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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The retinoids are natural and synthetic derivatives of vitamin A that regulate a variety of important cellular functions. Retinol (Figure 6.106), also known as vitamin A1, is a vitamin found in many food types and used as a dietary supplement to treat and prevent vitamin A deficiency. In the body retinol is converted to retinal and then retinoic acid which acts on cell-surface receptors to control processes including cell growth and metabolism (Figure 6.105). In particular, it is a regulator of epithelial and bone tissue cell growth and differentiation, and so analogues have been developed for use in skin-related proliferative diseases such as psoriasis and bone tissue disorders. Through the activation of tumor-suppressor genes, it is also known to play a role in maintaining vision and immune function. Retinol was discovered in 1909, isolated in 1931 and first synthesized in 1947, and dietary sources rich in the molecule include dairy products, meat, and fish. All-trans-retinoic acid (RA) works by activating the Nuclear Retinoic Acid receptors (RARs), while 9-cis-retinoic acid activates the non-classical nuclear Retinoid X Receptors (RXRs) along with the RARs. Altogether, there are six genes encoding the retinoid receptors: RARa, RARb, and RARg, and RXRa, RXRb, and RXRg (Figure 6.105).
Epigenetic mechanisms in bone development
Published in Nicholas C. Harvey, Cyrus Cooper, Osteoporosis: a lifecourse epidemiology approach to skeletal health, 2018
Elizabeth M Curtis, Nicholas C Harvey, Cyrus Cooper
In the Southampton Women’s Survey, greater methylation at four out of six CpG sites in the promoter region of retinoid X receptor-alpha (RXRA) in umbilical cord was correlated with lower offspring BMC corrected for body size at 4 years old, as shown in Figure 8.2 (β = −2.1 to −3.4 g/sd, p = 0.002 to 0.047), with the results supported by findings from a second independent cohort, the Princess Anne Hospital Study (14). In this study, an estimate of maternal free vitamin D index was inversely related to RXRA methylation at CpG 4/5 (chromosome 9, 136355593, 600+). As previously stated, RXRA forms a heterodimer with several nuclear hormones known to influence bone metabolism, including 1,25(OH)2-vitamin D, perhaps implying that maternal 25(OH)D status might play a permissive role in the transcriptional regulation of the RXRA gene. Evidence of functional significance was obtained through altered response to transcription factor binding and further characterization of these processes is ongoing, but clearly replication in independent cohorts will be required to validate such findings.
PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alicja M. Gruszkaa, Myriam Alcalay
The physiological roles of the two partners are multiple and complex. The PML protein is a member of the tripartite motif (TRIM) family [8]. The TRIM motif includes three zinc-binding domains, a RING, two B-boxes and a coiled-coil region (called jointly RBCC domain). Both the RING and coiled-coil moieties of PML are required for its localisation in complex subnuclear structures called nuclear bodies (NB), and for its interaction with other proteins within NBs such as p53, CBP, BLM, eIF-4, DAXX, Ubc9, pRb and sp100 [8]. PML protein, the exact functions of which are still elusive, has been implicated in a variety of processes, such as tumour suppression, senescence, apoptosis and telomere maintenance [35]. RARa, on the other hand, is a nuclear hormone receptor that confers the transcriptional response to retinoic acid (RA) [11]. RARa binds to specific DNA sequences, referred to as RA responsive elements (RARE), consisting of a PuGGTCA sequence spaced by two or five nucleotides (DR2, DR5), in a heterodimeric complex with retinoid-X receptor (RXRa). RARs have a common domain structure consisting of an N-terminal DNA-binding, a linker and a C-terminal ligand (RA)-binding domains. In the absence of RA, RARa/RXRa complexes repress transcription through interactions with NCoR and SMRT co-repressors that do not possess an enzymatic activity themselves, but recruit complexes with histone deacetylase activity (HDAC) generating a condensed chromatin structure. Physiological concentrations of RA induce a conformational change in the RARs causing release of these corepressors and recruitment of transcriptional co-activators from the p160 family, ultimately leading to activation of gene transcription through the association with histone acetyltransferases (HATs) and histone methyltransferases (HMT) [50]. Retinoid signalling has been implicated in the regulation of development, differentiation, apoptosis, granulopoeisis, stem cell differentiation and transcription of clock genes [26].
Steroid-resistant nephrotic syndrome: pharmacogenetics and epigenetic points and views
Published in Expert Review of Clinical Pharmacology, 2020
Seyede Mina Hejazian, Sepideh Zununi Vahed, Hakimeh Moghaddas Sani, Ziba Nariman-Saleh-Fam, Milad Bastami, Seyed Mahdi Hosseiniyan Khatibi, Mohammadreza Ardalan, Nasser Samadi
Pregnane X receptor (PXR), also known as steroid and xenobiotic receptor (SXR), is a nuclear hormone receptor involved in the steroid and xenobiotic substance metabolism through transcriptional regulation of multiple enzymes and transporters. Target genes include cytochrome P450 enzymes (CYPs), UDP-glucuronosyltransferase1, sulfotransferase2 A, adenosine triphosphate-binding cassette, sub-family B, member1 (ABCB1)/multidrug resistance gene1 (MDR1), multiple organic anion transporters (OATs) and multidrug-resistance protein 3 (MRP3) [39]. PXR is expressed in human hepatocytes through dexamethasone-mediated GR induction. Moreover, the expression of retinoid X receptor-alpha (RXRα), a member of the NR2B nuclear receptor family is increased in these cells. PXR/RXRα heterodimer plays a key role in the transcription of target genes [40]. PXR polymorphisms in the promoter and ligand-binding domains alter the transcriptional activity of downstream genes involved in xenobiotic clearance pathways including CYP3A4, CYP2C8, and MDR1 proteins and; consequently, influence steroid responsiveness in patients. For instance, SNPs of PXR promoter and intron1 are associated with a deficiency in CYP3A4 and MDR1 activity in Asian breast cancer patients [41]. In vitro studies revealed that PXR promoter polymorphism in the NF-κB binding site is associated with a higher rate of CYP3A4 expression in response to rifampicin, PXR agonist, whereas PXR R122Q and D163G polymorphisms in exon 4 lead to decreased rifampicin-induced CYP3A4 expression [42,43].
Identification of key transcription factors in preeclampsia
Published in Hypertension in Pregnancy, 2019
Junhu Wang, Huijie Liu, Yunxia Guo, Chunxiao Zhou, Tingting Qi
Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. It was proposed that increased RA may contribute to preeclampsia pathogenesis by reducing sFLT1 accumulation at the maternal–fetal interface (24). Thus, it is coincidence with our finding that RA was a key factor in preeclampsia. TP53 plays a crucial role in regulating cell apoptosis by activating the expression of proapoptotic protein Bax and inhibiting antiapoptotic protein Bcl-2 and BIRC5 expressions at the transcriptional level (25,26). It is proposed that upregulation of P53 was involved in triggering cell apoptosis in cultured human umbilical vein endothelial cell (HUVECs) from preeclampsia pregnancies by regulating Bax gene, Bcl-2, and BIRC5 genes (27). Besides, an upregulation of the TP53 pathway was reported to induce the deportation of microparticles, including high levels of antiangiogenic factors, and that this might facilitate maternal systemic symptoms in preeclampsia (28).
Indirect activation of pregnane X receptor in the induction of hepatic CYP3A11 by high-dose rifampicin in mice
Published in Xenobiotica, 2018
Yuki Yamasaki, Kaoru Kobayashi, Asumi Inaba, Daisuke Uehara, Hiroki Tojima, Satoru Kakizaki, Kan Chiba
It is acknowledged that induction of CYP3A4 is mainly mediated by pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily that regulates the induction process of CYP3A4 by acting as a xenosensor and a transcriptional activator (Willson & Kliewer, 2002). PXR ligands directly bind to the ligand-binding domain (LBD) of PXR (Jones et al., 2000; Zhu et al., 2004) and translocate PXR into the nucleus (Kawana et al., 2003; Squires et al., 2004). In the nucleus, PXR binds to its cognate DNA response elements as a heterodimer with retinoid X receptor alpha (RXRα) and activates the transcription of target genes, including CYP3A4 (Geick et al., 2001; Goodwin et al., 1999). This induction process is the same as that for other nuclear receptors such as constitutive androstane receptor (CAR, NR1I3) (Yang & Wang, 2014).