Reconfiguring the Electronic Structure of Heteroatom Doped Carbon Supported Bimetallic Oxide@Metal Sulfide Core-Shell Heterostructure via In Situ Nb Incorporation toward Extrinsic Pseudocapacitor.

High-energy-density battery-type materials have sparked considerable interest as supercapacitors electrode; however, their sluggish charge kinetics limits utilization of redox-active sites, resulting in poor electrochemical performance. Here, the unique core-shell architecture of metal organic framework derived N-S codoped carbon@Cox Sy micropetals decorated with Nb-incorporated cobalt molybdate nanosheets (Nb-CMO4 @Cx Sy NC) is demonstrated. Coordination bonding across interfaces and π-π stacking interactions between CMO4 @Cx Sy and N and, S-C can prevent volume expansion during cycling. Density functional theory analysis reveals that the excellent interlayer and the interparticle conductivity imparted by Nb doping in heteroatoms synergistically alter the electronic states and offer more accessible species, leading to increased electrical conductivity with lower band gaps. Consequently, the optimized electrode has a high specific capacity of 276.3 mAh g-1 at 1 A g-1 and retains 98.7% of its capacity after 10 000 charge-discharge cycles. A flexible quasi-solid-state SC with a layer-by-layer deposited reduced graphene oxide /Ti3 C2 TX anode achieves a specific energy of 75.5 Wh kg-1 (volumetric energy of 1.58 mWh cm-3 ) at a specific power of 1.875 kWh kg-1 with 96.2% capacity retention over 10 000 charge-discharge cycles.

Electronic Structure Engineered Heteroatom Doped All Transition Metal Sulfide Carbon Confined Heterostructure for Extrinsic Pseudocapacitor.

Ultra-high energy density battery-type materials are promising candidates for supercapacitors (SCs); however, slow ion kinetics and significant volume expansion remain major barriers to their practical applications. To address these issues, hierarchical lattice distorted α-/γ-MnS@Cox Sy core-shell heterostructure constrained in the sulphur (S), nitrogen (N) co-doped carbon (C) metal-organic frameworks (MOFs) derived nanosheets (α-/γ-MnS@Cox Sy @N, SC) have been developed. The coordination bonding among Cox Sy , and α-/γ-MnS nanoparticles at the interfaces and the π-π stacking interactions developed across α-/γ-MnS@Cox Sy and N, SC restrict volume expansion during cycling. Furthermore, the porous lattice distorted heteroatom-enriched nanosheets contain a sufficient number of active sites to allow for efficient electron transportation. Density functional theory (DFT) confirms the significant change in electronic states caused by heteroatom doping and the formation of core-shell structures, which provide more accessible species with excellent interlayer and interparticle conductivity, resulting in increased electrical conductivity. . The α-/γ-MnS@Cox Sy @N, SC electrode exhibits an excellent specific capacity of 277 mA hg-1 and cycling stability over 23 600 cycles. A quasi-solid-state flexible extrinsic pseudocapacitor (QFEPs) assembled using layer-by-layer deposited multi-walled carbon nanotube/Ti3 C2 TX nanocomposite negative electrode. QFEPs deliver specific energy of 64.8 Wh kg-1 (1.62 mWh cm-3 ) at a power of 933 W kg-1 and 92% capacitance retention over 5000 cycles.

Density functional theory study of the mechanical behavior of silicene and development of a Tersoff interatomic potential model tailored for elastic behavior.

Silicene, a graphene-like 2D material made from Si atoms, has been fabricated and studied for its promising applications in micro/nanoelectronics. For the reliable function of silicene devices, it is important to investigate silicene's mechanical properties. In this study, the authors conducted density functional theory (DFT) simulations of mechanical tests of silicene and investigated the elastic modulus and mechanical response such as structural transformation. In addition, the authors optimized the Tersoff potential parameters using a gradient-based minimization with a grid search method in hyperdimensional parameter space, to match the DFT calculation results in the elastic regime. With the new parameter set, the elastic moduli of silicene in the zigzag (ZZ) and armchair (AC) directions were computed with molecular statics (MS) simulations and compared with those of other Si interatomic potential models and DFT results. In addition, uniaxial tensile tests along the ZZ and AC directions were performed to examine how far the Tersoff model is transferable with our new parameter set to describe the nonlinear mechanical behavior of silicene. The results of uniaxial tensile tests suggest that the angle penalty function in the Tersoff model needs to be modified and that the stress-strain curve predicted with this modification shows improvement compared to the original function.

Gravitational Effect on the Advancing and Receding Angles of a Two-Dimensional Cassie-Baxter Droplet on a Textured Surface.

Advancing and receding angles are physical quantities frequently measured to characterize the wetting properties of a rough surface. Thermodynamically, the advancing and receding angles are often interpreted as the maximum and minimum contact angles that can be formed by a droplet without losing its stability. Despite intensive research on wetting of rough surfaces, the gravitational effect on these angles has been overlooked because most studies have considered droplets smaller than the capillary length. In this study, however, by combining theoretical and numerical modeling, we show that the shape of a droplet smaller than the capillary length can be substantially modified by gravity under advancing and receding conditions. First, based on the Laplace pressure equation, we predict the shape of a two-dimensional Cassie-Baxter droplet on a textured surface with gravity at each pinning point. Then, the stability of the droplet is tested by examining the interference between the liquid surface and neighboring pillars and analyzing the free energy change upon depinning. Interestingly, it turns out that the apparent contact angles under advancing and receding conditions are not affected by gravity, while the overall shape of a droplet and the position of the pinning point are affected by gravity. In addition, the advancing and receding of the droplet with continuously increasing or decreasing volume are analyzed, and it is shown that the gravitational effect plays a key role in the movement of the droplet tip. Also, the gravitational effect on the degree of the stability of the droplet upon the external effect such as vibration is discussed. Finally, the theoretical predictions were validated against line tension-based front tracking modeling (LTM) that seamlessly captures the attachment and detachment between the liquid surface and the solid substrate. Our findings provide a deeper understanding on the advancing and receding phenomena of a droplet and essential insight into designing devices that utilize the wettability of rough surfaces.

Singular orientations and faceted motion of dislocations in body-centered cubic crystals.

Dislocation mobility is a fundamental material property that controls strength and ductility of crystals. An important measure of dislocation mobility is its Peierls stress, i.e., the minimal stress required to move a dislocation at zero temperature. Here we report that, in the body-centered cubic metal tantalum, the Peierls stress as a function of dislocation orientation exhibits fine structure with several singular orientations of high Peierls stress-stress spikes-surrounded by vicinal plateau regions. While the classical Peierls-Nabarro model captures the high Peierls stress of singular orientations, an extension that allows dislocations to bend is necessary to account for the plateau regions. Our results clarify the notion of dislocation kinks as meaningful only for orientations within the plateau regions vicinal to the Peierls stress spikes. These observations lead us to propose a Read-Shockley type classification of dislocation orientations into three distinct classes-special, vicinal, and general-with respect to their Peierls stress and motion mechanisms. We predict that dislocation loops expanding under stress at sufficiently low temperatures, should develop well defined facets corresponding to two special orientations of highest Peierls stress, the screw and the M111 orientations, both moving by kink mechanism. We propose that both the screw and the M111 dislocations are jointly responsible for the yield behavior of BCC metals at low temperatures.

Entropic effect on the rate of dislocation nucleation.

Dislocation nucleation is essential to our understanding of plastic deformation, ductility, and mechanical strength of crystalline materials. Molecular dynamics simulation has played an important role in uncovering the fundamental mechanisms of dislocation nucleation, but its limited timescale remains a significant challenge for studying nucleation at experimentally relevant conditions. Here we show that dislocation nucleation rates can be accurately predicted over a wide range of conditions by determining the activation free energy from umbrella sampling. Our data reveal very large activation entropies, which contribute a multiplicative factor of many orders of magnitude to the nucleation rate. The activation entropy at constant strain is caused by thermal expansion, with negligible contribution from the vibrational entropy. The activation entropy at constant stress is significantly larger than that at constant strain, as a result of thermal softening. The large activation entropies are caused by anharmonic effects, showing the limitations of the harmonic approximation widely used for rate estimation in solids. Similar behaviors are expected to occur in other nucleation processes in solids.

Mixing behavior of Ti-Al interface during the ultrasonic welding process and its welding strength: Molecular dynamics study.

In this study, we conducted molecular dynamics simulations to investigate the mechanical mixing and deformation behavior of hcp Ti/fcc Al bimetal formed by ultrasonic welding (UW). To analyze the effect of the interface shape, we considered sixteen sinusoidal interfaces of various heights and spatial periods along with the flat interface. Mechanical mixing between Ti and Al occurs mainly in the vibrational loading direction, while it is suppressed in the interface-normal direction, as the loading direction lies within the slip planes of both the hcp and fcc structures. The degree of mechanical mixing depended on the shape of the interface. According to the simulation results, mechanical mixing becomes active as the sinusoidal height increases, and the spatial period decreases because of the enlarged interface areas. During the bonding process, phase transformation is observed at the sinusoidal interface; hcp Ti is converted to fcc Ti as misfit dislocations formed at the interface glide as Shockley partials on the slip plane owing to the applied vibrational loading. A simple shear test was performed to analyze the welding strength. Although sinusoidal Ti/Al interfaces can have a welding strength that is higher than that of a flat interface, we found that the welding strength was not closely related to the degree of mechanical mixing. Rather, the welding strength was affected by the interaction between a wall of misfit dislocations, stacking fault tetrahedra, and lattice dislocations generated near the interface during the UW process.

A parametric study regarding structural design of a bioprosthetic aortic valve by 3D fluid-structure interaction simulations.

Since the introduction of transcatheter aortic valve (AV) implantation as a viable option, surgical bioprosthetic AVs have recently started incorporating shorter struts considering future valve-in-valve procedures. However, the effect of leaflet coaptation geometry on the longevity of these valves remains unexplored. To address this gap, we performed a finite element analysis on bioprosthetic AVs with varying strut heights using a two-way fluid-structure interaction method. To establish a baseline, we used a standard height based on a rendered platform image of the CE PERIMOUNT Magna Ease valve from Edward Lifesciences in Irvine, CA. Bovine pericardium properties were assigned to the leaflets, while normal saline properties were used as the recirculating fluid in hemodynamic simulations. The physiological pressure profile of the cardiac cycle was applied between the aorta and left ventricle. We calculated blood flow velocity, effective orifice area (EOA), and mechanical stress on the leaflets. The results reveal that as the strut height increases, the stroke volume increases, leakage volume decreases, and EOA improves. Additionally, the maximum mechanical stress experienced by the leaflet decreases by 62% as the strut height increases to 1.2 times the standard height. This research highlights that a low-strut design in bioprosthetic AVs may negatively affect their durability, which can be useful in design of next-generation bioprosthetic AVs.

Nucleation-controlled distributed plasticity in penta-twinned silver nanowires.

A unique size-dependent strain hardening mechanism, that achieves both high strength and ductility, is demonstrated for penta-twinned Ag nanowires (NWs) through a combined experimental-computational approach. Thin Ag NWs are found to deform via the surface nucleation of stacking fault decahedrons (SFDs) in multiple plastic zones distributed along the NW. Twin boundaries lead to the formation of SFD chains that locally harden the NW and promote subsequent nucleation of SFDs at other locations. Due to surface undulations, chain reactions of SFD arrays are activated at stress concentrations and terminated as local stress decreases, revealing insensitivity to defects imparted by the twin structures. Thick NWs exhibit lower flow stress and number of distributed plastic zones due to the onset of necking accompanied by more complex dislocation structures.

Repeated dosing of piperine induced gene expression of P-glycoprotein via stimulated pregnane-X-receptor activity and altered pharmacokinetics of diltiazem in rats.

This study investigated the effect of piperine on the gene expression of P-glycoprotein (P-gp) as well as pregnane-X-receptor (PXR) activity and also its implication on the bioavailability of diltiazem, a P-gp substrate. The effect of piperine on the systemic exposure of diltiazem was examined in rats after the intravenous and oral administration of diltiazem with/without 2 week pretreatment with piperine. Compared with the control group given diltiazem (20 mg/kg) alone, the pretreatment with piperine (10 or 20 mg/kg, once daily for 2 weeks) decreased the oral exposure of diltiazem by 36-48% in rats. Consequently, the bioavailability of oral diltiazem was significantly lower (p < 0.05) after the 2 week pretreatment with piperine. The pretreatment with piperine for 2 weeks also reduced the systemic exposure of desacetyldiltiazem, a major active metabolite of diltiazem by approximately 73%, accompanied by a significant decrease in the metabolite-parent ratio. In contrast to the oral pharmacokinetics, piperine did not affect the intravenous pharmacokinetics of diltiazem in rats. Immunoblot analysis indicated that the protein expression level of intestinal P-gp was significantly enhanced after the 2 week pretreatment with piperine in rats. In addition, piperine increased the PXR reporter activity in human hepatoma cells. Taken together, the 2 week pretreatment with piperine significantly induced intestinal P-gp expression in conjunction with stimulated PXR activity and decreased the oral exposure of diltiazem and desacetyldiltiazem in rats.

Highly Dispersed Pt Clusters on F-Doped Tin(IV) Oxide Aerogel Matrix: An Ultra-Robust Hybrid Catalyst for Enhanced Hydrogen Evolution.

Dispersing the minuscule mass loading without hampering the high catalytic activity and long-term stability of a noble metal catalyst results in its ultimate efficacy for the electrochemical hydrogen evolution reaction (HER). Despite being the most efficient HER catalyst, the use of Pt is curtailed due to its scarcity and tendency to leach out in the harsh electrochemical reaction environment. In this study, we combined F-doped tin(IV) oxide (F-SnO2) aerogel with Pt catalyst to prevent metallic corrosion and to achieve abundant Pt active sites (approximately 5 nm clusters) with large specific surface area (321 cm2·g-1). With nanoscopic Pt loading inside the SnO2 aerogel matrix, the as-synthesized hybrid F-SnO2@Pt possesses a large specific surface area and high porosity and, thus, exhibits efficient experimental and intrinsic HER activity (a low overpotential of 42 mV at 10 mA·cm-2 in 0.5 M sulfuric acid), a 22-times larger turnover frequency (11.2 H2·s-1) than that of Pt/C at 50 mV, and excellent robustness over 10,000 cyclic voltammetry cycles. The existing metal support interaction and strong intermolecular forces between Pt and F-SnO2 account for the catalytic superiority and persistence against corrosion of F-SnO2@Pt compared to commercially used Pt/C. Density functional theory analysis suggests that hybridization between the Pt and F-SnO2 orbitals enhances intermediate hydrogen atom (H*) adsorption at their interface, which improves the reaction kinetics.

Alpinumisoflavone induces apoptosis and suppresses extracellular signal-regulated kinases/mitogen activated protein kinase and nuclear factor-κB pathways in lung tumor cells.

The extracellular signal-regulated kinases/mitogen activated protein kinase (ERK/MAPK) and nuclear factor-κB (NF-κB) pathways are critical for cell survival and proliferation. Alpinumisoflavone (AIF), isolated from the African medicinal plant Erythrina lysistemon, is a member of the isoflavone group. In this report, we demonstrated that AIF treatment induces cell death of human lung tumor cells. Incubation of lung tumor cells with AIF increased the sub-G1 population and caspase 3/7 activity, suggesting that the cell death is caused by apoptosis. To identify the signaling pathway involved in the tumor cell death, we examined the modulation of transcriptional activity using various reporter constructs and found that AIF significantly deregulated both the ERK/MAPK and NF-κB pathways. Western blot analysis with antibodies to MAP/ERK kinase (MEK) and ERK showed that AIF dephosphorylates both MEK and ERK. Alpinumisoflavone also repressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells by inhibiting NF-κB-dependent transcription. Therefore, the cell death induced by AIF may be via repressing both the ERK/MAPK and NF-κB pathways.

The lattice dislocation trapping mechanism at the ferrite/cementite interface in the Isaichev orientation relationship.

We analyze the lattice dislocation trapping mechanism at the ferrite/cementite interface of the Isaichev orientation relationship by atomistic simulations combined with the anisotropic linear elasticity theory and disregistry analysis. We find that the lattice dislocation trapping ability is varied by initial position of the lattice dislocation. The lattice dislocation near the interface is attracted to the interface by the image force generated by the interface shear, while the lattice dislocation located far is either attracted to or repelled from the interface, or even oscillates around the introduced position, depending on the combination of the stress field induced by the misfit dislocation array and the image stress field induced by the lattice dislocation.

Tpl-2 kinase downregulates the activity of p53 and enhances signaling pathways leading to activation of activator protein 1 induced by EGF.

Tumor progression locus-2 (Tpl-2) kinase is a member of the mitogen-activated protein kinase kinase kinase family that has been implicated in cellular transformation. The enhanced expression of this protein has been shown to activate both the mitogen-activated protein kinase and c-Jun N-terminal kinase pathways. However, the molecular mechanisms responsible for the oncogenic potential of Tpl-2 are still largely unknown. Here, we showed that Tpl-2 interacted with p53 both in vitro and ex vivo. The overexpression of Tpl-2 inhibited the epidermal growth factor (EGF)-induced p53 phosphorylation (Ser15) through upregulating the activity of protein phosphatase 2A, which interacted with p53 stimulated by EGF. Also, the EGF-induced p53 activity was suppressed in the Tpl-2 wild-type (WT)-transfected HEK 293 cells, but had no effect in the Tpl-2-mutant (S413A)-transfected cells. Furthermore, introduction of small interfering RNA-Tpl-2 into HEK 293 cells resulted in decreased cell viability compared with only adenovirus-p53-infected cells. In addition, the Tpl-2 WT, but not Tpl-2 mutant (S413A), showed increased EGF-induced c-fos promoter activity, followed by activator protein 1 (AP-1) transactivation activity, which was associated with the cell transformation prompted by the H-Ras-Tpl-2-AP-1 signaling axis. These results indicated that the Ser413 of Tpl-2 plays an important role in EGF-induced carcinogenesis as well as inactivation of the p53.

The prolyl isomerase Pin1 interacts with a ribosomal protein S6 kinase to enhance insulin-induced AP-1 activity and cellular transformation.

Phosphorylation of proteins on serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase Pin1 and is a central signaling mechanism in cell proliferation and transformation. Although Pin1 is frequently overexpressed in hepatocellular carcinoma (HCC), the molecular mechanism of Pin1 in HCC has not been completely elucidated. Here, we show that Pin1 interacts with p70S6K in vitro and ex vivo. Overexpression of Pin1 resulted in enhanced p70S6K phosphorylation induced by insulin in SK-HEP-1 cells. In contrast, Pin1(-/-) mouse embryonic fibroblasts (MEFs) exhibited significantly decreased insulin-induced p70S6K phosphorylation compared with Pin1(+/+) MEFs. Furthermore, Pin1 enhanced the insulin-induced extracellular signal-regulated protein kinase (ERK)1/2 phosphorylation through its interaction with p70S6K, whereas the inhibition of p70S6K activity by rapamycin suppressed insulin-induced ERK1/2 phosphorylation in SK-HEP-1 cells. Hence, Pin1 affected activator protein-1 activity through p70S6K-ERK1/2 signaling in SK-HEP-1 cells. Most importantly, Pin1-overexpressing JB6 Cl41 cells enhanced neoplastic cell transformation promoted by insulin much more than green fluorescent protein-overexpressing JB6 Cl41 control cells. These results imply that Pin1 amplifies insulin signaling in hepatocarcinoma cells through its interaction with p70S6K, suggesting that Pin1 plays an important role in insulin-induced tumorigenesis and is a potential therapeutic target in hepatocarcinoma.

High-energy proton irradiation damage on two-dimensional hexagonal boron nitride.

The dielectric layer, which is an essential building block in electronic device circuitry, is subject to intrinsic or induced defects that limit its performance. Nano-layers of hexagonal boron nitride (h-BN) represent a promising dielectric layer in nano-electronics owing to its excellent electronic and thermal properties. In order to further analyze this technology, two-dimensional (2D) h-BN dielectric layers were exposed to high-energy proton irradiation at various proton energies and doses to intentionally introduce defective sites. A pristine h-BN capacitor showed typical degradation stages with a hard breakdown field of 10.3 MV cm-1, while h-BN capacitors irradiated at proton energies of 5 and 10 MeV at a dose of 1 × 1013 cm-2 showed lower hard breakdown fields of 1.6 and 8.3 MV cm-1, respectively. Higher leakage currents were observed under higher proton doses at 5 × 1013 cm-2, resulting in lower breakdown fields. The degradation stages of proton-irradiated h-BN are similar to those of defective silicon dioxide. The degradation of the h-BN dielectric after proton irradiation is attributed to Frenkel defects created by the high-energy protons, as indicated by the molecular dynamics simulation. Understanding the defect-induced degradation mechanism of h-BN nano-layers can improve their reliability, paving the way to the implementation of 2D h-BN in advanced micro- and nano-electronics.

Diagnostic Reference Levels for Adult Nuclear Medicine Imaging Established from the National Survey in Korea.

PURPOSE: There is substantial need for optimizing radiation protection in nuclear medicine imaging studies. However, the diagnostic reference levels (DRLs) have not yet been established for nuclear medicine imaging studies in Korea. MATERIALS AND METHODS: The data of administered activity in 32 nuclear medicine imaging studies were collected from the Korean Society of Nuclear Medicine (KSNM) dose survey database from 2013 and 2014. Through the expert discussions and statistical analyses, the 75th quartile value (Q3) was suggested as the preliminary DRL values. Preliminary DRLs were subjected to approval process by the KSNM Board of Directors and KSNM Council, followed by clinical applications and performance rating by domestic institutes. RESULTS: DRLs were determined through 32 nuclear medicine imaging studies. The Q3 value was considered as appropriate selection as it was generally consistent with the most commonly administered activity. In the present study, the final version of initial DRL values for nuclear medicine imaging in Korean adults is described including various protocols of the brain and myocardial perfusion imaging. CONCLUSION: The first DRLs for nuclear medicine imaging in Korean adults were confirmed. The DRLs will enable optimized radiation protection in the field of nuclear medicine imaging in Korea.

Trastuzumab Specific Epitope Evaluation as a Predictive and Prognostic Biomarker in Gastric Cancer Patients.

While human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) antibodies bind to the intracellular domain, trastuzumab binds to the extracellular epitope of HER2 receptor: target of drug action. We aimed to evaluate clinical significance of the new IHC method assessing the target of trastuzumab in gastric cancer (GC) patients and compare with conventional methods. Sixty-nine trastuzumab-treated GC patients were enrolled from two different cohorts. Additionally, we enrolled 528 consecutive GC patients to evaluate prognostic implications of HER2 test methods. HER2 status was assessed by trastuzumab IHC, HER2 IHC (4B5), and HER2 silver in situ hybridization (SISH). HER2 IHC showed 3+ in 48/69 trastuzumab-treated patients (69.6%), however, trastuzumab IHC showed 3+ in 25 (36.2%). Patients with trastuzumab IHC ≥2+ had significantly better progression-free survival (PFS) and overall survival (OS) than their counterpart (p = 0.014). In univariate analysis, trastuzumab IHC ≥2+ and HER2 IHC 3+ were only significant predictive factors for OS in trastuzumab-treated patients. Of the 528 consecutive GCs, patients with trastuzumab IHC ≥2+ had shorter disease-free survival (DFS) and OS (p = 0.008 and 0.031, respectively), while conventional methods failed to reveal any significant survival differences. HER2 assessment by trastuzumab IHC was different from conventional HER2 test results. Trastuzumab IHC was suggested to be a significant predictive factor for trastuzumab responsiveness and prognostic factor for consecutive GCs.

Sulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A.

Inhibitors of the secretion of cancer exosomes, which promote cancer progression and metastasis, may not only accelerate exosome biology research but also offer therapeutic benefits for cancer patients. Here we identify sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA). SFX, an FDA-approved oral antibiotic, showed significant anti-tumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co-localization of multivesicular endosomes with lysosomes for degradation. We demonstrate the important role of ETA, as target of SFX, by gain- and loss-of-function studies of the ETA protein, through a direct binding assay, and pharmacological and genetic approaches. These findings may provide a foundation for sEV-targeted cancer therapies and the mechanistic studies on sEV biology.

Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells.

The development of multidrug resistance 1 (MDR1) can be mediated by a number of different mechanisms but elevated gene expression of MDR1 (P-glycoprotein) has often been a major cause of chemoresistance in many cancer cells. Therefore, the present study aimed to investigate the role of forkhead box-containing protein, O subfamily (FoxO), transcription factors in regulating the MDR1 gene expression. The proximal promoter region of the human MDR1 contained a putative FoxO-binding site, which partially overlapped with the enhancer/enhancer-binding protein beta-binding region. Gel shift and immunoblot analysis of subcellular fractions revealed that nuclear levels of FoxO1 and its DNA-binding activity were selectively enhanced in MCF-7/ADR cells, which was reversed by a FoxO1 antibody. Reporter gene assays showed that the transcription of MDR1 gene is stimulated by FoxO1 overexpression. Moreover, both MDR1 expression and doxorubicin resistance in MCF-7/ADR cells were reversed by FoxO1 small interfering RNA (siRNA). The MDR1 expression in MCF-7/ADR cells was also inhibited by insulin, a functional FoxO1 inactivator. In conclusion, FoxO1 is a novel transcriptional activator of MDR1 and is crucial for MDR1 induction in MCF-7/ADR cells.