2,243 publications from this institution
Gene expression is a complex process that is essential to living organisms. Gene expression plays the important role of converting information that is encoded in a gene into a functional product. The primary regulators of gene expression are transcription factors (TFs). TFs are proteins that can bind specific DNA sequences and regulate gene expression. Their evolution is influenced by a large number of factors, including epigenetic mechanisms, gene regulatory elements and molecular cofactors. These molecular mediators, along with transcription factors, form a network that governs gene expression. Elucidating the mechanisms through which TFs have evolved and how they influence the evolution of other regulatory molecules can provide information on organism evolution and on the development of phenotypic variations. The aim of this review article was to provide a summary of the current literature on transcription factor evolution, function and how such evolution has played an important role in the emergence of complex organisms.
In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GR) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GR at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GR and mitochondria number and function. Present understanding of the activated GC-GR's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GR interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.
