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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Bexarotene (Figure 6.106), marketed as TargtretinTM, has a similar structure to tretinoin and alitretinoin, and was approved by the FDA and EMA in 1999 and 2001, respectively, as a treatment for cutaneous T-cell lymphoma (CTCL). It acts as an agonist at the retinoid X receptor which is involved in the regulation of cellular differentiation and proliferation (Figure 6.105).
Pharmacological Management of Alzheimer’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rakesh Kumar, Rajan Kumar, Abhinav Anand, Neha Sharma, Navneet Khurana
The main use of pioglitazone is as a remedy for type 2 diabetes. It acts via receptor nuclear PPARγ. It attaches and forms a heterodimer with retinoid X receptor (RXR), which further leads to the alteration of the transcription of the gene and proteins related to the glucose and lipid metabolism (Application, 2013). Now it was reported that PPARγ is also involved in the neuroinflammation of the AD. Rosiglitazone is one of first PPARγ compound which was tested in the AD and entered in phase III of the clinical trials but later abandoned. Later on, pioglitazone was reported to reduce the glial cell inflammation and Aβ level in transgenic mice (Harrington et al., 2011).
Retinoic acid signaling in spermatogenesis and male (in)fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Dario Santos, Rita Payan-Carreira
In the classic signaling mechanism (canonical pathway), RA effects are mediated through binding to specific nuclear receptors (retinoid receptors) followed by changes of transcription of several genes (31,32). Retinoid receptors can be divided into two subgroups, RA receptors (RARs) and retinoid X receptors (RXRs) (33). The RAR has three isotypes (RARα, RARβ and RARγ) (34), and each is capable of heterodimerizing with a retinoid X receptor isotype (RXRα, RXRβ or RXRγ). The RAR–RXR heterodimer binds on the chromosome to sequence stretches called RA-response elements (RAREs) and functions as a transcriptional activator in the presence of its hormonal ligand and as a repressor in the absence of RA (35). Retinoid X receptor (RXR) interacts with RAR, allowing RXR to function as a master controller for signals from various hormonal pathways. In the nucleus, RAR and RXR form heterodimers bound to RAREs and associate with a co-repressor complex.
Health implication of vitamin D on the cardiovascular and the renal system
Published in Archives of Physiology and Biochemistry, 2021
Raghad Khalid Al-Ishaq, Peter Kubatka, Martina Brozmanova, Katarina Gazdikova, Martin Caprnda, Dietrich Büsselberg
Vitamin-D-receptor (VDR) is an intracellular polypeptide of 50–60 kDa which is produced in the liver (Cooke et al.1988), discovered by Simpson et al. (1985). Activation of VDR by (1,25(OH)2D) promotes cell division, growth, differentiation and apoptosis (Baker et al.1988). VDR are also important for calcium homeostasis (McDonnell et al.1989, MacDonald et al.1995). VDR derived form a nuclear receptor superfamily, therefore sharing some conserved domains with other steroid hormones (Gill et al.1998). Vitamin D receptors have short N-terminal domain which contains two zinc fingers hat obtain different functions. The first zinc figure is for vitamin D element specificity, while the second zinc is important for heterodimerisation (Haussler et al.1998). The activation process starts when 1,25(OH)2D binds to the vitamin D receptor. Heterodimerisation between VDR and retinoid X receptor (RXR) lead to the formation of a regulatory complex. Using a co-activator, the regulatory complex binds to the target gene which is vitamin D response element (VDRE) to start transcription (Haussler et al.2011) (Figure 1).
Retinoic acid receptor agonist as monotherapy for early-stage mycosis fungoides: does it work?
Published in Journal of Dermatological Treatment, 2019
Iris Amitay-Laish, Ofer Reiter, Hadas Prag-Naveh, Ruben Kershenovich, Emmilia Hodak
Retinoids are signaling molecules that are structurally related to vitamin A. Their biological effects are triggered through specific intracellular retinoic acid receptors (RAR) and/or retinoid X receptors (RXR) (1–3). By forming various heterodimers, they act as ligand-inducible transcription-regulatory factors and exert antiproliferative, antiangiogenic, immunomodulating and differentiation effects (3–6). Retinoids have been successfully used in the treatment of a broad range of inflammatory and neoplastic skin diseases and have proven effective in reducing cutaneous dysplasia as well as the frequency of squamous cell cancer developing in immunocompromised patients (7,8). In the treatment of cancer, retinoids are considered “biologic response modifiers” because they induce an effect without immune suppression and even frequently augment the immune response (8–14).
Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future
Published in Critical Reviews in Toxicology, 2018
Melissa A. Davidson, Donald R. Mattison, Laurent Azoulay, Daniel Krewski
PPARs undergo transactivation or transrepression through distinct mechanisms that lead to either the induction or repression of the expression of target genes (Oyekan 2011). Transactivation is DNA-dependent and binding requires dimerization with members of the retinoid X receptor (RXR) family (Willson et al. 2001). The heterodimerization between PPARs and RXR is ligand-independent, but relies on the interfaces between the ligand-binding domains and DNA-binding domains of each receptor (Chandra et al. 2008; Rochel et al. 2011). The obligate PPAR/RXR heterodimer in turn binds to PPAR responsive regulatory elements in the promoter region of target genes (Willson et al. 2001; Ajjan and Grant 2008), including those involved in adipogenesis, lipid metabolism, inflammation, and the maintenance of metabolic homeostasis (Barish et al. 2006). Activation of these genes by natural ligands or by drugs such as TZDs translates into clinically beneficial hypoglycemic and hypolipidemic effects, decreased insulin resistance, improved insulin sensitivity, and decreased inflammation (Grossman and Lessem 1997; Yki-Järvinen 2004).