Handbook of experimental pharmacology最新文献

The hematopoietic neoplasm chronic myeloid leukemia (CML) is a rare disease caused by chromosomal reciprocal translocation t(9;22)(q34:q11) with subsequent formation of the BCR-ABL1 fusion gene. This fusion gene encodes a constitutively active tyrosine kinase, which results in malignant transformation of the cells. Since 2001, CML can be effectively treated using tyrosine kinase inhibitors (TKIs) such as imatinib, which prevent phosphorylation of downstream targets by blockade of the BCR-ABL kinase. Due to its tremendous success, this treatment became the role model of targeted therapy in precision oncology. Here, we review the mechanisms of TKI resistance focusing on BCR-ABL1-dependent and -independent mechanisms. These include the genomics of the BCR-ABL1, TKI metabolism and transport and alternative signaling pathways.

The initial discovery and derivation of induced pluripotent stem cells (iPSCs) by Yamanaka and colleagues in 2006 revolutionized the field of personalized medicine, as it opened the possibility to model diseases using patient-derived stem cells. A decade of adoption of iPSCs within the community of the blood-brain barrier (BBB) significantly opened the door for modeling diseases at the BBB, a task until then considered challenging, if not impossible.In this book chapter, we provided an extensive review of the literature on the use of iPSC-based models of the human BBB to model neurological diseases including infectious diseases (COVID-19, Streptococcus, Neisseria) neurodevelopmental diseases (adrenoleukodystrophy, Allan-Herndon-Dudley Syndrome, Batten's disease, GLUT1 deficiency syndrome), and neurodegenerative diseases (Alzheimer's disease, the current findings and observations, but also the challenges and limitations inherent to the use of iPSC-based models in reproducing the human BBB during health and diseases in a Petri dish.

Parkinson's disease (PD) is a relentlessly progressive neurodegenerative disorder with typical motor symptoms that include rigidity, tremor, and akinesia/bradykinesia, in addition to a host of non-motor symptoms. Motor symptoms are caused by progressive and selective degeneration of dopamine (DA) neurons in the SN pars compacta (SNpc) and the accompanying loss of striatal DA innervation from these neurons. With the exception of monogenic forms of PD, the etiology of idiopathic PD remains unknown. While there are a number of symptomatic treatment options available to individuals with PD, these therapies do not work uniformly well in all patients, and eventually most are plagued with waning efficacy and significant side-effect liability with disease progression. The incidence of PD increases with aging, and as such the expected burden of this disease will continue to escalate as our aging population increases (Dorsey et al. Neurology 68:384-386, 2007). The daunting personal and socioeconomic burden has pressed scientists and clinicians to find improved symptomatic treatment options devoid side-effect liability and meaningful disease-modifying therapies. Federal and private sources have supported clinical investigations over the past two-plus decades; however, no trial has yet been successful in finding an effective therapy to slow progression of PD, and there is currently just one FDA approved drug to treat the antiparkinsonian side-effect known as levodopa-induced dyskinesia (LID) that impacts approximately 90% of all individuals with PD. In this review, we present biological rationale and experimental evidence on the potential therapeutic role of the L-type voltage-gated Cav1.3 calcium (Ca²⁺) channels in two distinct brain regions, with two distinct mechanisms of action, in impacting the lives of individuals with PD. Our primary emphasis will be on the role of Cav1.3 channels in the striatum and the compelling evidence of their involvement in LID side-effect liability. We also briefly discuss the role of these same Ca²⁺ channels in the SNpc and the longstanding interest in Cav1.3 in this brain region in halting or delaying progression of PD.

Precision medicine uses innovative approaches to improve disease prevention and treatment outcomes by taking into account people's genetic backgrounds, environments, and lifestyles. Treatment of depression is particularly challenging, given that 30-50% of patients do not respond adequately to antidepressants, while those who respond may experience unpleasant adverse drug reactions (ADRs) that decrease their quality of life and compliance. This chapter aims to present the available scientific data that focus on the impact of genetic variants on the efficacy and toxicity of antidepressants. We compiled data from candidate gene and genome-wide association studies that investigated associations between pharmacodynamic and pharmacokinetic genes and response to antidepressants regarding symptom improvement and ADRs. We also summarized the existing pharmacogenetic-based treatment guidelines for antidepressants, used to guide the selection of the right antidepressant and its dose based on the patient's genetic profile, aiming to achieve maximum efficacy and minimum toxicity. Finally, we reviewed the clinical implementation of pharmacogenomics studies focusing on patients on antidepressants. The available data demonstrate that precision medicine can increase the efficacy of antidepressants and reduce the occurrence of ADRs and ultimately improve patients' quality of life.

The ability to derive retinal ganglion cells (RGCs) from human pluripotent stem cells (hPSCs) provides an extraordinary opportunity to study the development of RGCs as well as cellular mechanisms underlying their degeneration in optic neuropathies. In the past several years, multiple approaches have been established that allow for the generation of RGCs from hPSCs, with these methods greatly improved in more recent studies to yield mature RGCs that more faithfully recapitulate phenotypes within the eye. Nevertheless, numerous differences still remain between hPSC-RGCs and those found within the human eye, with these differences likely explained at least in part due to the environment in which hPSC-RGCs are grown. With the ultimate goal of generating hPSC-RGCs that most closely resemble those within the retina for proper studies of retinal development, disease modeling, as well as cellular replacement, we review within this manuscript the current effective approaches for the differentiation of hPSC-RGCs, as well as how they have been applied for the investigation of RGC neurodegenerative diseases such as glaucoma. Furthermore, we provide our opinions on the characteristics of RGCs necessary for their use as effective in vitro disease models and importantly, how these current systems should be improved to more accurately reflect disease states. The establishment of characteristics in differentiated hPSC-RGCs that more effectively mimic RGCs within the retina will not only enable their use as effective models of RGC development, but will also create a better disease model for the identification of mechanisms underlying the neurodegeneration of RGCs in disease states such as glaucoma, further facilitating the development of therapeutic approaches to rescue RGCs from degeneration in disease states.

Ca²⁺ influx through high-voltage-gated Ca²⁺ channels (HVGCCs; Ca_V1/Ca_V2) is an exceptionally powerful and versatile signal that controls numerous cell and physiological functions including neurotransmission, muscle contraction, and regulation of gene expression. The impressive ability of a singular signal, Ca²⁺ influx, to have such a plethora of functional outcomes is enabled by: molecular diversity of HVGCC pore-forming α₁ and auxiliary subunits; organization of HVGCCs with extrinsic modulatory and effector protein to form discrete macromolecular complexes with unique properties; distinctive distribution of HVGCCs into separate subcellular compartments; and varying expression profiles of HVGCC isoforms among different tissues and organs. The capacity to block HVGCCs with selectivity and specificity with respect to the different levels of their organization is critical for fully understanding the scope of functional consequences of Ca²⁺ influx through them, and is also important for realizing their full potential as therapeutic targets. In this review, we discuss the gaps in the current landscape of small-molecule HVGCC blockers and how these may be addressed with designer genetically-encoded Ca²⁺ channel inhibitors (GECCIs) that draw inspiration from physiological protein inhibitors of HVGCCs.

Two-pore channels are ion channels expressed on acidic organelles such as the various vesicles that constitute the endo-lysosomal system. They are permeable to Ca²⁺ and Na⁺ and activated by the second messenger NAADP as well as the phosphoinositide, PI(3,5)P₂ and/or voltage. Here, we review the proteins that interact with these channels including recently identified NAADP receptors.

Calcium influx through voltage-gated calcium channels, Ca_v1.2, in cardiomyocytes initiates excitation-contraction coupling in the heart. The force and rate of cardiac contraction are modulated by the sympathetic nervous system, mediated substantially by changes in intracellular calcium. Norepinephrine released from sympathetic neurons innervating the heart and epinephrine secreted by the adrenal chromaffin cells bind to β-adrenergic receptors on the sarcolemma of cardiomyocytes initiating a signaling cascade that generates cAMP and activates protein kinase A, the targets of which control calcium influx. For decades, the mechanisms by which PKA regulated calcium channels in the heart were not known. Recently, these mechanisms have been elucidated. In this chapter, we will review the history of the field and the studies that led to the identification of the evolutionarily conserved process.

Sexual dimorphism has been demonstrated to have an effect on various physiological functions. In this regard, researchers have investigated its impact on glucose homeostasis in both preclinical and clinical studies. Sex differences mainly arise from physiological factors such as sex hormones, body fat and muscle distribution, and sex chromosomes. The sexual dimorphism has also been studied in the context of diabetes. Reflecting the prevalence of the disease among the population, studies focusing on the sex difference in type 1 diabetes (T1D) are not common as the ones in type 2 diabetes (T2D). T1D is reported as the only major specific autoimmune disease that exhibits a male predominance. Clinical studies have demonstrated that impaired fasting glucose is more frequent in men whereas women more commonly exhibit impaired glucose tolerance. Understanding the sex difference in glucose homeostasis becomes more attractive when focusing on the findings that highlight sexual dimorphism on the efficacy or adverse effect profile of antidiabetic medications. Thus, in this chapter, we aimed to discuss the impact of sex on the glucose homeostasis both in health and in diabetes.

Pharmacometabolomics applies the principles of metabolomics to therapeutics in order to elucidate the biological mechanisms underlying the variation in responses to drugs between groups and individuals. Asthma is associated with broad systemic effects and heterogeneity in treatment response and as such is ideally suited to pharmacometabolomics. In this chapter, we discuss the state of the emerging field of asthma pharmacometabolomics, with a particular focus on studies of steroids, bronchodilators, and leukotriene inhibitors. We also consider those studies concerned with subtyping cases to better understand the pharmacology of those groups and those looking to leverage pharmacometabolomics for asthma prevention. We finish with a discussion of the challenges and opportunities of asthma pharmacometabolomics and reflect upon where this field must go next in order to realize its precision medicine potential.