Drug Repurposing to Treat Glucocorticoid Resistance in Asthma

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV1). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV1, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.

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Benzisothiazolone Derivatives Exhibit Cytotoxicity in Hodgkin’s Lymphoma Cells through NF-κB Inhibition and are Synergistic with Doxorubicin and Etoposide

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200213103513 ◽

2020 ◽

Vol 20 (6) ◽

pp. 715-723

Author(s):

Natarajan Nandakumar ◽

Pushparathinam Gopinath ◽

Jacob Gopas ◽

Kannoth M. Muraleedharan

Keyword(s):

Synergistic Effect ◽

Hodgkin’S Lymphoma ◽

A549 Cells ◽

Hodgkin's Lymphoma ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Lymphoma Cells ◽

Nuclear Extracts ◽

Gene Assay

Background: The authors investigated the NF-κB inhibitory role of three Benzisothiazolone (BIT) derivatives (1, 2 and 3) in Hodgkin’s Lymphoma cells (L428) which constitutively express activated NF-κB. All three compounds showed dose-dependent NF-κB inhibition (78.3, 70.7 and 34.6%) in the luciferase reporter gene assay and were found cytotoxic at IC50 values of 3.3μg/ml, 4.35μg/ml and 13.8μg/ml, respectively by the XTT assay. BIT 1and BIT 2 (but not BIT 3) suppressed both NF-κB subunits p50 and p65 in cytoplasmic and nuclear extracts in a concentration-dependent manner. Furthermore, BIT 1 showed a moderate synergistic effect with the standard chemotherapy drugs etoposide and doxorubicin, whereas BIT 2 and 3 showed a moderate additive effect to antagonistic effect. Cisplatin exhibited an antagonist effect on all the compounds tested under various concentrations, except in the case of 1.56μg/ml of BIT 3 with 0.156μg/ml of cisplatin. The compounds also inhibited the migration of adherent human lung adenocarcinoma cells (A549) in vitro. We conclude that especially BIT 1 and BIT 2 have in vitro anti-inflammatory and anti-cancer activities, which can be further investigated for future potential therapeutic use. Methods: Inspired by the electrophilic sulfur in Nuphar alkaloids, monomeric and dimeric benzisothiazolones were synthesized from dithiodibenzoic acid and their NF-κB inhibitory role was explored. NF-κB inhibition and cytotoxicity of the synthesized derivatives were studied using luciferase reporter gene assay and XTTassay. Immunocytochemistry studies were performed using L428 cells. Cell migration assay was conducted using the A549 cell line. L428 cells were used to conduct combination studies and the results were plotted using CompuSyn software. Results: Benzisothiazolone derivatives exhibited cytotoxicity in Hodgkin’s Lymphoma cells through NF-κB inhibition. Potent compounds showed suppression of both NF-κB subunits p50 and p65 in a concentrationdependent manner, both in cytoplasmic and nuclear extracts. Combination studies suggest that benzisothiazolone derivatives possess a synergistic effect with etoposide and doxorubicin. Furthermore, the compounds also inhibited the migration of A549 cells. Conclusion: Benzisothiazolones bearing one or two electrophilic sulfur atoms as part of the heterocyclic framework exhibited cytotoxicity in Hodgkin’s Lymphoma cells through NF-κB inhibition. In addition, these derivatives also exhibited a synergistic effect with etoposide and doxorubicin along with the ability to inhibit the migration of A549 cells. Our study suggests that BIT-based new chemical entities could lead to potential anticancer agents.

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153 SUPPLEMENTATION WITH LINOLENIC ACID AND L-CARNITINE DURING IVM REDUCED THE EXPRESSION OF GENES RELATED TO LIPOGENESIS BUT DID NOT ALTER THE LIPID CONTENT AND CRYOTOLERANCE OF IN VITRO-PRODUCED EMBRYOS

Reproduction Fertility and Development ◽

10.1071/rdv29n1ab153 ◽

2017 ◽

Vol 29 (1) ◽

pp. 185 ◽

Cited By ~ 1

Author(s):

B. C. S. Leao ◽

N. A. S. Rocha Frigoni ◽

P. C. Dall'Acqua ◽

M. Ambrogi ◽

G. B. Nunes ◽

...

Keyword(s):

Gene Expression ◽

Linolenic Acid ◽

Lipid Content ◽

Control Group ◽

Intracellular Lipid ◽

Chi Square ◽

Sudan Black B ◽

Expression Of Genes ◽

The Impact

This study was conducted to evaluate the impact of supplementation during in vitro maturation (IVM) with linolenic acid (ALA), l-carnitine (L-car), or the combination of both supplements on the embryo intracellular lipid content and cryotolerance, as well as in the embryo expression of genes involved in lipid metabolism (lipogenesis regulation: SCD1, FASN, and SREBP1; and β-oxidation pathway: CPT1B and CPT2). Cumulus-oocyte complexes (n = 1076) were IVM for 22 h at 38.5°C and 5% CO2 in air, in TCM-199 medium with bicarbonate, hormones, and 10% FCS (control group), supplemented with 100 μM ALA (ALA group), 5 mM L-car (L-car group), or a combination of 100 μM ALA + 5 mM L-car (ALA + L-car group). After IVF, presumptive zygotes were in vitro cultured in SOFaa medium supplemented with 5 mg mL−1 BSA and 2.5% FCS, at 38.5°C and 5% CO2 in air during 7 days. Cleavage and blastocyst rates were evaluated on Day 3 and 7, respectively (IVF = Day 0). At Day 7, the blastocysts were stained with the lipophilic dye Sudan Black B (n = 60), vitrified/warmed (n = 260; Ingámed® protocol, Maringa-PR, Brazil), or collected for analysis of gene expression (n = 180). Embryonic development were analysed by ANOVA and the multiple comparisons of means were determined by Tukey’s test. The embryonic re-expansion data were subjected to chi-square test and the differences in gene expression among groups were evaluated by Duncan’s multiple range test (P < 0.05). Data are presented as means ± standard error means. There was no effect (P > 0.05) of the supplements used during IVM on cleavage (79.54 ± 2.76% to 82.16 ± 1.13%) and blastocyst rates (29.03 ± 3.07% to 30.46 ± 2.01%). Similarly, the intracellular lipid content in Day-7 blastocysts (1.03 ± 0.04 to 1.15 ± 0.07 pixels) and the embryonic cryotolerance, assessed by the re-expansion rates after 24 h (67.3 to 78.3%) hatching rates after 48 h (11.5 to 25.5%) of post-warming culture, were unaffected (P > 0.05) by the supplements of IVM medium. Although the treatments did not alter (P > 0.05) the expression of CPT1B and CPT2 genes, the expression of FASN gene was decreased (P < 0.05) in the ALA group and the expression of SREBP1 gene was decreased (P < 0.05) in the ALA and L-car groups. The expression of the gene SCD1 was reduced (P < 0.05) in all treatments compared with the control group. Thus, despite the lack of effects of the treatments performed during IVM on the intracellular lipid content and cryotolerance of the embryos derived from the treated oocytes, a reduction in the expression of genes related to lipogenesis was observed in Day-7 blastocysts. These results suggest that treatments performed in the oocytes during IVM may have prolonged effects, affecting the subsequent expression of genes in embryos. Further studies are needed to determine the mechanisms related to the differentiation of the oocyte machinery during maturation. Financial support was provided by FAPESP (#2012/10084–4 and #2013/07382–6).

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Aroyl-Pyrrolyl-Hydroxy-Amides (APHAs), a Novel Family of Synthetic Histone Deacetylases Inhibitors, Are Potent Inducers of Human g-Globin Gene Expression.

Blood ◽

10.1182/blood.v104.11.1216.1216 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1216-1216

Author(s):

Antonello Mai ◽

Silvio Massa ◽

Antonella Di Noia ◽

Katija Jelicic ◽

Elena Alfani ◽

...

Keyword(s):

Gene Expression ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Histone Deacetylases ◽

Globin Gene ◽

Renilla Luciferase ◽

In Vitro Assays ◽

Luciferase Reporter ◽

Globin Gene Expression

Abstract Post-natal pharmacological reactivation of HbF, by restoring the unbalanced α/non-α globin chain production in red cells of patients affected by β-thalassemia or sickle cell anemia, represents a potential cure for these diseases. Many classes of compounds have been identified capable to induce Hb F synthesis in vitro by acting at different levels of the globin gene expression regulatory machinery. One of these classes is represented by inhibitors of a family of enzymes, the histone deacetylases (HDACs), involved in chromatin remodelling and gene transcription regulation. HDACs act in multi-protein complexes that remove acetyl groups from lysine residues on several proteins, including histones and are divided into three distinct structural classes, depending on whether their catalytic activity is zinc (class I/II)- or NAD+ (class III)-dependent. The effects of the HDACs inhibitors identified so far on HbF synthesis is, however, modest and often associated with high toxicity. Therefore, the potential of their clinical use is unclear. We have recently described a new family of synthetic HDACs inhibitors, the Aroyl-pyrrolyl-hydroxy-amides (APHAs), that induce differentiation, growth arrest and/or apoptosis of transformed cell in culture [Mai A et al, J Med Chem2004;47:1098]. In this study, we investigate the capability of 10 different APHA compounds to induce Hb F in two in vitro assays. One assay is based on the ability of APHA compounds to activate either the human Aγ-driven Firefly (Aγ-F) or the β-promoter drives Renilla Luciferase (β-R) reporter in GM979 cells stably transfected with a Dual Luciferase Reporter construct. The second assay is represented by the induction of γ-globin expression (by quantitative RT-PCR) in primary adult erythroblasts obtained in HEMA cultures of mononuclear cells from normal donors. The majority of the compounds tested did not significantly increased the Aγ−F (Aγ−F+β−R) reporter ratio in GM979 cells. However, the compound MC1575 increased by 3-fold (from 0.09 to 0.30) the reporter ratio in GM979 cells at a concentration of 20 μM, with modest effects of the proliferation activity of GM979 cells over the three days of the assay. When MC1575 was added at a concentration of 2–10 μM in cultures of primary adult erythroblasts induced to differentiate in serum-free media for 4 days, it induced a three fold increase of the γ/(γ+β) globin ratio (from 0.04 to 0.12), with no apparent cellular toxicity. Among the HDAC inhibitors tested in this study, MC1575 was not the most potent inhibitor of total enzyme activity. However, it was the compound that most selectively inhibited the activity of the maize homologue of mammalian class IIa HDAC enzymes [Mai et al, J Med Chem2003;46:4826]. These results are consistent with the hypothesis that each class of histone deacetylases might have a specific biological function and indicate that those of class IIa might represent the enzymes most specifically involved in globin gene regulation. We suggest that, by targeting the chemical inhibitors toward the catalytic domain of this class of enzymes, it should be possible to identify more specific, more potent and less toxic compounds for pharmacological treatment of β-thalassemia or sickle cell anemia.

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The Immunomodulatory Effects of AlbuminIn VitroandIn Vivo

Advances in Pharmacological Sciences ◽

10.1155/2011/691928 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Derek S. Wheeler ◽

John S. Giuliano ◽

Patrick M. Lahni ◽

Alvin Denenberg ◽

Hector R. Wong ◽

...

Keyword(s):

Gene Expression ◽

Lethal Dose ◽

Intraperitoneal Administration ◽

Peritoneal Macrophages ◽

Luciferase Reporter Assay ◽

Luciferase Reporter ◽

Reporter Assay ◽

Dose Dependent

Albumin appears to have proinflammatory effectsin vitro. We hypothesized that albumin would induce a state of tolerance to subsequent administration of lipopolysaccharide (LPS)in vitroandin vivo. RAW264.7 and primary peritoneal macrophages were treated with increasing doses of bovine serum albumin (BSA) and harvested for NF-κB luciferase reporter assay or TNF-αELISA. In separate experiments, RAW264.7 cells were preconditioned with 1 mg/mL BSA for 18 h prior to LPS (10 μg/mL) treatment and harvested for NF-κB luciferase reporter assay or TNF-αELISA. Finally, C57Bl/6 mice were preconditioned with albumin via intraperitoneal administration 18 h prior to a lethal dose of LPS (60 mg/kg body wt). Blood was collected at 6 h after LPS administration for TNF-αELISA. Albumin produced a dose-dependent and TLR-4-dependent increase in NF-κB activation and TNF-αgene expressionin vitro. Albumin preconditioning abrogated the LPS-mediated increase in NF-κB activation and TNF-αgene expressionin vitroandin vivo. The clinical significance of these findings remains to be elucidated.

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Novel Disulfide-Containing Poly(β-amino ester)-Functionalised Magnetic Nanoparticles for Efficient Gene Delivery

Australian Journal of Chemistry ◽

10.1071/ch15293 ◽

2016 ◽

Vol 69 (3) ◽

pp. 349 ◽

Cited By ~ 1

Author(s):

Yucheng Liu ◽

Shufeng Li ◽

Liandong Feng ◽

Hao Yu ◽

Xiaoliang Qi ◽

...

Keyword(s):

Gene Expression ◽

Magnetic Nanoparticles ◽

Disulfide Bonds ◽

Transfection Efficiency ◽

A549 Cells ◽

Weight Ratio ◽

Cell Types ◽

Amino Ester ◽

Gene Complexes

Poly(β-amino ester)s (PBAEs) have been proved to effectively transfer DNA to various cell types. However, PBAEs with high molecular weights also show considerable toxicities, partly resulting from inadequate degradation of their polyester backbone. In this study, we created novel poly(β-amino ester)s (SF-1, 2, 3, and 4; notation SFs refers to all the four polymers) which were characterised by the cleavable disulfide bonds. Moreover, a new technique, termed magnetofection that uses magnetic nanoparticles to enhance gene expression, has recently been well developed. The negatively charged magnetic nanoparticles (MNPs) with good biocompatibility in vitro were prepared here to subsequently combine with SFs and DNA via electrostatic interaction, leading to the formation of the magnetic gene complexes MNP/SFs/DNA. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and transfection experiments were performed in A549 cells to investigate all the resulting complexes. Studies indicated that the synthesised PBAEs exhibited good biodegradation and regulated release of DNA as a result of the reductive cleavage of the disulfide bonds, giving higher transfection efficiency along with much lower cytotoxicity compared with commercially available transfection agent polyethylenimine (Mw 25 kDa). Furthermore, when MNP was involved at a MNP/DNA weight ratio of 0.5, the magnetic gene complexes MNP/SFs/DNA showed enhanced levels of gene expression while maintaining low cytotoxicity.

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The disruption of circadian clockwork in differentiating cells from rat reproductive tissues as identified by in vitro real-time monitoring system

Journal of Endocrinology ◽

10.1677/joe-07-0044 ◽

2007 ◽

Vol 193 (3) ◽

pp. 413-420 ◽

Cited By ~ 45

Author(s):

Pei-Jian He ◽

Masami Hirata ◽

Nobuhiko Yamauchi ◽

Seiichi Hashimoto ◽

Masa-aki Hattori

Keyword(s):

Gene Expression ◽

Real Time ◽

Monitoring System ◽

Cell Types ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Peripheral Tissues ◽

Reproductive Tissues ◽

Clock Gene Expression

The circadian clock, regulating hormonal secretion and metabolisms in accordance with the environmental light–dark cycle, resides in almost all peripheral tissues as well as in the superchiasmatic nucleus. Clock gene expression has been found to be noncyclic during spermatogenesis and the differentiation of thymocytes. However, currently little is known about how cell differentiation could affect circadian clockwork. We performed this study using the in vitro real-time oscillation monitoring system to examine the clockwork in several types of differentiating cells originated from reproductive tissues of transgenic rats (constructed with Period gene 2 (Per2) promoter-destabilized luciferase reporter gene). After treatment with dexamethasone (DXM), persistent oscillation of Per2 expression was observed in both gonadotropin-induced and pregnant ovarian luteal cells, proliferative uterine stromal cells (USCs), and nondifferentiating testicular interstitial cells, with a cyclic period of ~24 h. In contrast to these cell types, only one cycle of oscillation was sustained in granulosa cells undergoing differentiation. Additionally, Per2 oscillation was irregular in USCs undergoing decidualization induced by medroxyprogesterone acetate plus N6, 2-O-dibutyryl adenosine 3′:5′-cyclic monophosphate. Furthermore, no oscillation of Per2 expression was evoked by DXM in Leydig cells and thymocytes. In conclusion, the present study characterized the oscillation of Per2 gene expression in several types of ovarian, uterine, and testicular cells, and it is strongly suggested that circadian clockwork is affected during cellular differentiation.

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Downregulation of circ-PSMB6 suppresses NSCLC progression and metastasis through sponging miR-532-5p and regulating EZH1 expression

10.21203/rs.3.rs-392149/v1 ◽

2021 ◽

Author(s):

Mingming Jin ◽

Junqian Zhang ◽

Yue Wu ◽

Yitian Dai ◽

Gang Huang

Keyword(s):

Gene Expression ◽

High Throughput Sequencing ◽

Stem Cell Differentiation ◽

Nsclc Cell ◽

Cell Counting ◽

Regulatory Mechanisms ◽

Luciferase Reporter ◽

Circular Rnas

Abstract Background: Accumulating reports showed how circular RNAs (circRNAs) act importantly during tumor progression via regulating gene expression, but regulatory mechanisms remain largely unknown. Current investigation clarified circRNA regulatory mechanisms in non-small cell lung cancer (NSCLC).Methods: High-throughput sequencing and quantitative reverse transcription polymerase chain reaction (RT-qPCR) detection were utilized to explore circRNA expression in NSCLC tissues and cells. Our lab did statistical analyses and luciferase reporter analysis to validate correlations between circRNA, miRNA and gene expression. We transfected NSCLC cells with different vectors, and transwell migration, Cell Counting Kit-8 (CCK-8) proliferation along with colony formation assays were performed. In vivo tumorigenesis and metastasis assays were utilized to validate the circRNA role in NSCLC.Results: Data illustrated that hsa_circ_0041595 (circ-PSMB6) incremented in NSCLC cell lines and tissues, while circ-PSMB6 downregulation suppressed NSCLC cell proliferation and invasion in vitro and in vivo. Bioinformatics analysis and luciferase reporter data verified that miR-532-5p and Enhancer Of Zeste 1 Polycomb Repressive Complex 2 Subunit (EZH1) were circ-PSMB6 downstream targets in NSCLC cells. Overexpression of EZH1 or miR-532-5p inhibition reversed NSCLC cell invasion and proliferation after silencing circ-PSMB6. Further experiments discovered that circ-PSMB6 can influence cancer stem cell differentiation by regulating miR-532-5p/EZH1.Conclusions: Taken together, we found that circ-PSMB6 suppressed NSCLC metastasis and progression via sponging miR-532-5p and regulating EZH1 expression.

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Functional analysis of haplotypes and promoter activity at the 5' region of the DRD2 gene and associations with schizophrenia.

10.21203/rs.3.rs-15812/v1 ◽

2020 ◽

Author(s):

Xicen Zhang ◽

Mei Ding ◽

Yi Liu ◽

Yongping Liu ◽

Jiaxin Xing ◽

...

Keyword(s):

Gene Expression ◽

Cell Lines ◽

Promoter Region ◽

Regulatory Region ◽

Gene Promoter ◽

Luciferase Reporter ◽

Drd2 Gene ◽

Functional Regions

Abstract Background: In previous studies, we researched the association of the DRD2 gene promoter region SNP loci rs7116768, rs1047479195, rs1799732, rs1799978 and schizophrenia using Sanger sequencing. rs7116768 and rs1799978 were found to be slightly associated with schizophrenia. This study investigated the effects of haplotypes consisted of the four SNPs on protein expression level in vitro and identified the functional sequence in the 5’ regulatory region of DRD2 gene which has a potential link with schizophrenia.Methods: Recombinant plasmids with haplotypes, SNPs and 13 recombinant vectors containing deletion fragments from the DRD2 gene 5' regulatory region were transfected into HEK293 and SK-N-SH cell lines. Relative luciferase activity of the haplotypes, SNPs and different sequences was compared using a dual luciferase reporter assay system.Results: Haplotype H4(G-C-InsC-G) could significantly increase the gene expression in SK-N-SH cell lines. Allele C of rs7116768, allele A of rs1047479195 and allele del C of rs1799732 could up-regulate the gene expression. There were 5~7 functional regions in the promoter region of DRD2 gene that could affect the level of gene expression.Conclusion: We cannot rule out the possibility that different haplotypes may influence DRD2 gene expression in vivo. We observed that allele C of rs7116768, allele A of rs1047479195 and allele del C of rs1799732 could up-regulate gene expression. The truncation results confirmed the existence of functional regions in the promoter region of DRD2 gene that could affect the level of gene expression.

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Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21197148 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7148

Author(s):

Kamalakannan Radhakrishnan ◽

Yong-Hoon Kim ◽

Yoon Seok Jung ◽

Jina Kim ◽

Don-Kyu Kim ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Molecular Mechanism ◽

Nuclear Receptor ◽

Iron Homeostasis ◽

Luciferase Reporter ◽

Orphan Nuclear Receptor ◽

Knock Out

Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6.

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