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1.
Sci Rep ; 14(1): 16490, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39019967

RESUMO

Retinitis Pigmentosa is a leading cause of severe vision loss. Retinitis Pigmentosa can present with a broad range of phenotypes impacted by disease age of onset, severity, and progression. This variation is influenced both by different gene mutations as well as unique variants within the same gene. Mutations in the nuclear hormone receptor 2 family e, member 3 are associated with several forms of retinal degeneration, including Retinitis Pigmentosa. In our previous studies we demonstrated that subretinal administration of one Nr2e3 dose attenuated retinal degeneration in rd7 mice for at least 3 months. Here we expand the studies to evaluate the efficacy and longitudinal impact of the NR2E3 therapeutic by examining three different doses administered at early or intermediate stages of retinal degeneration in the rd7 mice. Our study revealed retinal morphology was significantly improved 6 months post for all doses in the early-stage treatment groups and for the low and mid doses in the intermediate stage treatment groups. Similarly, photoreceptor function was significantly improved in the early stage for all doses and intermediate stage low and mid dose groups 6 months post treatment. This study demonstrated efficacy in multiple doses of NR2E3 therapy.


Assuntos
Modelos Animais de Doenças , Receptores Nucleares Órfãos , Degeneração Retiniana , Animais , Camundongos , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Degeneração Retiniana/tratamento farmacológico , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Retinose Pigmentar/tratamento farmacológico , Retina/patologia , Retina/metabolismo , Retina/efeitos dos fármacos
2.
J Clin Invest ; 134(11)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38652563

RESUMO

While dysfunction and death of light-detecting photoreceptor cells underlie most inherited retinal dystrophies, knowledge of the species-specific details of human rod and cone photoreceptor cell development remains limited. Here, we generated retinal organoids carrying retinal disease-causing variants in NR2E3, as well as isogenic and unrelated controls. Organoids were sampled using single-cell RNA sequencing (scRNA-Seq) across the developmental window encompassing photoreceptor specification, emergence, and maturation. Using scRNA-Seq data, we reconstruct the rod photoreceptor developmental lineage and identify a branch point unique to the disease state. We show that the rod-specific transcription factor NR2E3 is required for the proper expression of genes involved in phototransduction, including rhodopsin, which is absent in divergent rods. NR2E3-null rods additionally misexpress several cone-specific phototransduction genes. Using joint multimodal single-cell sequencing, we further identify putative regulatory sites where rod-specific factors act to steer photoreceptor cell development. Finally, we show that rod-committed photoreceptor cells form and persist throughout life in a patient with NR2E3-associated disease. Importantly, these findings are strikingly different from those observed in Nr2e3 rodent models. Together, these data provide a road map of human photoreceptor development and leverage patient induced pluripotent stem cells to define the specific roles of rod transcription factors in photoreceptor cell emergence and maturation in health and disease.


Assuntos
Organoides , Receptores Nucleares Órfãos , Células Fotorreceptoras Retinianas Bastonetes , Humanos , Organoides/metabolismo , Organoides/patologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Células Fotorreceptoras Retinianas Cones/patologia , Retina/metabolismo , Retina/patologia , Retina/crescimento & desenvolvimento , Diferenciação Celular , Transdução de Sinal Luminoso/genética , Análise de Célula Única
3.
J Neuroinflammation ; 21(1): 97, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627787

RESUMO

The unfavorable prognosis of many neurological conditions could be attributed to limited tissue regeneration in central nervous system (CNS) and overwhelming inflammation, while liver X receptor (LXR) may regulate both processes due to its pivotal role in cholesterol metabolism and inflammatory response, and thus receives increasing attentions from neuroscientists and clinicians. Here, we summarize the signal transduction of LXR pathway, discuss the therapeutic potentials of LXR agonists based on preclinical data using different disease models, and analyze the dilemma and possible resolutions for clinical translation to encourage further investigations of LXR related therapies in CNS disorders.


Assuntos
Doenças do Sistema Nervoso Central , Receptores Nucleares Órfãos , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos/metabolismo , Sistema Nervoso Central/metabolismo , Inflamação , Doenças do Sistema Nervoso Central/tratamento farmacológico
4.
Int J Mol Sci ; 25(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38474099

RESUMO

Hypercapnia occurs when the partial pressure of carbon dioxide (CO2) in the blood exceeds 45 mmHg. Hypercapnia is associated with several lung pathologies and is transcriptionally linked to suppression of immune and inflammatory signalling through poorly understood mechanisms. Here we propose Orphan Nuclear Receptor Family 4A (NR4A) family members NR4A2 and NR4A3 as potential transcriptional regulators of the cellular response to hypercapnia in monocytes. Using a THP-1 monocyte model, we investigated the sensitivity of NR4A family members to CO2 and the impact of depleting NR4A2 and NR4A3 on the monocyte response to buffered hypercapnia (10% CO2) using RNA-sequencing. We observed that NR4A2 and NR4A3 are CO2-sensitive transcription factors and that depletion of NR4A2 and NR4A3 led to reduced CO2-sensitivity of mitochondrial and heat shock protein (Hsp)-related genes, respectively. Several CO2-sensitive genes were, however, refractory to depletion of NR4A2 and NR4A3, indicating that NR4As regulate certain elements of the cellular response to buffered hypercapnia but that other transcription factors also contribute. Bioinformatic analysis of conserved CO2-sensitive genes implicated several novel putative CO2-sensitive transcription factors, of which the ETS Proto-Oncogene 1 Transcription Factor (ETS-1) was validated to show increased nuclear expression in buffered hypercapnia. These data give significant insights into the understanding of immune responses in patients experiencing hypercapnia.


Assuntos
Receptores Nucleares Órfãos , Receptores de Esteroides , Humanos , Receptores Nucleares Órfãos/genética , Monócitos/metabolismo , Hipercapnia , Dióxido de Carbono , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Receptores de Esteroides/metabolismo , Proteínas de Ligação a DNA , Receptores dos Hormônios Tireóideos
5.
Int Ophthalmol ; 44(1): 133, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38480634

RESUMO

PURPOSE: To investigate the expression of nuclear receptor subfamily 1 group D member 1 (NR1D1) and nuclear receptor subfamily 2 group E Member 3 (NR2E3) in retinoblastoma (RB) and their correlation with the clinical and pathological features of RB. METHODS: Immunohistochemical (IHC) assays were performed to detect and evaluate the expression levels of NR1D1 and NR2E3 in paraffin-embedded tissue samples. The relationship between the expression levels and clinicopathological characteristics of RB patients was analyzed using the χ2 test or Fisher exact test. RESULTS: A total of 51 RB patients were involved in this research. The expression levels of NR1D1 (P = 0.004) and NR2E3 (P = 0.024) were significantly lower in RB tumor tissues than in normal retina. The expression levels of NR1D1 and NR2E3 were less positive in RB patients with advanced stages (P = 0.007, P = 0.015), choroidal infiltration (P = 0.003, P = 0.029), and optic nerve infiltration (P = 0.036, P = 0.003). In addition, a low expression level of NR2E3 was associated with high-risk pathology (P = 0.025) and necrosis (P = 0.035) of RB tissues. CONCLUSION: The expression levels of NR1D1 and NR2E3 were decreased in RB and closely associated with the clinical stage and high invasion of the disease. These findings provide new insights into the mechanism of RB progression and suggest that NR1D1 and NR2E3 could be potential targets for treatment strategies.


Assuntos
Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/patologia , Neoplasias da Retina/diagnóstico , Receptores Nucleares Órfãos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares
6.
Proc Natl Acad Sci U S A ; 121(11): e2316118121, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442152

RESUMO

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3 knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of Nr2e3 potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient Rho-/- mice), or abnormal phototransduction (phosphodiesterase-deficient rd10 mice). Nr2e3 knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by Nr2e3 knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in Nr2e3-deficient rods may be responsible for the neuroprotective effects we observe.


Assuntos
Fármacos Neuroprotetores , Distrofias Retinianas , Retinose Pigmentar , Animais , Camundongos , Células Fotorreceptoras Retinianas Cones , Retinose Pigmentar/genética , Modelos Animais de Doenças , Células Germinativas , Receptores Nucleares Órfãos
7.
Neurobiol Dis ; 194: 106463, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38485095

RESUMO

Mutations in NR2E3, a gene encoding an orphan nuclear transcription factor, cause two retinal dystrophies with a distinct phenotype, but the precise role of NR2E3 in rod and cone transcriptional networks remains unclear. To dissect NR2E3 function, we performed scRNA-seq in the retinas of wildtype and two different Nr2e3 mouse models that show phenotypes similar to patients carrying NR2E3 mutations. Our results reveal that rod and cone populations are not homogeneous and can be separated into different sub-classes. We identify a previously unreported cone pathway that generates hybrid cones co-expressing both cone- and rod-related genes. In mutant retinas, this hybrid cone subpopulation is more abundant and includes a subpopulation of rods transitioning towards a cone cell fate. Hybrid photoreceptors with high misexpression of cone- and rod-related genes are prone to regulated necrosis. Overall, our results shed light on the role of NR2E3 in modulating photoreceptor differentiation towards cone and rod fates and explain how different mutations in NR2E3 lead to distinct visual disorders in humans.


Assuntos
Receptores Nucleares Órfãos , Retina , Camundongos , Animais , Humanos , Receptores Nucleares Órfãos/metabolismo , Retina/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Diferenciação Celular , Regulação da Expressão Gênica
8.
J Nat Prod ; 87(2): 322-331, 2024 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-38334086

RESUMO

A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.


Assuntos
Hipercolesterolemia , Receptores Nucleares Órfãos , Animais , Camundongos , Colesterol/metabolismo , Hipercolesterolemia/tratamento farmacológico , Fígado , Receptores X do Fígado/metabolismo , Camundongos Knockout , Simulação de Acoplamento Molecular , Receptores Nucleares Órfãos/metabolismo , Receptores Nucleares Órfãos/farmacologia
9.
Dev Growth Differ ; 66(2): 145-160, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38263801

RESUMO

Nuclear receptor subfamily 2 group F (Nr2f) proteins are essential for brain development in mice, but little is known about their precise roles and their evolutionary diversification. In the present study, the expression patterns of major nr2f genes (nr2f1a, nr2f1b, and nr2f2) during early brain development were investigated in zebrafish. Comparisons of their expression patterns revealed similar but temporally and spatially distinct patterns after early somite stages in the brain. Frameshift mutations in the three nr2f genes, achieved using the CRISPR/Cas9 method, resulted in a smaller telencephalon and smaller eyes in the nr2f1a mutants; milder forms of those defects were present in the nr2f1b and nr2f2 mutants. Acridine orange staining revealed enhanced cell death in the brain and/or eyes in all nr2f homozygous mutants. The expression of regional markers in the brain did not suggest global defects in brain regionalization; however, shha expression in the preoptic area and hypothalamus, as well as fgf8a expression in the anterior telencephalon, was disturbed in nr2f1a and nr2f1b mutants, potentially leading to a defective telencephalon. Specification of the retina and optic stalk was also significantly affected. The overexpression of nr2f1b by injection of mRNA disrupted the anterior brain at a high dose, and the expression of pax6a in the eyes and fgf8a in the telencephalon at a low dose. The results of these loss- and gain-of-function approaches showed that nr2f genes regulate the development of the telencephalon and eyes in zebrafish embryos.


Assuntos
Olho , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares , Receptores Nucleares Órfãos , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Camundongos , Encéfalo/metabolismo , Olho/crescimento & desenvolvimento , Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Telencéfalo/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Receptores Nucleares Órfãos/metabolismo
10.
Gene Ther ; 31(5-6): 255-262, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38273095

RESUMO

Retinitis pigmentosa (RP) is a heterogeneous disease and the main cause of vision loss within the group of inherited retinal diseases (IRDs). IRDs are a group of rare disorders caused by mutations in one or more of over 280 genes which ultimately result in blindness. Modifier genes play a key role in modulating disease phenotypes, and mutations in them can affect disease outcomes, rate of progression, and severity. Our previous studies have demonstrated that the nuclear hormone receptor 2 family e, member 3 (Nr2e3) gene reduced disease progression and loss of photoreceptor cell layers in RhoP23H-/- mice. This follow up, pharmacology study evaluates a longitudinal NR2E3 dose response in the clinically relevant heterozygous RhoP23H mouse. Reduced retinal degeneration and improved retinal morphology was observed 6 months following treatment evaluating three different NR2E3 doses. Histological and immunohistochemical analysis revealed regions of photoreceptor rescue in the treated retinas of RhoP23H+/- mice. Functional assessment by electroretinogram (ERG) showed attenuated photoreceptor degeneration with all doses. This study demonstrates the effectiveness of different doses of NR2E3 at reducing retinal degeneration and informs dose selection for clinical trials of RhoP23H-associated RP.


Assuntos
Modelos Animais de Doenças , Receptores Nucleares Órfãos , Degeneração Retiniana , Retinose Pigmentar , Animais , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Camundongos , Receptores Nucleares Órfãos/genética , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Degeneração Retiniana/etiologia , Eletrorretinografia , Retina/metabolismo , Retina/patologia , Terapia Genética/métodos
12.
Phytomedicine ; 123: 155192, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37951148

RESUMO

BACKGROUND: Tetranucleotide repeat domain protein 39B (TTC39B) was found to combine with ubiquitin ligase E3, and promote the ubiquitination modification of liver X receptor (LXR), which led to the inhibition of reverse cholesterol transport and development of atherosclerosis. QiShenYiQi pill (QSYQ) is a modern Chinese patent drug for treating ischemic cardiovascular diseases, the underlying mechanism is found to promote the expression of LXR-α/ ATP-binding cassette transporter G5 (ABCG5) in the liver of atherosclerotic mice. PURPOSE: The aim of this study is to investigate the effect of QSYQ on TTC39B-LXR mediated reverse cholesterol transport in atherosclerotic mice. STUDY DESIGN AND METHODS: Male apolipoprotein E gene knockout mice (7 weeks old) were fed with high-fat diet and treated with low dose of QSYQ (QSYQ-l, 0.3 g/kg·d), high dose of QSYQ (QSYQ-H, 1.2 g/kg·d) and LXR-α agonist (LXR-A, GW3965 10 mg/kg·d) for 8 weeks. C57BL/6 J mice were fed with normal diet and used as negative control. Oil red O staining, HE staining, ELISA, RNA sequencing, western blot, immunohistochemistry, RT-PCR, cell culture and RNA interference were performed to analyze the effect of QSYQ on atherosclerosis. RESULTS: HE staining showed that QSYQ reduced the atherosclerotic lesion significantly when compared to the control group. ELISA measurement showed that QSYQ decreased serum VLDL and increased serum ApoA1. Oil Red O staining showed that QSYQ reduced the lipid content of liver and protect liver function. Comparative transcriptome RNA-sequence of liver showed that DEGs after QSYQ treatment enriched in high-density lipoprotein particle, ubiquitin ligase complex, bile secretion, etc. Immunohistochemical staining and western blot proved that QSYQ increased the protein expression of hepatic SR-B1, LXR-α, LXR-ß, CYP7A1 and ABCG5. Targeted inhibiting Ttc39b gene in vitro further established that QSYQ inhibited the gene expression of Ttc39b, increased the protein expression of SR-B1, LXR-α/ß, CYP7A1 and ABCG5 in rat hepatocyte. CONCLUSION: Our results demonstrated the new anti-atherosclerotic mechanism of QSYQ by targeting TTC39B-LXR mediated reverse cholesterol transport in liver. QSYQ not only promoted reverse cholesterol transport, but also improved fatty liver and protected liver function.


Assuntos
Aterosclerose , Compostos Azo , Medicamentos de Ervas Chinesas , Lipoproteínas , Masculino , Camundongos , Ratos , Animais , Receptores X do Fígado/metabolismo , Colesterol/metabolismo , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Receptores Nucleares Órfãos/uso terapêutico , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Camundongos Endogâmicos C57BL , Fígado , Camundongos Knockout , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo
13.
Asian Pac J Cancer Prev ; 24(12): 4103-4109, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38156844

RESUMO

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has an unfavorable outlook due to its aggressive characteristics, delayed diagnosis, and limited effective treatment options for advanced stages of the disease. The significant mortality rate has prompted investigations into additional factors that could aid in managing this type of cancer. Liver X receptors, specifically LXRα and LXRß, are nuclear receptors that oversee the expression of genes related to cholesterol, glucose, lipid metabolism, and inflammatory responses. LXRs have also emerged as potential targets for addressing PDAC, and recent findings have demonstrated that LXR ligands can impede cell proliferation in various cancer forms, notably pancreatic cancer. This comprehensive computational research study involving oncological in silico mechanism discovery explored inhibitory ligands for Liver X receptors (LXRα and LXRß), which are believed to have prognostic significance in PDAC. METHODS: The study utilized Baicalein, Beta-Sitosterol, Polydatin ligands in molecular docking and dynamics and post-molecular Hydrogen bonding contact analyses dynamics to characterize receptor inhibition. RESULT: The outcomes suggest that Baicalein exhibits versatile inhibitory effects on both receptors, while Beta-Sitosterol emerges as a highly effective inhibitor of LXRß. CONCLUSION: Further in vitro and in vivo investigations will be beneficial and would shed light onto the mechanism to decipher the suppression of PDAC evaluating the potential of Baicalein, Beta-Sitosterol, Polydatin natural ligand compounds.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Receptores X do Fígado/genética , Simulação de Acoplamento Molecular , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética
14.
J AAPOS ; 27(6): 363-366, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37806489

RESUMO

We report the case of an otherwise healthy 10-year-old girl referred to our institution for gradually decreasing vision and nyctalopia. Based on clinical examination, she was diagnosed with inherited retinal dystrophy, presumably due to enhanced S-cone syndrome (ESCS). Subsequent genetic testing confirmed a rare combination of NR2E3 heterozygous mutations: c.119-2A>C and c.932G>A p.(Arg311Gln).


Assuntos
Receptores Nucleares Órfãos , Degeneração Retiniana , Feminino , Humanos , Criança , Receptores Nucleares Órfãos/genética , Eletrorretinografia , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/genética , Mutação , Células Fotorreceptoras Retinianas Cones
15.
Front Endocrinol (Lausanne) ; 14: 1229033, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37664846

RESUMO

Endometrial function is dependent on a tight crosstalk between the epithelial and stromal cells of the endometrium. This communication is critical to ensure a fertile uterus and relies on progesterone and estrogen signaling to prepare a receptive uterus for embryo implantation in early pregnancy. One of the key mediators of this crosstalk is the orphan nuclear receptor NR2F2, which regulates uterine epithelial receptivity and stromal cell differentiation. In order to determine the molecular mechanism regulated by NR2F2, RNAseq analysis was conducted on the uterus of PgrCre;Nr2f2f/f mice at Day 3.5 of pregnancy. This transcriptomic analysis demonstrated Nr2f2 ablation in Pgr-expressing cells leads to a reduction of Hand2 expression, increased levels of Hand2 downstream effectors Fgf1 and Fgf18, and a transcriptome manifesting suppressed progesterone signaling with an altered immune baseline. ChIPseq analysis conducted on the Day 3.5 pregnant mouse uterus for NR2F2 demonstrated the majority of NR2F2 occupies genomic regions that have H3K27ac and H3K4me1 histone modifications, including the loci of major uterine transcription regulators Hand2, Egr1, and Zbtb16. Furthermore, functional analysis of an NR2F2 occupying site that is conserved between human and mouse was capable to enhance endogenous HAND2 mRNA expression with the CRISPR activator in human endometrial stroma cells. These data establish the NR2F2 dependent regulation of Hand2 in the stroma and identify a cis-acting element for this action. In summary, our findings reveal a role of the NR2F2-HAND2 regulatory axis that determines the uterine transcriptomic pattern in preparation for the endometrial receptivity.


Assuntos
Progesterona , Útero , Feminino , Humanos , Gravidez , Animais , Camundongos , Progesterona/farmacologia , Transdução de Sinais , Endométrio , Receptores Nucleares Órfãos , Fator II de Transcrição COUP
16.
Expert Opin Ther Targets ; 27(10): 989-998, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37753584

RESUMO

INTRODUCTION: Liver X receptors (LXRs) have emerged as novel targets for tumor treatment. LXRs within the tumor microenvironment show the capacity to impact tumorigenesis and tumor development by regulating the infiltration of immune cells and release of cytokines to moderate inflammation. AREAS COVERED: In this review, we present a systematic description of recent progress in understanding the impact of LXRs on the tumor microenvironment and tumorigenesis. We also summarize the antitumor effects mediated by LXRs via their regulation of cytokine expression. Additionally, we discuss the limitations of LXR research in tumor studies to date. EXPERT OPINION: Previous studies have demonstrated abnormal LXR expression in tumor tissues, and activation of LXRs has been shown to inhibit tumorigenesis and promote apoptosis in tumor cells. However, LXRs can also affect tumorigenesis by regulating immune cell functions within the tumor immune microenvironment. By summarizing the impact of LXRs on immune cells, we provide new insights into the multifaceted nature of LXRs as antitumor targets.


Assuntos
Neoplasias , Receptores Nucleares Órfãos , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos/metabolismo , Microambiente Tumoral , Inflamação , Citocinas , Carcinogênese
17.
Eur J Pharmacol ; 956: 175953, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37541371

RESUMO

Liver X receptors (LXRs) are master regulators of various biological processes, including metabolism, inflammation, development, and reproduction. As well-known nuclear oxysterol receptors of the nuclear receptor (NR) family, LXRs have two homologous subtypes, LXRα (NR1H3) and LXRß (NR1H2). Since the mid-1990s, numerous LXR-targeted drugs have been designed to treat diseases such as atherosclerosis, systemic lupus erythematosus, and cancer. These modulators include agonists and antagonists, and the selectivity of them have been development from diverse aspects, including subtype-specific, cell-specific, tissue-specific types. Meanwhile, advanced delivery systems are also exploreed to facilitate the application of LXR drugs in clinical setting. One of the most promising delivery systems involves the use of nanoparticles and is expected to increase the clinical potential of LXR modulators. This review discusses our current understanding of LXR biology and pharmacology, focusing on the development of modulators for LXRα and/or LXRß, and the nanoparticle-based delivery systems for promising LXR modulators with potential for use as drugs.


Assuntos
Aterosclerose , Receptores Nucleares Órfãos , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/metabolismo , Receptores Nucleares Órfãos/uso terapêutico , Aterosclerose/tratamento farmacológico
18.
Genes (Basel) ; 14(8)2023 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-37628579

RESUMO

(1) Background: NR2E3 encodes a nuclear receptor transcription factor that is considered to promote cell differentiation, affect retinal development, and regulate phototransduction in rods and cones. This study aimed to analyze the clinical characteristics and observe the prognosis of autosomal dominant retinopathy (ADRP) and autosomal recessive retinopathy (ARRP) associated with NR2E3; (2) Methods: NR2E3 variants were collected from our exome sequencing data and identified per the American College of Medical Genetics and Genomics criteria. Data from our cohort and a systemic literature review were conducted to explore the NR2E3 variants spectrum and potential genotype-phenotype correlations; (3) Results: Nine pathogenic variants/likely pathogenic variants in NR2E3, including five novel variants, were detected in eight families (four each with ADRP and ARRP). Follow-up data showed schisis/atrophy in the macula and retinal degeneration initiation around the vascular arcades with differences in ADRP and ARRP. A systemic literature review indicated patients with ADRP presented better visual acuity (p < 0.01) and later onset age (p < 0.0001) than did those with ARRP; (4) Conclusions: Macular schisis and retinal degeneration around vascular arcades may present as the prognosis of NR2E3-retinopathy, dominant, or recessive. Our data might further enrich our understanding of NR2E3 variants and associated inherited retinopathy.


Assuntos
Degeneração Retiniana , Humanos , Atrofia , Estudos Longitudinais , Receptores Nucleares Órfãos , Degeneração Retiniana/genética
19.
Sheng Li Xue Bao ; 75(4): 555-568, 2023 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-37583043

RESUMO

The development of chronic liver disease can be promoted by excessive fat accumulation, dysbiosis, viral infections and persistent inflammatory responses, which can lead to liver inflammation, fibrosis and carcinogenesis. An in-depth understanding of the etiology leading to chronic liver disease and the underlying mechanisms influencing its development can help identify potential therapeutic targets for targeted treatment. Orphan nuclear receptors (ONRs) are receptors that have no corresponding endogenous ligands to bind to them. The study of these ONRs and their biological properties has facilitated the development of synthetic ligands, which are important for investigating the effective targets for the treatment of a wide range of diseases. In recent years, it has been found that ONRs are essential for maintaining normal liver function and their dysfunction can affect a variety of liver diseases. ONRs can influence pathophysiological activities such as liver lipid metabolism, inflammatory response and cancer cell proliferation by regulating hormones/transcription factors and affecting the biological clock, oxidative stress, etc. This review focuses on the regulation of ONRs, mainly including retinoid related orphan nuclear receptors (RORs), pregnane X receptor (PXR), leukocyte cell derived chemotaxin 2 (LECT2), Nur77, and hepatocyte nuclear factor 4α (HNF4α), on the development of different types of chronic liver diseases in different ways, in order to provide useful references for the therapeutic strategies of chronic liver diseases based on the regulation of ONRs.


Assuntos
Hepatopatias , Receptores de Esteroides , Humanos , Receptores Nucleares Órfãos/metabolismo , Receptores de Esteroides/fisiologia , Ligantes , Fígado , Peptídeos e Proteínas de Sinalização Intercelular
20.
J Nat Prod ; 86(8): 1901-1909, 2023 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-37526502

RESUMO

In this study, the ability of six limonoids from Trichilia prieuriana (Meliaceae) to activate the liver X receptor (LXR) was assessed. One of these limonoids, flindissone, was shown to activate LXR by reporter-gene assays. Flindissone is a ring-intact limonoid, structurally similar to sterol-like LXR ligands. In endogenous cellular settings, flindissone showed an activity profile that is characteristic of LXR agonists. It induced cholesterol efflux in THP-1 macrophages by increasing the cholesterol transporter ABCA1 and ABCG1 gene expression. In HepG2 cells, flindissone induced the expression of IDOL, an LXR-target gene that is associated with the downregulation of the LDL receptor. However, unlike synthetic and similarly to sterol-based LXR agonists, flindissone did not induce the expression of the SREBP1c gene, a major transcription factor regulating de novo lipogenesis. Additionally, flindissone also appeared to be able to inhibit post-translational activation of SREBP1c. The results presented here reveal a natural product as a new LXR agonist and point to an additional property of T. prieuriana and other plant extracts containing flindissone.


Assuntos
Limoninas , Meliaceae , Receptores X do Fígado/metabolismo , Limoninas/farmacologia , Receptores Nucleares Órfãos/genética , Colesterol/metabolismo
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