Most studies in evolution are centered on how homologous genes, structures, and/or processes appeared and diverged. Although historical homology is well defined as a concept, in practice its establishment can be problematic, especially for some morphological traits or developmental processes. Metamorphosis in chordates is such an enigmatic character. Defined as a spectacular postembryonic larva-to-adult transition, it shows a wide morphological diversity between the different chordate lineages, suggesting that it might have appeared several times independently. In vertebrates, metamorphosis is triggered by binding of the thyroid hormones (THs) T(4) and T(3) to thyroid-hormone receptors (TRs). Here we show that a TH derivative, triiodothyroacetic acid (TRIAC), induces metamorphosis in the cephalochordate amphioxus. The amphioxus TR (amphiTR) mediates spontaneous and TRIAC-induced metamorphosis because it strongly binds to TRIAC, and a specific TR antagonist, NH3, inhibits both spontaneous and TRIAC-induced metamorphosis. Moreover, as in amphibians, amphiTR expression levels increase around metamorphosis and are enhanced by THs. Therefore, TH-regulated metamorphosis, mediated by TR, is an ancestral feature of all chordates. This conservation of a regulatory network supports the homology of metamorphosis in the chordate lineage.
Retinoic acid receptors (RARs), retinoid X receptors (RXRs) and thyroid hormone receptors (TRs) are nuclear receptors that are crucial transcriptional regulators of many cellular processes such as differentiation, development, apoptosis, carbohydrate and lipid metabolism, homeostasis etc. In addition, RXRs are common heterodimerization partners for several receptors including vitamin D receptor, pregnane X receptor (PXR), constitutive androstane receptor (CAR) etc. In the course of 90s', PXR and CAR were discovered as key xenosensors regulating drug-metabolizing enzymes. Since there exist various cross-talks between cell signaling pathways, this was not surprising that RXRs, RARs and TRs were identified as regulators of human drug-metabolizing cytochromes P450 and cytochromes P450 involved in metabolism of endogenous compounds. Hence, a link between regulation of xenobiotic metabolizing enzymes and regulatory pathways of intermediary metabolism was established. Additionally, several drug-metabolizing enzymes are involved in metabolism of retinoids, rexinoids and thyroid hormones. In the current paper, we summarize the knowledge on the role of RARs, RXRs and TRs in the regulation of drug metabolizing cytochromes P450, and vice versa on the role of P450s in homeostasis of retinoids, rexinoids and thyroid hormone.
Vitamin A and its biologically active derivatives are involved in a complex arrangements of physiological and developmental responses in many tissue of higher vertebrates. Retinoids are natural and synthetic compounds related to retinoic acid that act through interaction with two basic types of nuclear receptors: retinoic acid receptors (RAR alpha, RARbeta and RARgamma) and retinoid X receptors (RXRalpha, RXRbeta and RXRgamma) as retinoid-inducible transcription factors. Thus, the retinoid receptors are considered to be ligand-activated, DNA-binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes. They exert both beneficial and detrimental activity; they have tumor-suppressive activity but on the other hand they are teratogenic. Retinoids inhibit carcinogenesis, suppress premalignant epithelial lesions and tumor growth and invasion in a variety of tissues. Natural and synthetic retinoids have therapeutical effects due to their antiproliferative and apoptosis-inducing effects. They are known to cause redifferentiation or to prevent further dedifferentiation of various neoplastic tissues. A number of novel chemical compounds, receptor selective retinoids and rexinoids, have been synthesized up to now and tested both in vitro and in vivo, using animal models against different cancer cells. In spite of that progress, there is still an urgent call for novel synthetic retinoids and rexinoids with greater retinoid receptor selectivity, reasonable chemotherapeutic or chemopreventive effects and reduced toxicity and side effects. This article summarizes selected effects of biologically active natural or synthetic retinoids and rexinoids, acting through their cognate nuclear receptors, and their use in chemotherapy and chemoprevention of various types of cancer.
The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off‐target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first‐in‐class non‐cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR‐specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro‐inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.
Triorganotin compounds induce hormonal alterations, i.e., endocrine-disrupting effects in mammals, including humans. Tributyltin chloride (TBT-Cl) and triphenyltin chloride (TPT-Cl) are known to function as nuclear retinoid X receptor (RXR) agonists. Their cytotoxic effects in ER(+) luminal human breast cancer cell line MCF-7 and ER(-) basal-like human breast cancer cell line MDA-MB-231 were examined. We observed significantly higher toxicity of TBT-Cl in comparison with TPT-Cl in both cell lines. Comparable apoptosis-inducing concentrations were 200 and 800 nM, respectively, as shown by PARP cleavage and FDA staining. Both compounds activated executive caspases in the concentration-dependent manner in MDA-MB-231 cells, but the onset of TPT-Cl-induced caspase-3/7 activation was delayed in comparison with TBT-Cl. Both compounds slowed down the migration of these highly invasive cells, which was accompanied by RARbeta upregulation. Other RAR and RXR expressions were differentially modulated by studied organotins in both cell lines.
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