Synthesis and Characterization of Novel Triarylmethane-Based Dyes for Thermally Stable Blue Color Filters.

Two new triarylmethane-based dye molecules with a dimeric structure, TAM-1 and TAM-2, were designed and synthesized as potential blue color filter materials for liquid-crystal displays. The dimeric structure of TAM-1 was designed to improve the thermal stability of a well-known blue dye, Victoria Blue BO. TAM-2 was designed to further improve the solubility of TAM-1 by introducing long alkyl ester groups. The synthesized dyes TAM-1 and TAM-2 were transmissive in the wavelength range of 410-460 nm and showed good thermal stability with 5% weight degradation temperatures (T5d) of 259 °C and 289 °C, respectively, and less than 1% of weight loss at 230 °C. Moreover, TAM-2 showed excellent solubility (20.1 wt%) as opposed to Victoria Blue BO (0.03 wt%) and TAM-1 (3.5 wt%) in PGMEA.

Binge Alcohol Intake After Hypergravity Stress Sustainably Decreases AMPK and Transcription Factors Necessary for Hepatocyte Survival.

BACKGROUND: Binge alcohol consumption elicits mitochondrial dysfunction in hepatocytes. An understanding of the effect of ethanol (EtOH) exposure after hypergravity stress on liver function may assist in the implementation of pathophysiological countermeasures for aerospace missions. This study investigated whether a combination of hypergravity stress and binge alcohol intake has a detrimental effect on AMP-activated protein kinase (AMPK) and other molecules necessary for hepatocyte survival. METHODS: The mice were orally administered a single dose of EtOH (5 g/kg body weight, 20% EtOH) immediately after a load to +9 Gz hypergravity for 1 hour using a small animal centrifuge and sacrificed 24 hours after treatment. For the multiple-dose model, 3 consecutive daily treatments were carried out. Immunoblottings were carried out on liver homogenates. RESULTS: Binge alcohol intake in mice immediately after a 1-hour exposure to a +9 Gz hypergravity load repressed hepatic Akt and PARP-1 levels at 24 hours posttreatment. Moreover, it sustainably diminished the level of AMPKα, a key regulator of energy metabolism, as compared to each individual treatment. Similarly, the combination of alcohol and hypergravity suppressed the levels of STAT3, FOXO1/3, C/EBPß, and CREB, transcription factors necessary for cell survival. Similar changes were not detected after 3 consecutive daily combinatorial treatments, indicating that repetitive training with hypergravity loads provides hepatoprotective effects in a binge alcohol model. CONCLUSIONS: These results show that binge alcohol exposure in mice immediately following a +9 Gz hypergravity stress persistently decreased AMPKα and other key molecules required for hepatocyte survival, and these changes may be reversed by repetitive hypergravity loads.

Phlda3, a urine-detectable protein, causes p53 accumulation in renal tubular cells injured by cisplatin.

Measurable indicators of renal injury are required for the assessment of kidney function after toxicant challenge. In our previous study, pleckstrin homology-like domain, family A, member 3 (Phlda3) was a most greatly up-regulated molecule downstream from p53, culminating with kidney tubular injury. This study investigated the positive feedforward effect of Phlda3 on p53 in an effort to explain the largest increase of Phlda3 in injured tubules and the potential of its urine excretion. qRT-PCR assays confirmed a rapid and substantial increase in Phlda3 messenger RNA (mRNA) in the kidney cortex of mice treated with a single dose of cisplatin. Cisplatin overexpression of Phlda3 was verified by gene set analyses of three different microarray databases. In the immunohistochemistry, Phlda3 staining intensities were augmented in the tubules as kidney injury worsened. Moreover, the urinary content of Phlda3 was increased after cisplatin treatment, as were those of other kidney injury markers (Kim-1 and Timp-1). By contrast, cisplatin failed to increase Phlda3 mRNA in the liver despite hepatocyte necrosis and ensuing increases in serum transaminase activities. In NRK52E tubular cells, siRNA knockdown of Phlda3 enhanced the ability of cisplatin to increase p-Mdm2 presumably via Akt, enforcing the interaction between Mdm2 and p53. Consistently, a deficiency in Phlda3 abrogated p53 increase by cisplatin, indicating that Phlda3 promotes p53 accumulation. Phlda3 overexpression had the opposite effect. In addition, treatment with cyclosporine A or CdCl2, other nephrotoxicants, increased Phlda3 mRNA and protein levels in NRK52E cells, as did cisplatin treatment. Overall, Phlda3 may cause p53 accumulation through a feedforward pathway, facilitating tubular injury and its urine excretion.

Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury.

The contribution of miRNA to the pathogenesis of acute kidney injury (AKI) is not well understood. Here we evaluated an integrative network of miRNAs and mRNA data to discover a possible master regulator of AKI. Microarray analyses of the kidneys of mice treated with cisplatin were used to extract putative miRNAs that cause renal injury. Of them, miR-122 was mostly downregulated by cisplatin, whereas miR-34a was upregulated. A network integrating dysregulated miRNAs and altered mRNA expression along with target prediction enabled us to identify Foxo3 as a core protein to activate p53. The miR-122 inhibited Foxo3 translation as assessed using an miR mimic, an inhibitor, and a Foxo3 3'-UTR reporter. In a mouse model, Foxo3 levels paralleled the degree of tubular injury. The role of decreased miR-122 in inducing Foxo3 during AKI was strengthened by the ability of the miR-122 mimic or inhibitor to replicate results. Increase in miR-34a also promoted the acetylation of Foxo3 by repressing Sirt1. Consistently, cisplatin facilitated the binding of Foxo3 and p53 for activation, which depended not only on decreased miR-122 but also on increased miR-34a. Other nephrotoxicants had similar effects. Among targets of p53, Phlda3 was robustly induced by cisplatin, causing tubular injury. Consistently, treatment with miR mimics and/or inhibitors, or with Foxo3 and Phlda3 siRNAs, modulated apoptosis. Thus, our results uncovered an miR integrative network regulating toxicant-induced AKI and identified Foxo3 as a bridge molecule to the p53 pathway.

Influence of hydrothermal aging on the shear bond strength of 3D printed denture-base resin to different relining materials.

OBJECTIVES: This study evaluated the repairability of three-dimensional printed (3DP) denture bases based on different conventional relining materials and aging. MATERIAL AND METHODS: The groups for surface characterization (surface-roughness and contact-angle measurements) were divided based on the denture base and surface treatment. Shear bond strength test and failure-mode analysis were conducted by a combination of three variables: denture base, relining materials, and hydrothermal aging (HA). The initial characterization involved quantifying the surface roughness (n = 10) and contact angle (n = 10) of denture base specimens with and without sandblasting (SB) treatment. Four relining materials (Kooliner [K], Vertex Self-Curing [V], Tokuyama Rebase II (Normal) [T], and Ufi Gel Hard [U]) were applied to 3DP, heat-cured (HC), and self-cured (SC) denture-base resin specimens. Shear bond strength (n = 15) and failure-mode analyses (n = 15) were performed before and after HA, along with evaluations of the fractured surfaces (n = 4). Statistical analyses were performed using a two-way analysis of variance (ANOVA) for surface characterization, and a three-way ANOVA was conducted for shear bond strength. RESULTS: The surface roughness peaked in HC groups and increased after SB. The 3DP group displayed significantly lower contact angles, which increased after treatment, similar to the surface roughness. The shear bond strength was significantly lower for 3DP and HC denture bases than for SC denture bases, and peaked for U at 10.65 ± 1.88 MPa (mean ± SD). HA decreased the shear bond strength relative to untreated samples. Furthermore, 3DP, HC, and SC mainly showed mixed or cohesive failures with V, T, and U. K, on the other hand, trended toward adhesive failures when bonded with HC and SC. CONCLUSION: This study has validated the repairability of 3DP dentures through relining them with common materials used in clinical practice. The repairability of the 3DP denture base was on par with that of conventional materials, but it decreased after aging. Notably, U, which had a postadhesive application, proved to be the most effective material for repairing 3DP dentures.

Farnesoid X receptor protects hepatocytes from injury by repressing miR-199a-3p, which increases levels of LKB1.

BACKGROUND & AIMS: Hepatocyte injury occurs during liver fibrogenesis. MicroRNAs (miRNA) regulate some of these processes, and some are regulated by the farnesoid X receptor (FXR). We investigated the effect of repression of specific miRNAs by FXR in hepatocyte injury using fibrotic liver tissue from patients and hepatocytes. METHODS: We used immunohistochemistry or real-time polymerase chain reaction to analyze proteins and miRNAs in human and mouse liver samples. HepG2 cells were transfected with pre-miRNA, antisense oligonucleotides, small interfering RNAs, the 3'-untranslated region of liver kinase B1 (LKB1) (STK11), or constructs for overexpression, and analyzed. RESULTS: Liver tissue from patients with severe fibrosis had lower levels of FXR and greater amounts of hepatocyte death than samples from patients with mild disease. Levels of several miRNAs changed when FXR expression was disrupted in the liver; one of these, miR-199a-3p, was significantly up-regulated in patients with severe fibrosis. Activation of FXR by its ligand reduced the level of miR-199a-3p in HepG2 cells. LKB1 messenger RNA was identified as a target of miR-199a-3p, and its expression was reduced in human fibrotic liver tissue. Overexpression of FXR or incubation of cultured hepatocytes with the FXR ligand up-regulated LKB1; LKB1 was not induced in cells transfected with miR-199a-3p. Incubation of HepG2 cells with FXR ligand, or injection of the ligand into mice, protected hepatocytes from injury and increased levels of LKB1; levels of miR-199a-3p were reduced compared with cells that were not incubated with the FXR ligand. Activation of FXR reduced mitochondrial dysfunction and oxidative stress and increased hepatocyte survival. CONCLUSIONS: In hepatocytes, FXR represses production of miR-199a-3p. In fibrotic livers of humans and mice, FXR expression is reduced, increasing levels of miR-199a-3p, which reduces levels of LKB1. FXR therefore protects hepatocytes from injury by repressing miR-199a-3p and thereby increasing levels of LKB1.

Detection and determination of solute carbon in grain interior to correlate with the overall carbon content and grain size in ultra-low-carbon steel.

In this study, every effort was exerted to determine and accumulate data to correlate microstructural and compositional elements in ultra-low-carbon (ULC) steels to variation of carbon content (12-44 ppm), manganese (0.18-0.36%), and sulfur (0.0066-0.001%). Quantitative analysis of the ULC steel using optical microscope, scanning electron microscope, transmission electron microscope, and three-dimensional atom probe revealed the decrease of grain size and dislocation density with the increase of carbon contents and/or increase of the final delivery temperature. For a given carbon content, the grain interior carbon concentration increases as the grain size increases.

Effects of washing solution temperature on the biocompatibility and mechanical properties of 3D-Printed dental resin material.

The use of digital manufacturing, particularly additive manufacturing using three-dimensional (3D) printing, is expanding in the field of dentistry. 3D-printed resin appliances must undergo an essential process, post-washing, to remove residual monomers; however, the effect of the washing solution temperature on the biocompatibility and mechanical properties remains unclear. Therefore, we processed 3D-printed resin samples under different post-washing temperatures (without temperature control (N/T), 30 °C, 40 °C, and 50 °C) for different durations (5, 10, 15, 30, and 60 min) and evaluated the degree of conversion rate, cell viability, flexural strength, and Vickers hardness. Increasing the washing solution temperature significantly improved the degree of conversion rate and cell viability. Conversely, increasing the solution temperature and time decreased the flexural strength and microhardness. This study confirmed that the washing temperature and time influence the mechanical and biological properties of the 3D-printed resin. Washing 3D-printed resin at 30 °C for 30 min was most efficient to maintain optimal biocompatibility and minimize changes of mechanical properties.

Fyn inhibition by cycloalkane-fused 1,2-dithiole-3-thiones enhances antioxidant capacity and protects mitochondria from oxidative injury.

Fyn kinase has emerged as a regulator of diverse pathological processes. However, therapeutic Fyn inhibitors are not available. This study investigated the potential of a series of cycloalkane-fused dithiolethiones (CDTs) or other congeners to increase antioxidant capacity in association with Fyn inhibition, as well as the molecular basis for this effect. Treatment of HepG2 cells with each agent protected the mitochondria from oxidative injury elicited by arachidonic acid and iron, which increased cell viability; 4,5,6,7-tetrahydrobenzo-1,2-dithiole-3-thione (SNU1A) and 5,6-dihydro-4H-cyclopenta-1,2-dithiole-3-thione (SNU2A) were the most effective, whereas 5-methyl-1,2-dithiole-3-thione (SNU3A) was less active. 5-(Quinolin-2-yl)-1,2-dithiole-3-thione (SNU3E) had a minimal effect. SNU1A treatment decreased mitochondrial superoxide production and enabled cells to restore mitochondrial membrane permeability. Oxidative injury caused by arachidonic acid and iron enhanced Fyn phosphorylation at a tyrosine residue, which was decreased by SNU1A treatment. 2,3-Dihydro-N,N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide (SU6656), a known Fyn inhibitor, had a similar effect. Fyn inhibition contributed to protecting mitochondria from injury through AMP-activated protein kinase (AMPK), as supported by reversal of this effect with Fyn overexpression. Consistently, Fyn overexpression attenuated AMPK activation by SNU1A, which strengthens the inhibitory role of Fyn in AMPK activity. CDTs had antioxidant effects, as shown by increases in GSH contents and inhibition of H(2)O(2) production. They also had the ability to activate nuclear factor E2-related factor 2 (Nrf2), a key antioxidant transcription factor. Fyn overexpression decreased the Nrf2 activation induced by SNU1A. Our results demonstrate that CDTs exert cytoprotective effects by protecting mitochondria and increasing the cellular antioxidant capacity, which may result not only from Fyn inhibition leading to AMPK activation but also from Nrf2 activation.

Structural and magnetic properties of Zn1-xcoxO nanorods prepared by microwave irradiation technique.

We have successfully synthesized large-scale aggregative flowerlike Zn1-xCo(x)O (0.0 < or = x < or = 0.07) nanostructures, consisting of many branches of nanorods at different orientations with diameter within 100-150 nm (tip diameter approximately 50 nm) and length of approximately 1 microm. The rods were prepared using Zinc nitrate, cobalt nitrate and KOH in 180 Watt microwave radiation for short time interval. The synthesized nanorods were characterized using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), field emission transmission electron microscopy (FETEM) and DC magnetization measurements. XRD and TEM results indicate that the novel flowerlike nanostructures are hexagonal with wurtzite structure and Co ions were successfully incorporated into the lattice position of Zn ions in ZnO matrix. The selected area electron diffraction (SAED) pattern reveals that the nanorods are single crystal in nature and preferentially grow along [0 0 1] direction. Magnetic studies show that Zn1-xCo(x)O nanorods exhibit room temperature ferromagnetism. This novel nanostructure could be a promising candidate for a variety of future spintronic applications.

One step synthesis of rutile TiO2 nanoparticles at low temperature.

Sphere-like rutile TiO2 nanocrystals have been synthesized by sol-gel method followed by hydrolysis of titanium tetrachloride in deionized water in the presence of ammonium hydroxide as hydrolysis catalyst. The as-prepared TiO2 nanoparticles have single rutile phase with average diameter approximately 26.4 nm. The results show that the temperature has a great influence on the particle size distribution and also crystalline phase (rutile) of TiO2 nanoparticles is consistent with the temperature. Characterization of the as-prepared nanocrystalline powder was carried out by different techniques such as powder X-ray diffraction (XRD), field emission transmission electron microscopy (FE-TEM) and Raman spectroscopy.

Study on the microstructures and the magnetic properties of precipitates in a Cu75-Fe5-Ni20 alloy.

The microstructural evolutions of precipitates formed in a Cu75-Fe5-Ni20 alloy on isothermal annealing at 873 K and 1073 K have been investigated by means of transmission electron microscopy (TEM). Nano-scale magnetic particles were formed randomly in the Cu-rich matrix after receiving a short annealing due to phase decomposition in the alloy. With increasing the isothermal annealing time, however, the striking features that two or more nano-scale particles with a cubic shape and a rod shape were aligned linearly along (100) directions were observed on isothermal annealing at 873 K and 1073 K, respectively. To investigate electro-magnetic properties of precipitates in a Cu-Fe-Ni alloy, the superconducting quantum interference device (SQUID) magnetometer and physical property measurement system (PPMS) were also complemented. The present study revealed significant influences that the magnetic properties of the specimens were closely related to the microstructures in the Cu-Fe-Ni alloy, which microstructures significantly depend on the isothermal annealing temperature.

Effects of Post-Curing Light Intensity on the Mechanical Properties and Three-Dimensional Printing Accuracy of Interim Dental Material.

This study evaluated the effects of the light intensity of curing and the post-curing duration on the mechanical properties and accuracy of the interim dental material. After designing the specimen, 3D printing was performed, and the light intensity was divided into groups G20, G60, G80, and G120 (corresponding to 1.4−1.6, 2.2−3.0, 3.8−4.4, and 6.4−7.0 mW/cm2, respectively), with no post-curing or 5, 10, or 20 min of post-curing being performed. The flexural properties, Vickers microhardness, degree of conversion (DC), and 3D accuracy were then evaluated. The flexural properties and Vickers microhardness showed a sharp increase at the beginning of the post-curing and then tended to increase gradually as the light intensity and post-curing time increased (p < 0.001). On the other hand, there was no significant difference between groups in the accuracy analysis of a 3D-printed three-unit bridge. These results indicate that the light intensity of the post-curing equipment influences the final mechanical properties of 3D-printed resin and that post-curing can be made more efficient by optimizing the light intensity and post-curing time.

Electronic structure and magnetic properties of the Ni0.2Cd0.3Fe(2.5-x)A1(x)O4 (0 < or = x < or = 0.4) ferrite nanoparticles.

The structural, magnetic, and electronic structural properties of Ni0.2Cd0.3Fe(2.5-x)Al(x)O4 ferrite nanoparticles were studied via X-ray diffraction (XRD), transmission electron microscopy (TEM), DC magnetization, and near-edge X-ray absorption fine-structure spectroscopy (NEXAFS) measurements. Nanoparticles of Ni0.2Cd0.3Fe(2.5x)Al(x)O4 (0 < or = x < or = 0.4) ferrite were synthesized using the sol-gel method. The XRD and TEM measurements showed that all the samples had a single-phase nature with a cubic structure, and had nanocrystalline behavior. From the XRD and TEM analysis, it was found that the particle size increases with Al doping. The DC magnetization measurements revealed that the blocking temperature increases with increased Al doping. It was observed that the magnetic moment decreases with Al doping, which may be due to the dilution of the sublattice by the doping of the Al ions. The NEXAFS measurements performed at room temperature indicated that Fe exists in a mixed-valence state.

Structural and magnetic study of a diluted magnetic semiconductor: Fe-doped CeO2 nanoparticles.

This paper reports the effect of Fe doping on the structure and room temperature ferromagnetism of CeO2 nanoparticles. X-ray diffraction and the selective area electron diffraction measurements performed on the Ce(1-x)Fe(x)O2 (0 < or = x < or = 0.07) nanoparticles showed a single-phase nature with a cubic structure, and none of the samples showed the presence of any secondary phase. The mean particle size, which was calculated using transmission electron microscopy, increased with the increase in the Fe content. The DC magnetization measurements that were performed at room temperature showed that all the samples exhibited ferromagnetism. The saturation magnetic moment increased with the increase in the Fe content.

Structural and magnetic properties of Ni doped CeO2 nanoparticles.

We report room temperature ferromagnetism in Ni doped CeO2 nanoparticles using X-ray diffraction (XRD), high resolution transmission electron microscopy (HR-TEM), and dc magnetization measurements. Nanoparticles of Ce(1-x)Ni(x)O2 (0.0 < or = x < or = 0.10) were prepared by using a co-precipitation method. XRD measurements indicate that all samples exhibit single phase nature with cubic structure and ruled out the presence of any secondary phase. Lattice parameters, strain and particle size calculated from XRD data have been found to decrease with increase in Ni doping. Inter-planner distance measured from HR-TEM images for different Ni doped samples indicate that Ni ions are substituting Ce ions in CeO2 matrix. Magnetization measurements performed at room temperature display weak ferromagnetic behavior of Ce(1-x)Ni(x)O2 (0.0 < or = x < or = 0.10) nanoparticles. Magnetic moment calculated from magnetic hysteresis loop was found to increases with Ni doping up to 7% and then start decreasing with further doping.

Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing.

Type I interferon (IFN) has been approved as an anticancer agent to treat some malignancies. However, IFNs have a short in vivo half-life, systemic toxicity, and poor biophysical properties, which prevent it from being widely used for cancer therapy. This study aimed to construct recombinant IFN-ß-1a mutein immunocytokines that comprise a human epidermal growth factor receptor 2 (HER2)-targeting antibody and IFN-ß muteins with an additional glycosylation, which can overcome the limitation of the cytokine itself. Hence, the molecular design aims to 1) enhance productivity and biophysical properties by adding secondary glycosylation in IFN-ß, 2) increase the therapeutic index of IFN-ß therapy by preferential retention at the tumor by possessing high affinity for HER2-expressing cancer cells, and 3) improve the pharmacokinetics and, thus, the convenience of IFN-ß administration. The yield of trastuzumab-IFN-ß mutein was higher than that of trastuzumab-wild-type IFN-ß in the mammalian cell culture system. Trastuzumab-IFN-ß mutein showed similar IFN activity and HER2-targeting ability equivalent to that of IFN-ß mutein and trastuzumab, respectively. Trastuzumab-IFN-ß mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-ß mutein alone. Trastuzumab-IFN-ß mutein and IFN-ß mutein displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-ß mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Tumor-targeting effect of trastuzumab-IFN-ß mutein was analyzed using in vivo fluorescence imaging. The accumulation of trastuzumab-IFN-ß mutein was observed in HER2-positive tumors rather than other tissues except the liver. To evaluate the both direct tumor growth inhibition effect and indirect immune cell-mediated antitumor effect, we tested the effect of trastuzumab-IFN-ß mutein in HER2-positive cancer xenograft models using nude mice or humanized mice. Trastuzumab-IFN-ß mutein could significantly enhance tumor regression when compared with trastuzumab or IFN-ß mutein. In addition, an increase in tumor-infiltrating lymphocytes was observed in the trastuzumab-IFN-ß mutein-treated group, implying that the tumor-targeting IFN-ß may have an enhanced antitumor effect through increased immune response. Therefore, targeting IFN-ß with an anti-HER2 monoclonal antibody makes the immunocytokine more potent than either agent alone. These novel findings suggest that trastuzumab-IFN-ß mutein merits clinical evaluation as a new candidate of anticancer therapeutics.

Phytochemical regulation of Fyn and AMPK signaling circuitry.

During the past decades, phytochemical terpenoids, polyphenols, lignans, flavonoids, and alkaloids have been identified as antioxidative and cytoprotective agents. Adenosine monophosphate-activated protein kinase (AMPK) is a kinase that controls redox-state and oxidative stress in the cell, and serves as a key molecule regulating energy metabolism. Many phytochemicals directly or indirectly alter the AMPK pathway in distinct manners, exerting catabolic metabolism. Some of them are considered promising in the treatment of metabolic diseases such as type II diabetes, obesity, and hyperlipidemia. Another important kinase that regulates energy metabolism is Fyn kinase, a member of the Src family kinases that plays a role in various cellular responses such as insulin signaling, cell growth, oxidative stress and apoptosis. Phytochemical inhibition of Fyn leads to AMPK-mediated protection of the cell in association with increased antioxidative capacity and mitochondrial biogenesis. The kinases may work together to form a signaling circuitry for the homeostasis of energy conservation and expenditure, and may serve as targets of phytochemicals. This review is intended as a compilation of recent advancements in the pharmacological research of phytochemicals targeting Fyn and AMPK circuitry, providing information for the prevention and treatment of metabolic diseases and the accompanying tissue injuries.

Increase of miR-199a-5p by protoporphyrin IX, a photocatalyzer, directly inhibits E2F3, sensitizing mesenchymal tumor cells to anti-cancer agents.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Protoporphyrin IX (PPIX) has been used for photodynamic therapy. Mesenchymal cancer cells adapt to tumor microenvironments for growth and metastasis possibly in association with miRNA dysregulation. In view of the effect of PPIX on cancer-related genes, and its potential to inhibit tumor growth and migration/invasion, this study investigated whether PPIX enables mesenchymal liver tumor to restore dysregulated miRNAs, and if so, whether it sensitizes the cancer cells to chemotherapy. In addition, we explored new target(s) of the miRNA(s) that contribute to the anti-cancer effects. Of the ten miRNAs predicted by the 3'-UTR of HIF-1α mRNA, PPIX treatment increased miR-199a-5p, leading to the inhibition of E2F3 expression which is upregulated in mesenchymal liver tumor. miR-199a-5p levels were downregulated in HCC with E2F3 overexpression. An approach modulating epithelial-mesenchymal transition provided the expected changes in miR-199a-5p and E2F3 in vivo. PPIX prevented tumor cell growth and migration/invasion, and had a synergistic anti-cancer effect when combined with chemotherapeutics. In a xenograft model, PPIX treatment decreased overall growth and average tumor volume, which paralleled E2F3 inhibition. Overall, PPIX inhibited growth advantage and migratory ability of cancer cells and sensitized mesenchymal liver tumor cells to chemotherapeutics.

A load of mice to hypergravity causes AMPKα repression with liver injury, which is overcome by preconditioning loads via Nrf2.

An understanding of the effects of hypergravity on energy homeostasis is necessary in managing proper physiological countermeasures for aerospace missions. This study investigated whether a single or multiple load(s) of mice to hypergravity has an effect on molecules associated with energy metabolism. In the liver, AMPKα level and its signaling were repressed 6 h after a load to +9 Gz hypergravity for 1 h, and then gradually returned toward normal. AMPKα level was restored after 3 loads to +9 Gz, suggestive of preconditioning adaptation. In cDNA microarray analyses, 221 genes were differentially expressed by +9 Gz, and the down-regulated genes included Nrf2 targets. Nrf2 gene knockout abrogated the recovery of AMPKα elicited by 3 loads to +9 Gz, indicating that Nrf2 plays a role in the adaptive increase of AMPKα. In addition, +9 Gz stress decreased STAT3, FOXO1/3 and CREB levels, which was attenuated during the resting time. Similarly, apoptotic markers were enhanced in the liver, indicating that the liver may be vulnerable to hypergravity stress. Preconditioning loads prevented hepatocyte apoptosis. Overall, a load of mice to +9 Gz hypergravity causes AMPKα repression with liver injury, which may be overcome by multiple loads to hypergravity as mediated by Nrf2.