Human glutaredoxin 3 can bind and effectively transfer [4Fe-4S] cluster to apo-iron regulatory protein 1.

Glutaredoxin 3 (GLRX3) is a member of monothiol glutaredoxins with a CGFS active site that has been demonstrated to function in cellular iron sensing and trafficking via its bound iron-sulfur cluster. Human GLRX3 has been shown to form a dimer that binds two bridging [2Fe-2S] clusters with glutathione (GSH) as a ligand, assembling a compound 2GLRX3-2[2Fe-2S]-4GSH. Each iron of the iron-sulfur clusters is bound to the thiols of the cysteines, one of which is from the active site of GLRX3, the other from the noncovalently bound GSH. Here, we show that the recombinant human GLRX3 isolated anaerobically from Escherichia coli can incorporate [4Fe-4S] cluster in the absence of GSH, revealed by spectral and enzymatic analysis. [4Fe-4S] cluster-containing GLRX3 is competent for converting iron regulatory protein 1 (apo-IRP1) into aconitase within 30 min, via intact iron-sulfur cluster transfer. These in vitro studies suggest that human GLRX3 is important for cytosolic Fe-S protein maturation.

Fast magnetization switching by linear vertical microwave-assisted spin-transfer torque.

The effect of vertical microwave magnetic field on spin-transfer torque switching in elliptical magnetic spin valve has been investigated by performing micromagnetic simulations including a spin-transfer torque term. The speed of magnetization switching can be accelerated by applying a vertical microwave magnetic field. Magnetization switching time decreases with the increase of the amplitude of vertical microwave magnetic field for both the fixed microwave frequency and current density. When the frequency of the microwave magnetic field coincides with the natural ferromagnetic resonance frequency of the elliptical spin valve, magnetization switching time is reduced to the minimum. Magnetization switching time can be reduced from 9.44 to 2.4 ns due to an effect of vertical microwave magnetic field. In addition, critical current density of magnetization reversal is strongly lowered in the presence of vertical microwave magnetic field.

Green entrepreneurial orientation, boundary-spanning search and enterprise sustainable performance: The moderating role of environmental dynamism.

As an important strategic decision for enterprise sustainability, the green entrepreneurial orientation can facilitate boundary-spanning search for external knowledge and resources to achieve triadic sustainable economic, environmental, and social performance. Based on organizational search theory and dynamic capability theory, this study introduces environmental dynamism into the model of the relationship between green entrepreneurial orientation, boundary-spanning search and enterprise triadic sustainable performance. By analyzing the questionnaire data from 202 managers of manufacturing SMEs, the study explores the internal and external influences of green entrepreneurial orientation on the enterprise sustainable performance. The results show that: green entrepreneurial orientation has a positive impact on enterprise economic, environmental and social performance; boundary-spanning search plays a fully mediating role between green entrepreneurial orientation and enterprise economic, environmental and social performance; environmental dynamism, as a key external environmental factor, positively regulates the relationship between boundary-spanning search and enterprise economic performance and environmental performance, and negatively regulates the relationship between boundary-spanning search and social performance. This study clearly demonstrates how green entrepreneurial orientation in the environmental era can drive triadic sustainable performance improvement of enterprises. In addition, this study argues that boundary-spanning search is an important tool that enables manufacturing SMEs to achieve a triad of coordinated sustainable development of economic, environmental and social benefits in a dynamic environment.

A Novel Ruthenium-Fluvastatin Complex Downregulates SNCG Expression to Modulate Breast Carcinoma Cell Proliferation and Apoptosis via Activating the PI3K/Akt/mTOR/VEGF/MMP9 Pathway.

Breast cancer is the most common cause of malignancy and cancer-related morbidity and death worldwide that requests effective and safe chemotherapy. Evaluation of metallodrug-based anticancer agents and statins as chemotherapeutics with fewer side effects is a largely unexplored research field. Synthesis and characterization of the ruthenium-fluvastatin complex were achieved using multiple spectroscopic techniques and thus further examined to evaluate its chemotherapeutic prospects in both MDA-MB-231 and MCF-7 cancer lines and eventually in vivo models of DMBA-induced mammary carcinogenesis in rodents. Our studies indicate that the metal and ligand chelation was materialized by the ligand's functional groups of carbonyl (=O) oxygen and hydroxyl (-OH), and the complex has been observed to be crystalline and able to chelate with CT-DNA. The complex was able to reduce cell proliferation and activate apoptotic events in breast carcinoma cell lines MCF-7 and MDA-MB-231. In addition, the complex was able to modify p53 expressions to interfere with apoptosis in the carcinoma of the breast, stimulated by the intrinsic apoptotic path assisted by Bcl2 and Bax in vivo, yet at the same point, controlling the PI3K/Akt/mTOR/VEGF pathway, as obtained from western blotting, correlates with the MMP9-regulated tumor mechanisms. Our research reveals that ruthenium-fluvastatin chemotherapy may disrupt, rescind, or interrupt breast carcinoma progression by modifying intrinsic apoptosis as well as the antiangiogenic cascade, thereby taking the role of a potential candidate in cancer therapy for the immediate future.

HIST1H2BN induced cell proliferation and EMT phenotype in prostate cancer via NF-κB signal pathway.

BACKGROUND: The potential role of HIST1H2BN in prostate cancer remains unclear. OBJECTIVE: To evaluate the carcinogenic role of HIST1H2BN in prostate cancer. METHODS: The expression of HIST1H2BN in prostate cancer was analyzed using TCGA database and clinical samples. The roles and mechanisms of HIST1H2BN were investigated in DU145 and PC3 cells. RESULTS: HIST1H2BN was significantly upregulated in prostate cancer. HIST1H2BN knockdown inhibited cell proliferation, migration and EMT phenotype in prostate cancer cells. Downregulating HIST1H2BN diminished the expression and binding activity of NF-κB p65, then influenced the expression of MMP2 and MMP9. CONCLUSION : This is the first study to elaborate a HIST1H2BN-NF-κB-EMT regulatory axis in oncogenesis, indicating that HIST1H2BN might be potential therapeutic target for prostate cancer.

Pinning and rotation of a skyrmion in Co nanodisk with nanoengineered point and ring defects.

Magnetic skyrmions have been proposed as promising information carriers in the application of spintronics, while the material imperfections are inevitable, thus an understanding of pinning effects on skyrmions in confined geometry is crucial for both fundamental research and development of spintronic devices. Here, we present the interactions of a skyrmion with a point and an extended ring defect, in a Co nanodisk which can be applied in skyrmion oscillator, based on micromagnetic simulations. By comparing with the skyrmion preferred position which is in the nanodisk center without defects, we identify the pinning strength and skyrmion preferred positions with a point defect as a function of skyrmion-defect distance and different local parameters of defect region being considered. The pinning centers range from skyrmion center, domain wall and off-center regions. We find a confinement effect on the skyrmion size with a ring defect. Moreover, we also show the rotation of the skyrmion in the presence of a ring defect, that can lead to a variation of oscillation frequency in a large range. These findings provide a complete understanding of the interaction between skyrmion and defects in a nanodisk and may provide a guidance for the design of skyrmion oscillators.

Synthesis and characterization of zinc oxide nanoparticles from Morus nigra and its anticancer activity of AGS gastric cancer cells.

Gastric cancer was a foremost one among the majority of regular carcinoma cases globally. Even the achievements on enhanced treatment approaches and early findings cannot decrease the mortality and morbidity ranges of gastric cancer. This current work was planned to develop Morus nigra-loaded zinc oxide nanoparticles (MN-ZnONPs) and to evaluate the different characteristic methods likes UV-vis spectroscopy, TEM, SEM, FT-IR, EDX and XRD. Furthermore, the anticancer effect of MN-ZnONPs against AGS cells were analysed via cell viability, apoptotic morphological variations by AO/EtBr, alterations of mitochondrial membrane potential (MMP), cell cycle arrest, lipid peroxidation status (TBARS), antioxidants (SOD, GSH and CAT) and generation of ROS. Moreover, the status of apoptosis gene such as Bax, caspase-9, caspase-3 and Bcl-2 expressions was analysed by using RT-PCR techniques. We observed the synthesized MN-ZnONPs have a spherical shape, crystalline nature and present different functional groups. We also observed that gastric cancer cells demonstrated in cell death by MN-ZnONPs treatments. The MN-ZnONPs induced apoptosis by enhanced formation of ROS, decreased MMP, apoptotic morphological modifications were evaluated by AO/EtBr, increased lipid peroxidation, decreased antioxidants and induced cell cycle arrest were observed. Furthermore, to confirm the molecular mechanism demonstrated of MN-ZnONPs to induce apoptosis by altering the gene expressions of apoptosis markers were observed.

Investigation of 2π isolated skyrmion pinning using exchange bias.

The 2π isolated chiral skyrmion is a magnetic configuration. Since the total topological charge is zero, the 2π isolated skyrmion driven by a spin-polarized current propagates strictly along the racetrack. The manipulation of 2π-skyrmion, e.g., pinning/depinning at a specific position of the racetrack, is significant. Here, we investigated the 2π-skyrmion pinning in a racetrack using exchange bias. A series of transversal AFM wires were set above the ferromagnetic (FM) racetrack. Spin waves were employed to induce 2π-skyrmion motion to study the dynamics of the 2π-skyrmion pinning. The AFM wires induce exchange bias at the AFM/FM crossing points, which can act as pinning sites. The working window for a 2π-skyrmion in a racetrack was investigated as a function of the exchange bias field, the frequency and amplitude of the oscillating magnetic field for exciting spin waves. The interaction mechanism between the 2π-skyrmion and the exchange bias was also studied. This work may provide guidance for the design of next-generation spintronics.

On-line screening and identification of free radical scavenging compounds in Angelica dahurica fermented with Eurotium cristatum using an HPLC-PDA-Triple-TOF-MS/MS-ABTS system.

Eurotium cristatum, a beneficial fungus isolated from Fuzhuan tea, was used to ferment Angelica dahurica for the first time. The antioxidant capacities of the extracts before and after fermentation were compared using ABTS, DPPH and FRAP assays. The results showed that the antioxidant capacities of the extracts acquired using organic solvents were greater after fermentation. Moreover, based on a comparison of the HPLC chromatograms, the chemical composition of Angelica dahurica changed substantially during fermentation. To further understand the changes in its antioxidant constituents, an on-line HPLC-PDA-Triple-TOF-MS/MS-ABTS system was employed. Twelve antioxidants belonging to three different classes were detected and identified, and their antioxidant capacities were preliminarily evaluated. The results indicated that the substances produced during the fermentation of Eurotium cristatum played important roles in enhancing the antioxidant capacity.

The prognostic impacts of TEA domain (TEAD) transcription factor polymorphisms in Chinese hepatocellular carcinoma patients.

TEA domain (TEAD) transcription factors play an important role in hepatocellular carcinoma (HCC) development and progression by regulating the expression of a number of genes. However, the association of their genetic variations with HCC prognosis remains elusive. Seven potentially functional single nucleotide polymorphisms in TEAD1-4 (rs2304733, rs10831923, rs12104362, rs3745305, rs11756089, rs2076173, rs7135838) were genotyped from 331 hepatitis B virus positive HCC patients using the Sequenom MassARRAY iPLEX platform. The TEAD3 rs2076173 C allele and rs11756089 T allele were identified as protective alleles as they were significantly associated with longer median overall survival time (MST). The T allele of rs2076173 was significantly associated with HCC survival independent of age, gender, smoking and drinking status, BCLC stage, and chemotherapy or TACE status (HR = 0.73, 95% CI = 0.56-0.93, P = 0.012). This protective effect was more prominent for patients who were non-drinkers (P for multiplicative interaction = 0.002). Patients had more than one of these protective alleles had significant longer MST of 19.25 months than those had none (MST=12.85 months, adjusted HR = 0.56, 95% CI = 0.33-0.95, P=0.030), especially for those non-drinkers (adjusted HR = 0.48, 95% CI = 0.32-0.74, P = 0.001). These findings suggested that rs2076173 and rs11756089 in TEAD3 gene could serve as genetic markers for favorable survival in the Chinese HCC patients.

Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P = 0.044). Kaplan- Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCCspecific overall survival (HR, 2.799; 95% CI, 1.346-5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.

[99mTc]Technetium labelled PnAo-azomycin glucuronides: a novel class of imaging markers of tissue hypoxia.

Azomycin glucuronate was coupled to a PnAO ligand to create azomycin-based ligands that would form water-soluble 99mTc-azomycin complexes for imaging hypoxic tissue. 1-beta-D-(2-Nitroimidazolyl)glucuronic acid, (see structure in text), was synthesized by coupling 2-nitroimidazole with 1-alpha-bromo-2,3,4-tri-O-acetyl-6-methyl glucuronate, followed by deprotection. Reaction of (see structure in text) with 6-methyl-6-methylamino-HMPnAO (Pn-44) in the presence of BOP reagent in anhydrous dimethyl sulfoxide afforded the PnAO-glucuronides (see structure in text) and (see structure in text). Compound (see structure in text) was isolated in three rotomeric forms. Biological evaluation of (see structure in text) (99mTc-5) indicated selective binding to hypoxic EMT-6 cells, and cytotoxicity to fibroblasts and HeLa, sk24, sk23, and g361 cancer cell lines, at an IC20 <2.5 microgram/ml. In vivo biodistribution of two formulations of (see structure in text) in Balb/c mice with EMT-6 tumor produced diverse results, with one formulation showing no tumor preference, and the other providing a tumor/blood ratio of 2.3 at 4 h post-injection. The latter formulation delineated tumor, large intestine and liver in scintigraphic images.

Culture duration-, donor-, and medium-dependent changes in OATP1B3-mediated telmisartan uptake in human hepatocytes.

Human hepatic organic anion-transporting polypeptides (OATPs), including OATP1B1, 1B3, and 2B1, are expressed at the basolateral membrane of hepatocytes and mediate the uptake of a variety of compounds from blood into hepatocytes. The liver-specific OATPs are increasingly recognized as playing important roles in the pharmacokinetic (PK) of many drugs and thus, involved in the clinically significant drug-drug interactions (DDIs). However, the evaluation of the specific roles of individual OATPs in hepatocytes is challenging because of the lack of selective inhibitors and probe substrates for each OATP member. In the present study, the uptake activity of OATP1B3 was examined in human hepatocytes cultured up to 14 days using an in vitro uptake assay. The results showed that OATP-mediated uptake of rosuvastatin, a substrate for OATPs declined substantially in cultured human hepatocytes. In contrast, the uptake of OATP1B3-selective substrate telmisartan was not measureable at earlier culture periods, but became detectable on Day 7 and showed culture duration-dependent changes from Day 7 to 14. Quantitative polymerase chain reaction (qPCR) analyses illustrated that the OATP functional change was not correlated with messenger ribonucleic acid (mRNA) expression alteration in hepatocytes cultured for 3 hours or 7 days. The OATP1B3-mediated telmisartan uptake was also culture medium- and donor-dependent, and only observed in 3 of 5 lots of hepatocytes cultured in 2 of 3 media tested. These results show that using human hepatocytes cultured in certain conditions may provide an excellent addition to transfected cell lines as a way to distinguish OATP1B3 from other hepatic OATP family members, such as OATP1B1, to provide more understanding of OATP-mediated clinical DDI.

Novel frataxin isoforms may contribute to the pathological mechanism of Friedreich ataxia.

Friedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. The nervous system and heart are the most severely affected tissues. However, highly mitochondria-dependent tissues, such as kidney and liver, are not obviously affected, although the abundance of FXN is normally high in these tissues. In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. Increasing the abundance of the heart-specific isoform III significantly increased the mitochondrial aconitase activity, while over-expression of the cerebellum-specific isoform II protected against oxidative damage of Fe-S cluster-containing aconitase. Further, we observed that the protein level of isoform III decreased in FRDA patient heart, while the mRNA level of isoform II decreased more in FRDA patient cerebellum compared to total FXN mRNA. Our novel findings are highly relevant to understanding the mechanism of tissue-specific pathology in FRDA.

Green tea drinking habits and esophageal cancer in southern China: a case-control study.

AIM: To investigate effects of green tea drinking and its temperature on esophageal cancer development. METHODS: A 1:2 matched hospital-based case-control study including 150 cases and 300 controls was conducted in southern area of China from June 2004 to May 2010. A self-designed questionnaire was used to collect information on possible risk factors of esophageal cancer, and to assess the tea drinking habit and temperature. Conditional logistic regression was used to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs). RESULTS: We find a significant protective effect of high consumption of green tea on esophageal cancer with low temperature tea (OR=0.79, 95%CI=0.29-0.97). However, drinking tea at a temperature of 70-79° and above 80° was related to greatly elevated risk of esophageal cancer with ORs of 2.21 (1.57-5.53) and 4.74 (2.67-10.51). An agreement was found between reported tea temperature and measured temperature (correlation coefficient =0.62). Further analysis indicated hot tea temperature to be associated with heavy risk of esophageal cancer in former and current smokers and current drinkers (former and current smokers: OR=8.91(1.91-16.77) and 7.33(2.23-12.46), respectively; former and current drinkers: OR=7.58(0.83-9.53) and 6.93(2.01-10.65)). CONCLUSION: In the South China context, drinking tea at high temperature significantly increases risk of esophageal cancer, especially in drinkers and smokers.