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Results for “Enhancer”

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At least 181 records · Page 10Linked to original sources

PubMed2003

[Oleyl pyroglutamate for use as transdermal enhancer and its enhancing mechanism].

AIM: To test the enhancing activity and the mechanism of oleyl pyroglutamate used as transdermal enhancer. METHODS: The penetration-enhancing effects of oleyl pyroglutamate, oleyl alcohol and oleic acid on the three drugs (caffeine, tinidazole and cortisone) were observed; the transdermal enhancing mechanism of oleyl pyroglutamate was studied with the attenuated total reflectance Fourier-transfer infrared spectroscopy(ATR-FTIR) of the human stratum corneum in vivo. RESULTS: The penetration-enhancing ratio of the three drugs was 7.9 fold, 41.8 fold and 2.8 fold, respectively. The absorptions at 2,800-2,950 cm-1 and 1,642-1,646 cm-1 (amide-I) in the ATR-FTIR spectrum of the stratum were found to be shifted differently following removal of the stratum corneum which was treated with oleyl pyroglutamate. CONCLUSION: Oleyl pyroglutamate showed better penetration-enhancing effect on the penetration of drugs. Its transdermal enhancing mechanism may be that oleyl pyroglutamate induced not only disordering of the stratum corneum lipid, but also change of the secondary structure of keratin.

Administration, Cutaneous↗

PubMed1992

Enhancement of systemic delivery of met-enkephalin and leu-enkephalin eyedrops with permeation enhancers.

It was found that methionine enkephalin (Met-Enk) and leucine-enkephalin (Leu-Enk) can be delivered efficiently into the systemic circulation through the outer route in rabbits. When 50 mcl of 1% Met-Enk eyedrops without absorption enhancers were instilled into eyes, the rabbits' blood concentration rose from 92 pg/ml to 153 pg/ml in 10 min. When either of two permeation enhancers (BL-9 or Brij-78) was added at a 0.5% concentration to the ophthalmic solution, the systemic absorption of 1% Met-Enk was markedly improved. Its blood level was increased to approximately 3.4 times that without the enhancer. When the eyedrops of 0.3% Met-Enk plus 0.5% absorption enhancer were administered, the blood concentration reached higher than that reached by 1% Met-Enk without permeation enhancers. Similar results were obtained with Leu-Enk except the systemic absorption was enhanced by BL-9 and Brij-78 even further to 10-fold and 8.3-fold, respectively. These results indicate that the systemic delivery of Met-Enk and Leu-Enk through eyes, especially with the addition of permeation enhancers, is a feasible alternative route to parenteral injection.

Absorption↗

PubMed2026

ATRX Condensates as Candidate Organizers of Enhancer-Centered Nuclear Microenvironments in Neural Progenitors: A Hypothesis for Enhancer-Associated ATRX Function in Neural Progenitors.

Neural progenitor cells (NPCs) must preserve lineage identity while remaining responsive to developmental cues. Here, we discuss the hypothesis that ATRX condensates help organize enhancer-centered nuclear microenvironments in NPCs. ATRX has long been studied in heterochromatin maintenance, histone variant deposition, and chromatin remodeling; earlier work has also shown that ATRX can occupy euchromatic and active regulatory regions and contribute to transcriptional regulation. Recent evidence in human NPCs indicates that ATRX forms nuclear puncta with condensate-like properties, associates with neurogenic enhancer-rich regions, and incorporates regulatory factors such as CHD7 and p300. Perturbation of ATRX condensate formation is associated with changes in enhancer-associated ATRX occupancy, neural gene-expression programs, and neuroepithelial organization, suggesting a regulatory mode that may complement canonical heterochromatin-associated functions. We propose a dual-mode model in which folded domains contribute to chromatin anchoring at repressive regions, whereas intrinsically disordered regions support condensate-associated organization at active developmental enhancers. We emphasize that whether ATRX condensates activate enhancers de novo, stabilize pre-existing enhancer states, buffer transcriptional variability, or primarily organize cofactor localization remains unresolved. We also discuss limitations of the current evidence and outline acute, locus-specific experiments needed to test the model.

X-linked Nuclear Protein↗

PubMedDate not supplied

Comparison of contrast enhanced CT and Mn-DPDP enhanced MRI for detection of focal hepatic lesions. Initial findings.

Twenty-nine patients with known or suspected focal hepatic disease were evaluated in a retrospective multi-institutional study comparing T1-weighted manganese (II) N,N'-dipyridoxylethylenediamine-N,N'-diacetate 5,5'-bis (phosphate) (DPDP) enhanced magnetic resonance imaging (MRI) with dynamic sequential bolus contrast enhanced computed tomography (DBCT) for the detection of focal liver lesions. The patients were divided into four dose groups, receiving 3, 5, 8, or 10 mumol/kg of Mn-DPDP, delivered either via intravenous bolus (0.25 ml/sec) or infusion (1 ml/sec). Each of three readers, with varying levels of expertise in interpreting hepatic MRI and CT studies, identified more lesions on the Mn-DPDP enhanced MRI than the contrast enhanced CT images. Mn-DPDP enhanced MRI depicted the presence of extensive metastatic disease not seen with DBCT in three patients with fatty liver. The most experienced MRI reader saw more lesions per patient on the Mn-DPDP enhanced MRI than with DBCT, while the opposite held true for the most experienced CT reader. The best single exam for detection of hepatic lesions may be determined by the experience of the reader.

Adolescent↗

PubMed1994

Determination of tissue specificity of the enhancer by combinatorial operation of tissue-enriched transcription factors. Both HNF-4 and C/EBP beta are required for liver-specific activity of the ornithine transcarbamylase enhancer.

The enhancer of the rat ornithine transcarbamylase gene is located 11 kilobases upstream from the transcription start site and has been shown to be hepatoma cell-specific. Using transgenic mice, we showed that this enhancer is capable of activating transcription in a liver-specific manner, inverting the tissue specificity of the homologous promoter that is by itself more active in the small intestine than in the liver. Transient transfection analysis with cultured hepatoma cells indicated that the enhancer activity resides in the approximately 110-base pair region containing four protein-binding sites, two for hepatocyte nuclear factor-4 (HNF-4) and two for CCAAT/enhancer binding protein (C/EBP), both of which are liver-selective transcription factors. Concatemerization of a region containing one HNF-4 and one C/EBP site led to reconstitution of the hepatoma cell-specific enhancer, and intactness of these two sites was strictly required for the enhancer activity. Furthermore, cotransfection experiments showed that both HNF-4 and C/EBP beta are necessary, and neither alone sufficient, for activation of the reconstituted enhancer in nonhepatic cells. Requirement of combinatorial operation of at least two liver-enriched transcription factors for transcriptional activation successfully explains why these liver-selective but not strictly liver-specific factors can confer more restricted liver specificity on transcription of their target genes.

Animals↗

PubMed1995

Repression of the immunoglobulin heavy chain 3' enhancer by helix-loop-helix protein Id3 via a functionally important E47/E12 binding site: implications for developmental control of enhancer function.

The activity of the immunoglobulin 3' enhancer is restricted to the late stages of B lymphoid development. Here we further examine the molecular basis for the temporally restricted activity of the B-lymphoid IgH 3' enhancer. We demonstrate that a binding site (E5 site) for the E47 and/or E12 proteins is functionally important for enhancer activity. The multimerized E5 site acts as a B cell-specific enhancer and, when assayed in COS cells, can be transactivated by E47/E12 proteins. This transactivation in COS cells, as well as the activity of the full length 3' enhancer in plasma cells, can be repressed by overexpression of the dominant negative nuclear regulator Id3. When examining the tissue distribution of Id3 in murine cell lines, we find that Id3 is expressed throughout the pre-B and B cell stages, but is down-regulated at the plasma cell stage. Thus, Id3 may contribute to the temporal regulation of the IgH 3' enhancer.

Animals↗

PubMed1986

Tandem kappa immunoglobulin promoters are equally active in the presence of the kappa enhancer: implications for models of enhancer function.

Transcription of immunoglobulin kappa genes is regulated by enhancer and promoter elements, both of which function in a tissue-specific fashion. We have studied the interaction of these elements by transfecting plasmacytoma cells with genes that have tandem kappa promoters located next to a single kappa enhancer and assaying these genes for transient or stable transcription. We find that the promoters located proximal and distal to the enhancer function identically whether they are separated by 440 bp or by 2.7 kb or whether they are located 1.7 or 7.7 kb away from the enhancer. Our results indicate that the immunoglobulin kappa enhancer does not operate as a bidirectional entry site for RNA polymerase or for other factors associated with the transcription complex. Rather, they suggest that the enhancer exerts its influence uniformly over large distances and independently of the presence of intervening promoters.

Animals↗

PubMed2004

An enhancer trap in the ascidian Ciona intestinalis identifies enhancers of its Musashi orthologous gene.

The enhancer trap technique, established in Drosophila melanogaster, is a very sophisticated tool. Despite its usefulness, however, there have been very few reports on enhancer traps in other animals. The ascidian Ciona intestinalis, a splendid experimental system for developmental biology, provides good material for developmental genetics. Recently, germline transgenesis of C. intestinalis has been achieved using the Tc1/mariner superfamily transposon Minos. During the course of that study, one Minos insertion line that showed a different GFP expression pattern from other lines was isolated. One fascinating possibility is that an enhancer trap event occurred in this line. Here we show that a Minos insertion in the Ci-Musashi gene was responsible for the altered GFP expression. Ci-Musashi showed a similar expression pattern to GFP. In addition, introns of Ci-Musashi have enhancer activity that can alter the expression pattern of nearby genes to resemble that of GFP in this line. These results clearly demonstrate that an enhancer trap event that entrapped enhancers of Ci-Musashi occurred in C. intestinalis.

Alternative Splicing↗

PubMed2001

HMG-1 enhances HMG-I/Y binding to an A/T-rich enhancer element from the pea plastocyanin gene.

High-mobility-group proteins HMG-1 and HMG-I/Y bind at overlapping sites within the A/T-rich enhancer element of the pea plastocyanin gene. Competition binding experiments revealed that HMG-1 enhanced the binding of HMG-I/Y to a 31-bp region (P31) of the enhancer. Circularization assays showed that HMG-1, but not HMG-I/Y, was able to bend a linear 100-bp DNA containing P31 so that the ends could be ligated. HMG-1, but not HMG-I/Y, showed preferential binding to the circular 100-bp DNA compared with the equivalent linear DNA, indicating that alteration of the conformation of the DNA by HMG-1 was not responsible for enhanced binding of HMG-I/Y. Direct interaction of HMG-I/Y and HMG-1 in the absence of DNA was demonstrated by binding of 35S-labeled proteins to immobilized histidine-tagged proteins, and this was due to an interaction of the N-terminal HMG-box-containing region of HMG-1 and the C-terminal AT-hook region of HMG-I/Y. Kinetic analysis using the IAsys biosensor revealed that HMG-1 had an affinity for immobilized HMG-I/Y (Kd = 28 nM) similar to that for immobilized P31 DNA. HMG-1-enhanced binding of HMG-I/Y to the enhancer element appears to be mediated by the formation of an HMG-1-HMG-I/Y complex, which binds to DNA with the rapid loss of HMG-1.

Carrier Proteins↗

PubMed1996

Repression of transcriptional enhancer factor-1 and activator protein-1-dependent enhancer activity by vascular actin single-stranded DNA binding factor 2.

Transcriptional repression of the murine vascular smooth muscle alpha-actin gene in fibroblasts results from the interaction of two sequence-specific single-stranded DNA binding activities (VACssBF1 and VACssBF2) with opposite strands of an essential transcriptional enhancer factor-1 (TEF-1) element (Sun, S., Stoflet, E. S., Cogan, J. G., Strauch, A. R., and Getz, M. J. (1995) Mol. Cell. Biol. 15, 2429-2436). Here, we identify a sequence element located within a protein-coding exon of the gene that bears structural similarity with the TEF-1 enhancer. This includes a 30-base pair region of purine-pyrimidine asymmetry encompassing a perfect 6-base pair GGAATG TEF-1 recognition motif. Unlike the enhancer, however, the exon sequence exhibits no TEF-1 binding activity nor does the pyrimidine-rich strand bind VACssBF1. However, VACssBF2 interacts equally well with the purine-rich strand of both the enhancer and the exon sequence. To test the ability of VACssBF2 to independently repress transcription, the exon sequence was placed upstream of a deletionally activated promoter containing an intact TEF-1 binding site. The exon sequence repressed promoter activity, whereas a mutant deficient in VACssBF2 binding did not. Moreover, VACssBF2 similarly repressed activator protein-1-dependent transcription of a heterologous tissue factor promoter. These results suggest that VACssBF2 possesses an intrinsic ability to disrupt enhancer function independently of the enhancer-binding proteins involved.

3T3 Cells↗

PubMed2005

Calcium scoring of aortic valve calcification in aortic valve stenosis with a multislice computed tomography scanner: non-enhanced versus contrast-enhanced studies.

PURPOSE: Previous studies have shown a positive correlation between amount of aortic valve calcification (AVC) and degree of aortic valve stenosis (AVS). We have investigated whether calcium scoring of AVC from contrast-enhanced images is reliable. MATERIAL AND METHODS: Nineteen patients with suspected AVS underwent retrospectively ECG-gated multislice computed tomography (MSCT). Standardized scan protocols were applied prior to (120 KV, 133 mAseff) and after (120 KV, 500 mAseff) the administration of non-ionic contrast material. Image reconstruction was performed at 60% of the RR interval (slice thickness 3 mm, reconstruction increment 2 mm). AVC was quantified using Agatston score and calcium mass. The number of lesions was calculated. All nonenhanced images were scored using thresholds of 130 HU and 350 HU. Contrast-enhanced images were assessed with a threshold of 350 HU exclusively. RESULTS: Fifteen patients with AVCs were included in the statistical analysis. The mean Agatston score (calcium mass) in non-enhanced images was 2888.4 +/- 2844.4 (694.2 mg +/- 869.3 mg). Altering the threshold from 130 HU to 350 HU led to a 58.2% (30.5%) decrease in the AVC score (P values < 0.001). Contrast-enhanced images showed an increased Agatston score (calcium mass) of 56.2% (33.5%) compared to non-enhanced images (P values <0.05) with the same threshold of 350 HU. CONCLUSION: Quantification of AVC from contrast-enhanced images is not reliable, as contrast material simulates calcification.

Aortic Valve↗

PubMed2026

Hi-Enhancer: a two-stage framework for prediction and localization of enhancers based on Blending-KAN and Stacking-Auto models.

MOTIVATION: Gene expression plays a crucial role in cell function, and enhancers can regulate gene expression precisely. Therefore, accurate prediction of enhancers is particularly critical. However, existing prediction methods have low accuracy or rely on fixed multiple epigenetic signals, which may not always be available. RESULTS: We propose a two-stage framework that accurately predicts enhancers by flexibly combining multiple epigenetic signals. In the first stage, we designed a Blending-KAN model, which integrates the results of various base classifiers and employs Kolmogorov-Arnold Networks (KAN) as a meta-classifier to predict enhancers based on flexible combinations of multiple epigenetic signals. In the second stage, we developed a Stacking-Auto model, which extracted sequence features using DNABERT-2 and located the enhancers based on the Stacking strategy and AutoGluon framework. The accuracy of the Blending-KAN model reached 99.69 ± 0.11% when five epigenetic signals were used. In cross-cell line prediction, the accuracy was more significant than or equal to 93.72%. With Gaussian noise, it still maintains an accuracy of 98.74 ± 0.03%. In the second stage, the accuracy of the Stacking-Auto model is 80.50%, which is better than the existing 17 methods. The results show that our models can be flexibly used to predict and locate enhancers utilizing a combination of multiple epigenetic signals. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/emanlee/Hi-Enhancer and https://doi.org/10.6084/m9.figshare.29262158.v1.

Enhancer Elements, Genetic↗

PubMed1989

Determinant differences between the rabbit and mouse immunoglobulin kappa enhancers impair the activity of the rabbit enhancer in mouse myeloma cells.

Enhancer activity of the rabbit immunoglobulin kappa light chain gene intron conserved region (KICR) was examined in mouse myeloma cells using transient expression experiments. Compared to the homologous region of the mouse kappa light chain gene, the rabbit KICR shows nearly no stimulatory effect on expression of the indicator gene, cat. Experiments with mouse-rabbit chimeric KICRs indicated that differences in the region around the NF-kappa B binding site are responsible for the impaired activity of the rabbit KICR whereas mouse sequences covering the kappa E2 and kappa E3 motifs can be replaced by the equivalent rabbit fragment without affecting enhancer function. Creation of a perfect mouse NF-kappa B target sequence in the rabbit gene only partially restores enhancer activity. Furthermore, mouse and rabbit DNA fragments encompassing the NF-kappa B target sequence behave in an identical manner in an electrophoretic mobility shift assay. The results indicate species-related functional differences in the immunoglobulin kappa light chain gene enhancer and suggest that although the NF-kappa B binding site plays a crucial role in enhancer activity surrounding gene elements are also necessary for full enhancer effect.

Animals↗

PubMedDate not supplied

Multidetector multiphase contrast-enhanced liver CT: prospective study comparing two contrast material injection rates on vascular and liver parenchyma enhancement in patients with varied cirrhotic status.

BACKGROUND: To compare 2 rates of contrast material injection, with dose tailored to patient body weight (bw) and automatic bolus triggering system, on vascular and liver parenchyma enhancement at multidetector multiphase contrast-enhanced liver computed tomography (CT) of patients with varied cirrhotic status. METHODS: One hundred and thirty consecutive patients with varied cirrhotic status, referred for contrast-enhanced liver CT evaluation of focal liver nodule(s), were prospectively and randomly assigned to 1 of 2 routine contrast-enhanced liver CT protocols: 2 mL/kg of bw of a nonionic contrast agent (300 mg I/mL) injected at a 3 mL/sec, versus 2 mL/kg of bw of the same contrast agent injected at 4 mL/sec. Quantitative vascular and liver parenchyma enhancements were obtained. Attenuation values of the abdominal aorta during the arterial phase CT, of the main portal vein during the portal venous phase CT, and of the liver parenchyma during the arterial, the portal venous, and the equilibrium phases liver CT, were compared with multiple 2-way analysis of variance. RESULTS: Significantly higher attenuation values were noted in the abdominal aorta with a 4-mL/sec-flow rate. Attenuation values were not significantly different in the portal vein and in the liver parenchyma, whatever was the patient cirrhotic status. CONCLUSIONS: With dose tailored to body weight and automatic bolus triggering system, adjusting flow rate makes no difference in patients with regard to liver or portal vein enhancement, regardless of presence/absence of cirrhosis.

Adult↗

PubMed1990

The state of cellular differentiation determines the activity of the adenovirus E1A enhancer element: evidence for negative regulation of enhancer function.

Most of the eucaryotic enhancer elements so far described consist of multiple DNA binding sites for proteins that act either synergistically or antagonistically to modulate the rate of transcription. In this report, we show that the activity of the adenovirus E1A enhancer element is suppressed in virus-infected undifferentiated rodent fetal fibroblast cells (CREF and F111 cells) and primary rat liver hepatocytes that have lost their fully differentiated phenotype (dedifferentiated). This contrasts with the results obtained for virus-infected differentiated or partially dedifferentiated rodent hepatocytes or hepatoma cell lines and human HeLa cells, in which deletion of the E1A enhancer domain greatly reduces the rate of E1A gene transcription. An in vitro quantitation of the nuclear proteins (from HeLa and CREF cells) that interact with and modulate the activity of the E1A enhancer revealed similar binding activities for the E2f and ATF proteins. However, an AP3-like (phi AP3) activity was present at a 10- to 20-fold higher concentration in CREF cells than in HeLa cells, and removal of this phi AP3-binding site on the viral genome resulted in an increase in the rate of E1A gene transcription in virus-infected CREF cells. Together, these results demonstrated that the factors which positively regulate enhancer function were present in CREF cells and that the phi AP3 factor was acting to suppress the activity of the E1A enhancer. Furthermore, the level of this factor was found to increase to even higher levels in CREF cells treated with 12-O-tetradecanoylphorbol-13-acetate, and this induction resulted in a further suppression in the rate of E1A gene transcription. On the basis of these observations, we propose that E1A expression is negatively regulated by the phi AP3 factor in undifferentiated rodent fetal fibroblast cells and that this could be an important mechanism that distinguishes between establishment of the differentiated cell versus transformed cell phenotypes.

Adenovirus Early Proteins↗

PubMed1997

Second-site proviral enhancer alterations in lymphomas induced by enhancer mutants of SL3-3 murine leukemia virus: negative effect of nuclear factor 1 binding site.

SL3-3 is a highly T-lymphomagenic murine retrovirus. Previously, mutation of binding sites in the U3 repeat region for the AML1 transcription factor family (also known as core binding factor [CBF], polyomavirus enhancer binding protein 2 [PEBP2], and SL3-3 enhancer factor 1 [SEF1]) were found to strongly reduce the pathogenicity of SL3-3 (B. Hallberg, J. Schmidt, A. Luz, F. S. Pedersen, and T. Grundström, J. Virol. 65:4177-4181, 1991). We have now examined the few cases in which tumors developed harboring proviruses that besides the AML1 (core) site mutations carried second-site alterations in their U3 repeat structures. In three distinct cases we observed the same type of alteration which involved deletions of regions known to contain binding sites for nuclear factor 1 (NF1) and the addition of extra enhancer repeat elements. In transient-expression experiments in T-lymphoid cells, these new U3 regions acted as stronger enhancers than the U3 regions of the original viruses. This suggests that the altered proviruses represent more-pathogenic variants selected for in the process of tumor formation. To analyze the proviral alterations, we generated a series of different enhancer-promoter reporter constructs. These constructs showed that the additional repeat elements are not critical for enhancer strength, whereas the NF1 sites down-regulate the level of transcription in T-lymphoid cells whether or not the AML1 (core) sites are functional. We therefore also tested SL3-3 viruses with mutated NF1 sites. These viruses have unimpaired pathogenic properties and thereby distinguish SL3-3 from Moloney murine leukemia virus.

Base Sequence↗

PubMed1990

Complex regulation of the immunoglobulin mu heavy-chain gene enhancer: microB, a new determinant of enhancer function.

The B-lymphocyte-specific activity of the immunoglobulin mu heavy-chain gene enhancer has been attributed to the octamer motif (ATTTGCAT) present within the enhancer that binds a B-cell-specific factor designated NF-A2/OTF-2. However, significant residual enhancer activity even after deletion of this element has suggested the presence of a second critical functional determinant. We have used deletion and mutational analyses to define an element, microB (TTTGGGGAA), that is essential for B-cell-specific enhancer activity in S194 myeloma cells in the absence of the octamer. Transfection analysis in a panel of lymphoid cell lines suggests that the presence of either microB or octamer leads to considerable enhancer activity in cell lines representing later stages of B-cell differentiation, whereas both elements are needed for function in cell lines representing earlier stages. Furthermore, in contrast to the results in pre-B-cell lines, both microB and octamer elements function independently in certain T-cell lines in which the mu enhancer is active.

Animals↗

PubMed2004

The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5' bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1.

Analysis of cis-regulatory elements is central to understanding the genomic program for development. The scl/tal-1 transcription factor is essential for lineage commitment to blood cell formation and previous studies identified an scl enhancer (the +18/19 element) which was sufficient to target the vast majority of hematopoietic stem cells, together with hematopoietic progenitors and endothelium. Moreover, expression of scl under control of the +18/19 enhancer rescued blood progenitor formation in scl(-/-) embryos. However, here we demonstrate by using a knockout approach that, within the endogenous scl locus, the +18/19 enhancer is not necessary for the initiation of scl transcription or for the formation of hematopoietic cells. These results led to the identification of a bifunctional 5' enhancer (-3.8 element), which targets expression to hematopoietic progenitors and endothelium, contains conserved critical Ets sites, and is bound by Ets family transcription factors, including Fli-1 and Elf-1. These data demonstrate that two geographically distinct but functionally related enhancers regulate scl transcription in hematopoietic progenitors and endothelial cells and suggest that enhancers with dual hematopoietic-endothelial activity may represent a general strategy for regulating blood and endothelial development.

Animals↗