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Several commercially available triorganotin compounds were previously found to function as agonist ligands for nuclear retinoid X receptor (RXR) molecules. Triphenyltin isoselenocyanate (TPT-NCSe), a novel selenium atom containing a derivative of triorganotin origin, was found to represent a new cognate bioactive ligand for RXRs. TPT-NCSe displayed a concentration- and time-dependent decrease in the cell viability in both human breast carcinoma MCF-7 (estrogen receptor positive) and MDA‑MB‑231 (triple negative) cell lines. Reactive oxygen species levels generated in response to TPT-NCSe were significantly higher in both carcinoma cell lines treated with TPT-NCSe when compared to mock-treated samples. Treatment with 500 nM TPT-NCSe caused a decrease in SOD1 and increased SOD2 mRNA in MCF-7 cells. The levels of SOD2 mRNA were more increased following the treatment with TPT-NCSe along with 1 μM all-trans retinoic acid (AtRA) in MCF-7 cells. An increased superoxide dismutase SOD1 and SOD2 mRNA levels were also detected in combination treatment of 500 nM TPT-NCSe and 1 μM AtRA in TPT-NCSe-treated MDA-MB-231 cells. The data have also shown that TPT-NCSe induces apoptosis via a caspase cascade triggered by the mitochondrial apoptotic pathway. TPT-NCSe modulates the expression levels of apoptosis‑related proteins, Annexin A5, Bcl‑2 and BAX family proteins, and finally, it enhances the expression levels of its cognate nuclear receptor subtypes RXRalpha and RXRbeta. [ABSTRACT FROM AUTHOR]

Nuclear receptors (NRs) are key regulators of multiple physiological functions and pathological changes in the liver in response to a variety of extracellular signaling changes. Retinoid X receptor (RXR) is a special member of the NRs, which not only responds to cellular signaling independently, but also regulates multiple signaling pathways by forming heterodimers with various other NR. Therefore, RXR is widely involved in hepatic glucose metabolism, lipid metabolism, cholesterol metabolism and bile acid homeostasis as well as hepatic fibrosis. Specific activation of particular dimers regulating physiological and pathological processes may serve as important pharmacological targets. So here we describe the basic information and structural features of the RXR protein and its heterodimers, focusing on the role of RXR heterodimers in a number of physiological processes and pathological imbalances in the liver, to provide a theoretical basis for RXR as a promising drug target. [ABSTRACT FROM AUTHOR]

Abstract Understanding the mechanisms underlying alcohol metabolism and its regulation, including the effect of polymorphisms in alcohol-metabolizing enzymes, is crucial for research on Fetal Alcohol Spectrum Disorders. The aim of this study was to identify specific single nucleotide polymorphisms in key alcohol-metabolizing enzymes in a cohort of 71 children, including children with fetal alcohol syndrome, children prenatally exposed to ethanol but without fetal alcohol spectrum disorder, and controls. We hypothesized that certain genetic variants related to alcohol metabolism may be fixed in these populations, giving them a particular alcohol metabolism profile. In addition, the difference in certain isoforms of these enzymes determines their affinity for alcohol, which also affects the metabolism of retinoic acid, which is key to the proper development of the central nervous system. Our results showed that children prenatally exposed to ethanol without fetal alcohol spectrum disorder traits had a higher frequency of the ADH1B*3 and ADH1C*1 alleles, which are associated with increased alcohol metabolism and therefore a protective factor against circulating alcohol in the fetus after maternal drinking, compared to FAS children who had an allele with a lower affinity for alcohol. This study also revealed the presence of an ADH4 variant in the FAS population that binds weakly to the teratogen, allowing increased circulation of the toxic agent and direct induction of developmental abnormalities in the fetus. However, both groups showed dysregulation in the expression of genes related to the retinoic acid pathway, such as retinoic acid receptor and retinoid X receptor, which are involved in the development, regeneration, and maintenance of the nervous system. These findings highlight the importance of understanding the interplay between alcohol metabolism, the retinoic acid pathway and genetic factors in the development of fetal alcohol syndrome.

Treatment with bexarotene, a selective retinoid X receptor (RXR) agonist, significantly improves behavioral dysfunctions in various neurodegenerative animal models. Additionally, it activates neurodevelopmental and plasticity pathways in the brains of adult mice. Our objective was to investigate the impact of RXR activation by bexarotene on adult neural stem cells (aNSC) and their cell lineages. To achieve this, we treated NSCs isolated from the subventricular zone (SVZ) of adult rat brains from the proliferative stage to the differentiated status. The results showed that bexarotene‐treated aNSC exhibited increased BrdU incorporation, SOX2+ dividing cell pairs, and cell migration from neurospheres, revealing that the treatment promotes self‐renewing proliferation and cell motility in SVZ‐aNCS. Furthermore, bexarotene induced a cell fate shift characterized by a significant increase in GFAP+/S100B+ differentiated astrocytes, which uncovers the participation of activated‐RXR in astrogenesis. In the neuronal lineage, the fate shift was counteracted by bexarotene‐induced enhancement of NeuN+ nuclei together with neurite network outgrowth, indicating that the RXR agonist stimulates SVZ‐aNCS neuronal differentiation at later stages. These findings establish new connections between RXR activation, astro‐ and neurogenesis in the adult brain, and contribute to the development of therapeutic strategies targeting nuclear receptors for neural repair. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms underlying alcohol metabolism and its regulation, including the effect of polymorphisms in alcohol-metabolizing enzymes, is crucial for research on Fetal Alcohol Spectrum Disorders. The aim of this study was to identify specific single nucleotide polymorphisms in key alcohol-metabolizing enzymes in a cohort of 71 children, including children with fetal alcohol syndrome, children prenatally exposed to ethanol but without fetal alcohol spectrum disorder, and controls. We hypothesized that certain genetic variants related to alcohol metabolism may be fixed in these populations, giving them a particular alcohol metabolism profile. In addition, the difference in certain isoforms of these enzymes determines their affinity for alcohol, which also affects the metabolism of retinoic acid, which is key to the proper development of the central nervous system. Our results showed that children prenatally exposed to ethanol without fetal alcohol spectrum disorder traits had a higher frequency of the ADH1B*3 and ADH1C*1 alleles, which are associated with increased alcohol metabolism and therefore a protective factor against circulating alcohol in the fetus after maternal drinking, compared to FAS children who had an allele with a lower affinity for alcohol. This study also revealed the presence of an ADH4 variant in the FAS population that binds weakly to the teratogen, allowing increased circulation of the toxic agent and direct induction of developmental abnormalities in the fetus. However, both groups showed dysregulation in the expression of genes related to the retinoic acid pathway, such as retinoic acid receptor and retinoid X receptor, which are involved in the development, regeneration, and maintenance of the nervous system. These findings highlight the importance of understanding the interplay between alcohol metabolism, the retinoic acid pathway and genetic factors in the development of fetal alcohol syndrome. [ABSTRACT FROM AUTHOR]

Abstract Fascioliasis is a parasitic infection in animals and humans caused by the parasitic flatworm genus Fasciola, which has two major species, F. hepatica and F. gigantica. A major concern regarding this disease is drug resistance, which is increasingly reported worldwide. Hence, the discovery of a novel drug as well as drug targets is crucially required. Therefore, this study aims to characterize the novel drug target in the adult F. gigantica. In the beginning, we hypothesized that the parasite might interact with some host molecules when it lives inside the liver parenchyma or bile ducts, specifically hormones and hormone-like molecules, through the specific receptors, primarily nuclear receptors (NRs), which are recognized as a major drug target in various diseases. The retinoid X receptor (RXR) is a member of subfamily 2 NRs that plays multitudinous roles in organisms by forming homodimers or heterodimers with other NRs. We obtained the full-length amino acid sequences of F. gigantica retinoid X receptor-alpha (FgRXRα-A) from the transcriptome of F. gigantica that existed in the NCBI database. The FgRXRα-A were computationally predicted for the basic properties, multiple aligned, phylogeny analyzed, and generated of 2D and 3D models. Moreover, FgRXRα-A was molecular cloned and expressed as a recombinant protein (rFgRXRα-A), then used for immunization for specific polyclonal antibodies. The native FgRXRα-A was detected in the parasite extracts and tissues, and the function was investigated by in vitro binding assay. The results demonstrated the conservation of FgRXRα-A to the other RXRs, especially RXRs from the trematodes. Interestingly, the native FgRXRα-A could be detected in the testes of the parasite, where the sex hormones are accumulated. Moreover, the binding assay revealed the interaction of 9-cis retinoic acid and FgRXRα-A, suggesting the function of FgRXRα-A. Our findings suggested that FgRXRα-A will be involved with the sexual reproduction of the parasite by forming heterodimers with other NRs, and it could be the potential target for further drug development of fascioliasis.

AIM: To investigate the regulatory role of retinoid X receptor （RXR） in oxidative stress response of rat type II alveolar epithelial cells（ AECII） induced by hypoxia/reoxygenation（ HR）. METHODS: The AECII were divided into control （C） group, HR group, HR+solvent dimethyl sulfoxide （DMSO） group （HD group）, HR+RXR agonist 9-cis-retinoic acid （9-RA） group （RA group）, and HR+RXR antagonist HX531 group （HX group）. Cell Counting Kit-8 （CCK-8） method was used to measure the cell viability. Immunofluorescence staining was used to detect the expression of surfactant protein A （SP-A） and RXRα in AECII. Kits were detected to the levels of superoxide dismutase （SOD） and malondialdehyde （MDA） in cells. Transmission electron microscopy was used to observe the ultrastructural changes of the cells. Western blot was used to detect the protein level of nuclear factor E2-related factor 2 （Nrf2）. RT-PCR was used to detect the expression level of Nrf2 mRNA. RESULTS: Compared with C group, the cell viability and SOD activity in HR, HD, RA and HX groups were decreased significantly （P<0. 05）, the MDA content were increased significantly （P<0. 05）, the Nrf2 mRNA and protein expression levels were decreased significantly （P<0. 05 or P<0. 01）, and the immunofluorescence expression of RXRα was significantly increased （P<0. 01）. Compared with HR and HX groups, the cells in RA group showed significantly increased cell viability （P<0. 05）, increased SOD activity（ P<0. 05）, decreased MDA content （P<0. 05）, increased Nrf2 mRNA and protein expression levels （P<0. 01）, and significantly increased immunofluorescence expression of RXRα （P<0. 01）. CONCLUSION: Hypoxia/reoxygenation can aggravate the oxidative stress response of rat AECII, and RXR agonist intervention can alleviate HR-induced rat AECII injury by inhibiting oxidative stress. [ABSTRACT FROM AUTHOR]

As members of nuclear hormone receptor superfamily, retinoic acid receptor and retinoid X receptors are involved in the transduction of retinoic acid signaling. In this study, the full cDNA length of Ca-RARα, Ca-RARγ and Ca-RAR-RXRγ genes were cloned in Carassius auratus. Both Ca-RARα and Ca-RARγ proteins contain the AF-1, AF-2, P-box, D-box, DBD and LBD conservative domains, with 63.09% similarity, but the location of AF-2 in two isoforms is different, with located the end of LBD region in Ca-RARα, and behind the LBD region in Ca-RARγ. Phylogenetic tree indicated that RAR-RXRγ had more closely related to RARα than RARγ. Then the three-dimensional structure of Ca-RARα, Ca-RARγ and Ca-RAR-RXRγ proteins were constructed according to the highest identity with the Homo sapiens RARβ protein. Ca-RARα, Ca-RARγ and Ca-RAR-RXRγ mRNA in several tissues of C. auratus were determined byquantitative real-time PCR analysis. The results shown that Ca-RARα and Ca-RARγ mRNA present tissue-specific expression pattern, with the highest level of Ca-RARα mRNA in ovary, and that of Ca-RARγ mRNA in head kidney. However, Ca-RAR-RXRγ mRNA expression had a widespread distribution, with the highest level in the head kidney, then followed by heart, ovary, intestines, skin, blood and gill. This study lays a foundation for further explore the molecular regular mechanism of vitamin A by RA signaling. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is often accompanied with an induction of retinaldehyde dehydrogenase 1 (RALDH1 or ALDH1A1) expression and a consequent decrease in hepatic retinaldehyde (Rald) levels. However, the role of hepatic Rald deficiency in T2D progression remains unclear. In this study, we demonstrated that reversing T2D-mediated hepatic Rald deficiency by Rald or citral treatments, or liver-specific Raldh1 silencing substantially lowered fasting glycemia levels, inhibited hepatic glucogenesis, and downregulated phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) expression in diabetic db/db mice. Fasting glycemia and Pck1/G6pc mRNA expression levels were strongly negatively correlated with hepatic Rald levels, indicating the involvement of hepatic Rald depletion in T2D deterioration. A similar result that liver-specific Raldh1 silencing improved glucose metabolism was also observed in high-fat diet-fed mice. In primary human hepatocytes and oleic acid-treated HepG2 cells, Rald or Rald + RALDH1 silencing resulted in decreased glucose production and downregulated PCK1/G6PC mRNA and protein expression. Mechanistically, Rald downregulated direct repeat 1-mediated PCK1 and G6PC expression by antagonizing retinoid X receptor α, as confirmed by luciferase reporter assays and molecular docking. These results highlight the link between hepatic Rald deficiency, glucose dyshomeostasis, and the progression of T2D, whilst also suggesting RALDH1 as a potential therapeutic target for T2D.

Purpose: Molting is a pivotal biological process regulated by the ecdysteroid signaling pathway that requires molecular coordination of two transcription factors, Ecdysone receptor (EcR) and ultraspiracle (USP) in arthropods. However, the molecular interplay of EcR and Retinoid X receptor (RXR), the crustacean homolog of USP in the ecdysteroid signaling pathway, is not well understood. Methods: In this study, we conducted temporal and spatial expression, co-immuno-precipitation (CO-IP), and luciferase reporter assay experiments to investigate the molecular function and interplay of EcR and RXR during the molting process of the Chinese mitten crab, Eriocheir sinensis. Results: The results showed that the expression level of RXR was more stable and significantly higher than EcR during the entire molting process. However, the expression level of EcR fluctuated dynamically and increased sharply at the premolt stage. The CO-IP and luciferase reporter assay results confirmed the molecular interplay of EcR and RXR. The heterodimer complex formed by the two transcription factors significantly induced the transcription of E75, an essential gene in the ecdysteroid signaling pathway. Conclusions: Our study unveiled the diverse molecular function and molecular interplay of EcR and RXR; RXR is possibly a "constitutive-type" gene, and EcR is possibly a vital speed-limiting gene while both EcR and RXR are required to initiate the ecdysteroid signaling cascade, which may be indispensable for molting regulation in E. sinensis. The results provide a theoretical basis for the endocrine control of molting in E. sinensis and novel insights into the molecular mechanism of molting mediated by the ecdysteroid signaling pathway in crustaceans. [ABSTRACT FROM AUTHOR]

Background: A goal of developmental genetics is to identify functional interactions that underlie phenotypes caused by mutations. We sought to identify functional interactors of Vsx2, which when mutated, disrupts early retinal development. We utilized the Vsx2 loss‐of‐function mouse, ocular retardation J (orJ), to assess interactions based on principles of positive and negative epistasis as applied to bulk transcriptome data. This was first tested in vivo with Mitf, a target of Vsx2 repression, and then to cultures of orJ retina treated with inhibitors of Retinoid‐X Receptors (RXR) to target Rxrg, an up‐regulated gene in the orJ retina, and gamma‐Secretase, an enzyme required for Notch signaling, a key mediator of retinal proliferation and neurogenesis. Results: Whereas Mitf exhibited robust positive epistasis with Vsx2, it only partially accounts for the orJ phenotype, suggesting other functional interactors. RXR inhibition yielded minimal evidence for epistasis between Vsx2 and Rxrg. In contrast, gamma‐Secretase inhibition caused hundreds of Vsx2‐dependent genes associated with proliferation to deviate further from wild‐type, providing evidence for convergent negative epistasis with Vsx2 in regulating tissue growth. Conclusions: Combining in vivo and ex vivo testing with transcriptome analysis revealed quantitative and qualitative characteristics of functional interaction between Vsx2, Mitf, RXR, and gamma‐Secretase activities. Key Findings: The MItf‐mi allele exhibits positive epistasis with the Vsx2‐orJ allele, but Mitf activity only partially accounts for disrupted early retinal development in Vsx2 mutant mice.Rxrg is highly upregulated in the Vsx2 mutant retina, but RXR activity is not a strong driver of the early retinal phenotype.Gamma secretase activity regulates a large cohort of Vsx2‐dependent genes associated with proliferation, providing evidence for convergent negative epistasis, and could account for the continued but slow rate of proliferation in Vsx2 mutant retinal progenitor cells.Bulk RNA sequencing combined with tests of functional interaction can provide sufficient resolution to assess phenotypic changes and epistasis of complex developmental phenotypes [ABSTRACT FROM AUTHOR]

Previously, the RXR agonist UAB126 demonstrated therapeutic potential to treat obese mice by controlling blood glucose levels (BGL) and altering the expression of genes associated with lipid metabolism and inflammatory response. The purpose of the study was to assess the effects of UAB126 on the progression of diabetic retinopathy (DR) in rodent models of type 1 diabetes (T1D), streptozotocin-induced, and type 2 diabetes (T2D), in db/db mice. UAB126 treatment was delivered either by oral gavage for 6 weeks or by topical application of eye drops for 2 weeks. At the end of the treatment, the retinal function of diabetic mice was assessed by electroretinography (ERG), and their retinal tissue was harvested for protein and gene expression analyses. Bone-marrow cells were isolated and differentiated into bone marrow-derived macrophages (BMDMs). The glycolysis stress test and the 2-DG glucose uptake analysis were performed. Our results demonstrated that in the UAB126-treated diabetic BMDMs, the ECAR rate and the 2-DG uptake were improved as compared to untreated diabetic BMDMs. In UAB126-treated diabetic mice, hyperglycemia was reduced and associated with the preservation of ERG amplitudes and enhanced AMPK activity. Retinas from diabetic mice treated with topical UAB126 demonstrated an increase in Rxr and Ppar and the expression of genes associated with lipid metabolism. Altogether, our data indicate that RXR activation is beneficial to preclinical models of DR. [ABSTRACT FROM AUTHOR]

Endocrine‐disrupting chemicals (EDCs) often affect homeostatic regulation in living organisms by directly acting on nuclear receptors (NRs). Retinoid X receptors (RXRs), the most highly conserved members of the NR superfamily during evolution, function as partners to form heterodimers with other NRs, such as retinoic acid, thyroid hormone, and vitamin D3 receptors. RXRs also homodimerize and induce the expression of target genes upon binding with their natural ligand, 9‐cis‐retinoic acid (9cRA), and typical EDCs organotin compounds, such as tributyltin and triphenyltin. In the present study, we established a new yeast reporter gene assay (RGA) to detect the ligands of freshwater cladoceran Daphnia magna ultraspiracle (Dapma‐USP), a homolog of vertebrate RXRs. D. magna has been used as a representative crustacean species for aquatic EDC assessments in the Organization for Economic Corporation and Development test guidelines. Dapma‐USP was expressed along with the Drosophila melanogaster steroid receptor coactivator Taiman in yeast cells carrying the lacZ reporter plasmid. The RGA for detecting agonist activity of organotins and o‐butylphenol was improved by use of mutant yeast strains lacking genes encoding cell wall mannoproteins and/or plasma membrane drug efflux pumps as hosts. We also showed that a number of other human RXR ligands, phenol and bisphenol A derivatives, and terpenoid compounds such as 9c‐RA exhibited antagonist activity on Dapma‐USP. Our newly established yeast‐based RGA system is valuable as the first screening tool to detect ligand substances for Dapma‐USP and for evaluating the evolutionary divergence of the ligand responses of RXR homologs between humans and D. magna. The freshwater cladoceran Daphnia magna has been used as a representative crustacean species for aquatic assessments of endocrine‐disrupting chemicals (EDCs) in the Organization for Economic Corporation and Development test guidelines. The typical EDCs, organotin compounds, which include tributyltin and triphenyltin, exhibit ligand activities for nuclear receptor retinoid X receptors (RXRs). In the present study, a new reporter gene assay to detect ligands of D. magna ultraspiracle, a homolog of vertebrate RXRs, was established in the yeast Saccharomyces cerevisiae. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is often accompanied with an induction of retinaldehyde dehydrogenase 1 (RALDH1 or ALDH1A1) expression and a consequent decrease in hepatic retinaldehyde (Rald) levels. However, the role of hepatic Rald deficiency in T2D progression remains unclear. In this study, we demonstrated that reversing T2D-mediated hepatic Rald deficiency by Rald or citral treatments, or liver-specific Raldh1 silencing substantially lowered fasting glycemia levels, inhibited hepatic glucogenesis, and downregulated phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) expression in diabetic db/db mice. Fasting glycemia and Pck1/G6pc mRNA expression levels were strongly negatively correlated with hepatic Rald levels, indicating the involvement of hepatic Rald depletion in T2D deterioration. A similar result that liver-specific Raldh1 silencing improved glucose metabolism was also observed in high-fat diet-fed mice. In primary human hepatocytes and oleic acid-treated HepG2 cells, Rald or Rald + RALDH1 silencing resulted in decreased glucose production and downregulated PCK1 / G6PC mRNA and protein expression. Mechanistically, Rald downregulated direct repeat 1-mediated PCK1 and G6PC expression by antagonizing retinoid X receptor α , as confirmed by luciferase reporter assays and molecular docking. These results highlight the link between hepatic Rald deficiency, glucose dyshomeostasis, and the progression of T2D, whilst also suggesting RALDH1 as a potential therapeutic target for T2D. Rald inhibits RXR/DR1-mediated PCK1/G6PC expression. Type 2 diabetes (T2D)-induced hepatic Rald deficiency enhances gluconeogenesis by attenuating the inhibitory effects on the induction of PCK1/G6PC by RXR activation, which exacerbates the progression of T2D. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is an aggressive form of fatty liver disease with hepatic inflammation and fibrosis for which there is currently no drug treatment. This study determined whether an indoline derivative, AN1284, which significantly reduced damage in a model of acute liver disease, can reverse steatosis and fibrosis in mice with pre-existing NASH and explore its mechanism of action. The mouse model of dietary-induced NASH reproduces most of the liver pathology seen in human subjects. This was confirmed by RNA-sequencing analysis. The Western diet, given for 4 months, caused steatosis, inflammation, and liver fibrosis. AN1284 (1 mg or 5 mg/kg/day) was administered for the last 2 months of the diet by micro-osmotic-pumps (mps). Both doses significantly decreased hepatic damage, liver weight, hepatic fat content, triglyceride, serum alanine transaminase, and fibrosis. AN1284 (1 mg/kg/day) given by mps or in the drinking fluid significantly reduced fibrosis produced by carbon tetrachloride injections. In human HUH7 hepatoma cells incubated with palmitic acid, AN1284 (2.1 and 6.3 ng/ml), concentrations compatible with those in the liver of mice treated with AN1284, decreased lipid formation by causing nuclear translocation of the aryl hydrocarbon receptor (AhR). AN1284 downregulated fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c) and upregulated Acyl-CoA Oxidase 1 and Cytochrome P450-a1, genes involved in lipid metabolism. In conclusion, chronic treatment with AN1284 (1mg/kg/day) reduced pre-existing steatosis and fibrosis through AhR, which affects several contributors to the development of fatty liver disease. Additional pathways are also influenced by AN1284 treatment. [ABSTRACT FROM AUTHOR]

The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticlebased approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues. [ABSTRACT FROM AUTHOR]

Farnesoid X receptor (FXR) is a ligand-activated transcription factor known as bile acid receptor (BAR). FXR plays critical roles in various biological processes, including metabolism, immune inflammation, liver regeneration and liver carcinogenesis. FXR forms a heterodimer with the retinoid X receptor (RXR) and binds to diverse FXR response elements (FXREs) to exert its various biological functions. However, the mechanism by which the FXR/RXR heterodimer binds the DNA elements remains unclear. In this study, we aimed to use structural, biochemical and bioinformatics analyses to study the mechanism of FXR binding to the typical FXRE, such as the IR1 site, and the heterodimer interactions in the FXR-DBD/RXR-DBD complex. Further biochemical assays showed that RAR, THR and NR4A2 do not form heterodimers with RXR when bound to the IR1 sites, which indicates that IR1 may be a unique binding site for the FXR/RXR heterodimer. Our studies may provide a further understanding of the dimerization specificity of nuclear receptors.

Keywords: nuclear receptor signaling; retinoic acid receptor; retinoid X receptor; pharmacology; structure/function relationships; genomic and non-genomic signaling; post-translational modification; homeostasis and disease; development; origin and evolution EN nuclear receptor signaling retinoic acid receptor retinoid X receptor pharmacology structure/function relationships genomic and non-genomic signaling post-translational modification homeostasis and disease development origin and evolution 864 5 03/31/23 20230315 NES 230315 One of the most fundamental discoveries in human biology was that of the existence of essential micronutrients that the body cannot synthesize but nonetheless requires for proper functioning [[1]]. Nuclear receptor signaling, retinoic acid receptor, retinoid X receptor, pharmacology, structure/function relationships, genomic and non-genomic signaling, post-translational modification, homeostasis and disease, development, origin and evolution Only several decades later, all I trans i retinoic acid (RA) was identified as the biologically active metabolite of vitamin A, mediating the observable effects of vitamin A on cell growth and differentiation [[6]]. The intracellular receptor that transduces the signal conveyed by the presence of RA into a cellular response was finally discovered in 1987: the retinoic acid receptor (RAR or NR1B) [[8]]. [Extracted from the article]

Non-alcoholic steatohepatitis (NASH) is an aggressive form of fatty liver disease with hepatic inflammation and fibrosis for which there is currently no drug treatment. This study determined whether an indoline derivative, AN1284, which significantly reduced damage in a model of acute liver disease, can reverse steatosis and fibrosis in mice with pre-existing NASH and explore its mechanism of action. The mouse model of dietary-induced NASH reproduces most of the liver pathology seen in human subjects. This was confirmed by RNA-sequencing analysis. The Western diet, given for 4 months, caused steatosis, inflammation, and liver fibrosis. AN1284 (1 mg or 5 mg/kg/day) was administered for the last 2 months of the diet by micro-osmotic-pumps (mps). Both doses significantly decreased hepatic damage, liver weight, hepatic fat content, triglyceride, serum alanine transaminase, and fibrosis. AN1284 (1 mg/kg/day) given by mps or in the drinking fluid significantly reduced fibrosis produced by carbon tetrachloride injections. In human HUH7 hepatoma cells incubated with palmitic acid, AN1284 (2.1 and 6.3 ng/ml), concentrations compatible with those in the liver of mice treated with AN1284, decreased lipid formation by causing nuclear translocation of the aryl hydrocarbon receptor (AhR). AN1284 downregulated fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c) and upregulated Acyl-CoA Oxidase 1 and Cytochrome P450-a1, genes involved in lipid metabolism. In conclusion, chronic treatment with AN1284 (1mg/kg/day) reduced pre-existing steatosis and fibrosis through AhR, which affects several contributors to the development of fatty liver disease. Additional pathways are also influenced by AN1284 treatment.

The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.

Retinoid X receptor alpha (RXRα) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that show low affinity for RXRα, but nevertheless cause significant activation, though these may represent a human health hazard. We recently discovered that several industrial chemicals having 1,3-bis- tert -butylbenzene as a common chemical structure exhibit agonistic activity towards rat RXRα. In this study, we explored the structure-activity relationship of 1,3-bis- tert -butyl monocyclic benzene derivatives for RXRα activation by means of in vitro and in silico analyses. The results indicate that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXRα. Since 1,3-bis -tert -butyl monocyclic benzene derivatives with bulky hydrophobic moieties differ structurally from known RXRα ligands such as 9- cis -retinoic acid and bexarotene, our findings may be helpful for the development of structural alerts in the safety evaluation of industrial chemicals for RXRα-based toxicity to living organisms. [Display omitted] • 1,3-Bis- tert -butyl monocyclic benzene structure features in a variety of industrial chemicals. • Compounds containing 1,3-bis- tert -butyl monocyclic benzene structure exhibit RXRα-agonistic activity. • A bulky substituent at the 5-position of 1,3-bis- tert -butylbenzene is favorable for agonistic activity towards RXRα. [ABSTRACT FROM AUTHOR]

Previously, the RXR agonist UAB126 demonstrated therapeutic potential to treat obese mice by controlling blood glucose levels (BGL) and altering the expression of genes associated with lipid metabolism and inflammatory response. The purpose of the study was to assess the effects of UAB126 on the progression of diabetic retinopathy (DR) in rodent models of type 1 diabetes (T1D), streptozotocin-induced, and type 2 diabetes (T2D), in db/db mice. UAB126 treatment was delivered either by oral gavage for 6 weeks or by topical application of eye drops for 2 weeks. At the end of the treatment, the retinal function of diabetic mice was assessed by electroretinography (ERG), and their retinal tissue was harvested for protein and gene expression analyses. Bone-marrow cells were isolated and differentiated into bone marrow-derived macrophages (BMDMs). The glycolysis stress test and the 2-DG glucose uptake analysis were performed. Our results demonstrated that in the UAB126-treated diabetic BMDMs, the ECAR rate and the 2-DG uptake were improved as compared to untreated diabetic BMDMs. In UAB126-treated diabetic mice, hyperglycemia was reduced and associated with the preservation of ERG amplitudes and enhanced AMPK activity. Retinas from diabetic mice treated with topical UAB126 demonstrated an increase in Rxr and Ppar and the expression of genes associated with lipid metabolism. Altogether, our data indicate that RXR activation is beneficial to preclinical models of DR.

Background: Over the past decade, several controversial studies described a relationship between vitamin D and atopic diseases. Low plasma vitamin D levels or even vitamin D deficiency was associated with an increased incidence of atopic disease, postulating that a higher dietary intake of vitamin D may be a beneficial strategy against atopic diseases such as atopic dermatitis (AD). Objective: Our aim was to determine the relationship between plasma 25-hydroxyvitamin D3 (25(OH)D3) levels, the levels of the ligand of the vitamin D receptor (VDR) heterodimerization partner as well as the retinoid X receptor (RXR) and the active vitamin A5 derivative 9-cis-13,14-dihydroretinoic acid (9CDHRA) and AD severity. Methods/Results: Samples from AD patients (n = 20) and healthy volunteers (n = 20) were assessed. In our study, the frequently measured VDR ligand precursor 25(OH)D3 in addition to the VDR-ligand 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 9CDHRA displayed no different levels when compared with the plasma of AD patients and healthy volunteers. When performing further correlation studies focusing on AD patients, plasma 25(OH)D3 levels showed a negative correlation with eosinophils in blood (EOS) and SCORing Atopic Dermatitis (SCORAD) values, while 1,25(OH)2D3 and 9CDHRA levels correlated positively with plasma IgE, EOS, and SCORAD values. Conclusion: In consequence, the metabolic activation of vitamin D from 25(OH)D3 towards 1,25(OH)2D3 as well as the co-liganding of the RXR by 9CDHRA may be an important signalling mechanism, an important marker for AD development and severity as well as the basis for novel nutritional and pharmaceutical AD treatment options. [ABSTRACT FROM AUTHOR]

Nuclear receptors (NRs) are key regulators of multiple physiological functions and pathological changes in the liver in response to a variety of extracellular signaling changes. Retinoid X receptor (RXR) is a special member of the NRs, which not only responds to cellular signaling independently, but also regulates multiple signaling pathways by forming heterodimers with various other NR. Therefore, RXR is widely involved in hepatic glucose metabolism, lipid metabolism, cholesterol metabolism and bile acid homeostasis as well as hepatic fibrosis. Specific activation of particular dimers regulating physiological and pathological processes may serve as important pharmacological targets. So here we describe the basic information and structural features of the RXR protein and its heterodimers, focusing on the role of RXR heterodimers in a number of physiological processes and pathological imbalances in the liver, to provide a theoretical basis for RXR as a promising drug target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Zhang, Pan and Zhang.)

The RXR agonist (triphenyltin, TPT) and the RXR antagonist (UVI3003) both show teratogenicity and, unexpectedly, induce similar malformations in Xenopus tropicalis embryos. In the present study, we exposed X. tropicalis embryos to UVI3003 in seven specific developmental windows and identified changes in gene expression. We further measured the ability of UVI3003 to activate Xenopus RXRα (xRXRα) and PPARγ (xPPARγ) in vitro and in vivo. We found that UVI3003 activated xPPARγ either in Cos7 cells (in vitro) or Xenopus embryos (in vivo). UVI3003 did not significantly activate human or mouse PPARγ in vitro; therefore, the activation of Xenopus PPARγ by UVI3003 is novel. The ability of UVI3003 to activate xPPARγ explains why UVI3003 and TPT yield similar phenotypes in Xenopus embryos. Our results indicate that activating PPARγ leads to teratogenic effects in Xenopus embryos. More generally, we infer that chemicals known to specifically modulate mammalian nuclear hormone receptors cannot be assumed to have the same activity in non-mammalian species, such as Xenopus. Rather they must be tested for activity and specificity on receptors of the species in question to avoid making inappropriate conclusions.

The present review traces the road leading to discovery of L-thyroxine, thyroid hormone (3,5,3´-triiodo-L-thyronine, T3) and its cognate nuclear receptors. Thyroid hormone is a pleio-tropic regulator of growth, differentiation, and tissue homeostasis in higher organisms. The major site of the thyroid hormone action is predominantly a cell nucleus. T3 specific binding sites in the cell nuclei have opened a new era in the field of the thyroid hormone receptors (TRs) discovery. T3 actions are mediated by high affinity nuclear TRs, TRalpha and TRbeta, which function as T3-activated transcription factors playing an essential role as transcription-modulating proteins affecting the transcriptional responses in target genes. Discovery and characterization of nuclear retinoid X receptors (RXRs), which form with TRs a heterodimer RXR/TR, positioned RXRs at the epicenter of molecular endocrinology. Transcriptional control via nuclear RXR/TR heterodimer represents a direct action of thyroid hormone. T3 plays a crucial role in the development of brain, it exerts significant effects on the cardiovascular system, skeletal muscle contractile function, bone development and growth, both female and male reproductive systems, and skin. It plays an important role in maintaining the hepatic, kidney and intestine homeostasis and in pancreas, it stimulates the beta-cell proliferation and survival. The TRs cross-talk with other signaling pathways intensifies the T3 action at cellular level. The role of thyroid hormone in human cancers, acting via its cognate nuclear receptors, has not been fully elucidated yet. This review is aimed to describe the history of T3 receptors, starting from discovery of T3 binding sites in the cell nuclei to revelation of T3 receptors as T3-inducible transcription factors in relation to T3 action at cellular level. It also focuses on milestones of investigation, comprising RXR/TR dimerization, cross-talk between T3 receptors, and other regulatory pathways within the cell and mainly on genomic action of T3. This review also focuses on novel directions of investigation on relationships between T3 receptors and cancer. Based on the update of available literature and the author’s experimental experience, it is devoted to clinicians and medical students.

The effective treatment of diabetes with comorbid depression is a big challenge so far. Honokiol, a bioactive compound from the dietary supplement Magnolia officinalis extract, possesses multiple health benefits. The present study aims to propose a network pharmacology-based method to elucidate potential targets of honokiol in treating diabetes with comorbid depression and related mechanisms. The antidepressant-like efficacy of honokiol was evaluated in high-fat diet (HFD) induced diabetic mice using animal behavior testing, immuno-staining and western blotting assay. Through network pharmacology analysis, retinoid X receptor alpha (RXRα) and vitamin D receptor (VDR) were identified as potential targets related to diabetes and depression. The stable binding conformation between honokiol and RXR/VDR was determined by molecular docking simulation. Moreover, hononkiol effectively alleviated depression-like behaviors in HFD diabetic mice, presented anti-diabetic and anti-neuroinflammatory functions, and protected the hippocampal neuroplasticity. Importantly, honokiol could activate RXR/VDR heterodimer in vivo. The beneficial effects of honokiol on HFD mice were significantly suppressed by UVI3003 (a RXR antagonist), while enhanced by calcitriol (a VDR agonist). Additionally, the disruption of autophagy in the hippocampus of HFD mice was ameliorated by honokiol, which was attenuated by UVI3003 but strengthened by calcitriol. Taken together, the data provide new evidence that honokiol exerts the antidepressant-like effect in HFD diabetic mice via activating RXR/VDR heterodimer to restore the balance of autophagy. Our findings indicate that the RXR/VDR-mediated signaling might be a potential target for treating diabetes with comorbid depression. [ABSTRACT FROM AUTHOR]

One of the most fundamental discoveries in human biology was that of the existence of essential micronutrients that the body cannot synthesize but nonetheless requires for proper functioning [...]

Nuclear receptors are a superfamily of transcription factors that regulate gene transcription and intracellular function. They have a key role in various biological processes. Liver X receptors (LXR) mainly play role in lipid metabolism, cholesterol synthesis, glucose homeostasis, and inflammation whereas retinoid X receptor alpha (RXRa) plays important role in inflammation and immunity. In this study, Plantago holosteum, P. major subsp. major, P. lagopus, P. scabra, and Scutellaria salviifolia were selected for further investigation due to their anti-inflammatory activities. For this purpose, liver x receptor alpha (LXRa) and retinoid x receptor alpha (RXRa) agonist activity of the extracts was determined through luciferase reporter gene assay on HEK293 cells at a concentration of 100 µg/ml. P. holosteum, P. major subsp. major, P. lagopus, and P. scabra extracts showed weak LXRa agonist activity with the fold values in a range of 0.95-1.39. P. major showed the highest agonist activity among tested Plantago species. For LXRa agonist activity, S. salviifolia extract had a fold value of 2.37 which was comparable to the positive control T09011317 at 10 nM concentration. Results for RXRa agonist activity found to be similar to LXRa for all extracts. S. salviifolia showed the highest RXRa agonist activity with a fold value of 1.62. Results suggested that Scutellaria species, which are used as traditional medicine especially in eastern Asia due to its anti-inflammatory effects, might show this effect due to LXRa activation. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) andattenuate neurochemical and motor deficits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment.

Ex vivo expansion of human cord blood (CB) hematopoietic stem cells (HSCs) is one approach to overcome limited numbers of HSCs in single CB units. However, there is still no worldwide acceptable HSC ex vivo expansion system. A main reason is that we still have very limited knowldege regarding mechanisms underlying maintenance and expansion of CB HSCs. Here we report that retinoid X receptor (RXR) activity is of significance for CB HSC ex vivo expansion. RXR antagonist HX531 significantly promoted ex vivo expansion of CB HSCs and progenitor cells (HPCs). RXR agonist Bexarotene notably suppressed ex vivo expansion of CB HSCs. Activation of RXR by Bexarotene significantly blocked expansion of phenotypic HSCs and HPCs and expressed increased functional HPCs as assessed by colony formation induced by UM171 and SR1. In vivo transplantation experiments in immune-deficient mice demonstrated that HX531 expanded CB HSCs possess long-term reconstituting capacities, and Bexarotene treatment inhibited expansion of functional CB HSCs. RNA-seq analysis revealed that RXR regulates expression of FBP1 (a negative regulator of glucose metabolism) and many genes involved in differentation. ECAR analysis showed that HX531 significantly promoted glycolytic activity of CB CD34+ HSCs and HPCs. Our studies suggest that RXR is a negative regulator of ex vivo expansion of CB HSCs and HPCs. [ABSTRACT FROM AUTHOR]

Nuclear receptors (NRs) are a family of transcription factors that are regulated endogenously by small lipophilic ligands. Recently, liquid-liquid phase separation (LLPS) has appeared as a new aspect of NR function. In the human retinoid X receptor γ (h RXRγ), the inherently disordered AB region undergoes LLPS via homotypic multivalent interactions. To better understand the functions of liquid condensates, a clear view of the molecular interactions underlying the LLPS are required. The phase separation propensity of the AB region of h RXRγ (AB_ h RXG) at a high NaCl concentration, a lower critical solution temperature behavior, and also sensitivity to kosmotropic salts and 1,6-hexanediol, which all indicate the importance of hydrophobic interactions in the formation of AB_ h RXG liquid condensates, is presented in the paper. Additionally, molecular crowding agents and TMAO shift the equilibrium, in turn enabling phase transition at lower AB_ h RXG concentrations. Although the LLPS of the proteins can lead to aggregation, AB_ h RXG liquid condensates are not aggregation prone. Interestingly, the formation of AB_ h RXG liquid condensates has an impact on the rest of the receptor, as AB_ h RXG liquid condensates recruit the remaining fragment of h RXRγ into the droplets. The ability of AB_ h RXG to undergo LLPS might be important for gene expression regulation. [ABSTRACT FROM AUTHOR]

This study measured the sequelae of cholecalciferol (VD3) therapy on ovarian functions in adult VD-replete rats (n = 48). The animals were distributed into the control and VD groups following estrous cycle synchronisation. The VD group received VD3 injections for 4 weeks (600 IU/Kg; 3 times/week). Vaginal cytology and cycle durations were recorded throughout the study. Serum VD (25-OH VD), Ca2+, gonadotrophins (FSH & LH) and sex steroids (E2 & progesterone) were measured following euthanasia. Follicles and corpora lutea were counted in ovarian tissue sections. VD receptor, binding protein, Ca2+-sensing receptor and retinoid X receptor-α genes and proteins were measured by quantitative RT-PCR and immunohistochemistry. Serum VD, LH, E2 and progesterone levels were significantly higher, whereas FSH declined, in the VD group than controls. VD3 therapy was also associated with markedly higher rates alongside shorter durations of estrous cycles than controls. While serum Ca2+ levels were equal between the study groups, they correlated directly with serum 25-OH VD. The numbers of small and medium size ovarian follicles were equal in both study groups, whereas large follicles and corpora lutea counts were significantly higher in the VD group. The mRNAs and proteins of targeted molecules also increased substantially in the VD group than controls. In conclusion, treating VD-sufficient female rats with supraphysiological VD3 supplements was not associated with hypercalcaemia, and could contribute to ovarian functions by regulating the hypothalamic-pituitary-ovarian hormones and ovarian VD-related molecules. However, further studies are still needed to illustrate the clinical significance of VD3 in female reproduction. [ABSTRACT FROM AUTHOR]

Human skin is the natural source, place of metabolism, and target for vitamin D 3. The classical active form of vitamin D 3 , 1,25(OH) 2 D 3 , expresses pluripotent properties and is intensively studied in cancer prevention and therapy. To define the specific role of vitamin D 3 receptor (VDR) and its co-receptor retinoid X receptor alpha (RXRA) in genomic regulation, VDR or RXRA genes were silenced in the squamous cell carcinoma cell line A431 and treated with 1,25(OH) 2 D 3 at long incubation time points 24 h/72 h. Extending the incubation time of A431 WT (wild-type) cells with 1,25(OH) 2 D 3 resulted in a two-fold increase in DEGs (differentially expressed genes) and a change in the amount of downregulated from 37% to 53%. VDR knockout led to a complete loss of 1,25(OH) 2 D 3 -induced genome-wide gene regulation at 24 h time point, but after 72 h, 20 DEGs were found, of which 75% were downregulated, and most of them belonged to the gene ontology group "immune response". This may indicate the existence of an alternative, secondary response to 1,25(OH) 2 D 3. In contrast, treatment of A431 ΔRXRA cells with 1,25(OH) 2 D 3 for 24 h only partially affected DEGs, suggesting RXRA-independent regulation. Interestingly, overexpression of classic 1,25(OH) 2 D 3 targets, like CYP24A1 (family 24 of subfamily A of cytochrome P450 member 1) or CAMP (cathelicidin antimicrobial peptide) was found to be RXRA-independent. Also, immunofluorescence staining of A431 WT cells revealed partial VDR/RXRA colocalization after 24 h and 72 h 1,25(OH) 2 D 3 treatment. Comparison of transcriptome changes induced by 1,25(OH) 2 D 3 in normal keratinocytes vs. cancer cells showed high cell type specific expression pattern with only a few genes commonly regulated by 1,25(OH) 2 D 3. Activation of the genomic pathway at least partially reversed the expression of cancer-related genes, forming a basis for anti-cancer activates of 1,25(OH) 2 D 3. In summary, VDR or RXRA independent genomic activities of 1,25(OH) 2 D 3 suggest the involvement of alternative factors, opening new challenges in this field. [ABSTRACT FROM AUTHOR]

Abstract Background Subarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high mortality and disabilities. Retinoid X receptor (RXR) has been shown to be neuroprotective against ischemia/reperfusion injury. This study aimed to investigate the effects of the selective RXR agonist bexarotene on neuroinflammation in a rat model of SAH. Methods Two hundred male Sprague-Dawley rats were used. The endovascular perforation induced SAH. Bexarotene was administered intraperitoneally at 1 h after SAH induction. To investigate the underlying mechanism, the selective RXR antagonist UVI3003 and RXR siRNA or SIRT6 inhibitor OSS128167 was administered via intracerebroventricular 1 h before SAH induction. Post-SAH assessments including SAH grade, neurological score, brain water content, Western blot, and immunofluorescence were performed. Results The endogenous RXR and sirtuin 6 (SIRT6) protein levels were increased after SAH. Bexarotene treatment significantly reduced brain edema and improved the short-/long-term neurological deficit after SAH. Mechanistically, bexarotene increased the levels of PPARγ and SIRT6; decreased the expression of phosphorylated FoxO3a (p-FoxO3a), IL-6, IL-1β, and TNF-a; and inhibited the microglia activation and neutrophils infiltration at 24 h after SAH. Either UVI3003, OSS128167, or RXR siRNA abolished the neuroprotective effects of bexarotene and its regulation on protein levels of PPARγ/SIRT6/p-FoxO3a after SAH. Conclusions The activation of RXR by bexarotene attenuated neuroinflammation and improved neurological deficits after SAH. The anti-neuroinflammatory effect was at least partially through regulating PPARγ/SIRT6/FoxO3a pathway. Bexarotene may be a promising therapeutic strategy in the management of SAH patients.

Abstract Background Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined. Methods We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction. Results Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice. Conclusion These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.

Retinoic acid (RA) signaling pathways mediated by RA receptors (RARs) are essential for many physiological processes such as organ development, regeneration, and differentiation in animals. Recent studies reveal that RARs identified in several mollusks, including Pacific oyster Crassostrea gigas, have a different function mechanism compared with that in chordates. In this report, we identified the molecular characteristics of CgRAR to further explore the mechanism of RAR in mollusks. RT-qPCR analysis shows that CgRAR has a higher expression level in the hemocytes and gonads, indicating that CgRAR may play roles in the processes of development and metabolism. The mRNA expression level of both CgRAR and CgRXR was analyzed by RT-qPCR after injection with RA. The elevated expression of CgRAR and CgRXR was detected upon all-trans-RA (ATRA) exposure. Finally, according to the results of Yeast Two-Hybrid assay and co-immunoprecipitation analysis, CgRAR and CgRXR can interact with each other through the C-terminal region. Taken together, our results suggest that CgRAR shows a higher expression level in gonads and hemocytes. ATRA exposure up-regulates the expression of CgRAR and CgRXR. Besides, CgRAR can interact with CgRXR to form a heterodimer complex.

Vitamin D has a crucial role in cancer control and prevention. For its activity, VDR (vitamin D receptor) and its heterodimer RXR (Retinoid X receptor) are equally important in the cell. This ligand (vitamin D) and receptors (VDR-RXR) complex together triggers downstream DNA damage response in the cell and thus counters cancer in blood. 137 patients and 60 disease free controls were recruited for this study. The levels of vitamin D in patient and controls were analysed and compared using ELISA. The mRNA expression of the two receptor genes; VDR and RXR was also assessed by RT-PCR, to see their role in haematological malignancies. Their expression levels were corelated with the vitamin D levels in individuals to understand their mutual contribution in blood cancer prevention. The results confirmed a highly significant correlation between vitamin D levels of patients and controls (p < 0.001). The study also revealed that age of patients is a critical factor in determining the relative risk of blood cancer (p < 0.001), its types (leukaemia and lymphoma) and subtypes. Also, the mRNA expression of VDR showed a positive and non-significant relationship with vitamin D levels and RXR expression (p > 0.05). Based on our findings, and studies on other diseases it can be inferred that Vitamin D deficiency and dysregulation of its associated receptors may lead to cancer initiation and/or progression by failing to trigger the cellular DNA damage repair machinery. [ABSTRACT FROM AUTHOR]

Retinoic acid (RA) signaling pathways mediated by RA receptors (RARs) are essential for many physiological processes such as organ development, regeneration, and differentiation in animals. Recent studies reveal that RARs identified in several mollusks, including Pacific oyster Crassostrea gigas , have a different function mechanism compared with that in chordates. In this report, we identified the molecular characteristics of CgRAR to further explore the mechanism of RAR in mollusks. RT-qPCR analysis shows that CgRAR has a higher expression level in the hemocytes and gonads, indicating that CgRAR may play roles in the processes of development and metabolism. The mRNA expression level of both CgRAR and CgRXR was analyzed by RT-qPCR after injection with RA. The elevated expression of CgRAR and CgRXR was detected upon all- trans -RA (ATRA) exposure. Finally, according to the results of Yeast Two-Hybrid assay and co-immunoprecipitation analysis, CgRAR and CgRXR can interact with each other through the C-terminal region. Taken together, our results suggest that CgRAR shows a higher expression level in gonads and hemocytes. ATRA exposure up-regulates the expression of CgRAR and CgRXR. Besides, CgRAR can interact with CgRXR to form a heterodimer complex. [ABSTRACT FROM AUTHOR]

ω3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of ω3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12‐hydroxyeicosapentaenoic acid (12‐HEPE), which is a 12‐lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed ω3 fatty acid‐rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12‐HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12‐HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12‐HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12‐HEPE as the dominant ω3 fatty acid metabolite in the skin. [ABSTRACT FROM AUTHOR]

• The study assessed the role of promoter hypermethylation of VDR gene in CRC • Significant association was found between the VDR promoter methylation and VDR expression in the progression of colorectal cancer • Association between VDR expression and methylation data with clinico-pathological features was also discernible • VDR may potentially prove as a valuable prognostic tool in colorectal cancer Colorectal carcinogenesis (CRC) is a multistep process, involving both genetic and epigenetic modifications of genes involved in diverse pathways ranging from tumor suppression to DNA mismatch repair. This study was undertaken to assess the role of promoter methylation of vitamin D receptor (VDR) gene, a transcription factor with myriad biological functions, in relation to its expression and clinicopathological parameters. Tissue specimens were taken from a total of 75 colorectal cancer cases paired with their normal surrounding epithelium and analyzed by Real-time RT-PCR for assessing the expression profile and MS-PCR for analyzing the promoter methylation status of the VDR gene. Blood sample from the same patients was drawn for vitamin D estimation. The frequency of promoter methylation in cancerous tissue was 37.33% against 9.33% in normal tissues (p< 0.001). The hypermethylated status of VDR promoter showed significantly inverse association with its expression (p =0.008). Furthermore, when compared with the clinical parameters, methylation status of VDR promoter was significantly associated with tumor staging (p =0.008), grading (p< 0.001), depth of invasion (p =0.002) and lymph node metastases (p< 0.001). Univariate and multivariate analysis indicated patients with increased VDR expression (p< 0.001) and decreased methylation status (p =0.012) exhibited longer overall survival. Additionally, serum 25(OH)D 3 levels were not significantly associated with any of the patient characteristics. Our study, first of its kind from Kashmir, indicated that VDR shows aberrant methylation pattern in CRC with consequent loss in its expression. [ABSTRACT FROM AUTHOR]

Endocrine disruption compounds (EDC) are known to affect reproduction, development, and growth of exposed organisms. Although in vertebrates, EDCs mainly act through steroid receptors (e.g. androgen and estrogen receptors), their absence in many invertebrates suggests the involvement of another biological pathway in endocrine disruption effects. As retinoid signaling pathway is present in almost all Metazoa and its involvement in the endocrine disruption of gastropods (i.e. imposex) has been demonstrated, the present work was devoted to investigating the relative mRNA variations of two retinoid receptors genes, retinoid X receptor (RXR) and retinoid acid receptor (RAR), in the freshwater rotifer Brachionus calyciflorus exposed for 6, 12 and 24 h to flutamide, fenitrothion and cyproterone acetate, three anti-androgens known to disrupt sexual reproduction of Brachionus sp. Results revealed that fenitrothion did not affect the relative mRNA levels RXR and RAR in B. calyciflorus, whereas RXR and RAR mRNA levels could be significantly increased by 2 to 4.5-fold and from 2 to 7-fold after exposure to flutamide and cyproterone acetate, respectively. Moreover, the effects of flutamide and cyproterone acetate were measured from 6 and 12 h of exposure, respectively. Cyproterone acetate caused the highest increase of RXR and RAR mRNA levels, probably due to its progestin activity in addition to its anti-androgenic activity and the potential presence of a membrane-associated progesterone receptor as reported in Brachionus manjavacas. Consequently, although it is still difficult to evaluate the hormonal pathways involved in the endocrine disruption in Brachionus sp., this work suggests that the retinoid signaling pathway appears to be a good starting point to try to elucidate the molecular mechanisms involved in sexual reproductive dysfunction in Brachionidae. [ABSTRACT FROM AUTHOR]

Environmental sex determination implies that sex is defined by environmental factors influencing the maternal organism and/or oocytes. It provides population sex ratios that will maximise the sustainability of the population under incipient environmental conditions. Environmental factors responsible for sex determination include temperature, photoperiod, food availability, and population density. These cues stimulate the release of chemical signalling molecules (i.e. hormones) that determine the sex of newborns.We have analysed the responses of three Daphnia pulex clones (I, K, and S), isolated from different natural populations, to juvenile hormone methyl farnesoate (MF) in terms of survivorship, fecundity, production of males and ephippia, and expression of genes involved in sex determination (dsx1) and hormonal regulation (JHAMT, Met, RXR). Clonal individuals were exposed to: (1) high MF concentration (0.8 µM) combined with stressful conditions; (2) low MF concentration (0.15 µM) combined with optimal conditions of population density and food availability in two subsequent generations.The genetically different clones of D. pulex differed in the propensity for male and ephippia production and in the sensitivity to the stimuli that lead to the switch from parthenogenetic to sexual reproduction.A significant induction of male production was observed in all three clones when exposed to MF. In conditions mimicking crowding, only clone S produced male offspring even in absence of MF and showed higher expression levels of JHAMT and dsx1 genes. This response suggests that clone S has a high propensity to produce males probably due to a high sensitivity of receptors to environmental stimuli activating the endogenous biosynthesis of MF. However, clone S exposed to high MF concentration produced fewer males than clones I and K, which generally have a low natural propensity to produce males. High MF concentration coupled with conditions mimicking crowding, probably activated a feedback mechanism in clone S via the differential modulation of genes involved in the synthesis as well in the degradation of MF.Exposure to low MF concentration for two subsequent generations resulted in a reduction of male progeny production from the first (G1) to the second (G2) generation. All analysed genes were up‐regulated in both generations treated with MF, but with lower expression in G2. The reduced up‐regulation of the dsx1 gene matched with the lower male production. Based on our results and literature data, we hypothesised that the maternal dsx1 mRNA probably plays some role early in oocyte development, and causes the eggs that receive the dsx1 signal to develop into males.Exposure to MF for two generations significantly increased ephippia production. These results suggest that the induction of male and ephippia might have a common root in the MF pathway. The effect of MF on life‐history traits (delay in the age at maturity and fecundity reduction), sex ratio, and ephippia production suggests a direct impact of the juvenile hormone on the level of population growth. Thus, as a consequence of the switch from parthenogenetic to sexual reproduction, MF influences Daphnia population metrics and in this way probably maximises the sustainability of the population under variable environmental conditions. [ABSTRACT FROM AUTHOR]

Nuclear receptors (NRs) are a superfamily of transcription factors that play an important role in regulating many biological processes. The retinoid X receptor (RXR) is unique among NRs because it can form both homodimers and heterodimers with other representatives of the family. RXR modulates the expression of different genes and that is why it could be a good target for many therapies. Dysregulation of RXR signaling leads to various diseases, including neurodegenerative diseases, obesity, diabetes and cancer. Many molecules have been described as potential ligands for RXR. However, only a few of them are currently approved for clinical use. Retinoids play important role in regulation of skin cells growth and differentiation as well as have immunomodulatory and anti-inflammatory effects. Therefore they have found use in treatment of skin lesions and some types of cancers. This review summarizes general information about RXR, its structure, ligands and mechanism of action as well as its potential role in cancer therapy and metabolic syndrome. [ABSTRACT FROM AUTHOR]

The ligand-sensing transcription factor retinoid X receptor (RXR) is the universal heterodimer partner of nuclear receptors and involved in multiple physiological processes. Its pharmacological modulation holds therapeutic potential in cancer and neurodegeneration but many available RXR ligands lack specificity. The sesquiterpenoid valerenic acid has been identified as RXR agonist with unprecedented subtype and homodimer preference. Here, we identified simplified mimetics of the complex natural product by rational design and virtual screening that exhibited similar activity profiles on RXR and informed about structural elements contributing to the favorable activity., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)