Advances in drug design with RXR modulators

Vaz, Belén; Lera, Ángel R. de

doi:10.1517/17460441.2012.722992

Cited by 24 publications

(22 citation statements)

References 104 publications

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“…RXR regulates a wide variety of biological functions though its central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimerization partner of many nuclear receptors. [1,2] Although RXR has been reported to be expressed in the heart, little information is available regarding physiological and pathophysiological roles of this nuclear receptor in cardiovascular diseases and cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…RXR is unique among nuclear receptors because it forms heterodimers with many nuclear receptors, including retinoic acid receptor (RAR), peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR), [1,2] which play a critical role in regulating cardiovascular functions. Therefore, ligand activation of RXR has potentially pleiotropic effects on numerous biological pathways.…”

Section: Introductionmentioning

confidence: 99%

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Protective role of retinoid X receptor in H9c2 cardiomyocytes from hypoxia/reoxygenation injury in rats

Shan¹,

Xu²,

Huang³

et al. 2014

World Journal of Emergency Medicine

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BACKGROUND: Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H 2 O 2 -induced apoptosis of H9c2 ventricular cells in rats. But the protective effect and mechanism of activating RXR in cardiomyocytes against hypoxia/reoxygenation (H/R)-induced oxidative iniury are still unclear. METHODS:The model of H/R injury was established through hypoxia for 2 hours and reoxygenation for 4 hours in H9c2 cardiomyocytes of rats. 9-cis-retinoic acid (9-cis RA) was obtained as an RXR agonist, and HX531 as an RXR antagonist. Cultured cardiomyocytes were randomly divided into four groups: sham group, H/R group, H/R+9-cis RA -pretreated group (100 nmol/L 9-cis RA), and H/R+9-cis RA+HX531-pretreated group (2.5 μmol/L HX531). The cell viability was measured by MTT, apoptosis rate of cardiomyocytes by flow cytometry analysis, and mitochondrial membrane potential (ΔΨm) by JC-1 fluorescent probe, and protein expressions of Bcl-2, Bax and cleaved caspase-9 with Western blotting. All measurement data were expressed as mean±standard deviation, and analyzed using one-way ANOVA and the Dunnett test. Differences were considered signifi cant when P was <0.05. RESULTS:Pretreatment with RXR agonist enhanced cell viability, reduced apoptosis ratio, and stabled ΔΨm. Dot blotting experiments showed that under H/R stress conditions, Bcl-2 protein level decreased, while Bax and cleaved caspase-9 were increased. 9-cis RA administration before H/R stress prevented these effects, but the protective effects of activating RXR on cardiomyocytes against H/R induced oxidative injury were abolished when pretreated with RXR pan-antagonist HX531. CONCLUSION:The activation of RXR has protective effects against H/R injury in H9c2 cardiomyocytes of rats through attenuating signaling pathway of mitochondria apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective role of retinoid X receptor in H9c2 cardiomyocytes from hypoxia/reoxygenation injury in rats

Shan¹,

Xu²,

Huang³

et al. 2014

World Journal of Emergency Medicine

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“…The activation of IRF3, a key downstream nuclear factor of TLR3 signaling, in response to viral infection on the one hand stimulates antiviral response through the production of interferons, and on the other hand suppresses metabolic response by downregulating retinoid X receptor-α (RXRα) [24]. RXRα can form heterodimers with other nuclear factors including peroxisome proliferator-activated receptor-γ (PPARγ), LXR, and farnesoid X receptor (FXR) which together construct a nuclear network regulating metabolism-related genes [25]. Such suppression is key to prevent viral assembly, as viruses can utilize host’s lipids to facilitate their own replication [26].…”

Section: Metabolic Regulation By Tlr Pathway At Cellular Levelmentioning

confidence: 99%

Interaction between gut microbiota and toll-like receptor: from immunity to metabolism

2016

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The human gut contains trillions of commensal bacteria, and similar to pathogenic bacteria, the gut microbes and their products can be recognized by toll-like receptors (TLRs). It is well acknowledged that the interaction between gut microbiota and the local TLRs help to maintain the homeostasis of intestinal immunity. High-fat intake or obesity can weaken gut integrity leading to the penetration of gut microbiota or their bacterial products into the circulation, leading to the activation of TLRs on immune cells and subsequently low-grade systemic inflammation in host. Metabolic cells including hepatocytes and adipocytes also express TLRs. Although they are able to produce and secrete inflammatory molecules, the effectiveness remains low compared with the immune cells embedded in the liver and adipose tissue. The interaction of TLRs in these metabolic cells or organs with gut microbiota remains unclear, but a few studies have suggested that the functions of these TLRs are related to metabolism. Alteration of the gut microbiota is associated with body weight change and adiposity in human, and the interaction between the commensal gut microbiota and TLRs may possibly involve both metabolic and immunological regulation. In this review, we will summarize the current findings on the relationship between TLRs and gut microbiota with a focus on metabolic regulation and discuss how such interaction participates in host metabolism.

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“…Because specific Nurr1:RXRα activators do not exist (20), we confronted the challenge to discover compounds that would be specific for Nurr1:RXRα heterodimers, stable in vivo, and brain-penetrant. Based on existing chemical structures and their function on RXRα in a variety of assays, we synthesized several series of compounds (termed BRFs).…”

Section: Significancementioning

confidence: 99%

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

Spathis

Asvos

Ziavra

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.Parkinson's disease | target validation | neuroprotection

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Advances in drug design with RXR modulators

Cited by 24 publications

References 104 publications

Protective role of retinoid X receptor in H9c2 cardiomyocytes from hypoxia/reoxygenation injury in rats

Protective role of retinoid X receptor in H9c2 cardiomyocytes from hypoxia/reoxygenation injury in rats

Interaction between gut microbiota and toll-like receptor: from immunity to metabolism

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

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