Retinoid X Receptor Selective Agonists and their Synthetic Methods

Wagner, Carl E.; Jurutka, Peter W.; Marshall, Pamela A.; Heck, Michael

doi:10.2174/1568026616666160617091559

Cited by 25 publications

(13 citation statements)

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“…Retinoids and their receptors have a close relationship with PPAR. 36 , 37 RXRs and retinoic acid receptors (RAR) are two main nuclear receptors binding with retinoids. Retinoids are a group of structural and functional analogs of vitamin A and play an important role in the regulation of cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of peroxisome proliferator-activated receptor alpha indicates unfavorable outcomes in hepatocellular carcinoma

Xiao¹,

Cai²,

Liu³

et al. 2018

CMAR

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IntroductionHepatocellular carcinoma (HCC) has a close relationship with lipid metabolism. Peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the regulation of fatty acid oxidation in the liver. However, the role of PPARα in HCC remains unclear.MethodsA total of 804 HCC specimens were collected to construct a tissue microarray and for immunohistochemical analysis. The relationship between PPARα expression and clinical features of HCC patients was analyzed. Kaplan–Meier analysis was conducted to assess the prognostic value of PPARα expression levels.ResultsThe expression of PPARα in HCC was noticeably decreased in HCC tissues. HCC patients with high levels of PPARα expression in cytoplasm had smaller tumors (P=0.027), less vascular invasion (P=0.049), and a higher proportion of complete involucrum (P=0.038). Kaplan–Meier analysis showed that HCC patients with low PPARα expression in the cytoplasm had significantly worse outcomes in terms of overall survival (P<0.001), disease-free survival (P=0.024), and the probability of recurrence (P=0.037). Similarly, overall survival was significantly shorter in HCC patients with negative PPARα expression in the nucleus (P=0.034). Multivariate Cox analyses indicated that tumor size (P=0.001), TNM stage (P<0.001), vascular invasion (P<0.001), and PPARα expression in the cytoplasm (P<0.001) were found to be independent prognostic variables for overall survival.ConclusionOur data revealed that PPARα expression was decreased in HCC samples. High PPARα expression was correlated with longer survival times in HCC patients, and served as an independent factor for better outcomes. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 99%

Decreased expression of peroxisome proliferator-activated receptor alpha indicates unfavorable outcomes in hepatocellular carcinoma

Xiao¹,

Cai²,

Liu³

et al. 2018

CMAR

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“…The EECD34 cells are not a “pure” population [17], and this is probably reflected in the differential effectiveness of the agonists and antagonists used in this study to modulate Pitx2 expression for both the EOM- and LEG-derived EECD34 cells. In particular, RXR plays a number of roles outside of retinoic acid signaling, including signaling with the thyroid hormone receptor, peroxisome proliferator-activated receptor (PPAR) and others [42,43]. In addition, while the percent of serum was greatly reduced in low serum fusion medium compared to proliferation medium, retinoic acid was still present within the fusion medium.…”

Section: Discussionmentioning

confidence: 99%

Effects of retinoic acid signaling on extraocular muscle myogenic precursor cells in vitro

Hebert

Fitzpatrick

McConnell

et al. 2017

Experimental Cell Research

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One major difference between limb and extraocular muscles (EOM) is the presence of an enriched population of Pitx2-positive myogenic precursor cells in EOM compared to limb muscle. We hypothesize that retinoic acid regulates Pitx2 expression in EOM myogenic precursor cells and that its effects would differ in leg muscle. The two muscle groups expressed differential retinoic acid receptor (RAR) and retinoid X receptor (RXR) levels. RXR co-localized with the Pitx2-positive cells but not with those expressing Pax7. EOM-derived and LEG-derived EECD34 cells were treated with vehicle, retinoic acid, the RXR agonist bexarotene, the RAR inverse agonist BMS493, or the RXR antagonist UVI 3003. In vitro, fewer EOM-derived EECD34 cells expressed desmin and fused, while more LEG-derived cells expressed desmin and fused when treated with retinoic acid compared to vehicle. Both EOM and LEG-derived EECD34 cells exposed to retinoic acid showed a higher percentage of cells expressing Pitx2 compared to vehicle, supporting the hypothesis that retinoic acid plays a role in maintaining Pitx2 expression. We hypothesize that retinoic acid signaling aids in the maintenance of large numbers of undifferentiated myogenic precursor cells in the EOM, which would be required to maintain EOM normalcy throughout a lifetime of myonuclear turnover.

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“…In general, PXR and CAR are initially retained in the cytoplasm; once activated by the specific ligands, such as xenobiotics, drugs, herbal supplements, vitamins, and some endobiotics, they interact with the 9-cisretinoic acid receptor alpha (RXRα), another NRs member, to form a heterodimer [15]. Subsequently, the heterodimer translocates into the nucleus and then binds to the corresponding xenobiotic response elements (XREM) in the promoter regions of target genes [16]. In a word, PXR and CAR could lead to the biotransformation and disposition of related xenobiotics according to transcriptional control.…”

Section: Introductionmentioning

confidence: 99%

Constitutive Androstane Receptor-Mediated Inhibition of Metformin on Phase II Metabolic Enzyme SULT2A1

Zhang

et al. 2021

International Journal of Endocrinology

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Background. Metformin, as a first-line treatment for diabetes, interacts with many protein kinases and transcription factors which affect the expression of downstream target genes governing drug metabolism. Sulfotransferase, SULT2A1, one phase II metabolic enzyme, sulfonates both xenobiotic and endobiotic compounds to accelerate drug excretion. Herein, we designed experiments to investigate the effects and mechanisms of metformin on SULT2A1 expression in vitro. Methods. The hepatocellular carcinoma cell line, HepaRG, was cultured with different concentrations of metformin. The cell viability was measured using CCK8 kit. HepaRG was used to evaluate the protein expression of pregnane X receptor (PXR), the constitutive androstane receptor (CAR), SULT2A1, AMP-activated protein kinase (AMPK), and phosphorylation of AMPK (p-AMPK), respectively, at different concentrations of metformin with or without rifampin (human PXR activator) and CITCO (human CAR activator). The coregulators with CAR on SULT2A1 promoter response elements have also been characterized. Results. We showed that metformin did not affect the basic expression of SULT2A1 but could suppress the expression of SULT2A1 induced by the activator of human CAR. Investigations revealed that metformin which could block CAR nuclear translocation further suppress SULT2A1. In addition, we found that the prevented CAR transfer into the nucleus by metformin was partially an AMPK-dependent event. Conclusion. The present study indicated that the activation of AMPK-CAR pathway mediated the suppression of SULT2A1 by metformin. Metformin may affect the metabolism and clearance of drugs which are SULT2A1 substrates. The results that emerged from this work provide substantial insights into an appropriate medication in the treatment of diabetes patients.

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Retinoid X Receptor Selective Agonists and their Synthetic Methods

Cited by 25 publications

References 0 publications

Decreased expression of peroxisome proliferator-activated receptor alpha indicates unfavorable outcomes in hepatocellular carcinoma

Decreased expression of peroxisome proliferator-activated receptor alpha indicates unfavorable outcomes in hepatocellular carcinoma

Effects of retinoic acid signaling on extraocular muscle myogenic precursor cells in vitro

Constitutive Androstane Receptor-Mediated Inhibition of Metformin on Phase II Metabolic Enzyme SULT2A1

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