• Biomolecules & Therapeutics
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• v.18 no.1
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• pp.106-110
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• 2010

The pharmacokinetics and bioavailability of ambroxol, an expectoration improver and mucolytic agent, were studied to determine the feasibility of enhanced transdermal delivery of ambroxol from the ethylene-vinyl acetate (EVA) matrix system containing polyoxyethylene-2-oleyl ether as an enhancer in rats. The ambroxol-010 matrix system (15 mg/kg) was applied to abdominal skin of rats. Blood samples were collected via the femoral artery for 28 hrs and the plasma concentrations of ambroxol were determined by HPLC. Pharmacokinetic parameters were calculated using Lagran method computer program. The area under the curve (AUC) was significantly higher in the enhancer group ($1,678{\pm}1,413.3\;ng/ml{\cdot}hr$) than that in the control group $1,112{\pm}279\;ng/ml{\cdot}hr$), that is treated transdermally without enhancer, showing about 151% increased bioavailability (p<0.05). The average $C_{max}$ was increased in the enhancer group ($86.0{\pm}21.5\;ng$/ml) compared with the control group ($59.0{\pm}14.8\;ng$/ml). The absolute bioavailability was 13.9% in the transdermal control group, 21.1% in the transdermal enhancer group and 18.1% in the oral administration group compared with the IV group. The $T_{max}$, $K_a$, MRT and $t_{1/2}$ of ambroxol in transdermal enhancer group were increased significantly (p<0.01) compared to those of oral administration. As the ambroxol-EVA matrix containing polyoxyethylene-2-oleyl ether and tributyl citrate was administered to rats via the transdermal routes, the relative bioavailability increased about 1.51-fold compared to the control group, showing a relatively constant, sustained blood concentration. The results of this study show that ambroxol-EVA matrix could be developed as a transdermal delivery system providing sustained plasma concentration.

• Korean Journal of Microbiology
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• v.27 no.2
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• pp.85-91
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• 1989

The effect of SV40 and murine cytomegalovirus (MCMV) enhancers on the general and tissue-specific gene expression was investigated. Recombinant plasmids containing these transcriptional engancers downstream of a structural gene for chloramphenicol acetyl transferase (CAT) were constructed. The transient expression of CAT gene from these plasmids was measured in monkey (CV1PD) and HeLa cells. Both SV40 and MCMV engancers activated the expression of CAT gene by more than 20 and 150 folds, respectively, compared with engancerless plasmids. When the SV40 promoter, upstream of CAT gene, was replaced with 2.2 kbp of promoter regulatory region of bovine growth hormone (bGH) gene, there was no expression of CAT even in the presence of enhancers, reflecting the tissue-specific expression of bGH genes. However, when the bGH regulatory region was shortened to 230 bp, the expression level increased dramatically in the presence of SV40 enhancers. In contrast, the expression from the shortened promoter was only marginally activated by the stronger MCMV enhancer.

• BMB Reports
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• v.44 no.2
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• pp.113-117
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• 2011

Previous studies suggest that EphA7 plays a critical role in neural tube closure or cortical progenitor apoptosis. In this report, enhancer trap assay was used to modify various EphA7 BAC clones and screen a large genomic region spanning 570 kb downstream of the EphA7 gene. We found that the dorsal midline-specific EphA7 enhancer resides on the 457D20 EphA7 BAC clone and is localized to a 35 kb genomic region in between +345.7 kb to +379.8 kb downstream of the EphA7 transcription start site. Identification of the EphA7 BAC clone containing a long-range dorsal midline enhancer may constitute a useful tool for investigating the biological functions of EphA7 in vivo.

• Advances in Traditional Medicine
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• v.9 no.4
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• pp.269-276
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• 2009

Black pepper (family Piperaceae), is called king of spices because it is one of the oldest spice and alone accounts for about 35% of the world's total spice trade. The pepper is used in Ayurvedic medicine for the treatment of various ailments particularly neurological, broncho-pulmonary and gastrointestinal disorders. Pepper has also been reported to have various pharmacological actions but recently, it is highlighted as a bioavailability enhancer. This results in higher plasma concentration of drugs, nutrients, ions and other xenobiotics, rendering them more bioavailable for physiological as well as pharmacological actions in the body. Numerous scientific studies reported that piperine; a main bioactive compound of pepper, is responsible for its bioavailability enhancing property. It's a well known fact that pepper enhances bioavailability by inhibition of microsomal enzyme system but other mechanisms are also responsible to acts as a bioavailability enhancer. The brief overview of the mechanism of action of pepper as well as its applications as bioavailability enhancer is given in the present article.

• Molecules and Cells
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• v.40 no.3
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• pp.169-177
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• 2017

Tissue-specific transcription is critical for normal development, and abnormalities causing undesirable gene expression may lead to diseases such as cancer. Such highly organized transcription is controlled by enhancers with specific DNA sequences recognized by transcription factors. Enhancers are associated with chromatin modifications that are distinct epigenetic features in a tissue-specific manner. Recently, super-enhancers comprising enhancer clusters co-occupied by lineage-specific factors have been identified in diverse cell types such as adipocytes, hair follicle stem cells, and mammary epithelial cells. In addition, noncoding RNAs, named eRNAs, are synthesized at super-enhancer regions before their target genes are transcribed. Many functional studies revealed that super-enhancers and eRNAs are essential for the regulation of tissue-specific gene expression. In this review, we summarize recent findings concerning enhancer function in tissue-specific gene regulation and cancer development.

• Biomolecules & Therapeutics
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• v.16 no.3
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• pp.210-214
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• 2008

The pharmacokinetic parameters and bioavailability of pranoprofen from the gel were measured to determine the enhancing effect of octanoic acid on the transdermal absorption of pranoprofen in rats. 8 mg/kg of pranoprofen was administered from gel with octanoic acid (the enhancer group) or that without octanoic acid (the control group) via the transdermal route, and the results were compared with those obtained from the intravenously (0.5 mg/kg, IV group) or orally administered group (4 mg/kg, oral group). The AUC of the control, the enhancer, the IV, and the oral groups were $20.2{\pm}5.1$, $50.7{\pm}12.7$, $19.9{\pm}2.5$, and $70.5{\pm}17.6\;ug/ml{\cdot}h$ respectively. The average $C_{max}$ of the control and the enhancer group were $0.93{\pm}0.23$ and $2.82{\pm}0.71\;ug/ml$, respectively, and the mean $T_{max}$ of the control and the enhancer group was 7.00 h. The relative bioavailability of the transdermally administered pranoprofen gel containing octanoic acid was approximately 2.50 times higher than the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. This suggests that it might be feasible to develop a pranoprofen gel preparation containing an enhancer for the transdermal administration, which is more convenient dosage form than the oral dosage forms.

• Journal of Pharmaceutical Investigation
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• v.41 no.6
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• pp.337-345
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• 2011

The objective of this work is to investigate the effect of chemical enhancer and current on the flux of donepezil hydrochloride (DH) through skin. Ethanol and N-methyl pyrrolidone (NMP) were used as chemical enhancers in combination with iontophoresis. We also have studied the effect of pH on flux and evaluated the role of electroosmosis. In vitro flux study was performed at $33^{\circ}C$, using side-by-side diffusion cell and full thickness hairless mouse skin. Passive flux of DH without enhancer was very small. As the concentration of enhancer increased, passive flux increased. After current application, flux increased markedly and the time to reach maximum decreased. Without enhancer, maximum flux was about 50 fold larger than that obtained without current. These results indicate that electromigration is playing a major role for the transport. As the enhancer concentration increased, flux also increased. NMP and ethanol increased not only the passive delivery, but also the iontophoretic delivery. Flux results indicate that ethanol has better ability than NMP in enhancing the transport of DH. The magnitudes of increase in flux by these enhancers indicate that there is a large synergistic effect in flux enhancement. Flux results from pH study showed that electroosmotic flow is reversed at low pH and the flux is hindered. These results provided some information on the flux enhancing ability of ethanol and NMP in combination with iontophoresis. The data also provided some mechanistic insights into the role of electromigration and electroosmosis on flux through skin.

• Molecules and Cells
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• v.28 no.2
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• pp.87-92
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• 2009

Human SIRT3 gene contains an intronic VNTR enhancer. A T > C transition occurring in the second repeat of each VNTR allele implies the presence/absence of a putative GATA binding motif. A partially overlapping AP-1 site, not affected by the transition, was also identified. Aims of the present study were: 1) to verify if GATA and AP-1 sites could bind GATA2 and c-Jun/c-Fos factors, respectively; 2) to investigate whether such sites modulate the enhancer activity of the SIRT3-VNTR alleles. DAPA assay proved that GATA2 and c-Jun/c-Fos factors are able to bind the corresponding sites. Moreover, co-transfection experiments showed that the over-expression of GATA2 and c-Jun/c-Fos factors boosts the VNTR enhancer activity in an allelic-specific way. Furthermore, we established that GATA2 and c-Jun/c-Fos act additively in modulating the SIRT3-VNTR enhancer function. Therefore, GATA2 and AP-1 are functional sites and the T > C transition of the second VNTR repeat affects their activity.

• The Korean Journal of Zoology
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• v.37 no.2
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• pp.137-143
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• 1994

Microiniection of genes Into Xenopus laeuis oocvtes in highly useful in the annvsis of gene regulation, since a large number of oocvtes can be injected in a relatively short time. The GRP78 enhancer has been identified to a 291-bp fragment that spans a region of GRP78 promoter between -378 and -87 (Lin et at., 1986: Kim and Lee, 1989). We examined whether this GRP78 enhancer is effective in directing expression of heterologous gene in Xenopus laeuis oocytes. The chloramphenicol acetvltransferase (CAT) fusion constructs containing the GRP78 promoter and the SV4O early promoter were constructed and were injected into nuclei of Xencpus laeuis oocvtes. The recipient oocvtes were then assayed for CAT activity. The fusion constructs exhibited higher activity as compared to SV40 promoter tested here. The GRP78 enhancer showed 8.5- to 9.2-fold enhancement over that of the SV4O promoter. The orientation of GRP78 enhancer with respect to the direction of CAT transcription unit had no significant effect. Thus, the GRP78 enhancer is a viable candidate for the construction of expression system for use in Xenopus laevss oocvtes and will be important for the studY of a gene expression throughout development.

• BMB Reports
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• v.56 no.7
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• pp.398-403
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• 2023

Natural killer (NK) cells are an essential part of the innate immune system that helps control infections and tumors. Recent studies have shown that Vorinostat, a histone deacetylase (HDAC) inhibitor, can cause significant changes in gene expression and signaling pathways in NK cells. Since gene expression in eukaryotic cells is closely linked to the complex three-dimensional (3D) chromatin architecture, an integrative analysis of the transcriptome, histone profiling, chromatin accessibility, and 3D genome organization is needed to gain a more comprehensive understanding of how Vorinostat impacts transcription regulation of NK cells from a chromatin-based perspective. The results demonstrate that Vorinostat treatment reprograms the enhancer landscapes of the human NK-92 NK cell line while overall 3D genome organization remains largely stable. Moreover, we identified that the Vorinostat-induced RUNX3 acetylation is linked to the increased enhancer activity, leading to elevated expression of immune response-related genes via long-range enhancer-promoter chromatin interactions. In summary, these findings have important implications in the development of new therapies for cancer and immune-related diseases by shedding light on the mechanisms underlying Vorinostat's impact on transcriptional regulation in NK cells within the context of 3D enhancer network.