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Mechanism of Action of Bexarotene
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Catherine M. Ludwig, Claire Wilson, Brandon Roman, Maria M. Tsoukas
Retinoids are naturally occurring and synthetically derived compounds related to vitamin A (all-trans retinol). Retinoids interact with intracellular retinoid acid receptors (RARs) and retinoid X receptors (RXRs) to enter the nucleus and modulate gene transcription. There are three subtypes each of the RAR and RXR genes. Through alternative splicing, these nuclear receptors can become incredibly diverse (1). Once retinoids bind, the receptors dimerize and are able to recruit cofactors for transactivation or transrepression of retinoid acid response elements (RAREs) in the DNA to modulate cellular proliferation and differentiation. In vivo, retinoids primarily facilitate heterodimerization of an RAR with an RXR, especially RXR-α, to complete their intranuclear effects (2). The direct transcriptional effect of retinoids is inhibition of cellular proliferation, because many RAREs regulate genes that are pro-apoptotic or cause cell cycle arrest (3).
Pathophysiology and Clinical Management of Diabetes and Prediabetes
Published in Jeffrey I. Mechanick, Elise M. Brett, Nutritional Strategies for the Diabetic & Prediabetic Patient, 2006
Elliot J. Rayfield, Marilyn V. Valentine
These agents induce PPAR-γ binding to nuclear receptors in muscle and adipocytes, allowing insulin-stimulated glucose transport. Three PPARs have been identified to date: PPAR-α, PPAR-δ (also known as PPAR-β), and PPAR-γ [86]. After ligand binding, PPARs change their conformation to permit the recruitment of one or more coactivator proteins [87]. The first mechanism, transactivation, is DNA-dependent and consists of binding of PPAR components with target genes and heterodimerization with the retinoid X receptor [87]. The second mechanism, transrepression, interferes with other transcription factor pathways which are not DNA-dependent [88]. The PKC signaling pathway functions as a molecular switch that dissociates with transactivation and transrepression properties of PPAR-α [89]. PPAR-α resides mainly in the liver, heart muscle, and vascular endothelium; when it is activated, it controls genes that regulate lipoprotein levels and confers anti-inflammatory effects [90]. PPAR-γ is located mainly on adipocytes but is also found in pancreatic β-cells, vascular endothelium, and macrophages [87].
Pathophysiology and Management of Shock
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
The physiological circumstances that induce the cytosolic and ER UPR increase the generation of DNA damage such as nucleotide depurination or deamination, oxidative damage, single- and double-strand breaks, and the generation of nonsense mRNA. DNA damage is recognized by, and activates, a family of phosphoinositide-3-kinase-related protein kinases, including ataxia telangiectasia and Rad-3 related, ataxia telangiectasia mutated, DNA-dependent protein kinase, and SMG1, that not only effect DNA repair,j which is important in its own right, but also all converge on the activation of the transcription factor p53. Although more commonly viewed as a tumor suppressor because of its key role in precipitating cell cycle arrest, p53 also exerts pressure on other cellular processes where, for example, it suppresses translation,k increases antioxidant defenses (48), and enhances anaerobic metabolism by activation of AMPdependent protein kinase (49) (AMPK). In persistently unfavorable circumstances p53 enhances autophagy, a highly conserved mechanism for autocannibalizing and recycling old or damaged organelles (see below). This mechanism is invoked under these circumstances in a “last-ditch’’ bid to source cellular substrate for continued cell function, and is driven by p53 both through the downregulation of mTOR and the upregulation of damage-regulated autophagy modulator (50). Finally, where the situation is deemed irrecoverable, p53 invokes a dignified apoptotic cell death both through transrepression of BCL-2 (an inhibitor of apoptosis) as well as upregulation of PUMA, BAX, BIDD, and PIDD. However, in situations where the genetic damage is extensive, overwhelming activation of the enzyme poly-ADP ribose polymerase-1 leads to the rapid cellular depletion of both NAD+ and ATP, culminating in cellular necrosis (51).
State-of-the-art glucocorticoid-targeted drug therapies for the treatment of rheumatoid arthritis
Published in Expert Opinion on Pharmacotherapy, 2022
Eleftherios Pelechas, Alexandros A. Drosos
GCs circulate as free glucocorticoid or bound to cortisol-binding globulin. Free GC diffuses into the cytoplasm and attaches to the glucocorticoid receptor (GR). When GC binds to the GR, an activated GR-GC complex is formed which can then translocate into the nucleus. This gives the ability to enhance or inhibit gene expression. The enhancement of gene expression takes place by binding to specific short sequences of DNA called glucocorticoid responsive elements (GRE) resulting in the induction of gene transcription, a process called transactivation. However, the inhibition of gene expression takes place by binding to transcription factors like the activated protein-1 (AP-1) or nuclear factor-κΒ (NF-κΒ) preventing their interaction with DNA and thus inhibiting protein synthesis, a process called transrepression (Figure 1). GCs can inhibit the inflammatory process exerting multiple effects on immune response cells, cytokines, and other mediators, which are capable of producing tissue injury, as it is shown in Table 1 [7–9]. More specifically, GCs wield their beneficial pleiotropic effects through numerous mechanisms, but the most important are two: genomic and non-genomic.
Glucocorticoids in rheumatoid arthritis: the silent companion in the therapeutic strategy
Published in Expert Review of Clinical Pharmacology, 2020
Onorina Berardicurti, Piero Ruscitti, Viktoriya Pavlych, Alessandro Conforti, Roberto Giacomelli, Paola Cipriani
As above mentioned, the transrepression effects are mainly responsible for the anti-inflammatory and immunosuppressive effects of GCs. On these bases, selective GR ligands, such as selective GR agonists (SEGRAs) and the dissociated agonists of the GCs receptor (DAGRs), have been developed, to optimize GCs therapies. The proposed mechanism of action is the induction of GCs therapeutic activity via the transrepression-mediated GCs effects. In fact, transrepression effects are main responsible for GCs anti-inflammatory and immunomodulating properties. On the contrary, other actions are mediated by transactivation effects, the latter associated with frequent occurring side effects [66,67]. At present, although conclusive data concerning selective GR ligands efficacy are still missing, a longitudinal dose–response analysis to identify the efficacy of the DAGR PF-04171327 was performed [68]. In this work analyzing data from a phase II, RCT, the reduction of the disease activity was similar in patients treated with PF-04171327 when compared to oral GCs-treated patients [69,70].
Should we target TNF receptors in the intestinal epithelium with glucocorticoids during systemic inflammation?
Published in Expert Opinion on Therapeutic Targets, 2018
Kelly Van Looveren, Claude Libert
GCs in mammals are produced by the cortex of the adrenal gland, under the control of the hypothalamic-pituitary-adrenal (HPA) axis [37]. GCs bind to corticosterone-binding globulin (CBG) in the blood and diffuse freely from the extracellular milieu into cells through the plasma membrane. GCs bind to the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. GR is 777 amino acids long in humans and contains three major functional domains; the N-terminal domain (NTD), a DNA-binding domain (DBD), a short hinge region and a ligand-binding domain (LBD) and [38]. Once that GCs bind to GR, this complex moves to the nucleus. By-and-large, nuclear GR performs gene-expression modulation activities by two mechanisms. First, GR acts as a monomeric protein. Its best-known monomer activity is to bind to other proteins, for example the pro-inflammatory transcription factor NFkB, thereby inhibiting its biological activities. This process is referred to as trans-repression. GR can also homodimerize and then becomes a bona fide transcription factor, binding DNA, attracting transcriptional co-factors, including Mediator Complex and attracting RNA POL II. The result is the transcriptional induction of hundreds of genes, referred to as trans-activation [38].