The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases

Rodríguez-Calvo, Ricardo; Tajes, Marta; Vázquez‐Carrera, Manuel

doi:10.1080/14728222.2017.1279146

Cited by 97 publications

(82 citation statements)

References 153 publications

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“…which have potential to directly degrade the TLR-signaling molecules involved in MyD88-dependent or TRIF-dependent and MyD88independent TLR signaling. However, it is impossible to describe all the endogenous negative regulators of TLR signaling here in this manuscript whose detail can be found somewhere else [466][467][468][469][470].…”

Section: Current and Future Tlr Based Therapeuticsmentioning

confidence: 99%

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Kumar

2018

International Immunopharmacology

501

346

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The immune system is a very diverse system of the host that evolved during evolution to cope with various pathogens present in the vicinity of environmental surroundings inhabited by multicellular organisms ranging from achordates to chordates (including humans). For example, cells of immune system express various pattern recognition receptors (PRRs) that detect danger via recognizing specific pathogen-associated molecular patterns (PAMPs) and mount a specific immune response. Toll-like receptors (TLRs) are one of these PRRs expressed by various immune cells. However, they were first discovered in the Drosophila melanogaster (common fruit fly) as genes/proteins important in embryonic development and dorso-ventral body patterning/polarity. Till date, 13 different types of TLRs (TLR1-TLR13) have been discovered and described in mammals since the first discovery of TLR4 in humans in late 1997. This discovery of TLR4 in humans revolutionized the field of innate immunity and thus the immunology and host-pathogen interaction. Since then TLRs are found to be expressed on various immune cells and have been targeted for therapeutic drug development for various infectious and inflammatory diseases including cancer. Even, Single nucleotide polymorphisms (SNPs) among various TLR genes have been identified among the different human population and their association with susceptibility/resistance to certain infections and other inflammatory diseases. Thus, in the present review the current and future importance of TLRs in immunity, their pattern of expression among various immune cells along with TLR based therapeutic approach is reviewed.

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Section: Current and Future Tlr Based Therapeuticsmentioning

confidence: 99%

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Kumar

2018

International Immunopharmacology

501

346

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“…It is possible that the insulin‐resistant skeletal muscle in OB and T2DM subjects present with translational repression of Nur77 and NOR1 (Rodriguez‐Calvo et al. ). To compensate for this inability to translate the gene responses into functional protein, OB and T2DM skeletal muscle may bolster Nur77 and NOR1 gene expressions in response to insulin stimulation, without concomitant increases in protein expression.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle Nur77 and NOR1 insulin responsiveness is blunted in obesity and type 2 diabetes but improved after exercise training

et al. 2019

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Obesity and type 2 diabetes (T2 DM ) are characterized by a blunted metabolic response to insulin, and strongly manifests in skeletal muscle insulin resistance. The orphan nuclear receptors, Nur77 and NOR 1, regulate insulin‐stimulated nutrient metabolism where Nur77 and NOR 1 gene expression is increased with acute aerobic exercise and acute insulin stimulation. Whether Nur77 or NOR 1 are associated with the insulin‐sensitizing effects of chronic aerobic exercise training has yet to be elucidated. Fourteen lean healthy controls ( LHC ), 12 obese ( OB ), and 10 T2 DM individuals (T2 DM ) underwent hyperinsulinemic‐euglycemic clamps with skeletal muscle biopsies. Muscle was analyzed for Nur77 and NOR 1 gene and protein expression at basal and insulin‐stimulated conditions. Furthermore, a subcohort of 18 participants ( OB , n = 12; T2 DM , n = 6) underwent a 12‐week aerobic exercise intervention (85% HR max , 60 min/day, 5 days/week). In response to insulin infusion, LHC increased protein expression of Nur77 (8.7 ± 3.2‐fold) and NOR 1 (3.6 ± 1.1‐fold), whereas OB and T2 DM remained unaffected. Clamp‐derived glucose disposal rates correlated with Nur77 ( r 2 = 0.14) and NOR 1 ( r 2 = 0.12) protein expression responses to insulin, whereas age (Nur77: r 2 = 0.22; NOR 1: r 2 = 0.25) and BMI (Nur77: r 2 = 0.22; NOR 1: r 2 = 0.42) showed inverse correlations, corroborating preclinical data. In the intervention cohort, exercise improved Nur77 protein expression in response to insulin ( PRE : −1.2 ± 0.3%, POST : 6.2 ± 1.5%). Also, insulin treatment of primary human skeletal muscle cells increased Nur77 and NOR 1 protein. These findings highlight the multifactorial nature of insulin resistance in human obesity and T2 DM . Understanding the regulation of Nur77 and NOR 1 in skeletal muscle and other insulin‐sensitive tissues will create opportunities to advance therapies for T2 DM .

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“…In NOR1 knockout SMCs, PDGF‐induced proliferation and migration is almost completely inhibited, which coincides with a strong reduction in cyclin D1 expression (Nomiyama et al, ). Since the expression and roles of NR4A family are context‐ and tissue‐specific (Rodríguez‐Calvo, Tajes, & Vázquez‐Carrera, ), and the role of NOR1 in ASM biology has not been explored thus far, we attempted to investigate the expression and role of NOR1 in ASMC function. In the current study, we found that NOR1 is highly expressed in human ASMCs and its expression is markedly induced by PDGF‐BB stimulation and inhibited by miR‐638, which is consistent with our previous notion showing that miR‐638 directly binds to the 3′‐UTR of human NOR1 mRNA and downregulates its expression in vascular SMCs (Li et al, ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐638 inhibits human airway smooth muscle cell proliferation and migration through targeting cyclin D1 and NOR1

Wang

Yao

et al. 2018

Journal Cellular Physiology

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Abnormal airway smooth muscle cell (ASMC) proliferation and migration contribute significantly to increased ASM mass associated with asthma. MicroRNA (miR)-638 is a primate-specific miRNA that plays important roles in development, DNA damage repair, hematopoiesis, and tumorigenesis. Although it is highly expressed in ASMCs, its function in ASM remodeling remains unknown. In the current study, we found that in response to various mitogenic stimuli, including platelet-derived growth factor-two B chains (PDGF-BB), transforming growth factor β1, and fetal bovine serum, the expression of miR-638, as determined by quantitative real-time polymerase chain reaction (qRT-PCR), was significantly downregulated in the proliferative human ASMCs. Both gain- and loss-of-function studies were performed to study the role of miR-638 in ASMC proliferation and migration. We found that adenovirus-mediated miR-638 overexpression markedly inhibits ASMC proliferation and migration, while ablation of miR-638 by anti-miR-638 markedly increases cell proliferation and migration, as determined by WST-8 proliferation and scratch wound assays. Dual-luciferase reporter assay, qRT-PCR, and immunoblot analysis were used to investigate the effects of miR-638 on the expression of the downstream target genes in ASMCs. Our results demonstrated that miR-638 overexpression significantly reduced the expression of downstream target cyclin D1 and NOR1, both of which have been shown to be essential for cell proliferation and migration. Together, our study provides the first in vitro evidence highlighting the antiproliferative and antimigratory roles of miR-638 in human ASMC remodeling and suggests that targeted overexpression of miR-638 in ASMCs may provide a novel therapeutic strategy for preventing ASM hyperplasia associated with asthma.

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The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases

Cited by 97 publications

References 153 publications

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Skeletal muscle Nur77 and NOR1 insulin responsiveness is blunted in obesity and type 2 diabetes but improved after exercise training

MicroRNA‐638 inhibits human airway smooth muscle cell proliferation and migration through targeting cyclin D1 and NOR1

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