":null,"abstract":"<p><p>There is considerable inter-individual variability in the effectiveness and safety of pharmaceutical interventions. This phenomenon can be attributed to a multitude of factors; however, it is widely acknowledged that common genetic variation affecting drug absorption or metabolism play a substantial contributory role. This is a concept known as pharmacogenetics. Understanding how common genetic variants influence responses to medications, and using this knowledge to inform prescribing practice, could yield significant advantages for both patients and healthcare systems. Some health services around the world have introduced pharmacogenetics into routine practice, whereas others are less advanced along the implementation pathway. This chapter introduces the field of pharmacogenetics, the existing body of evidence, and discusses barriers to implementation. The chapter will specifically focus on efforts to introduce pharmacogenetics in the NHS, highlighting key challenges related to scale, informatics, and education.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"280 ","pages":"3-32"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10198355","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":"Electrophysiological Techniques on the Study of Endolysosomal Ion Channels.","authors":"Cheng-Chang Chen","doi":"10.1007/164_2023_638","DOIUrl":"https://doi.org/10.1007/164_2023_638","url":null,"abstract":"<p><p>Endolysosomal ion channels are a group of ion channel proteins that are functionally expressed on the membrane of endolysosomal vesicles. The electrophysiological properties of these ion channels in the intracellular organelle membrane cannot be observed using conventional electrophysiological techniques. This section compiles the different electrophysiological techniques utilized in recent years to study endolysosomal ion channels and describes their methodological characteristics, emphasizing the most widely used technique for whole endolysosome recordings to date. This includes the use of different pharmacological tools and genetic tools for the application of patch-clamping techniques for specific stages of endolysosomes, allowing the recording of ion channel activity in different organelles, such as recycling endosomes, early endosomes, late endosomes, and lysosomes. These electrophysiological techniques are not only cutting-edge technologies that help to investigate the biophysical properties of known and unknown intracellular ion channels but also help us to investigate the physiopathological role of these ion channels in the distribution of dynamic vesicles and to identify new therapeutic targets for precision medicine and drug screening.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"278 ","pages":"217-233"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9360389","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":"iPSC-Derived Corneal Endothelial Cells.","authors":"Qingjun Zhou, Zongyi Li, Haoyun Duan","doi":"10.1007/164_2023_644","DOIUrl":"10.1007/164_2023_644","url":null,"abstract":"<p><p>The corneal endothelium is the innermost monolayer of the cornea that maintains corneal transparency and thickness. However, adult human corneal endothelial cells (CECs) possess limited proliferative capacity, and injuries can only be repaired by migration and enlargement of resident cells. When corneal endothelial cell density is lower than the critical level (400-500 cells/mm²) due to disease or trauma, corneal endothelial dysfunction will occur and lead to corneal edema. Corneal transplantation remains the most effective clinical treatment therapy but is limited by the global shortage of healthy corneal donors. Recently, researchers have developed several alternative strategies for the treatment of corneal endothelial disease, including the transplantation of cultured human CECs and artificial corneal endothelial replacement. Early-stage results show that these strategies can effectively resolve corneal edema and restore corneal clarity and thickness, but the long-term efficacy and safety remain to be further validated. Induced pluripotent stem cells (iPSCs) represent an ideal cell source for the treatment and drug discovery of corneal endothelial diseases, which can avoid the ethical-related and immune-related problems of human embryonic stem cells (hESCs). At present, many approaches have been developed to induce the differentiation of corneal endothelial-like cells from human induced pluripotent stem cells (hiPSCs). Their safety and efficacy for the treatment of corneal endothelial dysfunction have been confirmed in rabbit and nonhuman primate animal models. Therefore, the iPSC-derived corneal endothelial cell model may provide a novel effective platform for basic and clinical research of disease modeling, drug screening, mechanistic investigation, and toxicology testing.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"257-276"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10867121","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":"iPSCs-Derived Neurons and Brain Organoids from Patients.","authors":"Wanying Zhu, Lei Xu, Xinrui Li, Hao Hu, Shuning Lou, Yan Liu","doi":"10.1007/164_2023_657","DOIUrl":"10.1007/164_2023_657","url":null,"abstract":"<p><p>Induced pluripotent stem cells (iPSCs) can be differentiated into specific neurons and brain organoids by adding induction factors and small molecules in vitro, which carry human genetic information and recapitulate the development process of human brain as well as physiological, pathological, and pharmacological characteristics. Hence, iPSC-derived neurons and organoids hold great promise for studying human brain development and related nervous system diseases in vitro, and provide a platform for drug screening. In this chapter, we summarize the development of the differentiation techniques for neurons and brain organoids from iPSCs, and their applications in studying brain disease, drug screening, and transplantation.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"59-81"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9613851","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}