Mechanism of Synergistic DNA Damage induced by the Hydroquinone Metabolite of Brominated Phenolic Environmental Pollutants and Cu(II): Formation of DNA-Cu Complex and Site-specific Production of Hydroxyl Radicals

Publication date: Available online 3 January 2017
Source:Free Radical Biology and Medicine
Author(s): Bo Shao, Li Mao, Na Qu, Ya-Fen Wang, Hui-Ying Gao, Feng Li, Li Qin, Jie Shao, Chun-Hua Huang, Dan Xu, Lin-Na Xie, Chen Shen, Xiang Zhou, Ben-Zhan Zhu
2,6-Dibromohydroquinone (2,6-DBrHQ) has been identified as an reactive metabolite of many brominated phenolic environmental pollutants such as tetrabromobisphenol-A (TBBPA), bromoxynil and 2,4,6-tribromophenol, and was also found as one of disinfection byproducts in drinking water. In this study, we found that the combination of 2,6-DBrHQ and Cu(II) together could induce synergistic DNA damage as measured by double strand breakage in plasmid DNA and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, while either of them alone has no effect. 2,6-DBrHQ/Cu(II)-induced DNA damage could be inhibited by the Cu(I)-specific chelating agent bathocuproine disulfonate and catalase, but not by superoxide dismutase, nor by the typical hydroxyl radical (•OH) scavengers such as DMSO and mannitol. Interestingly, we found that Cu(II)/Cu(I) could be combined with DNA to form DNA-Cu(II)/Cu(I) complex by complementary application of low temperature direct ESR, circular dichroism, cyclic voltammetry and oxygen consumption methods; and the highly reactive •OH were produced synergistically by DNA-bound-Cu(I) with H2O2 produced by the redox reactions between 2,6-DBrHQ and Cu(II), which then immediately attack DNA in a site-specific manner as demonstrated by both fluorescent method and by ESR spin-trapping studies. Further DNA sequencing investigations provided more direct evidence that 2,6-DBrHQ/Cu(II) caused preferential cleavage at guanine, thymine and cytosine residues. Based on these data, we proposed that the synergistic DNA damage induced by 2,6-DBrHQ/Cu(II) might be due to the synergistic and site-specific production of •OH near the binding site of copper and DNA. Our findings may have broad biological and environmental implications for future research on the carcinogenic polyhalogenated phenolic compounds.

Graphical abstract

http://ift.tt/2iBHzRc

Redox Signaling In The Gastrointestinal Tract

Publication date: Available online 3 January 2017
Source:Free Radical Biology and Medicine
Author(s): Salvador Pérez, Raquel Taléns-Visconti, Sergio Rius-Pérez, Isabela Finamor, Juan Sastre
Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.

Graphical abstract

http://ift.tt/2iBzHPC

Aspirin plus sorafenib potentiates cisplatin cytotoxicity in resistant head and neck cancer cells through xCT inhibition

Publication date: Available online 3 January 2017
Source:Free Radical Biology and Medicine
Author(s): Jong-Lyel Roh, Eun Hye Kim, Hyejin Jang, Daiha Shin
The nonsteroidal anti-inflammatory drug aspirin and the multikinase inhibitor sorafenib have both shown experimental and clinical anticancer activities. The present study investigated whether aspirin and sorafenib synergize to potentiate cisplatin treatment in resistant head and neck cancer (HNC) cells. The effects of aspirin, sorafenib and cisplatin, and combinations thereof were assessed by measuring cell viability, death, glutathione (GSH) and reactive oxygen species (ROS) levels, protein and mRNA expression, genetic inhibition and overexpression of cystine–glutamate antiporter (xCT) and tumor xenograft mouse models. Even at low concentrations, aspirin plus sorafenib synergized to induce cell death of cisplatin-resistant HNC cells. The combination of aspirin and sorafenib induced xCT inhibition, GSH depletion, and ROS accumulation in cancer cells. Genetic and pharmacological inhibition of xCT potentiated the cytotoxic effects of aspirin plus sorafenib; this effect was diminished by xCT overexpression. Low-dose aspirin plus sorafenib enhanced the cytotoxicity of cisplatin in resistant HNC cells through xCT inhibition and oxidant and DNA damage. The in vivo effects of aspirin plus sorafenib on cisplatin therapy were also confirmed in resistant HNC xenograft models, in terms of growth inhibition, GSH depletion, and increased γH2AX formation and apoptosis in tumors. Aspirin and sorafenib synergize to potentiate the cytotoxicity of cisplatin in resistant HNC cells. This therapeutic strategy may help to eliminate resistant HNC.

Graphical abstract

http://ift.tt/2iByDva

Oxysterols and 4-hydroxy-2-nonenal contribute to atherosclerotic plaque destabilization

Publication date: Available online 3 January 2017
Source:Free Radical Biology and Medicine
Author(s): Simona Gargiulo, Gabriella Testa, Paola Gamba, Erica Staurenghi, Giuseppe Poli, Gabriella Leonarduzzi
A growing bulk of evidence suggests that cholesterol oxidation products, known as oxysterols, and 4-hydroxy-2-nonenal (HNE), the major proatherogenic components of oxidized low density lipoproteins (oxLDLs), significantly contribute to atherosclerotic plaque progression and destabilization, with eventual plaque rupture. These oxidized lipids are involved in various key steps of this complex process, mainly thanks to their ability to induce inflammation, oxidative stress, and apoptosis. This review summarizes the current knowledge of the effects induced by these compounds on vascular cells, after their accumulation in the arterial wall and in the atherosclerotic plaque.



http://ift.tt/2iBzuvK

MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addisons disease

The treatment for autoimmune Addison's disease (AAD) has remained virtually unchanged in the last 60 years. Most patients have symptoms that are relatively well controlled with exogenous steroid replacement, but there may be persistent symptoms, recurrent adrenal crisis and poor quality of life, despite good compliance with optimal current treatments. Treatment with conventional exogenous steroid therapy is also associated with premature mortality, increased cardiovascular risk and complications related to excessive steroid replacement. Hence, novel therapeutic approaches have emerged in the last decade attempting to improve the long-term outcome and quality of life of patients with AAD. This review discusses the recent developments in treatment innovations for AAD, including the novel exogenous steroid formulations with the intention of mimicking the physiological biorhythm of cortisol secretion. Our group has also carried out a few studies attempting to restore endogenous glucocorticoid production via immunomodulatory and regenerative medicine approaches. The recent advances in the understanding of adrenocortical stem cell biology, and adrenal plasticity will also be discussed to help comprehend the science behind the therapeutic approaches adopted.

http://ift.tt/2iGn7kB

Association of adrenal insufficiency with insulin-dependent diabetes mellitus in a patient with inactivating mutations in nicotinamide nucleotide transhydrogenase: a phenocopy of the animal model

http://ift.tt/2j2Dg0i

MANAGEMENT OF ENDOCRINE DISEASE: Growth and growth hormone therapy in short children born preterm

Approximately 15 million babies are born preterm across the world every year, with less than 37 completed weeks of gestation. Survival rates increased during the last decades with the improvement of neonatal care. With premature birth, babies are deprived of the intense intrauterine growth phase, and postnatal growth failure might occur. Some children born prematurely will remain short at later ages and adult life. The risk of short stature increases if the child is also born small for gestational age. In this review, the effects of being born preterm on childhood growth and adult height and the hormonal abnormalities possibly associated with growth restriction are discussed, followed by a review of current information on growth hormone treatment for those who remain with short stature during infancy and childhood.

http://ift.tt/2iGiAi8

MECHANISMS IN ENDOCRINOLOGY: Diabetes mellitus, a state of low bone turnover - a systematic review and meta-analysis

Objective

To investigate the differences in bone turnover between diabetic patients and controls.

Design

A systematic review and meta-analysis.

Methods

A literature search was conducted using the databases Medline at PubMed and EMBASE. The free text search terms 'diabetes mellitus' and 'bone turnover', 'sclerostin', 'RANKL', 'osteoprotegerin', 'tartrate-resistant acid' and 'TRAP' were used. Studies were eligible if they investigated bone turnover markers in patients with diabetes compared with controls. Data were extracted by two reviewers.

Results

A total of 2881 papers were identified of which 66 studies were included. Serum levels of the bone resorption marker C-terminal cross-linked telopeptide (–0.10 ng/mL (–0.12, –0.08)) and the bone formation markers osteocalcin (–2.51 ng/mL (–3.01, –2.01)) and procollagen type 1 amino terminal propeptide (–10.80 ng/mL (–12.83, –8.77)) were all lower in patients with diabetes compared with controls. Furthermore, s-tartrate-resistant acid phosphatase was decreased in patients with type 2 diabetes (–0.31 U/L (–0.56, –0.05)) compared with controls. S-sclerostin was significantly higher in patients with type 2 diabetes (14.92 pmol/L (3.12, 26.72)) and patients with type 1 diabetes (3.24 pmol/L (1.52, 4.96)) compared with controls. Also, s-osteoprotegerin was increased among patients with diabetes compared with controls (2.67 pmol/L (0.21, 5.14)).

Conclusions

Markers of both bone formation and bone resorption are decreased in patients with diabetes. This suggests that diabetes mellitus is a state of low bone turnover, which in turn may lead to more fragile bone. Altered levels of sclerostin and osteoprotegerin may be responsible for this.

http://ift.tt/2j2DDrv

Use of nanoparticles with Escherichia coli receptors for prophylaxis of recurrent urinary tract infections in children

Publication date: Available online 3 January 2017
Source:Medical Hypotheses
Author(s): Ilke Beyitler, Salih Kavukcu




http://ift.tt/2iBooXC

Plant-based Diets Relatively Low in Bioavailable Phosphate and Calcium May Aid Prevention and Control of Prostate Cancer by Lessening Production of Fibroblast Growth Factor 23

Publication date: Available online 3 January 2017
Source:Medical Hypotheses
Author(s): Mark F. McCarty
Fibroblast growth factor 23 (FGF23), a hormonal regulator of phosphate and vitamin D metabolism produced primarily in bone by osteocytes and mature osteoblasts, is now known to have growth factor activity for many prostate cancers. In some of these cancers, autocrine production of FGF23 drives their proliferation. FGF23 synthesized within bone likely promotes the expansion of prostate cancer bone metastases. Hence, dietary or lifestyle factors which boost bone's production of FGF23 may encourage the induction and spread of prostate cancer. High dietary intakes of bioavailable phosphorus and of calcium have been found to boost FGF23 levels, and this accords well with prospective epidemiology pointing to high intakes of both phosphate and calcium as risk factors for aggressive prostate cancer. Hence, prospective studies correlating baseline FGF23 levels with subsequent risk for prostate cancer, or advanced prostate cancer, are needed. Natural plant-based diets, though not inherently low in calcium or phosphorus, provide forms of these that are less bioavailable than those in animal products, and hence may be expected to down-regulate bone's production of FGF23. This may play a role in the lower risk for clinical prostate cancer observed in vegans and quasi-vegan cultures. Other factors, such as decreased IGF-I levels and mTORC1 activity, may also play a role in this regard.



http://ift.tt/2hQhtLp

Responses of CO2 emission and pore water DOC concentration to soil warming and water table drawdown in Zoige Peatlands

Publication date: March 2017
Source:Atmospheric Environment, Volume 152
Author(s): Gang Yang, Mei Wang, Huai Chen, Liangfeng Liu, Ning Wu, Dan Zhu, Jianqing Tian, Changhui Peng, Qiuan Zhu, Yixin He
Peatlands in Zoige Plateau contains more than half of peatland carbon stock in China. This part of carbon is losing with climate change through dissolved organic carbon (DOC) export and carbon dioxide (CO2) emissions, both of which are vulnerable to the environmental changes, especially on the Zoige Plateau with a pace of twice the observed rate of global climate warming. This research aimed to understand how climate change including soil warming, rainfall reduction and water table change affect CO2 emissions and whether the trends of changes in CO2 emission are consistent with those of pore water DOC concentration. A mesocosm experiment was designed to investigate the CO2 emission and pore water DOC during the growing seasons of 2009–2010 under scenarios of passive soil warming, 20% rainfall reduction and changes to the water table levels. The results showed a positive relationship between CO2 emission and DOC concentration. For single factor effect, we found no significant relationship between water table and CO2 emission or DOC concentration. However, temperature at 5 cm depth was found to have positive linear relationship with CO2 emission and DOC concentration. The combined effect of soil warming and rainfall reduction increased CO2 emission by 96.8%. It suggested that the drying and warming could stimulate potential emission of CO2. Extending this result to the entire peatland area in Zoige Plateau translates into 0.45 Tg CO2 emission per year over a growing season. These results suggested that the dryer and warmer Zoige Plateau will increase CO2 emission. We also found the contribution rate of DOC concentration to CO2 emission was increased by 12.1% in the surface layer and decreased by 13.8% in the subsurface layer with combined treatment of soil warming and rainfall reduction, which indicated that the warmer and dryer environmental conditions stimulate surface peat decomposition process.

Graphical abstract

http://ift.tt/2hPewfP

Effects of low-level laser irradiation on human blood lymphocytes in vitro

Abstract

Low-level laser irradiation (LLLI) has various effects on cultured human lymphocytes in vitro, but little is known about such effects in whole blood. This study investigated whether LLLI affected lymphocyte count in human whole blood in vitro. A total number of 130 blood samples were collected from apparently healthy adult patients through venipuncture into tubes containing EDTA. Each sample was divided into two equal aliquots to be used as a non-irradiated control sample and an irradiated sample. The irradiated aliquot was subjected to laser wavelengths of 405, 589, and 780 nm with different fluences of 36, 54, 72, and 90 J/cm², at a fixed irradiance of 30 mW/cm². A paired student t test was used to compare between non-irradiated and irradiated samples. The lymphocyte counts were measured using a computerized hematology analyzer and showed a significant (P < 0.02) maximum increase (1.6%) at a fluence of 72 J/cm² when compared with non-irradiated samples. This increase in lymphocyte count upon irradiation was confirmed by flow cytometry. At a wavelength of 589 nm and fluence of 72 J/cm², irradiation of whole blood samples showed a significant increase in CD45 lymphocytes and natural killer (NK) (CD16, CD56) cells, but no significant changes in CD3 T lymphocytes, T-suppressor (CD3, CD8) cells, T-helper (CD3, CD4) cells, and CD19 B lymphocytes when compared with their non-irradiated counterparts. Our results clearly demonstrate that NK cell count is altered by irradiation, which ultimately affects the whole lymphocyte count significantly.

http://ift.tt/2j4nh60

Short-Chain Fatty Acids Inhibit Oxidative Stress and Inflammation in Mesangial Cells Induced by High Glucose and Lipopolysaccharide

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-121493

Recently, an connection between Short-chain fatty acids (SCFAs) produced by intestinal microbiota and kidney has been revealed. The aim of this study was to explore whether SCFAs or their specific G protein-coupled receptors 43 (GPR43) agonist inhibit oxidative stress and inflammatory response in glomerular mesangial cells (GMCs) induced by high glucose and lipopolysaccharide (LPS). Our research showed that treatment with SCFAs, especially acetate and butyrate, or GPR43 agonist significantly inhibited GMCs proliferation induced by high glucose and LPS, and then reversed the production of reactive oxygen species (ROS) and malondialdehyde (MDA) but increased levels of antioxidant enzyme superoxide dismutase (SOD). Furthermore, SCFAs or GPR43 agonist obviously increased the protein expression of GPR43 induced by high glucose and LPS, but diminished the expression of adhesion molecule intercellular adhesion molecule-1 (ICAM-1), and then decreased the proinflammatory cytokine monocyte chemoattractant protein (MCP-1) and interleukin-1β (IL-1β) release from GMCs stimulated by the high glucose and LPS. These combined results support the hypothesis that SCFAs or GPR43 agonist can inhibit oxidative stress and inflammation of GMCs induced by high glucose and LPS, suggesting that SCFAs induced signaling pathway may act as new therapeutic targets of diabetic nephropathy (DN).
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://ift.tt/2j2bhhj

Role of the polycarboxylic compounds in the response of Silene vulgaris to chromium

Abstract

This work aims to investigate the nature and the specific mechanisms by which polycarboxylic compounds participate in the tolerance of Silene vulgaris to Cr with special attention given to the rhizosphere system. This knowledge is important to use this species in the implementation of phytoremediation technologies in Cr-polluted soils. According to the results, chromium is chelated and mobilized by the citric and malic acids in plant tissues, while oxalic acid might participate in the reduction and chelation of Cr in the rhizosphere. At the applied doses, the response of both exudation rate and root exudate composition (total polyphenols and quercitin) seems to involve a rearrangement in the lignification of the plant cell wall to immobilize Cr. Quercetin-3-dirhamnosyl-galactoside and apiin (apigenin-7-O-apiosyl-glucoside) have been identified as the major polyphenols in the root exudates of S. vulgaris. The increments found in the apiin concentration in root exudates seem to be related to the protection against Cr toxicity by chelation of Cr or by free radical scavenging. Though earlier response is detected in plant tissues, results from this work together with previous studies in S. vulgaris indicate that exudation might be a regulated mechanism of protection under Cr exposition in S. vulgaris that may involve mainly Cr reduction and chelation.

http://ift.tt/2j6A87z

Analysis of the impact path on factors of China’s energy-related CO 2 emissions: a path analysis with latent variables

Abstract

Identifying the impact path on factors of CO₂ emissions is crucial for the government to take effective measures to reduce carbon emissions. The most existing research focuses on the total influence of factors on CO₂ emissions without differentiating between the direct and indirect influence. Moreover, scholars have addressed the relationships among energy consumption, economic growth, and CO₂ emissions rather than estimating all the causal relationships simultaneously. To fill this research gaps and explore overall driving factors' influence mechanism on CO₂ emissions, this paper utilizes a path analysis model with latent variables (PA-LV) to estimate the direct and indirect effect of factors on China's energy-related carbon emissions and to investigate the causal relationships among variables. Three key findings emanate from the analysis: (1) The change in the economic growth pattern inhibits the growth rate of CO₂ emissions by reducing the energy intensity; (2) adjustment of industrial structure contributes to energy conservation and CO₂ emission reduction by raising the proportion of the tertiary industry; and (3) the growth of CO₂ emissions impacts energy consumption and energy intensity negatively, which results in a negative impact indirectly on itself. To further control CO₂ emissions, the Chinese government should (1) adjust the industrial structure and actively develop its tertiary industry to improve energy efficiency and develop low-carbon economy, (2) optimize population shifts to avoid excessive population growth and reduce energy consumption, and (3) promote urbanization steadily to avoid high energy consumption and low energy efficiency.

http://ift.tt/2i82JoO

Occurrence, spatial distribution, and ecological risks of typical hydroxylated polybrominated diphenyl ethers in surface sediments from a large freshwater lake of China

Abstract

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been frequently observed in marine aquatic environments; however, little information is available on the occurrence of these compounds in freshwater aquatic environments, including freshwater lakes. In this study, we investigated the occurrence and spatial distribution of typical OH-PBDEs, including 2′-OH-BDE-68, 3-OH-BDE-47, 5-OH-BDE-47, and 6-OH-BDE-47 in surface sediments of Taihu Lake. 3-OH-BDE-47 was the predominant congener, followed by 5-OH-BDE-47, 2′-OH-BDE-68, and 6-OH-BDE-47. Distributions of these compounds are drastically different between sampling site which may be a result of differences in nearby point sources, such as the discharge of industrial wastewater and e-waste leachate. The positive correlation between ∑OH-PBDEs and total organic carbon (TOC) was moderate (r = 0.485, p < 0.05), and site S3 and S15 were excluded due to point source pollution, suggesting that OH-PBDEs concentrations were controlled by sediment TOC content, as well as other factors. The pairwise correlations between the concentrations of these compounds suggest that these compounds may have similar input sources and environmental behavior. The target compounds in the sediments of Lake Taihu pose low risks to aquatic organisms. Results show that OH-PBDEs in Lake Taihu are largely dependent on pollution sources. Because of bioaccumulation and subsequent harmful effects on aquatic organisms, the concentrations of OH-PBDEs in freshwater ecosystems are of environmental concern.

http://ift.tt/2j6Aifi

Effects of Long-Term Vitamin D Supplementation on Regression and Metabolic Status of Cervical Intraepithelial Neoplasia: a Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

We are not aware of any study examining the effects of long term vitamin D administration on regression and metabolic status of patients with cervical intraepithelial neoplasia grade 1 (CIN1). This study was performed to evaluate the effects of long-term vitamin D administration on regression and metabolic status of patients with CIN1. This randomized, double-blind, placebo-controlled trial was performed among 58 women diagnosed with CIN1. CIN1 diagnosis was performed based on specific diagnostic procedures of biopsy, pathological diagnosis, and colposcopy. Patients were randomly allocated into two groups to take 50,000 IU vitamin D3 supplements (n = 29) or placebo (n = 29) every 2 weeks for 6 months. Fasting blood samples were taken at the beginning of the study and end-of-trial to measure related markers. After 6 months of vitamin D administration, greater percentage of women in the vitamin D group had regressed CIN1 (84.6 vs. 53.8%, P = 0.01) than those in the placebo group. Long-term vitamin D supplementation increased serum-25(OH) vitamin D levels in the intervention group compared to the placebo group (+12.3 ± 11.4 vs. -0.1 ± 3.7 ng/mL, P < 0.001). In addition, vitamin D intake led to significant decreases in serum insulin levels (−5.3 ± 7.3 vs. +2.4 ± 5.9 μIU/mL, P < 0.001), homeostasis model of assessment-insulin resistance (−1.2 ± 1.6 vs. +0.5 ± 1.2, P < 0.001), homeostatic model assessment-Beta cell function (P = 0.005) and a significant elevation in quantitative insulin sensitivity check index (+0.03 ± 0.04 vs. -0.007 ± 0.02, P < 0.001) compared with the placebo group. Additionally, significant increases in plasma nitric oxide (NO) (+15.5 ± 10.3 vs. +4.0 ± 13.4 μmol/L, P = 0.001), total antioxidant capacity (TAC) (P = 0.04), total glutathione (GSH) (+11.8 ± 153.5 vs. -294.2 ± 595.1 μmol/L, P = 0.01) and a significant reduction in plasma malondialdehyde (MDA) levels (−0.8 ± 1.0 vs. -0.03 ± 1.4 μmol/L, P = 0.03) were observed following the administration of vitamin D supplements compared with the placebo group. In conclusion, vitamin D3 administration for 6 months among women with CIN1 resulted in its regression and had beneficial effects on markers of insulin metabolism, plasma NO, TAC, GSH and MDA levels.

Clinical trial registration number www.irct.ir: IRCT201412065623N30.

http://ift.tt/2iwZcUk

Thyroid Hormone Controls Breast Cancer Cell Movement via Integrin αV/β3/SRC/FAK/PI3-Kinases

Abstract

Thyroid hormones (TH) play a fundamental role in diverse processes, including cellular movement. Cell migration requires the integration of events that induce changes in cell structure towards the direction of migration. These actions are driven by actin remodeling and stabilized by the development of adhesion sites to extracellular matrix via transmembrane receptors linked to the actin cytoskeleton. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that promotes cell migration and invasion through the control of focal adhesion turnover. In this work, we demonstrate that the thyroid hormone triiodothyronine (T3) regulates actin remodeling and cell movement in breast cancer T-47D cells through the recruitment of FAK. T3 controls FAK phosphorylation and translocation at sites where focal adhesion complexes are assembled. This process is triggered via rapid signaling to integrin αV/β3, Src, phosphatidylinositol 3-OH kinase (PI3K), and FAK. In addition, we established a cellular model with different concentration of T3 levels: normal, absence, and excess in T-47D breast cancer cells. We found that the expression of Src, FAK, and PI3K remained at normal levels in the excess of T3 model, while it was significantly reduced in the absence model. In conclusion, these results suggest a novel role for T3 as an important modulator of cell migration, providing a starting point for the development of new therapeutic strategies for breast cancer treatment.

http://ift.tt/2hNvdmZ

Micro-RNA-204 Participates in TMPRSS2/ERG Regulation and Androgen Receptor Reprogramming in Prostate Cancer

Abstract

Cancer progression is driven by genome instability incurred rearrangements such as transmembrane protease, serine 2 (TMPRSS2)/v-ets erythroblastosis virus E26 oncogene (ERG) that could possibly turn some of the tumor suppressor micro-RNAs into pro-oncogenic ones. Previously, we found dualistic miR-204 effects, acting either as a tumor suppressor or as an oncomiR in ERG fusion-dependent manner. Here, we provided further evidence for an important role of miR-204 for TMPRSS2/ERG and androgen receptor (AR) signaling modulation and fine tuning that prevents TMPRSS2/ERG overexpression in prostate cancer. Based on proximity-based ligation assay, we designed a novel method for detection of TMPRSS2/ERG protein products. We found that miR-204 is TMPRSS2/ERG oncofusion negative regulator, and this was mediated by DNA methylation of TMPRSS2 promoter. Transcriptional factors runt-related transcription factor 2 (RUNX2) and ETS proto-oncogene 1 (ETS1) were positive regulators of TMPRSS2/ERG expression and promoter hypo-methylation. Clustering of patients' sera for fusion protein, transcript expression, and wild-type ERG transcript isoforms, demonstrated not all patients harboring fusion transcripts had fusion protein products, and only few fusion positive ones exhibited increased wild-type ERG transcripts. miR-204 upregulated AR through direct promoter hypo-methylation, potentiated by the presence of ERG fusion and RUNX2 and ETS1. Proteomics studies provided evidence that miR-204 has dualistic role in AR cancer-related reprogramming, promoting prostate cancer-related androgen-responsive genes and AR target genes, as well as AR co-regulatory molecules. miR-204 methylation regulation was supported by changes in molecules responsible for chromatin remodeling, DNA methylation, and its regulation. In summary, miR-204 is a mild regulator of the AR function during the phase of preserved AR sensitivity as the latter one is required for ERG-fusion translocation.

http://ift.tt/2ix5jaW

Image-based gradient non-linearity characterization to determine higher-order spherical harmonic coefficients for improved spatial position accuracy in magnetic resonance imaging

Publication date: May 2017
Source:Magnetic Resonance Imaging, Volume 38
Author(s): Paul T. Weavers, Shengzhen Tao, Joshua D. Trzasko, Yunhong Shu, Erik J. Tryggestad, Jeffrey L. Gunter, Kiaran P. McGee, Daniel V. Litwiller, Ken-Pin Hwang, Matt A. Bernstein
PurposeSpatial position accuracy in magnetic resonance imaging (MRI) is an important concern for a variety of applications, including radiation therapy planning, surgical planning, and longitudinal studies of morphologic changes to study neurodegenerative diseases. Spatial accuracy is strongly influenced by gradient linearity. This work presents a method for characterizing the gradient non-linearity fields on a per-system basis, and using this information to provide improved and higher-order (9th vs. 5th) spherical harmonic coefficients for better spatial accuracy in MRI.MethodsA large fiducial phantom containing 5229 water-filled spheres in a grid pattern is scanned with the MR system, and the positions all the fiducials are measured and compared to the corresponding ground truth fiducial positions as reported from a computed tomography (CT) scan of the object. Systematic errors from off-resonance (i.e., B0) effects are minimized with the use of increased receiver bandwidth (±125kHz) and two acquisitions with reversed readout gradient polarity. The spherical harmonic coefficients are estimated using an iterative process, and can be subsequently used to correct for gradient non-linearity. Test-retest stability was assessed with five repeated measurements on a single scanner, and cross-scanner variation on four different, identically-configured 3T wide-bore systems.ResultsA decrease in the root-mean-square error (RMSE) over a 50cm diameter spherical volume from 1.80mm to 0.77mm is reported here in the case of replacing the vendor's standard 5th order spherical harmonic coefficients with custom fitted 9th order coefficients, and from 1.5mm to 1mm by extending custom fitted 5th order correction to the 9th order. Minimum RMSE varied between scanners, but was stable with repeated measurements in the same scanner.ConclusionsThe results suggest that the proposed methods may be used on a per-system basis to more accurately calibrate MR gradient non-linearity coefficients when compared to vendor standard corrections.



http://ift.tt/2hPYC3d