scholarly journals Gold Nanoparticles Modified With Polyethyleneimine Disturbed the Activity of Drug-Metabolic Enzymes and Induced Inflammation-Mediated Liver Injury in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanqing Chen ◽  
Shuang Zhou ◽  
Meilin Zhu ◽  
Bing Wang ◽  
Wei Chen ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
De Novo ◽  
Biomedical Application ◽  
Thermal Characteristics ◽  
Metabolic Enzymes ◽  
Hepatic Uptake ◽  
Liver Inflammation ◽  
Element Binding Protein ◽  
Responsive Element

Gold nanoparticles (GNPs) have been used as a potential bioactive platform for drug delivery due to their unique optical and thermal characteristics. Liver is the main organ in orchestrating physiological homeostasis through metabolization of drugs and detoxification of exogenous substances. Therefore, it is crucial to deeply understand the mechanism of nanoparticle–liver interaction and the potential hepatic effects of GNPs in vivo. In this study, we studied the hepatic impacts of the intravenously injected polyethyleneimine (PEI)-modified GNPs (PEI-GNPs) on the expression of hepatic drug-metabolic enzymes and sterol responsive element binding protein 1c (SREBP-1c)-mediated de novo lipogenesis in mice for 24 h and 1 week. PEI-GNP accumulation in the liver is associated with increased liver inflammation, as evidenced by the gene expression of pro-inflammatory cytokines. Moreover, the GNP-induced hepatotoxicity in mice is partly due to liver inflammation–triggered disruption in the function of drug-metabolic enzymes, including hepatic uptake and efflux transporters, cytochrome P450 (CYP450), and UDP-glucuronosyltransferases (UGTs). The study provides evidence that it is necessary to consider the nanomaterial–liver interaction and manipulate the surface chemistry of GNPs prior to biomedical application of nanoparticles.

scholarly journals SREBP1 drives KRT80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer

2018 ◽  
Author(s):  
Ylenia Perone ◽  
Aaron J. Farrugia ◽  
Alba Rodriguez Meira ◽  
Balázs Győrffy ◽  
Charlotte Ion ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Invasion ◽  
De Novo ◽  
Regulatory Element ◽  
Leading Edge ◽  
Clinical Endpoints ◽  
Breast Cancer Relapse ◽  
Element Binding Protein ◽  
Cytoskeletal Rearrangements

AbstractApproximately 30% of women diagnosed with ERα breast cancer relapse with metastatic disease following adjuvant treatment with endocrine therapies1,2. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain (TAD)3 undergoes epigenetic reprogramming in cells that develop resistance to aromatase inhibitors (AI), leading to keratin 80 (KRT80) upregulation. In agreement, an increased number of KRT80-positive cells are observed at relapse in vivo while KRT80 expression associates with poor outcome using several clinical endpoints. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 14 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion maturation and cellular stiffening, which collectively promote cancer cell invasion. Shear-wave elasticity imaging of prospective patients shows that KRT80 levels correlate with stiffer tumors in vivo. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

scholarly journals FGIN-1-27 Inhibits Melanogenesis by Regulating Protein Kinase A/cAMP-Responsive Element-Binding, Protein Kinase C-β, and Mitogen-Activated Protein Kinase Pathways

2020 ◽  
Vol 11 ◽  
Author(s):  
Jinpeng Lv ◽  
Songzhou Jiang ◽  
Ying Yang ◽  
Ximei Zhang ◽  
Rongyin Gao ◽  
...  
Keyword(s):  
Protein Kinase ◽  
The Body ◽  
Tyrosinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Mushroom Tyrosinase ◽  
Mitogen Activated Protein ◽  
Element Binding Protein ◽  
Responsive Element

FGIN-1-27 is a synthetic mitochondrial diazepam binding inhibitor receptor (MDR) agonist that has demonstrated pro-apoptotic, anti-anxiety, and steroidogenic activity in various studies. Here we report, for the first time, the anti-melanogenic efficacy of FGIN-1-27 in vitro and in vivo. FGIN-1-27 significantly inhibited basal and α-melanocyte-stimulating hormone (α-MSH)-, 1-Oleoyl-2-acetyl-sn-glycerol (OAG)- and Endothelin-1 (ET-1)-induced melanogenesis without cellular toxicity. Mushroom tyrosinase activity assay showed that FGIN-1-27 did not directly inhibit tyrosinase activity, which suggested that FGIN-1-27 was not a direct inhibitor of tyrosinase. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, FGIN-1-27 downregulated the expression levels of key proteins that function in melanogenesis. FGIN-1-27 played these functions mainly by suppressing the PKA/CREB, PKC-β, and MAPK pathways. Once inactivated, it decreased the expression of MITF, tyrosinase, TRP-1, TRP-2, and inhibited the tyrosinase activity, finally inhibiting melanogenesis. During in vivo experiments, FGIN-1-27 inhibited the body pigmentation of zebrafish and reduced UVB-induced hyperpigmentation in guinea pig skin, but not a reduction of numbers of melanocytes. Our findings indicated that FGIN-1-27 exhibited no cytotoxicity and inhibited melanogenesis in both in vitro and in vivo models. It may prove quite useful as a safer skin-whitening agent.

scholarly journals cAMP-Responsive Element Binding Protein: A Vital Link in Embryonic Hormonal Adaptation

Endocrinology ◽  
2013 ◽  
Vol 154 (6) ◽  
pp. 2208-2221 ◽  
Author(s):  
Maria Schindler ◽  
Sünje Fischer ◽  
René Thieme ◽  
Bernd Fischer ◽  
Anne Navarrete Santos
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Binding Protein ◽  
Cell Lineage ◽  
Element Binding Protein ◽  
A Cell ◽  
Responsive Element ◽  
Camp Responsive Element Binding

Abstract The transcription factor cAMP responsive element-binding protein (CREB) and activating transcription factors (ATFs) are downstream components of the insulin/IGF cascade, playing crucial roles in maintaining cell viability and embryo survival. One of the CREB target genes is adiponectin, which acts synergistically with insulin. We have studied the CREB-ATF-adiponectin network in rabbit preimplantation development in vivo and in vitro. From the blastocyst stage onwards, CREB and ATF1, ATF3, and ATF4 are present with increasing expression for CREB, ATF1, and ATF3 during gastrulation and with a dominant expression in the embryoblast (EB). In vitro stimulation with insulin and IGF-I reduced CREB and ATF1 transcripts by approximately 50%, whereas CREB phosphorylation was increased. Activation of CREB was accompanied by subsequent reduction in adiponectin and adiponectin receptor (adipoR)1 expression. Under in vivo conditions of diabetes type 1, maternal adiponectin levels were up-regulated in serum and endometrium. Embryonic CREB expression was altered in a cell lineage-specific pattern. Although in EB cells CREB localization did not change, it was translocated from the nucleus into the cytosol in trophoblast (TB) cells. In TB, adiponectin expression was increased (diabetic 427.8 ± 59.3 pg/mL vs normoinsulinaemic 143.9 ± 26.5 pg/mL), whereas it was no longer measureable in the EB. Analysis of embryonic adipoRs showed an increased expression of adipoR1 and no changes in adipoR2 transcription. We conclude that the transcription factors CREB and ATFs vitally participate in embryo-maternal cross talk before implantation in a cell lineage-specific manner. Embryonic CREB/ATFs act as insulin/IGF sensors. Lack of insulin is compensated by a CREB-mediated adiponectin expression, which may maintain glucose uptake in blastocysts grown in diabetic mothers.

scholarly journals miR-205 Inhibits Neuroblastoma Growth by Targeting cAMP-Responsive Element-Binding Protein 1

2018 ◽  
Vol 26 (3) ◽  
pp. 445-455 ◽  
Author(s):  
Shu Chen ◽  
Lianhua Jin ◽  
Shu Nie ◽  
Lizhi Han ◽  
Na Lu ◽  
...  
Keyword(s):  
Binding Protein ◽  
Staging System ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Direct Target Gene ◽  
Element Binding Protein ◽  
Responsive Element ◽  
Camp Responsive Element Binding

Accumulating evidence indicates that microRNA-205 (miR-205) is involved in tumor initiation, development, and metastasis in various cancers. However, its functions in neuroblastoma (NB) remain largely unclear. Here we found that miR-205 was significantly downregulated in human NB tissue samples and cell lines. miR-205 expression was lower in poorly differentiated NB tissues and those of advanced International Neuroblastoma Staging System stage. In addition, restoration of miR-205 in NB cells suppressed proliferation, migration, and invasion and induced cell apoptosis in vitro, as well as impaired tumor growth in vivo. cAMP-responsive element-binding protein 1 (CREB1) was identified as a direct target gene of miR-205. Expression of an miR-205 mimic in NB cells significantly diminished expression of CREB1 and the CREB1 targets BCL-2 and MMP9. CREB1 was also found to be upregulated in human NB tissues, its expression being inversely correlated with miR-205 expression (r = −0.554, p = 0.003). Importantly, CREB1 upregulation partially rescued the inhibitory effects of miR-205 on NB cells. These findings suggest that miR-205 may function as a tumor suppressor in NB by targeting CREB1.

scholarly journals Attenuated c-fos mRNA Induction after Middle Cerebral Artery Occlusion in CREB Knockout Mice Does Not Modulate Focal Ischemic Injury

1998 ◽  
Vol 18 (12) ◽  
pp. 1325-1335 ◽  
Author(s):  
Ryuji Hata ◽  
Peter Gass ◽  
Gunter Mies ◽  
Christoph Wiessner ◽  
Konstantin-Alexander Hossmann
Keyword(s):  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Ischemic Injury ◽  
Gene Induction ◽  
Artery Occlusion ◽  
Targeted Disruption ◽  
Mrna Induction ◽  
Element Binding Protein ◽  
Responsive Element

To elucidate the mechanism of ischemia-induced signal transduction in vivo, we investigated the effect of the targeted disruption of the α and Δ isoforms of the cAMP-responsive element-binding protein (CREB) on c-fos and heat-shock protein (hsp) 72 gene induction, Permanent focal ischemia was induced by occlusion of the middle cerebral artery of the CREB mutant mice (CREB(−/–), n = 5) and the wild-type mice (n = 6). Three hours after onset of ischemia, the neurologic score was assessed and pictorial measurements of ATP and cerebral protein synthesis (CPS) were carried out to differentiate between the ischemic core (where ATP is depleted), the ischemic penumbra (where ATP is preserved but CPS is inhibited), and the intact tissue (where both ATP and CPS are preserved). There were no significant differences in neurologic score or in ATP, pH, and CPS between the two groups, suggesting that the sensitivity of both strains to ischemia is the same. Targeted disruption of the CREB gene significantly attenuated c-fos gene induction in the periischemic ipsilateral hemisphere but had no effect on either c-fos or hsp72 mRNA expression in the penumbra. The observations demonstrate that CREB expression, despite its differential effect on c-fos, does not modulate acute focal ischemic injury.

scholarly journals Open the LID: LXRα regulates ChREBPα transactivity in a target gene-specific manner through an agonist-modulated LBD-LID interaction

2019 ◽  
Author(s):  
Qiong Fan ◽  
Rikke C. Nørgaard ◽  
Ivar Grytten ◽  
Cecilie M. Ness ◽  
Christin Lucas ◽  
...  
Keyword(s):  
Target Genes ◽  
Glucose Sensing ◽  
Activation Domains ◽  
Specific Target ◽  
Glucose And Lipid Metabolism ◽  
Element Binding Protein ◽  
Underlying Mechanisms ◽  
Responsive Element

ABSTRACTThe cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in liver. We have previously shown that LXR regulates ChREBP transcription and activity; however, the underlying mechanisms are unclear. In the current study, we demonstrate that LXRα and ChREBPα interact physically, and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα, and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP, but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; ChREBPα’s low glucose inhibitory domain (LID) and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα that was overlooked due to LXR lipogenesis-promoting function.

Involvement of the cyclic AMP-responsive element binding protein in bovine leukemia virus expression in vivo.

1994 ◽  
Vol 68 (9) ◽  
pp. 5845-5853 ◽  
Author(s):  
E Adam ◽  
P Kerkhofs ◽  
M Mammerickx ◽  
R Kettmann ◽  
A Burny ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Bovine Leukemia Virus ◽  
Binding Protein ◽  
Leukemia Virus ◽  
Element Binding Protein ◽  
Responsive Element ◽  
Virus Expression

scholarly journals The role of the glucose-sensing transcription factor carbohydrate-responsive element-binding protein pathway in termite queen fertility

Open Biology ◽  
2016 ◽  
Vol 6 (5) ◽  
pp. 160080 ◽  
Author(s):  
David Sillam-Dussès ◽  
Robert Hanus ◽  
Michael Poulsen ◽  
Virginie Roy ◽  
Maryline Favier ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Binding Protein ◽  
Glucose Sensing ◽  
De Novo Lipogenesis ◽  
Organic Polymer ◽  
Key Factor ◽  
Element Binding Protein ◽  
Responsive Element

Termites are among the few animals that themselves can digest the most abundant organic polymer, cellulose, into glucose. In mice and Drosophila , glucose can activate genes via the transcription factor carbohydrate-responsive element-binding protein (ChREBP) to induce glucose utilization and de novo lipogenesis. Here, we identify a termite orthologue of ChREBP and its downstream lipogenic targets, including acetyl-CoA carboxylase and fatty acid synthase. We show that all of these genes, including ChREBP, are upregulated in mature queens compared with kings, sterile workers and soldiers in eight different termite species. ChREBP is expressed in several tissues, including ovaries and fat bodies, and increases in expression in totipotent workers during their differentiation into neotenic mature queens. We further show that ChREBP is regulated by a carbohydrate diet in termite queens. Suppression of the lipogenic pathway by a pharmacological agent in queens elicits the same behavioural alterations in sterile workers as observed in queenless colonies, supporting that the ChREBP pathway partakes in the biosynthesis of semiochemicals that convey the signal of the presence of a fertile queen. Our results highlight ChREBP as a likely key factor for the regulation and signalling of queen fertility.

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