دانلود کتاب انتقال سیگنال سلولی در سم شناسی و فارماکولوژی

“All the world’s a stage, and all the men and women are merely players; they have their exits and their entrances, and one man in his time plays many parts….” This famous phrase was penned by William Shakespeare in As You Like It, and he followed it with a description of what he called the seven ages, or phases, of life. While he was referring to the process of aging via a metaphor of actors playing roles in this grand production that is our existence, I often think of both the phases and roles that genes and proteins play as they enter and exit their stages of development. From an infancy represented by a group of linked nucleotides blissfully unaware of their surroundings through an awakening of transcription that is followed by the trials and tribulations of proper editing and posttranslational modifications, the next phase is a productive and functioning role in a new environment that is interacting with many other actors who are also playing their roles. However, unbeknownst to the protein, this phase of role‐playing usually begins to signal the end, when all activity will decrease and virility of function will cease. Ultimately, the once-powerful protein loses its ability to interact with partners, and now without the capacity to sense and respond its surroundings, it is devolved via catabolism back into the elements of its infancy, again unaware of what the future might bring. As pharmacologists and toxicologists today, we focus on the biological response of adding and removing actors, both heroes and villains, to the mixture of concurrent scenes that are happening on several different stages within the body (i.e. organ systems). Further, these actors are joining these ongoing scenes during different acts (i.e. phases), which greatly affects the role that existing genes and proteins may be playing now or in the future. Our goal is to understand how these new cast additions (or removals) might impact the overall production, and therefore we must dive into and dissect each potential role, or interaction, as it pertains to the overall structure and phases that are necessary for life. One means to achieve this is via monitoring alterations in cellular signal transduction cascades that are responsible for both functional interactions (roles) and the transitions between phases (or acts). The pharmacodynamic response of cells to xenobiotics is primarily coordinated by signal transduction networks. Signal transduction proteins are embedded in early response networks that use positive and negative feedback to generate extremely diverse functions like amplification and perfect adaptation, reversible and irreversible switches, homeostasis, and oscillations. Irregular signal transduction activity has been associated with many major human diseases, including several forms of cancer, age‐related diseases, and diabetes, to name a few. From a pharmacological perspective, proteins involved in signal transduction have become one of the most intensively pursued drug targets to date for several reasons, including their direct association with a wide variety of cellular functions (both proliferation and apoptosis), and previous success for the treatment of disease (chronic myeloid leukemia). Depending on the pharmacological effect, agonists/activators or antagonists/inhibitors can be used to harness the therapeutic benefits. The steroid hormone receptors, such as the estrogen receptor, androgen receptor, and glucocorticoid receptor, are among the best examples, because both the steroid receptor agonists and antagonists have been successful clinical drugs. From a toxicological perspective, modern evaluations have evolved to consider toxicity as a perturbation of biological pathways or networks. As such, toxicity testing approaches are shifting from common endpoint evaluations to pathway‐centered approaches based on signal transduction networks, where the degree of perturbation of select networks is monitored. These new approaches are greatly increasing the information available to toxicologists, but signal transduction in toxicological research is in its infancy. Therefore, toxicologists need a resource that will guide their future study design and interpretation.