In the earliest stage of drug discovery/development, various cell-based models and animal models were used for the prediction of human pharmacokinetics and toxicokinetics. Unfortunately, drugs under development are often discontinued because their nonclinical results do not extrapolate to human clinical studies in relation to either safety or efficacy. Therefore, it is important to improve the time- and cost-effectiveness of drug development. This might be achieved by developing new technologies including pharmacokinetics and toxicokinetics models that use human and mouse artificial chromosome vectors (HACs/MACs). HACs/MACs are unique vectors with several advantages: 1) independent maintenance, 2) defined copy number and mitotically stable, 3) no silencing of the transgene, and 4) no limitation of DNA insertion size. This review provides information on the advantages and examples of the utility of various models based on the recent advances in HAC/MAC technologies, including multifunctional cell-based models for assaying drug–drug interactions, bidirectional permeability, and cytotoxicity, as well as fully genetically humanized mouse models. We also discuss the future prospects of these technologies to advance drug discovery. In summary, these technologies offer advantages over current conventional models and should improve the success rate of drug development related to efficacy and safety for humans. 相似文献
Attention‐deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in children and adolescents, which is characterized by behavioral problems such as attention deficit, hyperactivity, and impulsivity. As the receptors of the major excitatory neurotransmitter in the mammalian central nervous system (CNS), glutamate receptors (GluRs) are strongly linked to normal brain functioning and pathological processes. Extensive investigations have been made about the structure, function, and regulation of GluR family, describing evidences that support the disruption of these mechanisms in mental disorders, including ADHD. In this review, we briefly described the family and function of GluRs in the CNS, and discussed what is recently known about the role of GluRs in ADHD, that including GluR genes, animal models, and the treatment, which would help us further elucidate the etiology of ADHD. 相似文献
Cardiac malformations (CVMs) are a leading cause of infant morbidity and mortality. CVMs are particularly prevalent when the developing fetus is exposed to high levels of phenylalanine in-utero in mothers with Phenylketonuria. Yet, elucidating the underlying molecular mechanism leading to CVMs has proven difficult. In this study we used RNA-Seq to investigate an avian model of MPKU and establish differential gene expression (DEG) characteristics of the early developmental stages HH10, 12, and 14. In total, we identified 633 significantly differentially expressed genes across stages HH10, 12, and 14. As expected, functional annotation of significant DEGs identified associations seen in clinical phenotypes of MPKU including CVMs, congenital heart defects, craniofacial anomalies, central nervous system defects, and growth anomalies. Additionally, there was an overrepresentation of genes involved in cardiac muscle contraction, adrenergic signaling in cardiomyocytes, migration, proliferation, metabolism, and cell survival. Strikingly, we identified significant changes in expression with multiple genes involved in Retinoic Acid (RA) metabolism and downstream targets. Using qRTPCR, we validated these findings and identified a total of 42 genes within the RA pathway that are differentially expressed. Here, we report the first elucidation of the molecular mechanisms of cardiovascular malformations in MPKU conducted at early developmental timepoints. We provide evidence suggesting a link between PHE exposure and the alteration of RA pathway. These results are promising and offer novel findings associated with congenital heart defects in MPKU. 相似文献
Biopolymers are playing a vital role in biomedical applications. Among them, protein‐based biopolymers are utilized for the fabrication of tissue‐engineering constructs, therapeutic molecule delivery carriers, emulsifiers, and food packaging materials. Wide ranges of proteins are extracted from animal or plant sources and are being utilized for the fabrication of scaffolds for regenerative tissue‐engineering application. Here, an overview about the protein structure, extraction procedure, solubility, and various formulation‐based proteins found in the literature are discussed. Biopolymers display several advantages such as biocompatibility and degradability by enzymes. Methods to overcome the disadvantages of these proteins such as immunogenicity, antigenicity, and solubility are reported. Various crosslinking reagents specific to protein chemistry are discussed as well. 相似文献
Introduction: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric illness estimated to affect between 1–3% of the population. In today’s literature, there are a number well-validated and convincing animal models of OCD described.
Areas covered: Herein, the authors look at the role that animal models of OCD (including transgenic models, deer mouse stereotypy, quinpirole sensitization, post-training signal attenuation, and mouse marble burying) have played in determining the current directions of OCD drug discovery. Specifically, the article reviews new OCD drug therapies currently under investigation including drugs that target glutamate, dopamine, serotonin, and endocannabinoid systems. The authors review the published results of these clinical trials, and critically examine the contribution of animal models to the development of these novel therapies.
Expert opinion: Nitric oxide inhibitors, oxycarbazepine, and modulators of serotonin and metabotropic glutamate receptors should be further explored in animal models as well as in clinical trials. Pregabalin, topiramate, lamotrigine, sarcosine, minocycline, L-carnosine, celecoxib, and ondansetron, which have shown promise in clinical trials, should be explored in animal models with the goal of understanding the neurobiology of their effects. A multidisciplinary, interactive approach to OCD drug discovery, where animal models generate neurobiological hypotheses that can be tested in the clinic, and vice versa, should be cultivated. 相似文献