FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway

Xu, Xin; Chen, Yidi; Zhu, Danyang; Zhao, Tong; Xu, Rui; Wang, Jiaying; Hu, Lihong; Shen, Xu

doi:10.18632/aging.202275

Cited by 7 publications

(4 citation statements)

References 62 publications

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“…FX5 was determined as a non-steroidal GR antagonist by mammalian one-hybrid and transactivation assays as well as nuclear translocation assay in our previous work [ 30 ]. Notably, the antagonistic activity of FX5 against other nuclear receptors was also evaluated by mammalian transactivation assay.…”

Section: Resultsmentioning

confidence: 99%

“…In the current work, we determined that small molecule 5-chloro-N-[4-chloro-3- (trifluoromethyl)phenyl] thiophene-2-sulfonamide (FX5, Fig. 1a [ 30 ]) as a non-steroidal GR antagonist improved learning and memory in both T1DM and T2DM mice. The underlying mechanisms have been intensively investigated by assay against the GR-specific knockdown diabetic mice treated with adeno-associated virus (AAV)-ePHP- si-GR .…”

Section: Introductionmentioning

confidence: 99%

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FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice

Zhu

et al. 2022

Acta Pharmacol Sin

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Diabetic cognitive impairment (DCI) is a common diabetic complication characterized by learning and memory deficits. In diabetic patients, hyperactivated hypothalamic-pituitary-adrenal (HPA) axis leads to abnormal increase of glucocorticoids (GCs), which causes the damage of hippocampal neurons and cognitive impairment. In this study we investigated the cognition-improving effects of a non-steroidal glucocorticoid receptor (GR) antagonist 5-chloro-N-[4-chloro-3-(trifluoromethyl) phenyl]thiophene-2-sulfonamide (FX5) in diabetic mice. Four weeks after T1DM or T2DM was induced, the mice were administered FX5 (20, 40 mg·kg−1·d−1, i.g.) for 8 weeks. Cognitive impairment was assessed in open field test, novel object recognition test, Y-maze test, and Morris water maze test. We showed that FX5 administration significantly ameliorated the cognitive impairments in both type 1 and 2 diabetic mice. Similar cognitive improvement was observed in diabetic mice following brain GR-specific knockdown by injecting AAV-si-GR. Moreover, AAV-si-GR injection occluded the cognition-improving effects of FX5, suggesting that FX5 functioning as a non-steroidal GR antagonist. In PA-treated primary neurons (as DCI model in vitro), we demonstrated that FX5 (2, 5, 10 μM) dose-dependently ameliorated synaptic impairment via upregulating GR/BDNF/TrkB/CREB pathway, protected against neuronal apoptosis through repressing GR/PI3K/AKT/GSK3β-mediated tauopathy and subsequent endoplasmic reticulum stress. In LPS-treated primary microglia, FX5 dose-dependently inhibited inflammation through GR/NF-κB/NLRP3/ASC/Caspase-1 pathway. These beneficial effects were also observed in the hippocampus of diabetic mice following FX5 administration. Collectively, we have elucidated the mechanisms underlying the beneficial effects of non-steroidal GR antagonist FX5 on DCI and highlighted the potential of FX5 in the treatment of the disease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice

Zhu

et al. 2022

Acta Pharmacol Sin

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“…miR-145-5p also protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury by suppressing Smad4 expression ( Li et al, 2020b ). miR-122-5p is involved in the inhibition of cardiac fibroblast differentiation induced by apigenin through targeting the transcription factor HIF-1α ( Feng et al, 2021 ); it is regulated by another transcription factor HNF4α in type 2 diabetic mice ( Xu et al, 2020 ), indicating a regulation between miRNA and TF in different diseases.…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing-based identification of the regulatory mechanism of microRNAs, transcription factors, and corresponding target genes involved in vascular dementia

et al. 2022

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Vascular dementia (VaD) is the second most common form of dementia with uncertain mechanisms and no effective treatments. microRNAs (miRNAs) and transcription factors (TFs) are considered regulatory factors of genes involved in many diseases. Therefore, this work investigated the aberrantly expressed miRNAs, TFs, corresponding target genes, and their co-regulatory networks in the cortex of rats with bilateral common carotid artery occlusion (2VO) to uncover the potential mechanism and biomarkers of VaD. Differentially expressed genes (DEGs), miRNAs (DEMs), and TFs (DETFs) were identified using RNA sequencing, and their interaction networks were constructed using Cytoscape. The results showed that rats with 2VO had declined cognitive abilities and neuronal loss in the cortex than sham rats. DEGs, DEMs, and DETFs were discriminated between rats with 2VO and sham rats in the cortex, as shown by the 13 aberrantly expressed miRNAs, 805 mRNAs, and 63 TFs. The miRNA-TF-target gene network was constructed, showing 523 nodes and 7237 edges. Five miRNAs (miR-5132-5p, miR-764-3p, miR-223-3p, miR-145-5p, and miR-122-5p), ten TFs (Mxi1, Nfatc4, Rxrg, Zfp523, Foxj2, Nkx6-1, Klf4, Klf5, Csrnp1, and Prdm6), and seven target genes (Serpine1, Nedd4l, Pxn, Col1a1, Plec, Trip12, and Tpm1) were chosen as the significant nodes to construct feed-forward loops (FFLs). Gene Ontology and pathway enrichment analysis revealed that these miRNA and TF-associated genes are mostly involved in the PI3K/Akt, neuroactive ligand–receptor interaction, calcium signaling, and Wnt signaling pathways, along with central locations around the cell membrane. They exert functions such as growth factor binding, integrin binding, and extracellular matrix structural constituent, with representative biological processes like vasculature development, cell–substrate adhesion, cellular response to growth factor stimulus, and synaptic transmission. Furthermore, the expression of three miRNAs (miR-145-5p, miR-122-5p, and miR-5132-5p), six TFs (Csrnp1, Klf4, Nfatc4, Rxrg, Foxj2, and Klf5), and five mRNAs (Serpine1, Plec, Nedd4l, Trip12, and Tpm1) were significantly changed in rats with VaD, in line with the outcome of RNA sequencing. In the potential FFL, miR-145-5p directly bound Csrnp1 and decreased its mRNA expression. These results might help the understanding of the underlying regulatory mechanisms of miRNA-TF-genes, providing potential therapeutic targets in VaD.

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“…The absence of GR in hepatocytes limits the development of hyperglycemia in streptozotocin-induced diabetes mellitus due to down-regulation of gluconeogenic enzyme genes, suggesting that GR is involved in the development of diabetic hyperglycemia [ 120 ]. Xu et al determined that 5-chloro-N-(4-chloro-3-(trifluoromethyl)phenyl)thiophene-2-sulfonamide (FX5), a non-steroidal GR inhibitor, effectively reduced gluconeogenesis and improved glucose homeostasis in diabetic model mice, either directly by antagonizing GR or via the GR/HNF4α/miR122–5p signaling pathways [ 121 ]. Chen et al investigated the expression levels of gluconeogenetic enzymes, PCK1 and G6PC , as well as GR mRNA levels in diabetic rats [ 122 ].…”

Section: Glucocorticoid Receptormentioning

confidence: 99%

Glucocorticoid Receptor Signaling in Diabetes

Kokkinopoulou

Diakoumi

Moutsatsou

2021

IJMS

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Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation.

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FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway

Cited by 7 publications

References 62 publications

FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice

FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice

RNA sequencing-based identification of the regulatory mechanism of microRNAs, transcription factors, and corresponding target genes involved in vascular dementia

Glucocorticoid Receptor Signaling in Diabetes

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