WorldWideScience

Sample records for retinoids arrest breast

  1. Retinoids, retinoic acid receptors, and cancer.

    Science.gov (United States)

    Tang, Xiao-Han; Gudas, Lorraine J

    2011-01-01

    Retinoids (i.e., vitamin A, all-trans retinoic acid, and related signaling molecules) induce the differentiation of various types of stem cells. Nuclear retinoic acid receptors mediate most but not all of the effects of retinoids. Retinoid signaling is often compromised early in carcinogenesis, which suggests that a reduction in retinoid signaling may be required for tumor development. Retinoids interact with other signaling pathways, including estrogen signaling in breast cancer. Retinoids are used to treat cancer, in part because of their ability to induce differentiation and arrest proliferation. Delivery of retinoids to patients is challenging because of the rapid metabolism of some retinoids and because epigenetic changes can render cells retinoid resistant. Successful cancer therapy with retinoids is likely to require combination therapy with drugs that regulate the epigenome, such as DNA methyltransferase and histone deacetylase inhibitors, as well as classical chemotherapeutic agents. Thus, retinoid research benefits both cancer prevention and cancer treatment.

  2. Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.

    Science.gov (United States)

    Koay, Debbie C; Zerillo, Cynthia; Narayan, Murli; Harris, Lyndsay N; DiGiovanna, Michael P

    2010-01-01

    HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects. The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed. In HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells. Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.

  3. Retinoids and breast cancer: from basic studies to the clinic and back again.

    Science.gov (United States)

    Garattini, Enrico; Bolis, Marco; Garattini, Silvio Ken; Fratelli, Maddalena; Centritto, Floriana; Paroni, Gabriela; Gianni', Maurizio; Zanetti, Adriana; Pagani, Anna; Fisher, James Neil; Zambelli, Alberto; Terao, Mineko

    2014-07-01

    All-trans retinoic acid (ATRA) is the most important active metabolite of vitamin A controlling segmentation in the developing organism and the homeostasis of various tissues in the adult. ATRA as well as natural and synthetic derivatives, collectively known as retinoids, are also promising agents in the treatment and chemoprevention of different types of neoplasia including breast cancer. The major aim of the present article is to review the basic knowledge acquired on the anti-tumor activity of classic retinoids, like ATRA, in mammary tumors, focusing on the underlying cellular and molecular mechanisms and the determinants of retinoid sensitivity/resistance. In the first part, an analysis of the large number of pre-clinical studies available is provided, stressing the point that this has resulted in a limited number of clinical trials. This is followed by an overview of the knowledge acquired on the role played by the retinoid nuclear receptors in the anti-tumor responses triggered by retinoids. The body of the article emphasizes the potential of ATRA and derivatives in modulating and in being influenced by some of the most relevant cellular pathways involved in the growth and progression of breast cancer. We review the studies centering on the cross-talk between retinoids and some of the growth-factor pathways which control the homeostasis of the mammary tumor cell. In addition, we consider the cross-talk with relevant intra-cellular second messenger pathways. The information provided lays the foundation for the development of rational and retinoid-based therapeutic strategies to be used for the management of breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Consequences of the natural retinoid/retinoid X receptor ligands action in human breast cancer MDA-MB-231 cell line: Focus on functional proteomics

    Czech Academy of Sciences Publication Activity Database

    Flodrová, Dana; Toporová, L.; Laštovičková, Markéta; Macejová, D.; Hunaková, L.; Brtko, J.; Bobálová, Janette

    2017-01-01

    Roč. 281, NOV (2017), s. 26-34 ISSN 0378-4274 R&D Projects: GA ČR(CZ) GA15-15479S Grant - others:AV ČR(CZ) SAV-15-01 Program:Bilaterální spolupráce Institutional support: RVO:68081715 Keywords : breast cancer * MDA-MB-231 * biomarker * retinoids Subject RIV: CB - Analytical Chemistry, Separation OBOR OECD: Analytical chemistry Impact factor: 3.858, year: 2016

  5. The retinoid anticancer signal: mechanisms of target gene regulation

    OpenAIRE

    Liu, T.; Bohlken, A; Kuljaca, S; Lee, M.; Nguyen, T; S.; Smith; Cheung, B; Norris, M D; Haber, M; Holloway, A.J.; Bowtell, D D L; Marshall, G M

    2005-01-01

    Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal...

  6. Retinoid N-(1H-benzo[d]imidazol-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide induces p21-dependent senescence in breast cancer cells.

    Science.gov (United States)

    Mumcuoglu, Mine; Gurkan-Alp, A Selen; Buyukbingol, Erdem; Cetin-Atalay, Rengul

    2016-04-01

    Retinoids have been implicated as pharmacological agents for the prevention and treatment of various types of cancers, including breast cancers. We analyzed 27 newly synthesized retinoids for their bioactivity on breast, liver, and colon cancer cells. Majority of the retinoids demonstrated selective bioactivity on breast cancer cells. Retinoid 17 had a significant inhibitory activity (IC50 3.5 μM) only on breast cancer cells while no growth inhibition observed with liver and colon cancer cells. The breast cancer selective growth inhibitory action by retinoid 17 was defined as p21-dependent cell death, reminiscent of senescence, which is an indicator of targeted receptor mediated bioactivity. A comparative analysis of retinoid receptor gene expression levels in different breast cancer cells and IC50 values of 17 indicated the involvement of Retinoid X receptors in the cytotoxic bioactivity of retinoid 17 in the senescence associated cell death. Furthermore, siRNA knockdown studies with RXRγ induced decrease in cell proliferation. Therefore, we suggest that retinoid derivatives that target RXRγ, can be considered for breast cancer therapies. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Retinoids, carotenoids, and tocopherols in breast adipose tissue and serum of benign breast disease and breast cancer patients

    Science.gov (United States)

    Various retinoic acid (RA) isomers (all-trans, 13-cis, 11-cis, and 9-cis) as well as retinol, carotenoids, and tocopherol concentrations were determined in both serum and breast adipose tissue of 22 benign breast disease patients and 52 breast cancer patients categorized into 4 stages by malignancy....

  8. Retinoid signalling during embryogenesis

    NARCIS (Netherlands)

    Pijnappel, W.W.M.; Hendriks, H.F.J.; Durston, A.J.

    1996-01-01

    Conclusion: Retinoids are suspected to have multiple functions during embryogenesis, which are carried out via various different signal transduction pathways involving active retinoids and nuclear retinoid receptors. Research focuses on the identification of the retinoid signal transduction

  9. The effect of doxorubicin and retinoids on proliferation, necrosis and apoptosis in MCF-7 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Tomasz Anchim

    2005-02-01

    Full Text Available Doxorubicin (Adriamycin is the most active drug in the treatment of breast cancer. The aim of this study was to investigate the interaction of doxorubicin and retinoids in the inhibition of proliferation of hormone sensitive (ER+ human breast cancer cell line MCF-7 and to find out whether this combination can result in the enhancement of its therapeutic effect. As a comparison we also used estradiol and tamoxifen. We also made an attempt to elucidate the effect of these compounds on the stimulation of the apoptotic pathway in breast cancer cells. Cell proliferation in a 24-hour culture was assessed by [3H] thymidine incorporation into cancer cells and by immunocytochemical analysis of cellular cycle-related PCNA and Ki-67 antigens expression, after the incubation of the cell culture with 10, 20 and 50 nM doxorubicin (DOX, 2 nM estradiol (E2, 10 microM tamoxifen (TAM and 1 nM, 0.01, 0.1, 1 and 10 microM of all-trans retinoid acid (ATRA. The assessment of cell viability and analysis of apoptotic and necrotic cells were performed after the 72-hour incubation of the culture with the examined substances and following apoptosis induction using acridine orange and ethidine bromide. Of the doxorubicin concentrations used in the study, 20 nM inhibited thymidine incorporation to 84.83 +/- 10.00% (control=100%. In the same culture conditions, 2 nM E2 stimulated cancer cells to 157.09 +/- 8.84%. Concentrations of 10 microM TAM and 10 microM ATRA inhibited the proliferation to 63.16 +/- 7.85% and 52.19 +/- 3.21%, respectively. A statistically significant reduction of these values was observed when 20 nM DOX was added to medium with E2 - 39.24 +/- 7.6%, TAM - 48.34 +/- 2.05% and ATRA - 21.98 +/- 1.69%, respectively; the percentage of PCNA- and Ki-67-positive cells was also reduced. Despite high antiproliferative efficacy of 20 nM DOX and 10 microM ATRA combination, the percentage of apoptotic cells was only 25 +/- 0.81%, being similar to that obtained in the

  10. Gene expression signature in organized and growth arrested mammaryacini predicts good outcome in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fournier, Marcia V.; Martin, Katherine J.; Kenny, Paraic A.; Xhaja, Kris; Bosch, Irene; Yaswen, Paul; Bissell, Mina J.

    2006-02-08

    To understand how non-malignant human mammary epithelial cells (HMEC) transit from a disorganized proliferating to an organized growth arrested state, and to relate this process to the changes that occur in breast cancer, we studied gene expression changes in non-malignant HMEC grown in three-dimensional cultures, and in a previously published panel of microarray data for 295 breast cancer samples. We hypothesized that the gene expression pattern of organized and growth arrested mammary acini would share similarities with breast tumors with good prognoses. Using Affymetrix HG-U133A microarrays, we analyzed the expression of 22,283 gene transcripts in two HMEC cell lines, 184 (finite life span) and HMT3522 S1 (immortal non-malignant), on successive days post-seeding in a laminin-rich extracellular matrix assay. Both HMECs underwent growth arrest in G0/G1 and differentiated into polarized acini between days 5 and 7. We identified gene expression changes with the same temporal pattern in both lines. We show that genes that are significantly lower in the organized, growth arrested HMEC than in their proliferating counterparts can be used to classify breast cancer patients into poor and good prognosis groups with high accuracy. This study represents a novel unsupervised approach to identifying breast cancer markers that may be of use clinically.

  11. Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Xiaolan, E-mail: huxiaolan1998@yahoo.com.cn [Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou (China); Zhang, Xianqi [The 2nd Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou (China); Qiu, Shuifeng [Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou (China); Yu, Daihua; Lin, Shuxin [Fourth Military Medical University, Xi' an (China)

    2010-07-16

    Research highlights: {yields} Salidroside inhibits the growth of human breast cancer cells. {yields} Salidroside induces cell-cycle arrest of human breast cancer cells. {yields} Salidroside induces apoptosis of human breast cancer cell lines. -- Abstract: Recently, salidroside (p-hydroxyphenethyl-{beta}-D-glucoside) has been identified as one of the most potent compounds isolated from plants of the Rhodiola genus used widely in traditional Chinese medicine, but pharmacokinetic data on the compound are unavailable. We were the first to report the cytotoxic effects of salidroside on cancer cell lines derived from different tissues, and we found that human breast cancer MDA-MB-231 cells (estrogen receptor negative) were sensitive to the inhibitory action of low-concentration salidroside. To further investigate the cytotoxic effects of salidroside on breast cancer cells and reveal possible ER-related differences in response to salidroside, we used MDA-MB-231 cells and MCF-7 cells (estrogen receptor-positive) as models to study possible molecular mechanisms; we evaluated the effects of salidroside on cell growth characteristics, such as proliferation, cell cycle duration, and apoptosis, and on the expression of apoptosis-related molecules. Our results demonstrated for the first time that salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells and may be a promising candidate for breast cancer treatment.

  12. Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptor γ are overexpressed in BRCA1 mutated breast cancer and predict prognosis.

    Science.gov (United States)

    Heublein, Sabine; Mayr, Doris; Meindl, Alfons; Kircher, Alexandra; Jeschke, Udo; Ditsch, Nina

    2017-04-20

    BRCA1 mutated breast cancers are commonly diagnosed as negative for classical hormone receptors i.e. estrogen receptor, progesterone receptor and/or Her2. Due to these common targets being absent the application of anti-endocrine therapies is rather limited and a certain focus has been set on discovering alternative target molecules. We recently highlighted thyroid hormone receptors (TRs) to predict prognosis in breast cancer patients that had been diagnosed a BRCA1 germline mutation. Vitamin D Receptor (VDR), Retinoid X Receptor (RXR) and Peroxisome Proliferator-activated Receptor γ (PPARγ) are known to interact with TRs by forming functional heterodimers. Whether VDR, RXR or PPARγ are expressed in BRCA1 mutated breast cancer or may even be present in case of triple negativity is not known. Hence the current study aimed to investigate VDR, RXR and PPARγ in BRCA1 mut breast cancer and to test whether any of the three may be associated with clinico-pathological criteria including overall survival. This study analyzed VDR, RXR and PPARγ by immunohistochemistry in BRCA1 associated (n = 38) and sporadic breast cancer (n = 79). Receptors were quantified by applying an established scoring system (IR-score) and were tested for association with clinico-pathological variables. VDR, RXR and PPARγ were detected in over 90% of triple negative BRCA1 mut breast cancer and were significantly (VDR: p < 0.001, RXR: p = 0.010, PPARγ: p < 0.001) overexpressed in BRCA1 mutated as compared to sporadic cancer cases. VDR and RXR positivity predicted prolonged overall survival only in BRCA1 mutated cases while such association was not observed in sporadic breast cancer. In conclusion, this is the first study to describe VDR, RXR and PPARγ in BRCA1 mutated breast cancer. Based on the data presented here these receptors may be hypothesized to potentially evolve as interesting markers or even targets in hereditary breast cancer. However, independent studies are

  13. Quantification of Endogenous Retinoids

    Science.gov (United States)

    Kane, Maureen A.; Napoli, Joseph L.

    2014-01-01

    Numerous physiological processes require retinoids, including development, nervous system function, immune responsiveness, proliferation, differentiation, and all aspects of reproduction. Reliable retinoid quantification requires suitable handling and, in some cases, resolution of geometric isomers that have different biological activities. Here we describe procedures for reliable and accurate quantification of retinoids, including detailed descriptions for handling retinoids, preparing standard solutions, collecting samples and harvesting tissues, extracting samples, resolving isomers, and detecting with high sensitivity. Sample-specific strategies are provided for optimizing quantification. Approaches to evaluate assay performance also are provided. Retinoid assays described here for mice also are applicable to other organisms including zebrafish, rat, rabbit, and human and for cells in culture. Retinoid quantification, especially that of retinoic acid, should provide insight into many diseases, including Alzheimer’s disease, type 2 diabetes, obesity, and cancer. PMID:20552420

  14. Osthole inhibits proliferation of human breast cancer cells by inducing cell cycle arrest and apoptosis

    Science.gov (United States)

    Wang, Lintao; Peng, Yanyan; Shi, Kaikai; Wang, Haixiao; Lu, Jianlei; Li, Yanli; Ma, Changyan

    2015-01-01

    Abstract Recent studies have revealed that osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, a traditional Chinese medicine, possesses anticancer activity. However, its effect on breast cancer cells so far has not been elucidated clearly. In the present study, we evaluated the effects of osthole on the proliferation, cell cycle and apoptosis of human breast cancer cells MDA-MB 435. We demonstrated that osthole is effective in inhibiting the proliferation of MDA-MB 435 cells, The mitochondrion-mediated apoptotic pathway was involved in apoptosis induced by osthole, as indicated by activation of caspase-9 and caspase-3 followed by PARP degradation. The mechanism underlying its effect on the induction of G1 phase arrest was due to the up-regulation of p53 and p21 and down-regulation of Cdk2 and cyclin D1 expression. Were observed taken together, these findings suggest that the anticancer efficacy of osthole is mediated via induction of cell cycle arrest and apoptosis in human breast cancer cells and osthole may be a potential chemotherapeutic agent against human breast cancer. PMID:25859268

  15. Lysophosphatidate induces chemo-resistance by releasing breast cancer cells from taxol-induced mitotic arrest.

    Directory of Open Access Journals (Sweden)

    Nasser Samadi

    Full Text Available Taxol is a microtubule stabilizing agent that arrests cells in mitosis leading to cell death. Taxol is widely used to treat breast cancer, but resistance occurs in 25-69% of patients and it is vital to understand how Taxol resistance develops to improve chemotherapy. The effects of chemotherapeutic agents are overcome by survival signals that cancer cells receive. We focused our studies on autotaxin, which is a secreted protein that increases tumor growth, aggressiveness, angiogenesis and metastasis. We discovered that autotaxin strongly antagonizes the Taxol-induced killing of breast cancer and melanoma cells by converting the abundant extra-cellular lipid, lysophosphatidylcholine, into lysophosphatidate. This lipid stimulates specific G-protein coupled receptors that activate survival signals.In this study we determined the basis of these antagonistic actions of lysophosphatidate towards Taxol-induced G2/M arrest and cell death using cultured breast cancer cells. Lysophosphatidate does not antagonize Taxol action in MCF-7 cells by increasing Taxol metabolism or its expulsion through multi-drug resistance transporters. Lysophosphatidate does not lower the percentage of cells accumulating in G2/M by decreasing exit from S-phase or selective stimulation of cell death in G2/M. Instead, LPA had an unexpected and remarkable action in enabling MCF-7 and MDA-MB-468 cells, which had been arrested in G2/M by Taxol, to normalize spindle structure and divide, thus avoiding cell death. This action involves displacement of Taxol from the tubulin polymer fraction, which based on inhibitor studies, depends on activation of LPA receptors and phosphatidylinositol 3-kinase.This work demonstrates a previously unknown consequence of lysophosphatidate action that explains why autotaxin and lysophosphatidate protect against Taxol-induced cell death and promote resistance to the action of this important therapeutic agent.

  16. Retinoids: Potent regulators of metabolism.

    Science.gov (United States)

    Brun, Pierre-Jacques; Yang, Kryscilla Jian Zhang; Lee, Seung-Ah; Yuen, Jason J; Blaner, William S

    2013-01-01

    Retinoids (vitamin A and its analogs) are highly potent regulators of cell differentiation, cell proliferation, and apoptosis. Because of these activities, retinoids have been most extensively studied in the contexts of embryonic development and of proliferative diseases, especially cancer and skin disease. Recently, there has been considerable new research interest focused on gaining understanding of the roles that retinoids and/or retinoid-related proteins may have in the development of metabolic diseases, primarily obesity, diabetes, and dyslipidemia. This review will summarize recent advances that have been made in these areas, focusing on the role of retinoids in modulating adipogenesis, the roles of retinoids and retinoid-related proteins as signaling molecules linking obesity with the development of type II diabetes, the roles of retinoids in pancreatic β-cell biology/insulin secretion, and the actions of retinoids in hepatic steatosis. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

  17. Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases.

    Science.gov (United States)

    Napoli, Joseph L

    2017-05-01

    Cellular binding-proteins (BP), including CRBP1, CRBP2, CRABP1, CRABP2, and FABP5, shepherd the poorly aqueous soluble retinoids during uptake, metabolism and function. Holo-BP promote efficient use of retinol, a scarce but essential nutrient throughout evolution, by sheltering it and its major metabolite all-trans-retinoic acid from adventitious interactions with the cellular milieu, and by imposing specificity of delivery to enzymes, nuclear receptors and other partners. Apo-BP reflect cellular retinoid status and modify activities of retinoid metabolon enzymes, or exert non-canonical actions. High ligand binding affinities and the nature of ligand sequestration necessitate external factors to prompt retinoid release from holo-BP. One or more of cross-linking, kinetics, and colocalization have identified these factors as RDH, RALDH, CYP26, LRAT, RAR and PPARβ/δ. Michaelis-Menten and other kinetic approaches verify that BP channel retinoids to select enzymes and receptors by protein-protein interactions. Function of the BP and enzymes that constitute the retinoid metabolon depends in part on retinoid exchanges unique to specific pairings. The complexity of these exchanges configure retinol metabolism to meet the diverse functions of all-trans-retinoic acid and its ability to foster contrary outcomes in different cell types, such as inducing apoptosis, differentiation or proliferation. Altered BP expression affects retinoid function, for example, by impairing pancreas development resulting in abnormal glucose and energy metabolism, promoting predisposition to breast cancer, and fostering more severe outcomes in prostate cancer, ovarian adenocarcinoma, and glioblastoma. Yet, the extent of BP interactions with retinoid metabolon enzymes and their impact on retinoid physiology remains incompletely understood. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Cucurbitacin B Causes Increased Radiation Sensitivity of Human Breast Cancer Cells via G2/M Cell Cycle Arrest

    Directory of Open Access Journals (Sweden)

    Suwit Duangmano

    2012-01-01

    Full Text Available Purpose. To explore the effects of cucurbitacin B on the radiation survival of human breast cancer cells and to elucidate the cellular mechanism of radiosensitization if any. Materials and Methods. Human breast carcinoma cell lines were treated with cucurbitacin B before irradiation with 0–10 Gy of C137s gamma rays. The effect of cucurbitacin B on cell-survival following irradiation was evaluated by colony-forming assay. Cell cycle distributions were investigated using flow cytometry. Real-time PCR and western blots were performed to investigate the expression of cell cycle checkpoints. Results. Cucurbitacin B inhibited breast cancer cell proliferation in a dose-dependent manner. Only MDA-MB-231 and MCF7:5C cells but not SKBR-3 cells were radiosensitized by cucurbitacin B. Flow cytometric analysis for DNA content indicated that cucurbitacin B resulted in G2/M arrest in MDA-MB-231 and MCF7:5C but not SKBR-3 cells. Moreover, Real-time PCR and western blot analysis demonstrated upregulated p21 expression before irradiation, a likely cause of the cell cycle arrest. Conclusion. Taken together, these findings suggest that cucurbitacin B causes radiosensitization of some breast cancer cells, and that cucurbitacin B induced G2/M arrest is an important mechanism. Therefore, combinations of cucurbitacin B with radiotherapy may be appropriate for experimental breast cancer treatment.

  19. [Retinoids: mechanisms of action].

    Science.gov (United States)

    Berbis, P

    2010-11-01

    Retinoids, vitamin A derivatives, are natural or synthetic molecules with pleiotropic effects, which regulate cell differentiation, proliferation and apoptosis. In target cell, the active natural metabolites retinoic acid (RA) and 9-cis-retinoic acid are synthetized from retinol by a two-step process with intermediate metabolite retinaldehyde. In 1987, the identification of the nuclear retinoic acid receptors that belong to the superfamily of nuclear receptors led to a significant progress in the comprehension of the mechanism of action of retinoids. There are two families of Retinoid Nuclear Receptors (RNR), the RA receptors (RAR), which natural ligand is RA, and the Retinoid X Receptors (RXR), which natural ligand is 9-cis-retinoic acid. Among synthetic retinoids, isotretinoin, acitretin, tazarotene and adapalene are ligands of the RAR, bexarotene is the first rexinoid (ligand of the RXR), alitretinoin the first panagonist (RAR+ RXR). For each family, there are 3 isotypes (α, β, γ), and for each isotype several isoforms. Each NRR is composed of 6 regions (A-F). 3 regions are of importance: the A/B region has a ligand-independent transcriptional activation function, the C region harbors the DNA binding domain, the E region harbors the ligand binding domain. To regulate the expression of target genes, NRR have to dimerize. RXR are obligatory in dimers (heterodimers RAR-RXR, homodimers RXR-RXR). Dimers binds specific sequences of DNA, present in the promoters of target genes. When the ligand, natural or synthetic, bind to RNR, coactivators are recruited and transcription factors are activated. In target cell, retinoids not utilized are degradated in polar metabolites by enzymes of cytochrome P450. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  20. Toward a New Chemotherapy for Breast Cancer: Structural and Functional Mechanism of the Retinoid Receptors Addressed by a Novel Computer Approach

    Science.gov (United States)

    1999-05-01

    Wesley Pike, Gunther Schutz, Ron Evans, and David Moore for plasmids and Richard Heyman of Ligand, Inc. for providing the retinoids. We thank Sanford...specific requirements for coactivators and their acetyltransferase functions. Science 279: 703-707. Kurokawa, R., J. DiRenzo, M. Boehm, J. Sugarman , B. Gloss

  1. Retinoid treatment of skin diseases.

    Science.gov (United States)

    Beckenbach, Lisa; Baron, Jens M; Merk, Hans F; Löffler, Harald; Amann, Philipp M

    2015-01-01

    Retinoids (vitamin A and its metabolites) are potent natural regulators of cellular activities, including cell growth and differentiation, and they mediate many essential regulatory functions, especially in the skin. Biologically active retinoids exert their effects by binding to nuclear retinoic acid receptors and retinoid-X-receptors. The group of pharmacologically used retinoids include naturally occurring and chemically synthesised vitamin A derivatives. Due to their influence on keratinocyte proliferation, epidermal differentiation and keratinisation, retinoids are commonly used in the field of dermatopharmacology. For safe administration of retinoids, in-depth information about adverse effects and comprehensive information of the patient are important. This article gives an overview on the effects, use, and side-effects of topical and systemic retinoids in dermatology.

  2. Alcohol and retinoids

    DEFF Research Database (Denmark)

    Crabb, D.W.; Pinairs, J.; Hasanadka, R.

    2001-01-01

    , M. Fang, and David W. Crabb; (2) Alcohol, vitamin A, and beta-carotene: Adverse interactions, by M. A. Leo and Charles S. Lieber; (3) Retinoic acid, hepatic stellate cells, and Kupffer cells, by Hidekazu Tsukamoto, K. Motomura, T. Miyahara, and M. Ohata; (4) Retinoid storage and metabolism in liver...

  3. Retinoid Pathway and Cancer Therapeutics

    Science.gov (United States)

    Bushue, Nathan; Wan, Yu-Jui Yvonne

    2010-01-01

    The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid × receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with the emphasis on the application of retinoids in cancer treatment and prevention. PMID:20654663

  4. Phytoestrogen bakuchiol exhibits in vitro and in vivo anti-breast cancer effects by inducing S phase arrest and apoptosis

    Directory of Open Access Journals (Sweden)

    Li eLi

    2016-05-01

    Full Text Available Phytoestrogen has been proposed as an alternative to hormone replacement therapy, which has been demonstrated to promote a high risk of breast cancer. However, the effect of phytoestrogen on breast cancer development has not been fully understood. Bakuchiol is an active ingredient of a traditional Chinese herbal medicine Fructus Psoraleae, the dried ripe fruit of Psoralea corylifolia L. (Fabaceae. The in vitro and in vivo estrogenic activities and anti-breast cancer effects of bakuchiol have not been well studied. We found that bakuchiol induced the GFP expression in transgenic medaka (Oryzias melastigma, Tg, Chg:GFP dose-dependently (0-1 µg/ml, demonstrating its in vivo estrogenic activity. Low dose of bakuchiol (1 µg/ml induced the cell proliferation and ERα expression in MCF-7 cells, which could be blocked by the antiestrogen ICI 182780, suggesting the in vitro estrogenic activity of bakuchiol. Our data indicated that high doses of bakuchiol (>2 µg/ml inhibited breast cancer cell growth, with a stronger antiproliferative effect than resveratrol, a widely studied analogue of bakuchiol. High doses of bakuchiol (4 µg/ml, 7 µg/ml and 10 µg/ml were used for the further in vitro anti-breast cancer studies. Bakuchiol induced ERβ expression and suppressed ERα expression in MCF-7 cells. It also induced S phase arrest in both MCF-7 and MDA-MB-231 cells, which could be rescued by caffeine. Knock-down of p21 also marginally rescued S phase arrest in MCF-7 cells. The S phase arrest was accompanied by the upregulation of ATM, P-Cdc2 (Tyr15, Myt1, P-Wee1 (Ser642, p21 and Cyclin B1, suggesting that blocking of Cdc2 activation may play an important role in bakuchiol-induced S phase arrest. Furthermore, bakuchiol induced cell apoptosis and disturbed mitochondrial membrane potential in MCF-7 cells. The bakuchiol-induced apoptosis was associated with increased expression of Caspase family and Bcl-2 family proteins, suggesting that bakuchiol may induce

  5. Retinoids Bias Integrin Expression and Function in Cutaneous T-Cell Lymphoma.

    Science.gov (United States)

    Wang, Lei; DeMarco, Sebastian S; Chen, JianMing; Phillips, Charles M; Bridges, Lance C

    2015-08-01

    Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of malignancies characterized by accumulation of malignant T-cells within the skin. Retinoids, metabolic derivatives, and synthetic analogs of vitamin A embody an effective CTCL therapy with over three decades of clinical use. The established mechanism of action is induction of growth arrest and apoptosis. However, the natural role of retinoids in T-cell biology is imprinting gut-homing properties by inducing integrin α4β7 expression. How the natural role of retinoids relates to therapeutic effectiveness in CTCL has not been addressed and merits investigation. Here we provide evidence that retinoids, including Bexarotene, selectively induce CTCL lineages to increase integrin β7 expression and function prior to growth arrest and apoptosis. Interestingly, augmented CTCL cell adhesion obtained with retinoid exposure was potently attenuated by 1,25-dihydroxyvitamin D3, a metabolic vitamin derivative involved in prompting immune cell skin homing. The integrin-dependent adhesion changes in CTCL cells occurred through synergistic activation of RAR and RXR nuclear receptors. These data explore the early cellular changes induced by retinoids that may be pivotal to sensitizing CTCL cells to growth arrest and apoptosis.

  6. Differential effects of doxorubicin treatment on cell cycle arrest and Skp2 expression in breast cancer cells.

    Science.gov (United States)

    Bar-On, Ortal; Shapira, Ma'anit; Hershko, Dan D

    2007-11-01

    Overexpression of Skp2, the ubiquitin ligase subunit that targets p27 for degradation, is often observed in cancers, and is associated with aggressive tumor proliferation and poor prognosis. As there is no drug at present that specifically targets Skp2, studies were undertaken to examine the effects of commonly used drugs on Skp2 regulation. Doxorubicin is among the most effective antitumor agents used for the management of breast cancer, but its effect on Skp2 expression is unknown. The objective of this study was to examine the effect of doxorubicin on Skp2 expression regulation in breast cancer cell lines. The expression of Skp2 mRNA and the protein levels of Skp2, p27, p21 and cyclin B were examined in doxorubicin-treated MCF-7 and MDA-MB-231 breast cancer cells. The effect of doxorubicin on the cell cycle profile was assessed by fluorescence-activated cell sorting analysis. Doxorubicin decreased Skp2 mRNA and protein levels in MCF-7 cells, but had the opposite effect in MDA-MB-231 cells. p27 levels were slightly decreased, whereas p53 and p21 levels were significantly upregulated in doxorubicin-treated MCF-7 cells. In contrast, p27 levels were unaffected by doxorubicin treatment in MDA-MB-231 cells, but cyclin B levels were markedly increased. Doxorubicin arrested MCF-7 cells at G1/S and G2/M checkpoints, whereas MDA-MB-231 cells were arrested at G2/M only. The differential effects of doxorubicin on Skp2 expression in breast cancer cells depend upon the specific cell cycle checkpoints activated by the drug. These changes induced by doxorubicin, however, do not significantly affect p27 expression in these cell lines, suggesting that the potential of a given drug to alter p27 expression through Skp2 modulation might depend on its specific action on cell cycle arrest.

  7. Cellular Effect of Curcumin and Citral Combination on Breast Cancer Cells: Induction of Apoptosis and Cell Cycle Arrest.

    Science.gov (United States)

    Patel, Pinaki B; Thakkar, Vasudev R; Patel, Jagdish S

    2015-09-01

    The unmanageable side effects caused by current chemotherapy regimens to treat cancer are an unresolved problem. Although many phytonutrients are useful as chemoprevention without side effects, their effects are slower and smaller than conventional chemotherapy. In the present work, we examined the cumulative effect of two phytonutrients, curcumin and citral, on breast cancer cell lines and compared their effect with the known chemotherapy regimen of cyclophosphamide, methotrexate, and 5-fluorouracil. Using cultured breast cancer and normal epithelial cells, the cytotoxic and apoptotic effect of curcumin and citral was evaluated in vitro. The synergistic effect of curcumin and citral was calculated by a combination index study using the method by Chou and Talalay. Cell death pathways and mechanisms were analyzed by measuring intracellular reactive oxygen species (ROS) and apoptotic protein levels. Curcumin and citral caused dose and time dependent cell death and showed a synergistic effect at effective concentration EC50 and above concentrations in breast cancer cells without disturbing normal breast epithelial cells. With combination curcumin and citral treatment, apoptosis induction and cell cycle arrest at G0/G1 phase in breast cancer cells were observed. Curcumin and citral generated ROS and activated p53 and poly (ADP-ribose) polymerase-1 mediated apoptotic pathways. The results of this study suggest that curcumin and citral in combination may be a useful therapeutic intervention for breast cancer.

  8. Gallotannin imposes S phase arrest in breast cancer cells and suppresses the growth of triple-negative tumors in vivo.

    Directory of Open Access Journals (Sweden)

    Tiejun Zhao

    Full Text Available Triple-negative breast cancers are associated with poor clinical outcomes and new therapeutic strategies are clearly needed. Gallotannin (Gltn has been previously demonstrated to have potent anti-tumor properties against cholangiocarcinoma in mice, but little is known regarding its capacity to suppress tumor outgrowth in breast cancer models. We tested Gltn for potential growth inhibitory properties against a variety of breast cancer cell lines in vitro. In particular, triple-negative breast cancer cells display higher levels of sensitivity to Gltn. The loss of proliferative capacity in Gltn exposed cells is associated with slowed cell cycle progression and S phase arrest, dependent on Chk2 phosphorylation and further characterized by changes to proliferation related genes, such as cyclin D1 (CcnD1 as determined by Nanostring technology. Importantly, Gltn administered orally or via intraperitoneal (IP injections greatly reduced tumor outgrowth of triple-negative breast cells from mammary fat pads without signs of toxicity. In conclusion, these data strongly suggest that Gltn represents a novel approach to treat triple-negative breast carcinomas.

  9. Licochalcone B Arrests Cell Cycle Progression and Induces Apoptosis in Human Breast Cancer MCF-7 Cells.

    Science.gov (United States)

    Yu, Lina; Ma, Jun; Han, Jichun; Wang, Bo; Chen, Xiaoyu; Gao, Caixia; Li, Defang; Zheng, Qiusheng

    2016-01-01

    Recent patent of licochalcone B (LCB) as an antiinflammatory agent has been developed. Emerging evidence shows that LCB may be a promising alternative compound with anti-cancer activities. However, the anticancer mechanism of LCB in MCF-7 cells has not been fully investigated. We aimed to unearth the anti-cancer effect and mechanism of LCB in MCF-7 cells. Cell proliferation activity and cell-cycle progression were determined by sulforhodamine B assay and flow cytometry, respectively. The mRNA and protein levels of cell cycle-related proteins and apoptosis-associated proteins were examined by RT-qPCR and western blot, respectively. Mitochondrial membrane potential (MMP) was measured by flow cytometry after JC-1 staining. We found that LCB inhibited MCF-7 cells proliferation in a concentration- and time-dependent manner. Moreover, LCB-treatment led to S phase arrest in MCF-7 cells, which could be elucidated by the decreased mRNA and protein levels of Cyclin A, Cdk2 and Cdc25 A, and the increased protein level of p21. LCB also induced such apoptosis morphology as phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Moreover, LCB led to the loss of MMP, resulting in the release of cytochrome C. The above apoptotic events were supported by the fact that LCB upregulated the mRNA and protein levels of Caspase 3, Caspase 9 and Bax, and downregulated the mRNA and protein level of Bcl-2, which was triggered by the increased p53 protein level in LCB-treated MCF-7 cells. These findings suggested that LCB could be a promising agent for treatment of human breast cancer.

  10. Retinoid Metabolism and Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Eun-Jung Rhee

    2012-06-01

    Full Text Available Retinoid acid is a metabolite of vitamin A and functions as an important factor in cell survival, differentiation and death. Most previous studies on retinoid metabolism have focused on its association with cancer, hematologic and dermatologic disorders. Given the special concern over the recent increase in the prevalence of diabetes worldwide, the role of retinoid metabolism on glucose metabolism and insulin resistance in the human body is of marked importance. Therefore, in this issue, we review the literature on the association of retinoid metabolism with glucose tolerance, with regard to insulin secretion, pancreatic autoimmunity, insulin sensitivity and lipid metabolism. Further, we tried to assess the possibility of using retinoids as a novel therapeutic strategy for diabetes.

  11. DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERα-positive breast cancer cells.

    Science.gov (United States)

    Ansems, Marleen; Søndergaard, Jonas Nørskov; Sieuwerts, Anieta M; Looman, Maaike W G; Smid, Marcel; de Graaf, Annemarie M A; de Weerd, Vanja; Zuidscherwoude, Malou; Foekens, John A; Martens, John W M; Adema, Gosse J

    2015-02-01

    Breast cancer is one of the most common causes of cancer-related deaths in women. The estrogen receptor (ERα) is well known for having growth promoting effects in breast cancer. Recently, we have identified DC-SCRIPT (ZNF366) as a co-suppressor of ERα and as a strong and independent prognostic marker in ESR1 (ERα gene)-positive breast cancer patients. In this study, we further investigated the molecular mechanism on how DC-SCRIPT inhibits breast cancer cell growth. DC-SCRIPT mRNA levels from 190 primary ESR1-positive breast tumors were related to global gene expression, followed by gene ontology and pathway analysis. The effect of DC-SCRIPT on breast cancer cell growth and cell cycle arrest was investigated using novel DC-SCRIPT-inducible MCF7 breast cancer cell lines. Genome-wide expression profiling of DC-SCRIPT-expressing MCF7 cells was performed to investigate the effect of DC-SCRIPT on cell cycle-related gene expression. Findings were validated by real-time PCR in a cohort of 1,132 ESR1-positive breast cancer patients. In the primary ESR1-positive breast tumors, DC-SCRIPT expression negatively correlated with several cell cycle gene ontologies and pathways. DC-SCRIPT expression strongly reduced breast cancer cell growth in vitro, breast tumor growth in vivo, and induced cell cycle arrest. In addition, in the presence of DC-SCRIPT, multiple cell cycles related genes were differentially expressed including the tumor suppressor gene CDKN2B. Moreover, in 1,132 primary ESR1-positive breast tumors, DC-SCRIPT expression also correlated with CDKN2B expression. Collectively, these data show that DC-SCRIPT acts as a novel regulator of CDKN2B and induces cell cycle arrest in ESR1-positive breast cancer cells.

  12. Secretion modification region-derived peptide blocks exosome release and mediates cell cycle arrest in breast cancer cells.

    Science.gov (United States)

    Huang, Ming-Bo; Gonzalez, Ruben R; Lillard, James; Bond, Vincent C

    2017-02-14

    Discovery and development of a novel anticancer PEG-SMR-Clu peptide to prevent breast cancer metastasis. How breast cancer cells and primary mammary epithelial cells interact and communicate with each other to promote tumorigenesis and how to prevent tumor metastasis has long been a concern of researchers. Cancer cells secrete exosomes containing proteins and RNA. These factors can influence tumor development by directly targeting cancer cells and tumor stroma. In this study, we determined the effects of a peptide as an inhibitor of exosome secretion on breast tumors. We developed a peptide derived from the Secretion Modification Region (SMR) of HIV-1 Nef protein that was modified with PEG on the N-terminus and with a Clusterin (Clu)-binding peptide on the C-terminus. Attachment of PEG to the SMR peptide, termed PEGylation, offers improved water solubility and stability as well as reduced clearance through the kidneys, leading to a longer circulation time. The 12-mer Clu-binding peptide plays multiple roles in tumor development and metastasis. The Clu peptide can be detected by antibody in vivo, thus it has the potential to be used to monitor tumor status and treatment efficacy in animal studies and eventually in cancer patients. PEG-SMRwt-Clu and PEG-SMRwt peptides inhibited the growth of both of MCF-7 (estrogen responsive, ER+) and MDA-MD-231 (estrogen non-responsive, ER-) human breast cancer cells in a dose and time-dependent manner, without inducing cytotoxic effects. The SMRwt peptide, combined with paclitaxel, induced G2/M phase cell cycle arrest on MCF-7 and MDA-MB-231 cells but did not promote apoptosis. PEG-SMRwt-Clu peptide treatment blocked exosome release from both MCF-7 and MDA-MB-231 cells. This effect was blocked by knockdown of the chaperone protein mortalin by either antibody or siRNA. MCF-7 and MDA-MB-231 breast tumor cells were treated with PEG-SMR-Clu peptide alone and in combination with paclitaxel and cisplatin. Cell proliferation and viabilty

  13. Isotretinoin and Other Retinoids During Pregnancy

    Science.gov (United States)

    ... Global Map Premature Birth Report Cards Careers Archives Pregnancy Before or between pregnancies Nutrition, weight & fitness Prenatal ... retinoids during pregnancy Isotretinoin and other retinoids during pregnancy E-mail to a friend Please fill in ...

  14. Hepatic metabolism of retinoids and disease associations.

    Science.gov (United States)

    Shirakami, Yohei; Lee, Seung-Ah; Clugston, Robin D; Blaner, William S

    2012-01-01

    The liver is the most important tissue site in the body for uptake of postprandial retinoid, as well as for retinoid storage. Within the liver, both hepatocytes and hepatic stellate cells (HSCs) are importantly involved in retinoid metabolism. Hepatocytes play an indispensable role in uptake and processing of dietary retinoid into the liver, and in synthesis and secretion of retinol-binding protein (RBP), which is required for mobilizing hepatic retinoid stores. HSCs are the central cellular site for retinoid storage in the healthy animal, accounting for as much as 50-60% of the total retinoid present in the entire body. The liver is also an important target organ for retinoid actions. Retinoic acid is synthesized in the liver and can interact with retinoid receptors which control expression of a large number of genes involved in hepatic processes. Altered retinoid metabolism and the accompanying dysregulation of retinoid signaling in the liver contribute to hepatic disease. This is related to HSCs, which contribute significantly to the development of hepatic disease when they undergo a process of cellular activation. HSC activation results in the loss of HSC retinoid stores and changes in extracellular matrix deposition leading to the onset of liver fibrosis. An association between hepatic disease progression and decreased hepatic retinoid storage has been demonstrated. In this review article, we summarize the essential role of the liver in retinoid metabolism and consider briefly associations between hepatic retinoid metabolism and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. © 2011 Elsevier B.V. All rights reserved.

  15. Notch3 overexpression causes arrest of cell cycle progression by inducing Cdh1 expression in human breast cancer cells.

    Science.gov (United States)

    Chen, Chun-Fa; Dou, Xiao-Wei; Liang, Yuan-Ke; Lin, Hao-Yu; Bai, Jing-Wen; Zhang, Xi-Xun; Wei, Xiao-Long; Li, Yao-Chen; Zhang, Guo-Jun

    2016-01-01

    Uncontrolled cell proliferation, genomic instability and cancer are closely related to the abnormal activation of the cell cycle. Therefore, blocking the cell cycle of cancer cells has become one of the key goals for treating malignancies. Unfortunately, the factors affecting cell cycle progression remain largely unknown. In this study, we have explored the effects of Notch3 on the cell cycle in breast cancer cell lines by 3 methods: overexpressing the intra-cellular domain of Notch3 (N3ICD), knocking-down Notch3 by RNA interference, and using X-ray radiation exposure. The results revealed that overexpression of Notch3 arrested the cell cycle at the G0/G1 phase, and inhibited the proliferation and colony-formation rate in the breast cancer cell line, MDA-MB-231. Furthermore, overexpressing N3ICD upregulated Cdh1 expression and resulted in p27(Kip) accumulation by accelerating Skp2 degradation. Conversely, silencing of Notch3 in the breast cancer cell line, MCF-7, caused a decrease in expression levels of Cdh1 and p27(Kip) at both the protein and mRNA levels, while the expression of Skp2 only increased at the protein level. Correspondingly, there was an increase in the percentage of cells in the G0/G1 phase and an elevated proliferative ability and colony-formation rate, which may be caused by alterations of the Cdh1/Skp2/p27 axis. These results were also supported by exposing MDA-MB-231 cells or MCF-7 treated with siN3 to X-irradiation at various doses. Overall, our data showed that overexpression of N3ICD upregulated the expression of Cdh1 and caused p27(Kip) accumulation by accelerating Skp2 degradation, which in turn led to cell cycle arrest at the G0/G1 phase, in the context of proliferating breast cancer cell lines. These findings help to illuminate the precision therapy targeted to cell cycle progression, required for cancer treatment.

  16. Update on retinoid therapy of psoriasis in: an update on the use of retinoids in dermatology.

    Science.gov (United States)

    van de Kerkhof, Peter C M

    2006-01-01

    Both in the topical and systemic treatment of psoriasis, retinoids are mainstays. In this chapter the history and modes of actions of retinoids are presented. Tazarotene and acitretin are the only retinoids that are available in both topical and systemic formulations. A more extensive description of their pharmacology, modes of action, indications and contraindications, clinical results, and treatment strategies will be presented. Finally, retinoid X receptor ligands and retinoic acid metabolism blocking agents will be introduced as potential future retinoid mimetics in psoriasis.

  17. Toward a New Chemotherapy for Breast Cancer: Structural and Functional Mechanism of the Retinoid Receptors Addressed by a Novel Computer Approach

    Science.gov (United States)

    2002-01-01

    Article 3). Little is known about the natural ligands to RXR. Crystallographic data of RXRc bound to agonist 9-cis RA were published recently ( Egea et...breast cancer, Clin. Cancer Res. 4, 635-642. Egea PF, Mitshcler A, Rochel N, Ruff M, Chambon P and Moras D (2000). Crystal structure of the human RXRa

  18. Osthole inhibits proliferation of human breast cancer cells by inducing cell cycle arrest and apoptosis

    OpenAIRE

    Wang, Lintao; Peng, Yanyan; Shi, Kaikai; Wang, Haixiao; Lu, Jianlei; Li, Yanli; Ma, Changyan

    2012-01-01

    Abstract Recent studies have revealed that osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, a traditional Chinese medicine, possesses anticancer activity. However, its effect on breast cancer cells so far has not been elucidated clearly. In the present study, we evaluated the effects of osthole on the proliferation, cell cycle and apoptosis of human breast cancer cells MDA-MB 435. We demonstrated that osthole is effective in inhibiting the proliferation ...

  19. Synthetic retinoids: structure-activity relationships.

    Science.gov (United States)

    Barnard, Jonathan H; Collings, Jonathan C; Whiting, Andrew; Przyborski, Stefan A; Marder, Todd B

    2009-11-02

    Retinoid signalling pathways are involved in numerous processes in cells, particularly those mediating differentiation and apoptosis. The endogenous ligands that bind to the retinoid receptors, namely all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, are prone to double-bond isomerisation and to oxidation by metabolic enzymes, which can have significant and deleterious effects on their activities and selectivities. Many of these problems can be overcome through the use of synthetic retinoids, which are often much more stable, as well as being more active. Modification of their molecular structures can result in retinoids that act as antagonists, rather than agonists, or exhibit a large degree of selectivity for particular retinoid-receptor isotypes. Several such selective retinoids are likely to be of value as pharmaceutical agents with reduced toxicities, particularly in cancer therapy, as reagents for controlling cell differentiation, and as tools for elucidating the precise roles that specific retinoid signalling pathways play within cells.

  20. The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer.

    Directory of Open Access Journals (Sweden)

    Tingxiu Xiang

    Full Text Available Breast cancer (BrCa is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl- terminal esterase L1 (UCHL1 is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear.We found that UCHL1 was frequently downregulated or silenced in breast cancer cell lines and tumor tissues, but readily expressed in normal breast tissues and mammary epithelial cells. Promoter methylation of UCHL1 was detected in 9 of 10 breast cancer cell lines (90% and 53 of 66 (80% primary tumors, but rarely in normal breast tissues, which was statistically correlated with advanced clinical stage and progesterone receptor status. Pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. Ectopic expression of UCHL1 significantly suppressed the colony formation and proliferation of breast tumor cells, through inducing G0/G1 cell cycle arrest and apoptosis. Subcellular localization study showed that UCHL1 increased cytoplasmic abundance of p53. We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S-expressed cells.UCHL1 exerts its tumor suppressive functions by inducing G0/G1cell cycle arrest and apoptosis in breast tumorigenesis, requiring its deubiquitinase activity. Its frequent silencing by promoter CpG methylation may serve as a potential tumor marker for breast cancer.

  1. Retinoids as potential targets for Alzheimer's disease.

    Science.gov (United States)

    Sodhi, Rupinder K; Singh, Nirmal

    2014-05-01

    Vitamin A and its derivatives, the retinoids, modulate several physiological and pathological processes through their interactions with nuclear retinoid receptor proteins termed as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). An increasing body of evidence signifies the existence of retinoid signaling in diverse brain areas including cortex, amygdala, hypothalamus, hippocampus, and striatum suggesting its involvement in adult brain functions. Defective retinoid signaling has been evidenced in the pathology of Alzheimer's disease. Reports demonstrate that vitamin A deprived mice exhibit serious defects in spatial learning and memory signifying its importance in the maintenance of memory functions. Retinoid signaling impacts the development of AD pathology through multiple pathways. Ligand activation of RAR and RXR in APP/PS1 transgenic mice ameliorated the symptoms of AD and reduced amyloid accumulation and tau hyperphosphorylation. Retinoids also reduce the production of pro-inflammatory cytokines and chemokines by astrocytes and the microglia. Studies also suggest that neuronal cell lines treated with retinoid agonists exhibit an up-regulation in the expression and activity of choline acetyltransferase (ChAT). Reports depict that retinoic acid isomers enhance, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1 and abcg-1 proteins in astrocytes. Furthermore numerous studies also indicate antioxidant potential of retinoids. Through this review we concisely summarize the biology of retinoids, emphasizing on their probable neuroprotective mechanisms that will help to elucidate the pivotal role of these receptors in AD pathology. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Inhibition of carcinogenesis by retinoids. [Review

    Energy Technology Data Exchange (ETDEWEB)

    Nettesheim, P.

    1979-01-01

    Progress made in recent years in the search for retinoids with anticarcinogenic activity is reviewed. There are many studies to be found in the literature which show no substantial effect of retinoids on carcinogenesis or tumor growth. Some of these negative findings may be related to the carcinogen dose used, the type of retinoid used, the dose, dose schedule or mode of administration of the retinoid. Others may indicate that the particular type of tumor or tumor system is, indeed, refractory to retinoids in general or to those retinoids that were tested. A great gap still exists in our knowledge concerning the pharmake-kinetics of most retinoids their availability to various normal and cancerous tissues, and the role and existence of transport and binding proteins. There are studies which indicate that under certain conditions, particularly conditions of topical application, some retinoids may even enhance carcinogenesis. It seems, however, indisputable by now that some retinoids are effective inhibitors of carcinogenesis in some organ systems and can even inhibit the growth of some established tumors. While the mechanisms of these inhibitory effects are presently not understood, it does seem clear that they are not mediated via the cytotoxic mechanisms typical of chemotherapeutic agents. The hope that retinoids might become an effective tool to halt the progression of some neoplastic diseases, seems to be justified.

  3. Up-regulation of human arrest-defective 1 protein is correlated with metastatic phenotype and poor prognosis in breast cancer.

    Science.gov (United States)

    Wang, Ze-Hua; Gong, Jun-Li; Yu, M; Yang, H; Lai, J H; Ma, M X; Wu, H; Li, L; Tan, D Y

    2011-01-01

    Human arrest defective 1 protein (ARD1), as a N-terminal acetyltransferase, has been reported to play a crucial role in tumorigenesis, but the results are somewhat controversial. To explore the clinical and pathological significance of ARD1 in breast tumorigenesis, we analyzed ARD1 status in multiple types of breast disease. The expression of ARD1 protein was assessed by immunohistochemistry in 356 cases including 82 invasive ductal carcinomas (IDC), 159 fibroadenomas, 66 hyperplasia of mammary glands, 19 inflammatory breast disease, 30 breast cysts, and in 29 postoperative treatment patients. We assessed the relationship of ARD1 protein with clinical and pathological characteristics using χ2 test. ARD1 protein was observed at 61.0% (50/82), 54.7% (87/159), 37.9% (25/66), 36.8% (7/19) in IDC, fibroadenoma, hyperplasia, and inflammation, respectively, and less than 30.0% for breast cyst. Thus, high ARD1 expression correlated with breast cancer (relative risk = 1.32, P breast cancer patients after postoperative therapy. These results suggest that ARD1 expression may be as a potential target for exploring the mechanism of breast cancer metastasic to lymph nodes and hormone-responsive regulation.

  4. Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin

    Directory of Open Access Journals (Sweden)

    Danielle D. Jandial

    2017-03-01

    Full Text Available HER2/neu positive breast tumors predict a high mortality and comprise 25%–30% of breast cancer. We have shown that Flavokawain A (FKA preferentially reduces the viabilities of HER2-overexpressing breast cancer cell lines (i.e., SKBR3 and MCF7/HER2 versus those with less HER2 expression (i.e., MCF7 and MDA-MB-468. FKA at cytotoxic concentrations to breast cancer cell lines also has a minimal effect on the growth of non-malignant breast epithelial MCF10A cells. FKA induces G2M arrest in cell cycle progression of HER2-overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and downregulation of expression of Myt1 and Wee1 leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl2, BclX/L, XIAP, and survivin. FKA also downregulates the protein expression of HER-2 and inhibits AKT phosphorylation. Herceptin plus FKA treatment leads to an enhanced growth inhibitory effect on HER-2 overexpressing breast cancer cell lines through downregulation of Myt1, Wee1, Skp2, survivin, and XIAP. Our results suggest FKA as a promising and novel apoptosis inducer and G2 blocking agent that, in combination with Herceptin, enhances for the treatment of HER2-overexpressing breast cancer.

  5. Interphotoreceptor retinoid-binding protein protects retinoids from photodegradation.

    Science.gov (United States)

    Gonzalez-Fernandez, Federico; Betts-Obregon, Brandi; Yust, Brian; Mimun, Joshua; Sung, Dongjin; Sardar, Dhiraj; Tsin, Andrew T

    2015-01-01

    Retinol degrades rapidly in light into a variety of photoproducts. It is remarkable that visual cycle retinoids can evade photodegradation as they are exchanged between the photoreceptors, retinal pigment epithelium and Müller glia. Within the interphotoreceptor matrix, all-trans retinol, 11-cis retinol and retinal are bound by interphotoreceptor retinoid-binding protein (IRBP). Apart from its role in retinoid trafficking and targeting, could IRBP have a photoprotective function? HPLC was used to evaluate the ability of IRBP to protect all-trans and 11-cis retinols from photodegradation when exposed to incandescent light (0 to 8842 μW cm(-2)); time periods of 0-60 min, and bIRBP: retinol molar ratios of 1:1 to 1:5. bIRBP afforded a significant prevention of both all-trans and 11-cis retinol to rapid photodegradation. The effect was significant over the entire light intensity range tested, and extended to the bIRBP: retinol ratio 1:5. In view of the continual exposure of the retina to light, and the high oxidative stress in the outer retina, our results suggest IRBP may have an important protective role in the visual cycle by reducing photodegradation of all-trans and 11-cis retinols. This role of IRBP is particularly relevant in the high flux conditions of the cone visual cycle. © 2015 The American Society of Photobiology.

  6. AEG-1 regulates retinoid X receptor and inhibits retinoid signaling.

    Science.gov (United States)

    Srivastava, Jyoti; Robertson, Chadia L; Rajasekaran, Devaraja; Gredler, Rachel; Siddiq, Ayesha; Emdad, Luni; Mukhopadhyay, Nitai D; Ghosh, Shobha; Hylemon, Phillip B; Gil, Gregorio; Shah, Khalid; Bhere, Deepak; Subler, Mark A; Windle, Jolene J; Fisher, Paul B; Sarkar, Devanand

    2014-08-15

    Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)-mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics. ©2014 American Association for Cancer Research.

  7. A multimodality imaging model to track viable breast cancer cells from single arrest to metastasis in the mouse brain

    Science.gov (United States)

    Parkins, Katie M.; Hamilton, Amanda M.; Makela, Ashley V.; Chen, Yuanxin; Foster, Paula J.; Ronald, John A.

    2016-10-01

    Cellular MRI involves sensitive visualization of iron-labeled cells in vivo but cannot differentiate between dead and viable cells. Bioluminescence imaging (BLI) measures cellular viability, and thus we explored combining these tools to provide a more holistic view of metastatic cancer cell fate in mice. Human breast carcinoma cells stably expressing Firefly luciferase were loaded with iron particles, injected into the left ventricle, and BLI and MRI were performed on days 0, 8, 21 and 28. The number of brain MR signal voids (i.e., iron-loaded cells) on day 0 significantly correlated with BLI signal. Both BLI and MRI signals decreased from day 0 to day 8, indicating a loss of viable cells rather than a loss of iron label. Total brain MR tumour volume on day 28 also correlated with BLI signal. Overall, BLI complemented our sensitive cellular MRI technologies well, allowing us for the first time to screen animals for successful injections, and, in addition to MR measures of cell arrest and tumor burden, provided longitudinal measures of cancer cell viability in individual animals. We predict this novel multimodality molecular imaging framework will be useful for evaluating the efficacy of emerging anti-cancer drugs at different stages of the metastatic cascade.

  8. Update on retinoid therapy of psoriasis in: an update on the use of retinoids in dermatology.

    NARCIS (Netherlands)

    Kerkhof, P.C.M. van de

    2006-01-01

    Both in the topical and systemic treatment of psoriasis, retinoids are mainstays. In this chapter the history and modes of actions of retinoids are presented. Tazarotene and acitretin are the only retinoids that are available in both topical and systemic formulations. A more extensive description of

  9. Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells.

    Science.gov (United States)

    Mohamad Fairus, A K; Choudhary, B; Hosahalli, S; Kavitha, N; Shatrah, O

    2017-04-01

    Dihydroorotate dehydrogenase (DHODH) is the key enzyme in de novo biosynthesis of pyrimidine in both prokaryotes and eukaryotes. The de novo pathway of pyrimidine biosynthesis is essential in cancer cells proliferation. Leflunomide is an approved DHODH inhibitor that has been widely used for the treatment of arthritis. Similarly, brequinar sodium is another DHODH inhibitor that showed anti-tumour effect in MC38 colon carcinoma cells when used in combination with fluorouracil. Despite the potential role of DHODH inhibitors in cancer therapy, their mechanisms of action remain obscure and await further elucidation. Here, we evaluated the effect of DHODH inhibitors on the production of ATP and ROS in sensitive and non-sensitive breast cancer cells. Subsequently, the effects of DHODH inhibitors on cell cycle as well as on signalling molecules such as p53, p65 and STAT6 were evaluated in sensitive T-47D and non-sensitive MDAMB-436 cells. The correlations between DHODH protein expression, proliferation speed and sensitivity to DHODH inhibitors were also investigated in a panel of cancer cell lines. DHODH inhibitors-sensitive T-47D and MDAMB-231 cells appeared to preserve ROS production closely to endogenous ROS level whereas the opposite was observed in non-sensitive MDAMB-436 and W3.006 cells. In addition, we observed approximately 90% of intracellular ATP depletion in highly sensitive T-47D and MDAMB-231 cells compared to non-sensitive MDAMB-436 cells. There was significant over-expression of p53, p65 and STAT6 signalling molecules in sensitive cells which may be involved in mediating the S-phase arrest in cell cycle progression. The current study suggests that DHODH inhibitors are most effective in cells that express high levels of DHODH enzyme. The inhibition of cell proliferation by these inhibitors appears to be accompanied by ROS production as well as ATP depletion. The increase in expression of signalling molecules observed may be due to pyrimidine depletion

  10. Tolerability of Topical Retinoids: Are There Clinically Meaningful Differences Among Topical Retinoids?

    Science.gov (United States)

    Culp, Leonora; Moradi Tuchayi, Sara; Alinia, Hossein; Feldman, Steven R

    2015-01-01

    Topical retinoids are first-line treatment options for acne vulgaris. These drugs, however, produce varying degree of cutaneous irritation within the first few weeks of treatment. Our purpose was to examine differences in tolerability of topical retinoids and assess whether these differences would be clinically meaningful. A PubMed search was performed for sources on topical retinoids in acne vulgaris treatment. Thirty-four clinical studies were analyzed. Thirteen studies had statistically significant results on tolerability of retinoid based on retinoid, vehicle, concentration, or skin type. All studies classified most of skin reactions as mild-moderate. Large differences in the number of dropouts due to irritation were not identified. Irritation studies did not show a high frequency of clinically significant irritation with topical retinoids. We anticipate that the large variation in patient use of topical retinoids would likely account for more variation in response than differences between drug formulations. © The Author(s) 2015.

  11. A Novel Function for the nm23-Hl Gene: Overexpression in Human Breast Carcinoma Cells Leads to the Formation of Basement Membrane and Growth Arrest

    Energy Technology Data Exchange (ETDEWEB)

    Howlett, Anthony R; Petersen, Ole W; Steeg, Patricia S; Bissell, Mina J

    1994-01-01

    We have developed a culture system using reconstituted basement membrane components in which normal human mammary epithelial cells exhibit several aspects of the development and differentiation process, including formation of acinar-like structures, production and basal deposition of basement membrane components, and production and apical secretion of sialomucins. Cell lines and cultures from human breast carcinomas failed to recapitulate this process. The data indicate the importance of cellular interactions with the basement membrane in the regulation of normal breast differentiation and, potentially, its loss in neoplasia. Our purpose was to use this assay to investigate the role of the putative metastasis suppressor gene nm23-H1 in mammary development and differentiation. The metastatic human breast carcinoma cell line MDA-MB-435, clones transfected with a control pCMVBamneo vector, and clones transfected with pCMVBamneo vector containing nm23-H1 complementary DNA (the latter of which exhibited a substantial reduction in spontaneous metastatic potential in vivo) were cultured within a reconstituted basement membrane. Clones were examined for formation of acinus-like spheres, deposition of basement membrane components, production of sialomucin, polarization, and growth arrest. In contrast to the parental cell line and control transfectants, MDA-MB-435 breast carcinoma cells overexpressing Nm23-H1 protein regained several aspects of the normal phenotype within reconstituted basement membrane. Nm23-H1 protein-positive cells formed organized acinus-like spheres, deposited the basement membrane components type IV collagen and, to some extent, laminin to the outside of the spheres, expressed sialomucin, and growth arrested. Growth arrest of Nm23-H1 protein-positive cells was preceded by and correlated with formation of a basement membrane, suggesting a causal relationship. The data indicate a previously unidentified cause-and-effect relationship between nm23-H1 gene

  12. Biochemical properties of retinoid-converting enzymes and biotechnological production of retinoids.

    Science.gov (United States)

    Hong, Seung-Hye; Kim, Kyoung-Rok; Oh, Deok-Kun

    2015-10-01

    Retinoids are a class of compounds that are forms of vitamin A and include retinal, retinol, retinoic acid, and retinyl ester. Retinal is involved in visual cycle, retinol has anti-infective, anticancer, antioxidant, and anti-wrinkle functions, and retinoic acid is used to treat acne and cancer. Retinol, retinoic acid, and retinyl ester are used in cosmetic and pharmaceutical industries. In this article, the biochemical properties and active sites and reaction mechanisms of retinoid-converting enzymes in animals and bacteria, including retinol dehydrogenase, alcohol dehydrogenase, aldo-keto reductase, and aldehyde dehydrogenase, are reviewed. The production of retinoids, using retinoid-producing enzymes and metabolically engineered cells, is also described. Uncharacterized bacterial proteins are suggested as retinoid-converting enzymes, and the production of retinoids using metabolically engineered cells is proposed as a feasible method.

  13. Evaluation of cell cycle arrest in estrogen responsive MCF-7 breast cancer cells: pitfalls of the MTS assay.

    Science.gov (United States)

    McGowan, Eileen M; Alling, Nikki; Jackson, Elise A; Yagoub, Daniel; Haass, Nikolas K; Allen, John D; Martinello-Wilks, Rosetta

    2011-01-01

    Endocrine resistance is a major problem with anti-estrogen treatments and how to overcome resistance is a major concern in the clinic. Reliable measurement of cell viability, proliferation, growth inhibition and death is important in screening for drug treatment efficacy in vitro. This report describes and compares commonly used proliferation assays for induced estrogen-responsive MCF-7 breast cancer cell cycle arrest including: determination of cell number by direct counting of viable cells; or fluorescence SYBR®Green (SYBR) DNA labeling; determination of mitochondrial metabolic activity by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay; assessment of newly synthesized DNA using 5-ethynyl-2'-deoxyuridine (EdU) nucleoside analog binding and Alexa Fluor® azide visualization by fluorescence microscopy; cell-cycle phase measurement by flow cytometry. Treatment of MCF-7 cells with ICI 182780 (Faslodex), FTY720, serum deprivation or induction of the tumor suppressor p14ARF showed inhibition of cell proliferation determined by the Trypan Blue exclusion assay and SYBR DNA labeling assay. In contrast, the effects of treatment with ICI 182780 or p14ARF-induction were not confirmed using the MTS assay. Cell cycle inhibition by ICI 182780 and p14ARF-induction was further confirmed by flow cytometric analysis and EdU-DNA incorporation. To explore this discrepancy further, we showed that ICI 182780 and p14ARF-induction increased MCF-7 cell mitochondrial activity by MTS assay in individual cells compared to control cells thereby providing a misleading proliferation readout. Interrogation of p14ARF-induction on MCF-7 metabolic activity using TMRE assays and high content image analysis showed that increased mitochondrial activity was concomitant with increased mitochondrial biomass with no loss of mitochondrial membrane potential, or cell death. We conclude that, whilst p14ARF and ICI 182780 stop cell cycle progression, the

  14. Magnolol induces apoptosis in MCF-7 human breast cancer cells through G2/M phase arrest and caspase-independent pathway.

    Science.gov (United States)

    Zhou, Yongfeng; Bi, Yanying; Yang, Chunhui; Yang, Jingbo; Jiang, Yu; Meng, Fanmin; Yu, Bo; Khan, Muhammad; Ma, Tonghui; Yang, Hong

    2013-09-01

    Magnolol, a small-molecule hydroxylated biphenol, isolated from the root and stem bark of Magnolia officinalis, has been shown to possess antiproliferative effect on various cancer cell lines. In the current study, we found that magnolol potently inhibited proliferation and induced apoptosis in MCF-7 human breast cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with cell cycle arrest at G2/M phase, increased generation of reactive oxygen species (ROS), reduced mitochondrial membrane potential (MMP), release of cytochrome c (Cyto c) and apoptosis inducing factor (AIF) from mitochondria to cytosol, upregulation of Bax, p21 and p53, and down-regulation of Bcl-2, cyclin B1 and cyclin-dependent kinase 1 (CDK1). Our findings indicated that magnolol induced apoptosis in MCF-7 cells via the intrinsic pathway with release of AIF from mitochondrial and G2/M phase arrest pathway. Therefore, magnolol might be a potential lead compound in the therapy of breast cancer.

  15. Tristetraprolin induces cell cycle arrest in breast tumor cells through targeting AP-1/c-Jun and NF-κB pathway.

    Science.gov (United States)

    Xu, Li; Ning, Huan; Gu, Ling; Wang, Qinghong; Lu, Wenbao; Peng, Hui; Cui, Weiguang; Ying, Baoling; Ross, Christina R; Wilson, Gerald M; Wei, Lin; Wold, William S M; Liu, Jianguo

    2015-12-08

    The main characteristic of cancers, including breast cancer, is the ability of cancer cells to proliferate uncontrollably. However, the underlying mechanisms of cancer cell proliferation, especially those regulated by the RNA binding protein tristetraprolin (TTP), are not completely understood. In this study, we found that TTP inhibits cell proliferation in vitro and suppresses tumor growth in vivo through inducing cell cycle arrest at the S phase. Our studies demonstrate that TTP inhibits c-Jun expression through the C-terminal Zn finger and therefore increases Wee1 expression, a regulatory molecule which controls cell cycle transition from the S to the G2 phase. In contrast to the well-known function of TTP in regulating mRNA stability, TTP inhibits c-Jun expression at the level of transcription by selectively blocking NF-κB p65 nuclear translocation. Reconstitution of NF-κB p65 completely abolishes the inhibition of c-Jun transcription by TTP. Moreover, reconstitution of c-Jun in TTP-expressing breast tumor cells diminishes Wee1 overexpression and promotes cell proliferation. Our results indicate that TTP suppresses c-Jun expression that results in Wee1 induction which causes cell cycle arrest at the S phase and inhibition of cell proliferation. Our study provides a new pathway for TTP function as a tumor suppressor which could be targeted in tumor treatment.

  16. Cytotoxicity and Proapoptotic Effects of Allium atroviolaceum Flower Extract by Modulating Cell Cycle Arrest and Caspase-Dependent and p53-Independent Pathway in Breast Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Somayeh Khazaei

    2017-01-01

    Full Text Available Breast cancer is the second leading cause of cancer death among women and despite significant advances in therapy, it remains a critical health problem worldwide. Allium atroviolaceum is an herbaceous plant, with limited information about the therapeutic capability. We aimed to study the anticancer effect of flower extract and the mechanisms of action in MCF-7 and MDA-MB-231. The extract inhibits the proliferation of the cells in a time- and dose-dependent manner. The underlying mechanism involved the stimulation of S and G2/M phase arrest in MCF-7 and S phase arrest in MDA-MB-231 associated with decreased level of Cdk1, in a p53-independent pathway. Furthermore, the extract induces apoptosis in both cell lines, as indicated by the percentage of sub-G0 population, the morphological changes observed by phase contrast and fluorescent microscopy, and increase in Annexin-V-positive cells. The apoptosis induction was related to downregulation of Bcl-2 and also likely to be caspase-dependent. Moreover, the combination of the extract and tamoxifen exhibits synergistic effect, suggesting that it can complement current chemotherapy. LC-MS analysis displayed 17 major compounds in the extract which might be responsible for the observed effects. Overall, this study demonstrates the potential applications of Allium atroviolaceum extract as an anticancer drug for breast cancer treatment.

  17. Long Term Exposure to Polyphenols of Artichoke (Cynara scolymus L.) Exerts Induction of Senescence Driven Growth Arrest in the MDA-MB231 Human Breast Cancer Cell Line.

    Science.gov (United States)

    Mileo, Anna Maria; Di Venere, Donato; Abbruzzese, Claudia; Miccadei, Stefania

    2015-01-01

    Polyphenolic extracts from the edible part of artichoke (Cynara scolymus L.) have been shown to be potential chemopreventive and anticancer dietary compounds. High doses of polyphenolic extracts (AEs) induce apoptosis and decrease the invasive potential of the human breast cancer cell line, MDA-MB231. However, the molecular mechanism underlying AEs antiproliferative effects is not completely understood. We demonstrate that chronic and low doses of AEs treatment at sublethal concentrations suppress human breast cancer cell growth via a caspases-independent mechanism. Furthermore, AEs exposure induces a significant increase of senescence-associated β-galactosidase (SA-β-gal) staining and upregulation of tumour suppressor genes, p16(INK4a) and p21(Cip1/Waf1) in MDA-MB231 cells. AEs treatment leads to epigenetic alterations in cancer cells, modulating DNA hypomethylation and lysine acetylation levels in total proteins. Cell growth arrest correlates with increased reactive oxygen species (ROS) production in AEs treated breast cancer cells. Inhibition of ROS generation by N-acetylcysteine (NAC) attenuates the antiproliferative effect. These findings demonstrate that chronic AEs treatment inhibits breast cancer cell growth via the induction of premature senescence through epigenetic and ROS-mediated mechanisms. Our results suggest that artichoke polyphenols could be a promising dietary tool either in cancer chemoprevention or/and in cancer treatment as a nonconventional, adjuvant therapy.

  18. Long Term Exposure to Polyphenols of Artichoke (Cynara scolymus L. Exerts Induction of Senescence Driven Growth Arrest in the MDA-MB231 Human Breast Cancer Cell Line

    Directory of Open Access Journals (Sweden)

    Anna Maria Mileo

    2015-01-01

    Full Text Available Polyphenolic extracts from the edible part of artichoke (Cynara scolymus L. have been shown to be potential chemopreventive and anticancer dietary compounds. High doses of polyphenolic extracts (AEs induce apoptosis and decrease the invasive potential of the human breast cancer cell line, MDA-MB231. However, the molecular mechanism underlying AEs antiproliferative effects is not completely understood. We demonstrate that chronic and low doses of AEs treatment at sublethal concentrations suppress human breast cancer cell growth via a caspases-independent mechanism. Furthermore, AEs exposure induces a significant increase of senescence-associated β-galactosidase (SA-β-gal staining and upregulation of tumour suppressor genes, p16INK4a and p21Cip1/Waf1 in MDA-MB231 cells. AEs treatment leads to epigenetic alterations in cancer cells, modulating DNA hypomethylation and lysine acetylation levels in total proteins. Cell growth arrest correlates with increased reactive oxygen species (ROS production in AEs treated breast cancer cells. Inhibition of ROS generation by N-acetylcysteine (NAC attenuates the antiproliferative effect. These findings demonstrate that chronic AEs treatment inhibits breast cancer cell growth via the induction of premature senescence through epigenetic and ROS-mediated mechanisms. Our results suggest that artichoke polyphenols could be a promising dietary tool either in cancer chemoprevention or/and in cancer treatment as a nonconventional, adjuvant therapy.

  19. Lunasin, a novel seed peptide, sensitizes human breast cancer MDA-MB-231 cells to aspirin-arrested cell cycle and induced apoptosis.

    Science.gov (United States)

    Hsieh, Chia-Chien; Hernández-Ledesma, Blanca; de Lumen, Ben O

    2010-07-30

    Breast cancer is one of the most common tumors in women of Western countries. The high aggressiveness and therapeutic resistance of estrogen-independent breast tumors have motivated the development of new strategies for prevention and/or treatment. Combinations of two or more chemopreventive agents are currently being used to achieve greater inhibitory effects on breast cancer cells. This study reveals that both aspirin and lunasin inhibit, in a dose-dependent manner, human estrogen-independent breast cancer MDA-MB-231 cell proliferation. These compounds arrest the cell cycle in the S- and G1-phases, respectively, acting synergistically to induce apoptosis. To begin elucidating the mechanism(s) of action of these compounds, different molecular targets involved in cell cycle control, apoptosis and signal transduction have been evaluated by real-time polymerase chain reaction (RT-PCR) array. The cell growth inhibitory effect of a lunasin/aspirin combination is achieved, at least partially, by modulating the expression of genes encoding G1 and S-phase regulatory proteins. Lunasin/aspirin therapy exerts its potent pro-apoptotic effect is at least partially achieved through modulating the extrinsic-apoptosis dependent pathway. Synergistic down-regulatory effects were observed for ERBB2, AKT1, PIK3R1, FOS and JUN signaling genes, whose amplification has been reported as being responsible for breast cancer cell growth and resistance to apoptosis. Therefore, our results suggest that a combination of these two compounds is a promising strategy to prevent/treat breast cancer. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  20. Retinoids modulate thioacetamide-induced acute hepatotoxicity.

    Science.gov (United States)

    Shmarakov, Igor O; Borschovetska, Vira L; Marchenko, Mykhailo M; Blaner, William S

    2014-06-01

    The literature indicates that retinoids can influence the metabolism and actions of xenobiotics and conversely that xenobiotics can influence the metabolism and actions of retinoids. We were interested in understanding the degree to which hepatic retinoid stores, accumulated over a lifetime, affect xenobiotic metabolism, and actions. To investigate this, we induced liver injury through administration of the hepatotoxin thioacetamide (TAA) to chow fed wild type (WT) mice and lecithin:retinol acyltransferase-deficient (Lrat(-/-)) mice that are genetically unable to accumulate hepatic retinoid stores. Within 48 h of TAA-treatment, WT mice develop liver injury as evidenced by focal necrotic areas and increases in serum ALT activity and myeloperoxidase activity in hepatic parenchyma. Simultaneously, features of hepatic encephalopathy develop, as evidenced by a 25% increase in blood ammonia and a threefold reduction of blood glucose levels. This is accompanied by reduced hepatic glutathione, and increased thiobarbituric acid reactive substances, protein carbonyl and sulfhydryl groups, and increased cytochrome P450-catalyzed hydroxylation activity and flavin-containing monooxygenase activity in microsomes prepared from WT liver. Strikingly, none of these TAA-induced effects were observed for matched Lrat(-/-) mice. To confirm that TAA hepatotoxicity depends on retinoid availability, we administered, over 48 h, four oral doses of 3000 IU retinyl acetate each to the mice. This led to the development of hepatotoxicity in Lrat(-/-) mice that was similar in extent to that observed in WT mice. Our findings establish that endogenous hepatic retinoid stores can modulate the toxicity of TAA in mice.

  1. Regulation of gene expression by retinoids.

    Science.gov (United States)

    Amann, P M; Eichmüller, S B; Schmidt, J; Bazhin, A V

    2011-01-01

    Vitamin A serves as substrate for the biosynthesis of several derivates (retinoids) which are important for cell growth and cell differentiation as well as for vision. Retinoic acid is the major physiologically active form of vitamin A regulating the expression of different genes. At present, hundreds of genes are known to be regulated by retinoic acid. This regulation is very complex and is, in turn, regulated on many levels. To date, two families of retinoid nuclear receptors have been identified: retinoic acid receptors and retinoid X receptors, which are members of the steroid hormone receptor superfamily of ligand-activated transcription factors. In order to regulate gene expression, all-trans retinal needs to be oxidized to retinoic acid. All-trans retinal, in turn, can be produced during oxidation of all-trans retinol or in a retinol-independent metabolic pathway through cleavage of β-carotene with all-trans retinal as an intermediate metabolite. Recently it has been shown that not only retinoic acid is an active form of vitamin A, but also that all-trans retinal can play an important role in gene regulation. In this review we comprehensively summarize recent literature on regulation of gene expression by retinoids, biochemistry of retinoid receptors, and molecular mechanisms of retinoid-mediated effects on gene regulation.

  2. Retinoids inhibit measles virus in vitro via nuclear retinoid receptor signaling pathways.

    Science.gov (United States)

    Trottier, Claire; Chabot, Sophie; Mann, Koren K; Colombo, Myrian; Chatterjee, Avijit; Miller, Wilson H; Ward, Brian J

    2008-10-01

    Measles virus (MV) infects 30 million children every year, resulting in more than half a million deaths. Vitamin A (retinol) treatment of acute measles can reduce measles-associated mortality by 50-80%. We sought to determine whether or not retinoids can act directly to limit MV output from infected cells. Physiologic concentrations of retinol were found to inhibit MV output in PBMC and a range of cell lines of epithelial and endothelial origin (40-50%). Near complete inhibition of viral output was achieved in some cells/lines treated with all-trans retinoic acid (ATRA) and 9-cis RA (9cRA). Important attenuation of the anti-MV effect of retinoids in R4 cells, a subclone of a retinoid-responsive cell line (NB4) deficient in RAR signaling, demonstrates that this effect is mediated at least in part by nuclear retinoid receptor signaling pathways. Inhibition of MV replication could not be fully explained as a result of retinoid effects on cell differentiation, proliferation or viability, particularly at low retinoid concentrations (1-10nM). These data provide the first evidence that retinoids can directly inhibit MV in vitro, and raise the possibility that retinoids may have similar actions in vivo.

  3. Role of retinoid signalling in the adult brain.

    Science.gov (United States)

    Lane, Michelle A; Bailey, Sarah J

    2005-03-01

    Vitamin A (all-trans-retinol) is the parent compound of a family of natural and synthetic compounds, the retinoids. Retinoids regulate gene transcription in numerous cells and tissues by binding to nuclear retinoid receptor proteins, which act as transcription factors. Much of the research conducted on retinoid signalling in the nervous system has focussed on developmental effects in the embryonic or early postnatal brain. Here, we review the increasing body of evidence indicating that retinoid signalling plays an important role in the function of the mature brain. Components of the metabolic pathway for retinoids have been identified in adult brain tissues, suggesting that all-trans-retinoic acid (ATRA) can be synthesized in discrete regions of the brain. The distribution of retinoid receptor proteins in the adult nervous system is different from that seen during development; and suggests that retinoid signalling is likely to have a physiological role in adult cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions. A number of neuronal specific genes contain recognition sequences for the retinoid receptor proteins and can be directly regulated by retinoids. Disruption of retinoid signalling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behaviours. Retinoid signalling pathways have also been implicated in the pathophysiology of Alzheimer's disease, schizophrenia and depression. Overall, the data underscore the likely importance of adequate nutritional Vitamin A status for adult brain function and highlight retinoid signalling pathways as potential novel therapeutic targets for neurological diseases.

  4. Functions of Intracellular Retinoid Binding-Proteins.

    Science.gov (United States)

    Napoli, Joseph L

    Multiple binding and transport proteins facilitate many aspects of retinoid biology through effects on retinoid transport, cellular uptake, metabolism, and nuclear delivery. These include the serum retinol binding protein sRBP (aka Rbp4), the plasma membrane sRBP receptor Stra6, and the intracellular retinoid binding-proteins such as cellular retinol-binding proteins (CRBP) and cellular retinoic acid binding-proteins (CRABP). sRBP transports the highly lipophilic retinol through an aqueous medium. The major intracellular retinol-binding protein, CRBP1, likely enhances efficient retinoid use by providing a sink to facilitate retinol uptake from sRBP through the plasma membrane or via Stra6, delivering retinol or retinal to select enzymes that generate retinyl esters or retinoic acid, and protecting retinol/retinal from excess catabolism or opportunistic metabolism. Intracellular retinoic acid binding-proteins (CRABP1 and 2, and FABP5) seem to have more diverse functions distinctive to each, such as directing retinoic acid to catabolism, delivering retinoic acid to specific nuclear receptors, and generating non-canonical actions. Gene ablation of intracellular retinoid binding-proteins does not cause embryonic lethality or gross morphological defects. Metabolic and functional defects manifested in knockouts of CRBP1, CRBP2 and CRBP3, however, illustrate their essentiality to health, and in the case of CRBP2, to survival during limited dietary vitamin A. Future studies should continue to address the specific molecular interactions that occur between retinoid binding-proteins and their targets and their precise physiologic contributions to retinoid homeostasis and function.

  5. Original research paper. Hydrazinyldiene-chroman-2,4-diones in inducing growth arrest and apoptosis in breast cancer cells: Synergism with doxorubicin and correlation with physicochemical properties.

    Science.gov (United States)

    Ballazhi, Lulzime; Imeri, Faik; Jashari, Ahmed; Popovski, Emil; Stojković, Goran; Dimovski, Aleksandar J; Mikhova, Bozhana; Mladenovska, Kristina

    2017-03-01

    This study evaluates the effects of previously synthesized hydrazinyldiene-chroman-2,4-diones on cell proliferation and apoptosis, cell cycle distribution and migration capacity of MCF-7 breast cancer cells in synergy with doxorubicin. Physicochemical properties of the synthesized compounds were correlated with their structure and activity. Significant cell viability decrease in comparison with the effect of doxorubicin alone and the reference 4-hydroxycoumarin was observed when combination treatment comprising doxorubicin and the title compounds was applied. Synergistic effect with doxorubicin was also observed in down-regulation of phospho-Thr308Akt levels, confirming reduced proliferation and increased apoptosis. Combined treatment increased the percentage of cells arrested at the G2/M stage. Additive inhibition of cell migration was also observed, pointing to the possibility of reducing the risk of metastases. With their solubility profile and log D7.4, all the synthesized compounds follow Lipinski's rule of five for good permeability (absorption) potential.

  6. Green tea polyphenols induce cell death in breast cancer MCF-7 cells through induction of cell cycle arrest and mitochondrial-mediated apoptosis.

    Science.gov (United States)

    Liu, Shu-Min; Ou, Shi-Yi; Huang, Hui-Hua

    In order to study the molecular mechanisms of green tea polyphenols (GTPs) in treatment or prevention of breast cancer, the cytotoxic effects of GTPs on five human cell lines (MCF-7, A549, Hela, PC3, and HepG2 cells) were determined and the antitumor mechanisms of GTPs in MCF-7 cells were analyzed. The results showed that GTPs exhibited a broad spectrum of inhibition against the detected cancer cell lines, particularly the MCF-7 cells. Studies on the mechanisms revealed that the main modes of cell death induced by GTPs were cell cycle arrest and mitochondrial-mediated apoptosis. Flow cytometric analysis showed that GTPs mediated cell cycle arrest at both G1/M and G2/M transitions. GTP dose dependently led to apoptosis of MCF-7 cells via the mitochondrial pathways, as evidenced by induction of chromatin condensation, reduction of mitochondrial membrane potential (ΔΨm), improvement in the generation of reactive oxygen species (ROS), induction of DNA fragmentation, and activations of caspase-3 and caspase-9 in the present paper.

  7. Effect of Hyperoxia on Retinoid Metabolism and Retinoid Receptor Expression in the Lungs of Newborn Mice.

    Science.gov (United States)

    Chen, Hsing-Jin; Chiang, Bor-Luen

    2015-01-01

    Preterm newborns that receive oxygen therapy often develop bronchopulmonary dysplasia (BPD), which is abnormal lung development characterized by impaired alveologenesis. Oxygen-mediated injury is thought to disrupt normal lung growth and development. However, the mechanism of hyperoxia-induced BPD has not been extensively investigated. We established a neonatal mouse model to investigate the effects of normobaric hyperoxia on retinoid metabolism and retinoid receptor expression. Newborn mice were exposed to hyperoxic or normoxic conditions for 15 days. The concentration of retinol and retinyl palmitate in the lung was measured by HPLC to gauge retinoid metabolism. Retinoid receptor mRNA levels were assessed by real-time PCR. Proliferation and retinoid receptor expression in A549 cells were assessed in the presence and absence of exogenous vitamin A. Hyperoxia significantly reduced the body and lung weight of neonatal mice. Hyperoxia also downregulated expression of RARα, RARγ, and RXRγ in the lungs of neonatal mice. In vitro, hyperoxia inhibited proliferation and expression of retinoid receptors in A549 cells. Hyperoxia disrupted retinoid receptor expression in neonatal mice.

  8. Benzylidene derivatives of andrographolide inhibit growth of breast and colon cancer cells in vitro by inducing G(1) arrest and apoptosis.

    Science.gov (United States)

    Jada, S R; Matthews, C; Saad, M S; Hamzah, A S; Lajis, N H; Stevens, M F G; Stanslas, J

    2008-11-01

    Andrographolide, the major phytoconstituent of Andrographis paniculata, was previously shown by us to have activity against breast cancer. This led to synthesis of new andrographolide analogues to find compounds with better activity than the parent compound. Selected benzylidene derivatives were investigated for their mechanisms of action by studying their effects on the cell cycle progression and cell death. Microculture tetrazolium, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and sulphorhodamine B (SRB) assays were utilized in assessing the in vitro growth inhibition and cytotoxicity of compounds. Flow cytometry was used to analyse the cell cycle distribution of control and treated cells. CDK1 and CDK4 levels were determined by western blotting. Apoptotic cell death was assessed by fluorescence microscopy and flow cytometry. Compounds, in nanomolar to micromolar concentrations, exhibited growth inhibition and cytotoxicity in MCF-7 (breast) and HCT-116 (colon) cancer cells. In the NCI screen, 3,19-(2-bromobenzylidene) andrographolide (SRJ09) and 3,19-(3-chloro-4-fluorobenzylidene) andrographolide (SRJ23) showed greater cytotoxic potency and selectivity than andrographolide. SRJ09 and SRJ23 induced G(1) arrest and apoptosis in MCF-7 and HCT-116 cells, respectively. SRJ09 downregulated CDK4 but not CDK1 level in MCF-7 cells. Apoptosis induced by SRJ09 and SRJ23 in HCT-116 cells was confirmed by annexin V-FITC/PI flow cytometry analysis. The new benzylidene derivatives of andrographolide are potential anticancer agents. SRJ09 emerged as the lead compound in this study, exhibiting anticancer activity by downregulating CDK4 to promote a G(1) phase cell cycle arrest, coupled with induction of apoptosis.

  9. Hwanggeumchal sorghum Induces Cell Cycle Arrest, and Suppresses Tumor Growth and Metastasis through Jak2/STAT Pathways in Breast Cancer Xenografts

    Science.gov (United States)

    Lim, Eun Joung; Joung, Youn Hee; Hong, Dae Young; Park, Eui U.; Park, Seung Hwa; Choi, Soo Keun; Moon, Eon-Soo; Cho, Byung Wook; Park, Kyung Do; Lee, Hak Kyo; Kim, Myong-Jo; Park, Dong-Sik; Yang, Young Mok

    2012-01-01

    Background Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer. Methodology/Principal Findings Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model. Conclusions/Significance Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer. PMID:22792362

  10. Hwanggeumchal sorghum induces cell cycle arrest, and suppresses tumor growth and metastasis through Jak2/STAT pathways in breast cancer xenografts.

    Directory of Open Access Journals (Sweden)

    Jin Hee Park

    Full Text Available BACKGROUND: Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model. CONCLUSIONS/SIGNIFICANCE: Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer.

  11. Up-regulation of cell cycle arrest protein BTG2 correlates with increased overall survival in breast cancer, as detected by immunohistochemistry using tissue microarray

    Directory of Open Access Journals (Sweden)

    Jirström Karin

    2010-06-01

    Full Text Available Abstract Background Previous studies have shown that the ADIPOR1, ADORA1, BTG2 and CD46 genes differ significantly between long-term survivors of breast cancer and deceased patients, both in levels of gene expression and DNA copy numbers. The aim of this study was to characterize the expression of the corresponding proteins in breast carcinoma and to determine their correlation with clinical outcome. Methods Protein expression was evaluated using immunohistochemistry in an independent breast cancer cohort of 144 samples represented on tissue microarrays. Fisher's exact test was used to analyze the differences in protein expression between dead and alive patients. We used Cox-regression multivariate analysis to assess whether the new markers predict the survival status of the patients better than the currently used markers. Results BTG2 expression was demonstrated in a significantly lower proportion of samples from dead patients compared to alive patients, both in overall expression (P = 0.026 and cell membrane specific expression (P = 0.013, whereas neither ADIPOR1, ADORA1 nor CD46 showed differential expression in the two survival groups. Furthermore, a multivariate analysis showed that a model containing BTG2 expression in combination with HER2 and Ki67 expression along with patient age performed better than a model containing the currently used prognostic markers (tumour size, nodal status, HER2 expression, hormone receptor status, histological grade, and patient age. Interestingly, BTG2 has previously been described as a tumour suppressor gene involved in cell cycle arrest and p53 signalling. Conclusions We conclude that high-level BTG2 protein expression correlates with prolonged survival in patients with breast carcinoma.

  12. Retinoid metabolism in invertebrates: when evolution meets endocrine disruption.

    Science.gov (United States)

    André, A; Ruivo, R; Gesto, M; Castro, L Filipe C; Santos, M M

    2014-11-01

    Recent genomic and biochemical evidence in invertebrate species pushes back the origin of the retinoid metabolic and signaling modules to the last common ancestor of all bilaterians. However, the evolution of retinoid pathways are far from fully understood. In the majority of non-chordate invertebrate lineages, the ongoing functional characterization of retinoid-related genes (metabolism and signaling pathways), as well as the characterization of the endogenous retinoid content (precursors and active retinoids), is still incomplete. Despite limited, the available data supports the presence of biologically active retinoid pathways in invertebrates. Yet, the mechanisms controlling the spatial and temporal distribution of retinoids as well as their physiological significance share similarities and differences with vertebrates. For instance, retinol storage in the form of retinyl esters, a key feature for the maintenance of retinoid homeostatic balance in vertebrates, was only recently demonstrated in some mollusk species, suggesting that such ability is older than previously anticipated. In contrast, the enzymatic repertoire involved in this process is probably unlike that of vertebrates. The suggested ancestry of active retinoid pathways implies that many more metazoan species might be potential targets for endocrine disrupting chemicals. Here, we review the current knowledge about the occurrence and functionality of retinoid metabolic and signaling pathways in invertebrate lineages, paying special attention to the evolutionary origin of retinoid storage mechanisms. Additionally, we summarize existing information on the endocrine disruption of invertebrate retinoid modules by environmental chemicals. Research priorities in the field are highlighted. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Ziyuglycoside II Inhibits the Growth of Human Breast Carcinoma MDA-MB-435 Cells via Cell Cycle Arrest and Induction of Apoptosis through the Mitochondria Dependent Pathway

    Directory of Open Access Journals (Sweden)

    Bin Zhou

    2013-09-01

    Full Text Available Ziyuglycoside II is one of the major active compounds of Sanguisorba officinalis L., which has a wide range of clinical applications including hemostasis, antibiosis, anti-inflammation and anti-oxidation. This study investigated the effect of ziyuglycoside II on the growth of human breast carcinoma MDA-MB-435 cells for the first time. The results showed that ziyuglycoside II could significantly inhibit the growth of MDA-MB-435 cells through blocking cell cycle progression at G0/G1 and S phase as well as via inducing cell apoptosis. Accumulation of reactive oxygen species (ROS was observed in the progression of cell cycle arrest, which was associated with the increased expression of cell cycle regulating factors, p53 and p21. Subsequent apoptosis induced by ziyuglycoside II was accompanied with the activation of mitochondrial pathway, in particular a decreased mitochondrial membrane potential (MMP as well as increased Bax/Bcl-2 ratio, cytochrome c release and the activity of caspase-3 and caspase-9. In conclusion, our study was the first to report that ziyuglycoside II has inhibitory effect on the growth of MDA-MB-435 cells, which might become a potential therapeutic approach of breast cancer in the future.

  14. Retinoids: novel immunomodulators and tumour-suppressive agents?

    Science.gov (United States)

    Carratù, MR; Marasco, C; Mangialardi, G; Vacca, A

    2012-01-01

    Retinoids play important roles in the transcriptional activity of normal, degenerative and tumour cells. Retinoid analogues may be promising therapeutic agents for the treatment of immune disorders as different as type I diabetes and systemic lupus erythematosus. In addition, the use of retinoids in cancer treatment has progressed significantly in the last two decades; thus, numerous retinoid compounds have been synthesized and tested. In this paper, the actual or potential use of retinoids as immunomodulators or tumour-suppressive agents is discussed. PMID:22577845

  15. TGF-β-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b

    Directory of Open Access Journals (Sweden)

    Catharina Melzer

    2017-07-01

    Full Text Available Despite improvements in diagnosis and treatment, breast cancer is still the most common cancer type among non-smoking females. TGF-β can inhibit breast cancer development by inducing cell cycle arrest in both, cancer cells and, as part of a senescence program in normal human mammary epithelial cells (HMEC. Moreover, TGF-β also drives cell migration and invasion, in part through the small GTPases Rac1 and Rac1b. Depletion of Rac1b or Rac1 and Rac1b in MDA-MB-231 or MDA-MB-435s breast cancer cells by RNA interference enhanced or suppressed, respectively, TGF-β1-induced migration/invasion. Rac1b depletion in MDA-MB-231 cells also increased TGF-β-induced p21WAF1 expression and ERK1/2 phosphorylation. Senescent HMEC (P15/P16, when compared to their non-senescent counterparts (P11/P12, presented with dramatically increased migratory activity. These effects were paralleled by elevated expression of genes associated with TGF-β signaling and metastasis, downregulated Rac1b, and upregulated Rac1. Our data suggest that acquisition of a motile phenotype in HMEC resulted from enhanced autocrine TGF-β signaling, invasion/metastasis-associated gene expression, and a shift in the ratio of antimigratory Rac1b to promigratory Rac1. We conclude that although enhanced TGF-β signaling is considered antioncogenic in HMEC by suppressing oncogene-induced transformation, this occurs at the expense of a higher migration and invasion potential.

  16. Retinoids and retinoid-metabolic gene expression in mouse adipose tissues.

    Science.gov (United States)

    Sima, Aurelia; Manolescu, Daniel-Constantin; Bhat, Pangala

    2011-12-01

    Vitamin A and its analogs (retinoids) regulate adipocyte differentiation. Recent investigations have demonstrated a relationship among retinoids, retinoid-binding-protein 4 (RBP4) synthesized in adipose tissues, and insulin-resistance status. In this study, we measured retinoid levels and analyzed the expression of retinoid homeostatic genes associated with retinol uptake, esterification, oxidation, and catabolism in subcutaneous (Sc) and visceral (Vis) mouse fat tissues. Both Sc and Vis depots were found to contain similar levels of all-trans retinol. A metabolite of retinol with characteristic ultraviolet absorption maxima for 9-cis retinol was observed in these 2 adipose depots, and its level was 2-fold higher in Sc than in Vis tissues. Vis adipose tissue expressed significantly higher levels of RBP4, CRBP1 (intracellular retinol-binding protein 1), RDH10 (retinol dehydrogenase), as well as CYP26A1 and B1 (retinoic acid (RA) hydroxylases). No differences in STRA6 (RBP4 receptor), LRAT (retinol esterification), CRABP1 and 2 (intracellular RA-binding proteins), and RALDH1 (retinal dehydrogenase) mRNA expressions were discerned in both fat depots. RALDH1 was identified as the only RALDH expressed in both Sc and Vis adipose tissues. These results indicate that Vis is more actively involved in retinoid metabolism than Sc adipose tissue.

  17. Retinoid (vitamin A) metabolism : a review

    NARCIS (Netherlands)

    Hendriks, H.F.J.

    1996-01-01

    Objective and conclusion: An overview is given of our understanding of the uptake and metabolism of retinoids. The mechanisms underlying retinol uptake by organs and tissues are still unsettled. The retinol-binding proteins CRBP I and CRBP II appear to play an essential role in retinyl ester

  18. Induction of cell cycle arrest in human MCF-7 breast cancer cells by cis-stilbene derivatives related to VIOXX.

    NARCIS (Netherlands)

    Sangjun, S.; de Jong, E.|info:eu-repo/dai/nl/331376326; Nijmeijer, S.; Mutarapat, T.; Ruchirawat, S.; van den Berg, M.|info:eu-repo/dai/nl/08660466X; van Duursen, M.B.M.|info:eu-repo/dai/nl/181957701

    2009-01-01

    In our present study, 12 new cis-stilbene derivatives (CRI-1-CRI-13) related to VIOXX((R)) were synthesized and studied for their inhibitory effects on cell cycle progression and anti-estrogenicity in human adenoma breast cancer MCF-7 cells. Based on the different substituents in the cis-stilbene

  19. Retinoid quantification by HPLC/MS(n)

    Science.gov (United States)

    McCaffery, Peter; Evans, James; Koul, Omanand; Volpert, Amy; Reid, Kevin; Ullman, M. David

    2002-01-01

    Retinoic acid (RA) mediates most of the biological effects of vitamin A that are essential for vertebrate survival. It acts through binding to receptors that belong to the nuclear receptor transcription factor superfamily (Mangelsdorf et al. 1994). It is also a highly potent vertebrate teratogen. To determine the function and effects of endogenous and exogenous RA, it is important to have a highly specific, sensitive, accurate, and precise analytical procedure. Current analyses of RA and other retinoids are labor intensive, of poor sensitivity, have limited specificity, or require compatibility with RA reporter cell lines (Chen et al. 1995. BIOCHEM: Pharmacol. 50: 1257-1264; Creech Kraft et al. 1994. BIOCHEM: J. 301: 111-119; Lanvers et al. 1996. J. Chromatogr. B Biomed. Appl. 685: 233-240; Maden et al. 1998. DEVELOPMENT: 125: 4133-4144; Wagner et al. 1992. DEVELOPMENT: 116: 55-66). This paper describes an HPLC/mass spectrometry/mass spectrometry product ion scan (HPLC/MS(n)) procedure for the analysis of retinoids that employs atmospheric pressure chemical ionization MS. The retinoids are separated by normal-phase column chromatography with a linear hexane-isopropanol-dioxane gradient. Each retinoid is detected by a unique series of MS(n) functions set at optimal collision-induced dissociation energy (30% to 32%) for all MS(n) steps. The scan events are divided into three segments, based on HPLC elution order, to maximize the mass spectrometer duty cycle. The all-trans, 9-cis, and 13-cis RA isomers are separated, if desired, by an isocratic hexane-dioxane-isopropanol mobile phase. This paper describes an HPLC/MS(n) procedure possessing high sensitivity and specificity for retinoids.

  20. Retinoid metabolism and its effects on the vasculature.

    Science.gov (United States)

    Rhee, Eun-Jung; Nallamshetty, Shriram; Plutzky, Jorge

    2012-01-01

    Retinoids, the metabolically-active structural derivatives of vitamin A, are critical signaling molecules in many fundamental biological processes including cell survival, proliferation and differentiation. Emerging evidence, both clinical and molecular, implicates retinoids in atherosclerosis and other vasculoproliferative disorders such as restenosis. Although the data from clinical trials examining effect of vitamin A and vitamin precursors on cardiac events have been contradictory, this data does suggest that retinoids do influence fundamental processes relevant to atherosclerosis. Preclinical animal model and cellular studies support these concepts. Retinoids exhibit complex effects on proliferation, growth, differentiation and migration of vascular smooth muscle cells (VSMC), including responses to injury and atherosclerosis. Retinoids also appear to exert important inhibitory effects on thrombosis and inflammatory responses relevant to atherogenesis. Recent studies suggest retinoids may also be involved in vascular calcification and endothelial function, for example, by modulating nitric oxide pathways. In addition, established retinoid effects on lipid metabolism and adipogenesis may indirectly influence inflammation and atherosclerosis. Collectively, these observations underscore the scope and complexity of retinoid effects relevant to vascular disease. Additional studies are needed to elucidate how context and metabolite-specific retinoid effects affect atherosclerosis. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism. © 2011 Elsevier B.V. All rights reserved.

  1. Daily Arrests

    Data.gov (United States)

    Montgomery County of Maryland — This dataset provides the public with arrest information from the Montgomery County Central Processing Unit (CPU) systems. The data presented is derived from every...

  2. Cardiac arrest

    Science.gov (United States)

    ... also run other tests, depending on your health history and the results of these tests. Treatment Cardiac arrest needs emergency treatment right away to get the heart started again. Cardiopulmonary resuscitation (CPR) . This is often the first type of ...

  3. Antrodia salmonea induces G2 cell-cycle arrest in human triple-negative breast cancer (MDA-MB-231) cells and suppresses tumor growth in athymic nude mice.

    Science.gov (United States)

    Chang, Chia-Ting; Hseu, You-Cheng; Thiyagarajan, Varadharajan; Huang, Hui-Chi; Hsu, Li-Sung; Huang, Pei-Jane; Liu, Jer-Yuh; Liao, Jiunn-Wang; Yang, Hsin-Ling

    2017-01-20

    Antrodia salmonea (AS), is a well-known folk medicinal mushroom in Taiwan, has been reported to exhibit anti-oxidant, anti-angiogenic, and anti-inflammatory effects. In the present study, we examined the effects of AS on cell-cycle arrest in vitro in MDA-MB-231 cells and on tumor regression in vivo using an athymic nude mice model. AS (0-200μg/mL) treatment significantly induced G2 cell-cycle arrest in MDA-MB-231 cells by reducing the levels of cyclin B1, cyclin A, cyclin E, and CDC2 proteins. In addition, N-acetylcysteine (NAC) pretreatment prevented AS induced G2 cell-cycle arrest, indicating that ROS accumulation and subsequent cell cycle arrest might be a major mechanism of AS-induced cytotoxicity. Further, AS treatment decreased COX-2 expression and induced PARP cleavage was significantly reversed by NAC pretreatment in MDA-MB-231 cells. The in vivo study results revealed that AS treatment was effective in terms of delaying the tumor incidence and reducing the tumor growth in MDA-MB-231-xenografted nude mice. TUNEL assay, immunohistochemical staining and Western blotting confirmed that AS significantly modulated the xenografted tumor progression as demonstrated by induction of apoptosis, autophagy, and cell-cycle arrest. Our data strongly suggest that Antrodia salmonea could be an anti-cancer agent for human breast cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. [10]-Gingerol, a major phenolic constituent of ginger root, induces cell cycle arrest and apoptosis in triple-negative breast cancer cells.

    Science.gov (United States)

    Bernard, Megan M; McConnery, Jason R; Hoskin, David W

    2017-04-01

    The ginger rhizome is rich in bioactive compounds, including [6]-gingerol, [8]-gingerol, and [10]-gingerol; however, to date, most research on the anti-cancer activities of gingerols have focused on [6]-gingerol. In this study, we compared [10]-gingerol with [8]-gingerol and [6]-gingerol in terms of their ability to inhibit the growth of human and mouse mammary carcinoma cells. A colorimetric assay based on the enzymatic reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide revealed that [10]-gingerol was more potent than [6]-gingerol and at least as potent as [8]-gingerol for the inhibition of triple-negative human (MDA-MB-231, MDA-MB-468) and mouse (4T1, E0771) mammary carcinoma cell growth. Further investigation of [10]-gingerol showed that it suppressed the growth of estrogen receptor-bearing (MCF-7, T47D) and HER2-overexpressing (SKBR3) breast cancer cells. The inhibitory effect of [10]-gingerol on the growth of MDA-MB-231 cells was associated with a reduction in the number of rounds of cell division and evidence of S phase-cell cycle arrest, as well as induction of apoptosis due to mitochondrial outer membrane permeabilization and the release of proapoptotic mitochondrial cytochrome c and SMAC/DIABLO into the cytoplasm. Surprisingly, killing of MDA-MB-231 cells by [10]-gingerol was not affected by a pan-caspase inhibitor (zVAD-fmk) or an anti-oxidant (N-acetylcysteine), suggesting that the cytotoxic effect of [10]-gingerol did not require caspase activation or the accumulation of reactive oxygen species. These findings suggest that further investigation of [10]-gingerol is warranted for its possible use in the treatment of breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. An antioxidant extract of tropical lichen, Parmotrema reticulatum, induces cell cycle arrest and apoptosis in breast carcinoma cell line MCF-7.

    Directory of Open Access Journals (Sweden)

    Nikhil Baban Ghate

    Full Text Available This report highlights the phytochemical analysis, antioxidant potential and anticancer activity against breast carcinoma of 70% methanolic extract of lichen, Parmotrema reticulatum (PRME. Phytochemical analysis of PRME confirms the presence of various phytoconstituents like alkaloids, carbohydrates, flavonoids, glycosides, phenols, saponins, tannins, anthraquinones, and ascorbic acid; among which alkaloids, phenols and flavonoids are found in abundant amount. High performance liquid chromatography (HPLC analysis of PRME revealed the presence of catechin, purpurin, tannic acid and reserpine. Antioxidant activity was evaluated by nine separate methods. PRME showed excellent hydroxyl and hypochlorous radical scavenging as well as moderate DPPH, superoxide, singlet oxygen, nitric oxide and peroxynitrite scavenging activity. Cytotoxicity of PRME was tested against breast carcinoma (MCF-7, lung carcinoma (A549 and normal lung fibroblast (WI-38 using WST-1 method. PRME was found cytotoxic against MCF-7 cells with an IC50 value 130.03 ± 3.11 µg/ml while negligible cytotoxicity was observed on A549 and WI-38 cells. Further flow cytometric study showed that PRME halted the MCF-7 cells in S and G2/M phases and induces apoptosis in dose as well as time dependent manner. Cell cycle arrest was associated with downregulation of cyclin B1, Cdk-2 and Cdc25C as well as slight decrease in the expression of Cdk-1 and cyclin A1 with subsequent upregulation of p53 and p21. Moreover PRME induced Bax and inhibited Bcl-2 expression, which results in increasing Bax/Bcl-2 ratio and activation of caspase cascade. This ultimately leads to PARP degradation and induces apoptosis in MCF-7 cells. It can be hypothesised from the current study that the antioxidant and anticancer potential of the PRME may reside in the phytoconstitutents present in it and therefore, PRME may be used as a possible source of natural antioxidant that may be developed to an anticancer agent.

  6. Mitotic Arrest and Apoptosis in Breast Cancer Cells Induced by Origanum majorana Extract: Upregulation of TNF-α and Downregulation of Survivin and Mutant p53

    Science.gov (United States)

    Al Dhaheri, Yusra; Eid, Ali; AbuQamar, Synan; Attoub, Samir; Khasawneh, Mohammad; Aiche, Ghenima; Hisaindee, Soleiman; Iratni, Rabah

    2013-01-01

    Background In the present study, we investigated the effect of Origanum majorana ethanolic extract on the survival of the highly proliferative and invasive triple-negative p53 mutant breast cancer cell line MDA-MB-231. Results We found that O. majorana extract (OME) was able to inhibit the viability of the MDA-MB-231 cells in a time- and concentration-dependent manner. The effect of OME on cellular viability was further confirmed by the inhibition of colony growth. We showed, depending on the concentration used, that OME elicited different effects on the MDA-MB 231 cells. Concentrations of 150 and 300 µg/mL induced an accumulation of apoptotic–resistant population of cells arrested in mitotis and overexpressing the cyclin-dependent kinase inhibitor, p21 and the inhibitor of apoptosis, survivin. On the other hand, higher concentrations of OME (450 and 600 µg/mL) triggered a massive apoptosis through the extrinsic pathway, including the activation of tumor necrosis factor-α (TNF-α), caspase 8, caspase 3, and cleavage of PARP, downregulation of survivin as well as depletion of the mutant p53 in MDA-MB-231 cells. Furthermore, OME induced an upregulation of γ-H2AX, a marker of double strand DNA breaks and an overall histone H3 and H4 hyperacetylation. Conclusion Our findings provide strong evidence that O. majorana may be a promising chemopreventive and therapeutic candidate against cancer especially for highly invasive triple negative p53 mutant breast cancer; thus validating its complementary and alternative medicinal use. PMID:23451065

  7. Mitotic arrest and apoptosis in breast cancer cells induced by Origanum majorana extract: upregulation of TNF-α and downregulation of survivin and mutant p53.

    Directory of Open Access Journals (Sweden)

    Yusra Al Dhaheri

    Full Text Available BACKGROUND: In the present study, we investigated the effect of Origanum majorana ethanolic extract on the survival of the highly proliferative and invasive triple-negative p53 mutant breast cancer cell line MDA-MB-231. RESULTS: We found that O. majorana extract (OME was able to inhibit the viability of the MDA-MB-231 cells in a time- and concentration-dependent manner. The effect of OME on cellular viability was further confirmed by the inhibition of colony growth. We showed, depending on the concentration used, that OME elicited different effects on the MDA-MB 231 cells. Concentrations of 150 and 300 µg/mL induced an accumulation of apoptotic-resistant population of cells arrested in mitotis and overexpressing the cyclin-dependent kinase inhibitor, p21 and the inhibitor of apoptosis, survivin. On the other hand, higher concentrations of OME (450 and 600 µg/mL triggered a massive apoptosis through the extrinsic pathway, including the activation of tumor necrosis factor-α (TNF-α, caspase 8, caspase 3, and cleavage of PARP, downregulation of survivin as well as depletion of the mutant p53 in MDA-MB-231 cells. Furthermore, OME induced an upregulation of γ-H2AX, a marker of double strand DNA breaks and an overall histone H3 and H4 hyperacetylation. CONCLUSION: Our findings provide strong evidence that O. majorana may be a promising chemopreventive and therapeutic candidate against cancer especially for highly invasive triple negative p53 mutant breast cancer; thus validating its complementary and alternative medicinal use.

  8. Retinoids and rexinoids inhibit hepatitis C virus independently of retinoid receptor signaling.

    Science.gov (United States)

    Murakami, Yuko; Fukasawa, Masayoshi; Kaneko, Yukihiro; Suzuki, Tetsuro; Wakita, Takaji; Fukazawa, Hidesuke

    2014-02-01

    Using a high-throughput screening system involving HCV JFH-1-Huh 7.5.1 cells, we determined that the ligands of class II nuclear receptors, retinoids and rexinoids inhibit HCV infection. Retinoids, ligands of retinoic acid receptor (RAR), and rexinoids, ligands of retinoid X receptor (RXR), reduced extracellular HCV RNA of HCV infected cells in a dose-dependent manner. The 50% effective concentrations were below 10 nM, and the 50% cytotoxic concentrations were over 10 μM. Both agonists and antagonists demonstrated inhibition, which indicates that the effect is not dependent on retinoic acid signaling. These chemicals reduced HCV RNA and NS5A protein levels in cells harboring the subgenomic HCV replicon RNA, which suggests that the chemicals affect HCV RNA replication. These compounds were also effective against persistently infected cells, although the reduction in the intracellular HCV RNA was smaller than that of the extracellular HCV RNA, suggesting that viral post-replication step is also inhibited. In combination with interferon (IFN), retinoid exhibited a synergistic effect. Retinoids did not enhance expression of the IFN effector molecule PKR. These series of compounds warrant further investigation as new class of HCV drugs, for the clinical translation of our observation may lead to increased anti-HCV efficacy. Copyright © 2013 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  9. Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor : Contribution to the hypertriglyceridemic action of retinoids

    NARCIS (Netherlands)

    Vu-Dac, N.; Gervois, P.; Torra, I.P.; Fruchart, J.C.; Kosykh, V.; Kooistra, T.; Princen, H.M.G.; Dallongeville, J.; Staels, B.

    1998-01-01

    Hypertriglyceridemia is a metabolic complication of retinoid therapy. In this study, we analyzed whether retinoids increase the expression of apo C- III, an antagonist of plasma triglyceride catabolism. In men, isotretinoin treatment (80 mg/d; 5 d) resulted in elevated plasma apo C-III, but not apo

  10. Vitamin A and Retinoids as Mitochondrial Toxicants

    Directory of Open Access Journals (Sweden)

    Marcos Roberto de Oliveira

    2015-01-01

    Full Text Available Vitamin A and its derivatives, the retinoids, are micronutrient necessary for the human diet in order to maintain several cellular functions from human development to adulthood and also through aging. Furthermore, vitamin A and retinoids are utilized pharmacologically in the treatment of some diseases, as, for instance, dermatological disturbances and some types of cancer. In spite of being an essential micronutrient with clinical application, vitamin A exerts several toxic effects regarding redox environment and mitochondrial function. Moreover, decreased life quality and increased mortality rates among vitamin A supplements users have been reported. However, the exact mechanism by which vitamin A elicits its deleterious effects is not clear yet. In this review, the role of mitochondrial dysfunction in the mechanism of vitamin A-induced toxicity is discussed.

  11. Ursolic acid derivative FZU-03,010 inhibits STAT3 and induces cell cycle arrest and apoptosis in renal and breast cancer cells.

    Science.gov (United States)

    Li, Wei; Zhang, Hongxiu; Nie, Mingxiu; Tian, Yanlei; Chen, Xu; Chen, Ceshi; Chen, Haijun; Liu, Rong

    2017-04-01

    Advanced renal cell carcinoma and triple negative breast cancer (TNBC) are malignancies without effective therapeutics currently. Ursolic acid (UA) has been previously reported to have anti-cancer effects in multiple solid tumors. In order to develop more potent anti-cancer reagents, FZU-03,010 based on the chemical structure of UA were synthesized. The results demonstrated that, compared with UA, FZU-03,010 could suppress renal cancer cell 786-0 and TNBC cell HCC1806 cell viability more potently.  Furthermore, FZU-03,010 could induce G1 cell cycle arrest and cell apoptosis more efficiently than UA. FZU-03,010 could also inhibit signal transducer and activator of transcription 3 activation, induce the expression of cell cycle-dependent kinase inhibitors (p21 and p27) and promote cell apoptosis. In conclusion, our results suggest that the UA derivative FZU-03,010 is more potent in inhibiting cancer cell survival, and FZU-03,010 has the potential to be developed as a therapeutic for renal cell cancers and TNBCs. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. Acne Fulminans Treated with Oral Retinoids

    Directory of Open Access Journals (Sweden)

    Mohan B Gharpuray

    1989-01-01

    Full Text Available A 22 year old male patient suffering for 4 year from severe nodulo-cystic acne and scarring by systemic signs like fever, malaise, polyarthralgia, loss of; weight and leucocytosis was diagnosed as a case of acne fulminans. When there was no response to routine, treatment and even systemic corticosteroid, he-was treated - with a low dose of oral retinoid, isotretinoin. He improved dramatically within 2 weeks, and there was no relapse after 18 weeks follow - UP.

  13. Expression of the human ABCC6 gene is induced by retinoids through the retinoid X receptor.

    Science.gov (United States)

    Ratajewski, Marcin; Bartosz, Grzegorz; Pulaski, Lukasz

    2006-12-01

    Mutations in the human ABCC6 gene are responsible for the disease pseudoxanthoma elasticum, although the physiological function or substrate of the gene product (an ABC transporter known also as MRP6) is not known. We found that the expression of this gene in cells of hepatic origin (where this gene is predominantly expressed in the body) is significantly upregulated by retinoids, acting as agonists of the retinoid X receptor (RXR) rather than the retinoid A receptor (RAR). The direct involvement of this nuclear receptor in the transcriptional regulation of ABCC6 gene expression was confirmed by transient transfection and chromatin immunoprecipitation assays. This constitutes the first direct proof of previously suggested involvement of nuclear hormone receptors in ABCC6 gene expression and the first identification of a transcription factor which may be relevant to regulation of ABCC6 level in tissues and in some PXE patients.

  14. ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model.

    Science.gov (United States)

    Nasr, Rihab R; Hmadi, Raed A; El-Eit, Rabab M; Iskandarani, Ahmad N; Jabbour, Mark N; Zaatari, Ghazi S; Mahon, Francois-Xavier; Pisano, Claudio C P; Darwiche, Nadine D

    2015-08-01

    The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy. © 2014 UICC.

  15. Demethylation and alterations in the expression level of the cell cycle-related genes as possible mechanisms in arsenic trioxide-induced cell cycle arrest in human breast cancer cells.

    Science.gov (United States)

    Moghaddaskho, Farima; Eyvani, Haniyeh; Ghadami, Mohsen; Tavakkoly-Bazzaz, Javad; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

    2017-02-01

    Arsenic trioxide (As2O3) has been used clinically as an anti-tumor agent. Its mechanisms are mostly considered to be the induction of apoptosis and cell cycle arrest. However, the detailed molecular mechanisms of its anti-cancer action through cell cycle arrest are poorly known. Furthermore, As2O3 has been shown to be a potential DNA methylation inhibitor, inducing DNA hypomethylation. We hypothesize that As2O3 may affect the expression of cell cycle regulatory genes by interfering with DNA methylation patterns. To explore this, we examined promoter methylation status of 24 cell cycle genes in breast cancer cell lines and in a normal breast tissue sample by methylation-specific polymerase chain reaction and/or restriction enzyme-based methods. Gene expression level and cell cycle distribution were quantified by real-time polymerase chain reaction and flow cytometric analyses, respectively. Our methylation analysis indicates that only promoters of RBL1 (p107), RASSF1A, and cyclin D2 were aberrantly methylated in studied breast cancer cell lines. As2O3 induced CpG island demethylation in promoter regions of these genes and restores their expression correlated with DNA methyltransferase inhibition. As2O3 also induced alterations in messenger RNA expression of several cell cycle-related genes independent of demethylation. Flow cytometric analysis revealed that the cell cycle arrest induced by As2O3 varied depending on cell lines, MCF-7 at G1 phase and both MDA-MB-231 and MDA-MB-468 cells at G2/M phase. These changes at transcriptional level of the cell cycle genes by the molecular mechanisms dependent and independent of demethylation are likely to represent the mechanisms of cell cycle redistribution in breast cancer cells, in response to As2O3 treatment.

  16. Sudden Cardiac Arrest (SCA)

    Science.gov (United States)

    ... Arrest (SCA) Back to Heart Diseases & Disorders Sudden Cardiac Arrest (SCA) Sudden Cardiac Arrest ( SCA ) occurs when the heart stops beating, abruptly ... to saving someone who is having a sudden cardiac arrest , it is important to understand the difference. The ...

  17. Arsenic trioxide-induced growth arrest of breast cancer MCF-7 cells involving FOXO3a and IκB kinase β expression and localization.

    Science.gov (United States)

    Liu, Wenlou; Gong, Yusen; Li, Haili; Jiang, Guan; Zhan, Shining; Liu, Hong; Wu, Yongping

    2012-10-01

    Currently, arsenic has been clinically investigated as a therapeutic agent for a variety of solid malignancies, including breast cancer. However, the exact underlying molecular mechanisms through which arsenic trioxide (As(2)O(3)) induces cell growth arrest and apoptosis in solid tumors have not been clearly understood. The aim of our study was to gain an insight into the effect of As(2)O(3) on the human breast cancer MCF-7 cell line and investigate cell growth inhibition, apoptosis, and the molecular mechanism after As(2)O(3) treatment in MCF-7 cells. Expression of FOXO3a, nuclear-FOXO3a, caspase-3, and IκB kinase β (IKKβ) mRNA levels in MCF-7 cells was determined by reverse transcription-polymerase chain reaction (RT-PCR). The protein expression was examined by the Western blot analysis and immunocytochemical staining. The distribution of apoptotic cells was assessed by flow cytometry, and the morphology of the apoptotic cells was investigated by Hoechest33258 staining. Our results showed that As(2)O(3) significantly induced the apoptosis of MCF-7 cells tested in this study in a dose-dependent manner. As(2)O(3) induced the decrease of IKKβ expression and the increase of total as well as nuclear FOXO3a expression, which triggered the phosphorylation of cytoplasmic FOXO3a at the Thr32 residue decrease. RT-PCR, Western blot analysis, and immunocytochemistry revealed that the expression of IKKβ in MCF-7 cells was upregulated when As(2)O(3) was combined with tumor necrosis factor-α (TNF-α), whereas the expression of FOXO3a was downregulated in comparison with the As(2)O(3)-alone group. These findings indicated a specific molecular mechanism by which MCF-7 cell lines were susceptible to the As(2)O(3) therapy through FOXO3a expression and localization. This FOXO3a accumulation may be well correlated with the As(2)O(3)-induced reduction of active IKKβ, which may provide new insights into As(2)O(3)-related signaling activities.

  18. In vitro inhibition of mumps virus by retinoids.

    Science.gov (United States)

    Soye, Kaitlin J; Trottier, Claire; Di Lenardo, Thomas Z; Restori, Katherine H; Reichman, Lee; Miller, Wilson H; Ward, Brian J

    2013-11-14

    Mumps virus (MuV) is a highly infectious paramyxovirus closely related to measles virus (MeV). Despite the availability of a mumps vaccine, outbreaks continue to occur and no treatment options are available. Vitamin A and other naturally occurring retinoids inhibit the replication of MeV in vitro. Anti-viral effects of retinoids were observed in cell culture using the myelomonocytic U937, NB4/R4, and Huh7/7.5 cells. Observations of anti-viral effect were quantified using TCID50 analysis. Molecular properties of the antiviral effect were analysed using quantitative RT-PCR and western blot. The current work demonstrates that retinoids inhibit MuV in vitro due to up-regulation of type I interferon (IFN) and IFN stimulated genes. This effect is mediated by nuclear retinoid receptor signalling and RIG-I is required. The antiviral retinoid-induced state makes cells less permissive to viral replication from subsequent challenge with either MuV or MeV for less than 12 hours. These results demonstrate that retinoids inhibit MuV replication in uninfected bystander cells through a retinoid inducible gene I (RIG-I), retinoic acid receptor (RAR) and IFN dependent manner making them refractory to subsequent rounds of viral replication. These observations raise the possibility that pharmacological doses of retinoids might have clinical benefit in MuV infection.

  19. Retinoids and their target genes in liver functions and diseases.

    Science.gov (United States)

    Shiota, Goshi; Kanki, Keita

    2013-08-01

    Retinoids have been reported to prevent several kinds of cancers, including hepatocellular carcinoma (HCC). Retinoic acid (RA) coupled with retinoic acid receptor/retinoid X receptor heterodimer exerts its functions by regulating its target genes. We previously reported that transgenic mice, in which RA signaling is suppressed in a hepatocyte-specific manner, developed liver cancer at a high rate, and that disruption of RA functions led to the increased oxidative stress via aberrant metabolisms of lipid and iron, indicating that retinoids play an important role in liver pathophysiology. These data suggest that exploring the metabolism of retinoids in liver diseases and their target genes provides us with useful information to understand the liver functions and diseases. Consequently, the altered metabolism of retinoids was observed in liver diseases, including non-alcoholic fatty liver disease. In this review, we summarize the metabolism of retinoids in the liver, highlight the functions of retinoids in HCC, non-alcoholic fatty liver disease, and alcoholic liver disease, and discuss the target genes of RA. Investigation of retinoids in the liver will likely help us identify novel therapies and diagnostic modalities for HCC. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  20. Liposomal Formulation of Retinoids Designed for Enzyme Triggered Release

    DEFF Research Database (Denmark)

    Pedersen, Palle Jacob; Adolph, Sidsel Kramshøj; Subramanian, Arun Kumar

    2010-01-01

    The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. The prodrugs are degradable by secretory phospholipase A(2) IIA and have potential in liposomal drug delivery targeting tumors. We have synthesi...

  1. Cytotoxicity of trans-chalcone and licochalcone A against breast cancer cells is due to apoptosis induction and cell cycle arrest.

    Science.gov (United States)

    Bortolotto, Luis Felipe Buso; Barbosa, Flávia Regina; Silva, Gabriel; Bitencourt, Tamires Aparecida; Beleboni, Rene Oliveira; Baek, Seung Joon; Marins, Mozart; Fachin, Ana Lúcia

    2017-01-01

    Chalcones are precursors of flavonoids that exhibit structural heterogeneity and potential antitumor activity. The objective of this study was to characterize the cytotoxicity of trans-chalcone and licochalcone A (LicoA(1)) against a breast cancer cell line (MCF-7) and normal murine fibroblasts (3T3). Also the mechanisms of the anti-cancer activity of these two compounds were studied. The alkaline comet assay revealed dose-dependent genotoxicity, which was more responsive against the tumor cell line, compared to the 3T3 mouse fibroblast cell line. Flow cytometry showed that the two chalcones caused the cell cycle arrest in the G1 phase and induced apoptosis in MCF-7 cells. Using PCR Array, we found that trans-chalcone and LicoA trigger apoptosis mediated by the intrinsic pathway as demonstrated by the inhibition of Bcl-2 and induction of Bax. In western blot assay, the two chalcones reduced the expression of cell death-related proteins such as Bcl-2 and cyclin D1 and promoted the cleavage of PARP. However, only trans-chalcone induced the expression of the CIDEA gene and protein in these two experiments. Furthermore, transient transfections of MCF-7 using a construction of a promoter-luciferase vector showed that trans-chalcone induced the expression of the CIDEA promoter activity in 24 and 48h. In conclusion, the results showed that trans-chalcone promoted high induction of the CIDEA promoter gene and protein, which is related to DNA fragmentation during apoptosis. Copyright © 2016. Published by Elsevier Masson SAS.

  2. Retinoid plus antimicrobial combination treatments for acne

    Science.gov (United States)

    Feneran, Ashley N; Kaufman, William S; Dabade, Tushar S; Feldman, Steven R

    2011-01-01

    Background: Acne vulgaris is a chronic disease with several pathogenic factors. Multiple medications are typically used that can lead to nonadherence and treatment failure. Combination medications target multiple pathways of acne formation and may offer therapeutic benefit. Purpose: To explore the efficacy and tolerability of combination retinoid plus antimicrobial treatments in acne vulgaris. Methods: A PubMed and Google search was conducted for combination therapies of clindamycin and tretinoin, with secondary analysis of related citations and references. Similar searches were completed for the combination medications of benzoyl peroxide plus clindamycin or erythromycin, and for the combination therapy of adapalene and benzoyl peroxide. Results: Combination clindamycin phosphate and tretinoin gel was found to be more efficacious than monotherapy of either drug or its vehicle for acne, including inflammatory acne, and has a greater onset of action than either drug alone. Clindamycin phosphate and tretinoin gel was well-tolerated, and adherence to its use exceeded that of using both medications in separate formulations. Benzoyl peroxide-containing combination medications with clindamycin or erythromycin were both more effective in the treatment of acne than either drug alone. Both medications were well-tolerated, with dry skin being the most common adverse effect. Conclusions: Combination medications have superior efficacy and adherence, and have a similar tolerability profile compared with monotherapy of its components. Several studies have found antibiotic-containing combination products with a retinoid effective for acne. The use of antibiotic-containing combination medications for acne can lead to bacterial resistance. Due to this potential for bacterial resistance, benzoyl peroxide treatments are also recommended in combination with a retinoid. PMID:21760743

  3. Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival.

    Science.gov (United States)

    Bleul, Tim; Rühl, Ralph; Bulashevska, Svetlana; Karakhanova, Svetlana; Werner, Jens; Bazhin, Alexandr V

    2015-09-01

    Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the components of retinoid signaling in PDAC compared to in the normal pancreas and to prove the clinical importance of retinoid receptor expression. For the study, human tumor tissues obtained from PDAC patients and murine tumors from the orthotopic Panc02 model were used for the analysis of retinoids, using high performance liquid chromatography mass spectrometry and real-time RT-PCR gene expression analysis. Survival probabilities in univariate analysis were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for the multivariate analysis. In this work, we showed for the first time that the ATRA and all-trans retinol concentration is reduced in PDAC tissue compared to their normal counterparts. The expression of RARα and β as well as RXRα and β are down-regulated in PDAC tissue. This reduced expression of retinoid receptors correlates with the expression of some markers of differentiation and epithelial-to-mesenchymal transition as well as of cancer stem cell markers. Importantly, the expression of RARα and RXRβ is associated with better overall survival of PDAC patients. Thus, reduction of retinoids and their receptors is an important feature of PDAC and is associated with worse patient survival outcomes. © 2014 Wiley Periodicals, Inc.

  4. New insights into retinoid metabolism and cycling within the retina

    Science.gov (United States)

    Tang, Peter H.; Kono, Masahiro; Koutalos, Yiannis; Ablonczy, Zsolt; Crouch, Rosalie K.

    2013-01-01

    The retinoid cycle is a series of biochemical reactions within the eye that is responsible for synthesizing the chromophore, 11-cis retinal, for visual function. The chromophore is bound to G-protein coupled receptors, opsins, within rod and cone photoreceptor cells forming the photosensitive visual pigments. Integral to the sustained function of photoreceptors is the continuous generation of chromophore by the retinoid cycle through two separate processes, one that supplies both rods and cones and another that exclusively supplies cones. Recent findings such as RPE65 localization within cones and the pattern of distribution of retinoid metabolites within mouse and human retinas have challenged previous proposed schemes. This review will focus on recent findings regarding the transport of retinoids, the mechanisms by which chromophore is supplied to both rods and cones, and the metabolism of retinoids within the posterior segment of the eye. PMID:23063666

  5. Retinoid-like activity and teratogenic effects of cyanobacterial exudates.

    Science.gov (United States)

    Jonas, Adam; Buranova, Veronika; Scholz, Stefan; Fetter, Eva; Novakova, Katerina; Kohoutek, Jiri; Hilscherova, Klara

    2014-10-01

    Retinoic acids and their derivatives have been recently identified by chemical analyses in cyanobacteria and algae. Given the essential role of retinoids for vertebrate development this has raised concerns about a potential risk for vertebrates exposed to retinoids during cyanobacterial blooms. Our study focuses on extracellular compounds produced by phytoplankton cells (exudates). In order to address the capacity for the production of retinoids or compounds with retinoid-like activity we compared the exudates of ten cyanobacteria and algae using in vitro reporter gene assay. Exudates of three cyanobacterial species showed retinoid-like activity in the range of 269-2,265 ng retinoid equivalents (REQ)/L, while there was no detectable activity in exudates of the investigated algal species. The exudates of one green alga (Desmodesmus quadricaudus) and the two cyanobacterial species with greatest REQ levels, Microcystis aeruginosa and Cylindrospermopsis raciborskii, were selected for testing of the potential relation of retinoid-like activity to developmental toxicity in zebrafish embryos. The exudates of both cyanobacteria were indeed provoking diverse teratogenic effects (e.g. tail, spine and mouth deformation) and interference with growth in zebrafish embryos, while such effects were not observed for the alga. Fish embryos were also exposed to all-trans retinoic acid (ATRA) in a range equivalent to the REQ concentrations detected in exudates by in vitro bioassays. Both the phenotypes and effective concentrations of exudates corresponded to ATRA equivalents, supporting the hypothesis that the teratogenic effects of cyanobacterial exudates are likely to be associated with retinoid-like activity. The study documents that some cyanobacteria are able to produce and release retinoid-like compounds into the environment at concentrations equivalent to those causing teratogenicity in zebrafish. Hence, the characterization of retinoid-like and teratogenic potency should be

  6. LL-202, a newly synthesized flavonoid, inhibits tumor growth via inducing G(2)/M phase arrest and cell apoptosis in MCF-7 human breast cancer cells in vitro and in vivo.

    Science.gov (United States)

    Tao, Lei; Fu, Rong; Wang, Xiaoping; Yao, Jing; Zhou, Yuxin; Dai, Qinsheng; Li, Zhiyu; Lu, Na; Wang, Weiyun

    2014-07-03

    We recently established that LL-202, a newly synthesized flavonoid, exhibited obvious anticancer effects against human breast cells in vivo and in vitro. The underlying mechanism of its anticancer activity remains to be elucidated. In this study, we demonstrated that LL-202 inhibited the growth and proliferation of human breast cancer MCF-7 cells in a concentration and time-dependent manner. We reported that LL-202 induced both mitochondrial- and death-receptor-mediated apoptosis, which were characterized by the dissipation of mitochondrial membrane potential (ΔΨm), cytochrome c (Cyt c) release from mitochondria to cytosol, the activation of several caspases and induction of poly (ADP-ribose) polymerase (PARP) and Bid cleavage. N-acetylcysteine (NAC), a general ROS scavenger, partly blocked the LL-202-induced ROS levels and apoptosis. In addition, LL-202 induced arrest in cell cycle progression at G2/M phase in MCF-7 cells. After the treatment with LL-202, the expression of cell cycle-related proteins, such as cyclin B1, cyclin A, and p-CDK1 (Thr161) were down-regulated, whereas the expression of p21(WAF1/Cip1) and p-CDK1 (Thr14/Tyr15) were up-regulated. Finally, in vivo studies, LL-202 significantly suppressed the growth of MCF-7 breast cancer xenograft tumors in a dose-dependent manner with low systemic toxicity. In conclusion, the results showed that LL-202 had significant anticancer effects against human breast cells via the induction of apoptosis and G2/M phase arrest and it may be a novel anticancer agent for treatment of breast cancer. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Carotenoids and Retinoids: Nomenclature, Chemistry, and Analysis.

    Science.gov (United States)

    Harrison, Earl H; Curley, Robert W

    Carotenoids are polyenes synthesized in plants and certain microorganisms and are pigments used by plants and animals in various physiological processes. Some of the over 600 known carotenoids are capable of metabolic conversion to the essential nutrient vitamin A (retinol) in higher animals. Vitamin A also gives rise to a number of other metabolites which, along with their analogs, are known as retinoids. To facilitate discussion about these important molecules, a nomenclature is required to identify specific substances. The generally accepted rules for naming these important molecules have been agreed to by various Commissions of the International Union of Pure and Applied Chemistry and International Union of Biochemistry. These naming conventions are explained along with comparisons to more systematic naming rules that apply for these organic chemicals. Identification of the carotenoids and retinoids has been advanced by their chemical syntheses, and here, both classical and modern methods for synthesis of these molecules, as well as their analogs, are described. Because of their importance in biological systems, sensitive methods for the detection and quantification of these compounds from various sources have been essential. Early analyses that relied on liquid adsorption and partition chromatography have given way to high-performance liquid chromatography (HPLC) coupled with various detection methods. The development of HPLC coupled to mass spectrometry, particularly LC/MS-MS with Multiple Reaction Monitoring, has resulted in the greatest sensitivity and specificity in these analyses.

  8. Could retinoids be a potential treatment for rheumatic diseases?

    Science.gov (United States)

    Miyabe, Yoshishige; Miyabe, Chie; Nanki, Toshihiro

    2015-01-01

    Retinoid, a derivative of vitamin A, is a general term used to describe compounds that bind to and activate retinoic acid receptors [RARs (RARα, RARβ, and RARγ)] and/or retinoid X receptors [RXRs (RXRα, RXRβ, and RXRγ)]. They have been shown to surpress the differentiation of Th1/Th17 cells and induce the development of Th1/regulatory T cells. They also affect the proliferation of B cells as both an inducer and suppressor. Furthermore, retinoids may induce the maturation of dendritic cells and production of interleukin-10 from monocytes/macrophages. We recently demonstrated that retinoids suppressed the production of reactive oxygen species, the release of elastase from neutrophils by inhibiting mitogen-activated protein kinase signals, and both the migration speed and chemotaxis directionality of neutrophils. Retinoids, such as all-trans retinoic acid and tamibarotene, were previously shown to have positive effects on animal models of several rheumatic diseases, including arthritis, myositis, and vasculitis in vivo. Moreover, retinoids have been used in a pilot study to effectively treat patients with lupus nephritis and systemic sclerosis. We herein reviewed the effects of retinoids on immune cells, animal models of rheumatic diseases, and rheumatic patients.

  9. Factors associated with topical retinoid prescriptions for acne.

    Science.gov (United States)

    Tan, Xi; Davis, Scott A; Balkrishnan, Rajesh; Krowchuk, Daniel P; Feldman, Steven R

    2014-04-01

    Topical retinoids are recommended as the main therapy for most acne patients. To examine the factors associated with topical retinoid prescriptions for acne. Retrospective analyses used data from the 2005-2010 National Ambulatory Medical Care Survey (NAMCS) and the 2004-2007 Marketscan Medicaid Database. Multivariate logistic regression models were used to assess the impact of patient and physician factors on the probability of getting a topical retinoid prescription. Results from analyzing the NAMCS data showed that topical retinoids were prescribed in 40.9% of acne-related physician visits. Older age, male gender, and having Medicaid insurance were associated with a lower likelihood of getting a topical retinoid prescription. Moreover, we found in the Medicaid dataset that seeing a pediatrician or family doctor was associated with lower odds of getting a topical retinoid prescription than seeing a dermatologist (OR = 0.24, 95% CI: 0.23, 0.25). The available databases do not provide an assessment of the severity of the lesions either at baseline or over time. The frequency of receiving a topical retinoid prescription among acne patients was low and it was associated with age, gender, insurance type and physician specialty.

  10. Differences in retinoid levels and metabolism among gastropod lineages: imposex-susceptible gastropods lack the ability to store retinoids in the form of retinyl esters.

    Science.gov (United States)

    Gesto, Manuel; Castro, L Filipe C; Santos, Miguel Machado

    2013-10-15

    The presence of a complex retinoid system was long believed to be a chordate/vertebrate novelty. However, recent findings indicate otherwise since the gastropod mollusk Osilinus lineatus was found to have the capacity to store retinoids in the form of retinyl esters (REs), a key feature to maintain a homeostatic control of retinoid levels. Here, we investigated whether such a complex retinoid system is widely distributed among gastropod lineages. Additionally, since one of the most spectacular examples of endocrine disruption in the wild, the masculinization of female gastropods (imposex) by the retinoid X receptor (RXR) agonist, tributyltin (TBT), has been linked with perturbed retinoid signaling, we also investigated if retinoid storage mechanisms in the form of retinyl esters were present in imposex-susceptible gastropods. Initially, we determined the presence of both polar (active retinoic acid isomers) and nonpolar retinoids (retinol, REs) in selected gastropod species: the limpet Patella depressa and the imposex-susceptible whelks Nucella lapillus and Nassarius reticulatus. Although all species presented active retinoid forms, N. lapillus and N. reticulatus were shown to lack nonpolar retinoids. The absence of REs, which are the common retinoid storage form found in vertebrates and in O. lineatus suggest that those species are unable to use them to maintain a homeostatic control of their retinoid levels. In order to further clarify the retinoid metabolic pathways in imposex-susceptible gastropods, a retinoid exposure study was carried out with N. lapillus. The results demonstrate that although N. lapillus is able to metabolize several retinoid precursors, it lacks the capacity to store retinoids as REs. Whether the lack of retinoid storage mechanisms in the form of REs in imposex-susceptible gastropods plays an important role in the susceptibility to RXR agonists warrants additional studies. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Retinoids and rexinoids in cancer prevention: from laboratory to clinic.

    Science.gov (United States)

    Uray, Iván P; Dmitrovsky, Ethan; Brown, Powel H

    2016-02-01

    Early in the age of modern medicine the consequences of vitamin A deficiency drew attention to the fundamental link between retinoid-dependent homeostatic regulation and malignant hyperproliferative diseases. The term "retinoid" includes a handful of endogenous and a large group of synthetic derivatives of vitamin A. These multifunctional lipid-soluble compounds directly regulate target genes of specific biological functions and critical signaling pathways to orchestrate complex functions from vision to development, metabolism, and inflammation. Many of the retinoid activities on the cellular level have been well characterized and translated to the regulation of processes like differentiation and cell death, which play critical roles in the outcome of malignant transformation of tissues. In fact, retinoid-based differentiation therapy of acute promyelocytic leukemia was one of the first successful examples of molecularly targeted treatment strategies. The selectivity, high receptor binding affinity and the ability of retinoids to directly modulate gene expression programs present a distinct pharmacological opportunity for cancer treatment and prevention. However, to fully exploit their potential, the adverse effects of retinoids must be averted. In this review we provide an overview of the biology of retinoid (activated by nuclear retinoic acid receptors [RARs]) and rexinoid (engaged by nuclear retinoid X receptors [RXRs]) action concluded from a long line of preclinical studies, in relation to normal and transformed states of cells. We will also discuss the past and current uses of retinoids in the treatment of malignancies, the potential of rexinoids in the cancer prevention setting, both as single agents and in combinations. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN): Could Retinoids Play a Causative Role?

    Science.gov (United States)

    Mawson, Anthony R.; Eriator, Ike; Karre, Sridhar

    2015-01-01

    Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are overlapping manifestations on a spectrum of acute drug-induced conditions associated with severe blistering, skin peeling, and multi-organ damage. TEN is an eruption resembling severe scalding, with ≥30% skin detachment. SJS is a mild form of TEN, characterized histologically by epidermal keratinocyte apoptosis with dermo-epidermal separation and extensive small blisters with syndrome can be induced by numerous medications and typically occurs 1–4 weeks after the initiation of therapy. Granulysin is found in the lesions of patients with SJS/TEN and plays a significant pathogenic role in the condition, but the overall mechanisms linking medications, granulysin, and disease manifestations remain obscure. This paper reviews evidence suggesting that the different medications implicated in SJS/TEN have the common property of interacting and synergizing with endogenous retinoids (vitamin A and its congeners), in many instances causing the latter to accumulate in and damage the liver, the main storage organ for vitamin A. It is hypothesized that liver damage leads to the spillage of toxic retinoid compounds into the circulation, resulting in an endogenous form of hypervitaminosis A and cytotoxicity with widespread apoptosis, mediated by granulysin and recognized as SJS/TEN. Subject to testing, the model suggests that symptom worsening could be arrested at onset by lowering the concentration of circulating retinoids and/or granulysin via phlebotomy or plasmapheresis or by pharmacological measures to limit their expression. PMID:25579087

  13. Retinoid plus antimicrobial combination treatments for acne

    Directory of Open Access Journals (Sweden)

    Feneran A

    2011-07-01

    Full Text Available Ashley N Feneran1, William S Kaufman2, Tushar S Dabade1, Steven R Feldman1,3,41Department of Dermatology, Center for Dermatology Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 2Medical College of Virginia, Richmond, VA, USA; 3Department of Pathology, Center for Dermatology Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 4Department of Public Health Sciences, Center for Dermatology Research, Wake Forest University School of Medicine, Winston-Salem, NC, USABackground: Acne vulgaris is a chronic disease with several pathogenic factors. Multiple medications are typically used that can lead to nonadherence and treatment failure. Combination medications target multiple pathways of acne formation and may offer therapeutic benefit.Purpose: To explore the efficacy and tolerability of combination retinoid plus antimicrobial treatments in acne vulgaris.Methods: A PubMed and Google search was conducted for combination therapies of clindamycin and tretinoin, with secondary analysis of related citations and references. Similar searches were completed for the combination medications of benzoyl peroxide plus clindamycin or erythromycin, and for the combination therapy of adapalene and benzoyl peroxide.Results: Combination clindamycin phosphate and tretinoin gel was found to be more efficacious than monotherapy of either drug or its vehicle for acne, including inflammatory acne, and has a greater onset of action than either drug alone. Clindamycin phosphate and tretinoin gel was well-tolerated, and adherence to its use exceeded that of using both medications in separate formulations. Benzoyl peroxide-containing combination medications with clindamycin or erythromycin were both more effective in the treatment of acne than either drug alone. Both medications were well-tolerated, with dry skin being the most common adverse effect.Conclusions: Combination medications have superior efficacy and adherence, and

  14. Side effects of retinoid therapy on the quality of vision

    Directory of Open Access Journals (Sweden)

    Bergler-Czop Beata

    2016-12-01

    Full Text Available Retinoids are compounds chemically related to vitamin A, which are frequently used in dermatological practice (1. They are characterized by numerous mechanisms of action leading to normalization of keratinocyte proliferation and maturation. They have anti-seborrhoeic, immunomodulatory and anti-inflammatory effects (1, 2. A number of side effects to retinoid treatment have been recorded; one group of such side effects relates to eyes and vision. Dry eye syndrome and blepharoconjunctivitis are the most common side effects, appearing in 20-50 % of patients treated with retinoids. They often contribute to the occurrence of other side-effects such as eye discomfort and contact lens intolerance. Due to the widespread use in clinical practice, the adverse effects, including ocular side effects, should be studied. To confirm the variety of adverse effects of retinoids, several case reports of rare side-effects are presented.

  15. Side effects of retinoid therapy on the quality of vision.

    Science.gov (United States)

    Bergler-Czop, Beata; Bilewicz-Stebel, Monika; Stańkowska, Anna; Bilewicz-Wyrozumska, Teresa

    2016-12-01

    Retinoids are compounds chemically related to vitamin A, which are frequently used in dermatological practice (1). They are characterized by numerous mechanisms of action leading to normalization of keratinocyte proliferation and maturation. They have anti-seborrhoeic, immunomodulatory and anti-inflammatory effects (1, 2). A number of side effects to retinoid treatment have been recorded; one group of such side effects relates to eyes and vision. Dry eye syndrome and blepharoconjunctivitis are the most common side effects, appearing in 20-50 % of patients treated with retinoids. They often contribute to the occurrence of other side-effects such as eye discomfort and contact lens intolerance. Due to the widespread use in clinical practice, the adverse effects, including ocular side effects, should be studied. To confirm the variety of adverse effects of retinoids, several case reports of rare side-effects are presented.

  16. Retinoid signaling in pathological remodeling related to cardiovascular disease.

    Science.gov (United States)

    Kotake, Daisuke; Sato, Taiki; Hirasawa, Noriyasu

    2014-04-15

    Retinoids, the active derivatives of vitamin A, are critical signaling molecules in crucial biological processes such as embryonic development, the maintenance of immune function, and cellular differentiation and proliferation. Preclinical studies have shown that retinoids also regulate morphological changes during the progression of cardiovascular disease (CVD). CVD is complexly formed in a mutual chain reaction of various modern lifestyle-related risk factors such as dyslipidemia, hypertension, diabetes, and obesity. These factors induce the pathological remodeling of adipose tissue, the vasculature, and the ventricles, which are a potential target for retinoid signaling. This perspective highlights emerging topics and future prospectives on the relationship between CVD and retinoid signaling. © 2013 Elsevier B.V. All rights reserved.

  17. Retinoids induce Nur77-dependent apoptosis in mouse thymocytes.

    Science.gov (United States)

    Kiss, Beáta; Tóth, Katalin; Sarang, Zsolt; Garabuczi, Éva; Szondy, Zsuzsa

    2015-03-01

    Nur77 is a transcription factor, which plays a determinant role in mediating T cell receptor-induced cell death of thymocytes. In addition to regulation of transcription, Nur77 contributes to apoptosis induction by targeting mitochondria, where it can convert Bcl-2, an anti-apoptotic protein into a proapoptotic molecule. Previous studies have demonstrated that retinoids are actively produced in the mouse thymus and can induce a transcription-dependent apoptosis in mouse thymocytes. Here we show that retinoic acids induce the expression of Nur77, and retinoid-induced apoptosis is completely dependent on Nur77, as retinoids were unable to induce apoptosis in Nur77 null thymocytes. In wild-type thymocytes retinoids induced enhanced expression of the apoptosis-related genes FasL, TRAIL, NDG-1, Gpr65 and Bid, all of them in a Nur77-dependent manner. The combined action of these proteins led to Caspase 8-dependent Bid cleavage in the mitochondria. In addition, we could demonstrate the Nur77-dependent induction of STAT1 leading to enhanced Bim expression, and the mitochondrial translocation of Nur77 leading to the exposure of the Bcl-2/BH3 domain. The retinoid-induced apoptosis was dependent on both Caspase 8 and STAT1. Our data together indicate that retinoids induce a Nur77-dependent cell death program in thymocytes activating the mitochondrial pathway of apoptosis. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Catalytic mechanism of a retinoid isomerase essential for vertebrate vision.

    Science.gov (United States)

    Kiser, Philip D; Zhang, Jianye; Badiee, Mohsen; Li, Qingjiang; Shi, Wuxian; Sui, Xuewu; Golczak, Marcin; Tochtrop, Gregory P; Palczewski, Krzysztof

    2015-06-01

    Visual function in vertebrates is dependent on the membrane-bound retinoid isomerase RPE65, an essential component of the retinoid cycle pathway that regenerates 11-cis-retinal for rod and cone opsins. The mechanism by which RPE65 catalyzes stereoselective retinoid isomerization has remained elusive because of uncertainty about how retinoids bind to its active site. Here we present crystal structures of RPE65 in complex with retinoid-mimetic compounds, one of which is in clinical trials for the treatment of age-related macular degeneration. The structures reveal the active site retinoid-binding cavity located near the membrane-interacting surface of the enzyme as well as an Fe-bound palmitate ligand positioned in an adjacent pocket. With the geometry of the RPE65-substrate complex clarified, we delineate a mechanism of catalysis that reconciles the extensive biochemical and structural research on this enzyme. These data provide molecular foundations for understanding a key process in vision and pharmacological inhibition of RPE65 with small molecules.

  19. Retinoid receptor signaling and autophagy in acute promyelocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Orfali, Nina [Cork Cancer Research Center, University College Cork, Cork (Ireland); Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States); McKenna, Sharon L. [Cork Cancer Research Center, University College Cork, Cork (Ireland); Cahill, Mary R. [Department of Hematology, Cork University Hospital, Cork (Ireland); Gudas, Lorraine J., E-mail: ljgudas@med.cornell.edu [Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States); Mongan, Nigel P., E-mail: nigel.mongan@nottingham.ac.uk [Faculty of Medicine and Health Science, School of Veterinary Medicine and Science, University of Nottingham, LE12 5RD (United Kingdom); Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States)

    2014-05-15

    Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. - Highlights: • Normal and aberrant retinoid signaling in hematopoiesis and leukemia is reviewed. • We suggest a novel role for RARα in the development of X-RARα gene fusions in APL. • ATRA therapy in APL activates transcription and promotes onco-protein degradation. • Autophagy may be involved in both onco-protein degradation and differentiation. • Pharmacologic autophagy induction may potentiate ATRA's therapeutic effects.

  20. [Heart arrest].

    Science.gov (United States)

    Chiarella, F; Giovannini, E; Bozzano, A; Caristo, G; Delise, P; Fedele, F; Fera, M S; Lavalle, C; Roghi, A; Valagussa, F

    2001-03-01

    Cardiac arrest is one of the leading causes of mortality in industrialized countries and is mainly due to ischemic heart disease. According to ISTAT estimates, approximately 45,000 sudden deaths occur annually in Italy whereas according to the World Health Organization, its incidence is 1 per 1000 persons. The most common cause of cardiac arrest is ventricular fibrillation due to an acute ischemic episode. During acute ischemia the onset of a ventricular tachyarrhythmia is sudden, unpredictable and often irreversible and lethal. Each minute that passes, the probability that the patient survives decreases by 10%. For this reason, the first 10 min are considered to be priceless for an efficacious first aid. The possibility of survival depends on the presence of witnesses, on the heart rhythm and on the resolution of the arrhythmia. In the majority of cases, the latter is possible by means of electrical defibrillation followed by the reestablishment of systolic function. An increase in equipment alone does not suffice for efficacious handling of cardiac arrest occurring outside the hospital premises. Above all, an adequate intervention strategy is required. Ambulance personnel must be well trained and capable of intervening rapidly, possibly within the first 5 min. The key to success lies in the diffusion and proper use of defibrillators. The availability of new generation instruments, the external automatic defibrillators, encourages their widespread use. On the territory, these emergencies are the responsibility of the 118 organization based, according to the characteristics specific to each country, on the regulated coordination between the operative command, the crews and the first-aid means. Strategies for the handling of these emergencies within hospitals have been proposed by the Conference of Bethesda and tend to guarantee an efficacious resuscitation with a maximum latency of 2 min between cardiac arrest and the first electric shock. The diffusion of external

  1. Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue*

    Science.gov (United States)

    Guo, Hong; Foncea, Rocio; O'Byrne, Sheila M.; Jiang, Hongfeng; Zhang, Yuanyuan; Deis, Jessica A.; Blaner, William S.; Bernlohr, David A.; Chen, Xiaoli

    2016-01-01

    We have recently characterized the role of lipocalin 2 (Lcn2) as a new adipose-derived cytokine in the regulation of adaptive thermogenesis via a non-adrenergic pathway. Herein, we explored a potential non-adrenergic mechanism by which Lcn2 regulates thermogenesis and lipid metabolism. We found that Lcn2 is a retinoic acid target gene, and retinoic acid concurrently stimulated UCP1 and Lcn2 expression in adipocytes. Lcn2 KO mice exhibited a blunted effect of all-trans-retinoic acid (ATRA) on body weight and fat mass, lipid metabolism, and retinoic acid signaling pathway activation in adipose tissue under the high fat diet-induced obese condition. We further demonstrated that Lcn2 is required for the full action of ATRA on the induction of UCP1 and PGC-1α expression in brown adipocytes and the restoration of cold intolerance in Lcn2 KO mice. Interestingly, we discovered that Lcn2 KO mice have decreased levels of retinoic acid and retinol in adipose tissue. The protein levels of STRA6 responsible for retinol uptake were significantly decreased in adipose tissue. The retinol transporter RBP4 was increased in adipose tissue but decreased in the circulation, suggesting the impairment of RBP4 secretion in Lcn2 KO adipose tissue. Moreover, Lcn2 deficiency abolished the ATRA effect on RBP4 expression in adipocytes. All the data suggest that the decreased retinoid level and action are associated with impaired retinol transport and storage in adipose tissue in Lcn2 KO mice. We conclude that Lcn2 plays a critical role in regulating metabolic homeostasis of retinoids and retinoid-mediated thermogenesis in adipose tissue. PMID:27008859

  2. Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue.

    Science.gov (United States)

    Guo, Hong; Foncea, Rocio; O'Byrne, Sheila M; Jiang, Hongfeng; Zhang, Yuanyuan; Deis, Jessica A; Blaner, William S; Bernlohr, David A; Chen, Xiaoli

    2016-05-20

    We have recently characterized the role of lipocalin 2 (Lcn2) as a new adipose-derived cytokine in the regulation of adaptive thermogenesis via a non-adrenergic pathway. Herein, we explored a potential non-adrenergic mechanism by which Lcn2 regulates thermogenesis and lipid metabolism. We found that Lcn2 is a retinoic acid target gene, and retinoic acid concurrently stimulated UCP1 and Lcn2 expression in adipocytes. Lcn2 KO mice exhibited a blunted effect of all-trans-retinoic acid (ATRA) on body weight and fat mass, lipid metabolism, and retinoic acid signaling pathway activation in adipose tissue under the high fat diet-induced obese condition. We further demonstrated that Lcn2 is required for the full action of ATRA on the induction of UCP1 and PGC-1α expression in brown adipocytes and the restoration of cold intolerance in Lcn2 KO mice. Interestingly, we discovered that Lcn2 KO mice have decreased levels of retinoic acid and retinol in adipose tissue. The protein levels of STRA6 responsible for retinol uptake were significantly decreased in adipose tissue. The retinol transporter RBP4 was increased in adipose tissue but decreased in the circulation, suggesting the impairment of RBP4 secretion in Lcn2 KO adipose tissue. Moreover, Lcn2 deficiency abolished the ATRA effect on RBP4 expression in adipocytes. All the data suggest that the decreased retinoid level and action are associated with impaired retinol transport and storage in adipose tissue in Lcn2 KO mice. We conclude that Lcn2 plays a critical role in regulating metabolic homeostasis of retinoids and retinoid-mediated thermogenesis in adipose tissue. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Esculetin, a natural coumarin compound, evokes Ca(2+) movement and activation of Ca(2+)-associated mitochondrial apoptotic pathways that involved cell cycle arrest in ZR-75-1 human breast cancer cells.

    Science.gov (United States)

    Chang, Hong-Tai; Chou, Chiang-Ting; Lin, You-Sheng; Shieh, Pochuen; Kuo, Daih-Huang; Jan, Chung-Ren; Liang, Wei-Zhe

    2016-04-01

    Esculetin (6,7-dihydroxycoumarin), a derivative of coumarin compound, is found in traditional medicinal herbs. It has been shown that esculetin triggers diverse cellular signal transduction pathways leading to regulation of physiology in different models. However, whether esculetin affects Ca(2+) homeostasis in breast cancer cells has not been explored. This study examined the underlying mechanism of cytotoxicity induced by esculetin and established the relationship between Ca(2+) signaling and cytotoxicity in human breast cancer cells. The results showed that esculetin induced concentration-dependent rises in the intracellular Ca(2+) concentration ([Ca(2+)]i) in ZR-75-1 (but not in MCF-7 and MDA-MB-231) human breast cancer cells. In ZR-75-1 cells, this Ca(2+) signal response was reduced by removing extracellular Ca(2+) and was inhibited by the store-operated Ca(2+) channel blocker 2-aminoethoxydiphenyl borate (2-APB). In Ca(2+)-free medium, pre-treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) abolished esculetin-induced [Ca(2+)]i rises. Conversely, incubation with esculetin abolished TG-induced [Ca(2+)]i rises. Esculetin induced cytotoxicity that involved apoptosis, as supported by the reduction of mitochondrial membrane potential and the release of cytochrome c and the proteolytic activation of caspase-9/caspase-3, which were partially reversed by pre-chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). Moreover, esculetin increased the percentage of cells in G2/M phase and regulated the expressions of p53, p21, CDK1, and cyclin B1. Together, in ZR-75-1 cells, esculetin induced [Ca(2+)]i rises by releasing Ca(2+) from the ER and causing Ca(2+) influx through 2-APB-sensitive store-operated Ca(2+) entry. Furthermore, esculetin activated Ca(2+)-associated mitochondrial apoptotic pathways that involved G2/M cell cycle arrest. Graphical abstract The summary of esculetin

  4. The inhibition of PI3K and NFκB promoted curcumin-induced cell cycle arrest at G2/M via altering polyamine metabolism in Bcl-2 overexpressing MCF-7 breast cancer cells.

    Science.gov (United States)

    Berrak, Özge; Akkoç, Yunus; Arısan, Elif Damla; Çoker-Gürkan, Ajda; Obakan-Yerlikaya, Pınar; Palavan-Ünsal, Narçin

    2016-02-01

    Bcl-2 protein has been contributed with number of genes which are involved in oncogenesis. Among the many targets of Bcl-2, NFκB have potential role in induction of cell cycle arrest. Curcumin has potential therapeutic effects against breast cancer through multiple signaling pathways. In this study, we investigated the role of curcumin in induction of cell cycle arrest via regulating of NFκB and polyamine biosynthesis in wt and Bcl-2+ MCF-7 cells. To examine the effect of curcumin on cell cycle regulatory proteins, PI3K/Akt, NFκB pathways and polyamine catabolism, we performed immunoblotting assay. In addition, cell cycle analysis was performed by flow cytometry. The results indicated that curcumin induced cell cycle arrest at G2/M phase by downregulation of cyclin B1 and Cdc2 and inhibited colony formation in MCF-7wt cells. However, Bcl-2 overexpression prevented the inhibition of cell cycle associated proteins after curcumin treatment. The combination of LY294002, PI3K inhibitor, and curcumin induced cell cycle arrest by decreasing CDK4, CDK2 and cyclin E2 in Bcl-2+ MCF-7 cells. Moreover, LY294002 further inhibited the phosphorylation of Akt in Bcl-2+ MCF-7 cells. Curcumin could suppress the nuclear transport of NFκB through decreasing the interaction of P-IκB-NFκB. The combination of wedelolactone, NFκB inhibitor, and curcumin acted different on SSAT expression in wt MCF-7 and Bcl-2+ MCF-7 cells. NFκB inhibition increased the SSAT after curcumin treatment in Bcl-2 overexpressed MCF-7 cells. Inhibition of NFκB activity as well as suppression of ROS generation with NAC resulted in the partial relief of cells from G2/M checkpoint after curcumin treatment in wt MCF-7 cells. In conclusion, the potential role of curcumin in induction of cell cycle arrest is related with NFκB-regulated polyamine biosynthesis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Mefloquine use, psychosis, and violence: a retinoid toxicity hypothesis.

    Science.gov (United States)

    Mawson, Anthony

    2013-07-15

    Mefloquine use has been linked to severe gastrointestinal and neuropsychiatric adverse effects, including cognitive disturbances, anxiety, depression, psychosis, and violence. The adverse effects of the drug are thought to result from the secondary consequences of hepatocellular injury; in fact, mefloquine is known to cause a transient, anicteric chemical hepatitis. However, the mechanism of mefloquine-associated liver damage and the associated neuropsychiatric and behavioral effects of the drug are not well understood. Mefloquine and other 8-amino-quinolines are the only antimalarial drugs that target the liver-stage malaria parasites, which selectively absorb vitamin A from the host. Vitamin A is also stored mainly in the liver, in potentially poisonous concentrations. These observations suggest that both the therapeutic effectiveness of mefloquine and its adverse effects are related to the ability of the 8-aminoquinolines to alter the metabolism of retinoids (vitamin A and its congeners). Several lines of evidence support the hypothesis that mefloquine neurotoxicity and other adverse effects reflect an endogenous form of hypervitaminosis A due to a process involving: mefloquine-induced dehydrogenase inhibition; the accumulation of retinoids in the liver; retinoid-induced hepatocellular damage; the spillage of stored retinoids into the circulation; and the transport of these compounds to the gut and brain in toxic concentrations. The retinoid hypothesis could be tested clinically by comparing cases of mefloquine toxicity and untreated controls in terms of retinoid profiles (retinol, retinyl esters, percent retinyl esters, and retinoic acid). Subject to such tests, retinoid profiling could provide an indicator for assessing mefloquine-associated adverse effects.

  6. About Cardiac Arrest

    Science.gov (United States)

    ... Artery Disease Venous Thromboembolism Aortic Aneurysm More About Cardiac Arrest Updated:Mar 10,2017 What is cardiac arrest? ... and procedures related to heart disease and stroke. Cardiac Arrest • Home • About Cardiac Arrest • Understand Your Risk for ...

  7. DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERα-positive breast cancer cells

    NARCIS (Netherlands)

    M. Ansems (Marleen); J.N. Søndergaard (Jonas Nørskov); A.M. Sieuwerts (Anieta); M.W.G. Looman (Maaike W. G.); M. Smid (Marcel); A.M.A. de Graaf (Annemarie M. A.); V. de Weerd (Vanja); M. Zuidscherwoude (Malou); J.A. Foekens (John); J.W.M. Martens (John); G.J. Adema (Gosse J.)

    2015-01-01

    textabstractBreast cancer is one of the most common causes of cancer-related deaths in women. The estrogen receptor (ERα) is well known for having growth promoting effects in breast cancer. Recently, we have identified DC-SCRIPT (ZNF366) as a co-suppressor of ERα and as a strong and independent

  8. DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERalpha-positive breast cancer cells

    NARCIS (Netherlands)

    Ansems, M.; Sondergaard, J.N.; Sieuwerts, A.M.; Looman, M.W.G.; Smid, M.; Graaf, A.M.A. de; Weerd, V. de; Zuidscherwoude, M.; Foekens, J.A.; Martens, J.W.; Adema, G.J.

    2015-01-01

    Breast cancer is one of the most common causes of cancer-related deaths in women. The estrogen receptor (ERalpha) is well known for having growth promoting effects in breast cancer. Recently, we have identified DC-SCRIPT (ZNF366) as a co-suppressor of ERalpha and as a strong and independent

  9. Molecular Mechanism by Which Retinoids Prevent Breast Cancer Development

    Science.gov (United States)

    2007-06-01

    204078_at synaptonemal complex protein SC65 -2.9 203881_s_at dystrophin ( muscular dystrophy , Duchenne and Becker types) -2.88 209717_at ecotropic viral...for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection...and therapeutic role in cervical cancer. Lancet Oncol. 2005 Sep;6(9):712-20. Review . 4. De Luca LM, Darwiche N, Celli G, Kosa K, Jones C, Ross S

  10. Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity.

    Science.gov (United States)

    Yin, Shijin; Luo, Jialie; Qian, Aihua; Du, Junhui; Yang, Qing; Zhou, Shentai; Yu, Weihua; Du, Guangwei; Clark, Richard B; Walters, Edgar T; Carlton, Susan M; Hu, Hongzhen

    2013-09-01

    Retinoids are structurally related derivatives of vitamin A and are required for normal vision as well as cell proliferation and differentiation. Clinically, retinoids are effective in treating many skin disorders and cancers. Application of retinoids evokes substantial irritating side effects, including pain and inflammation; however, the precise mechanisms accounting for the sensory hypersensitivity are not understood. Here we show that both naturally occurring and synthetic retinoids activate recombinant or native transient receptor potential channel vanilloid subtype 1 (TRPV1), an irritant receptor for capsaicin, the pungent ingredient of chili peppers. In vivo, retinoids produced pain-related behaviors that were either eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1 function. These findings identify TRPV1 as an ionotropic receptor for retinoids and provide cellular and molecular insights into retinoid-evoked hypersensitivity. These findings also suggest that selective TRPV1 antagonists are potential therapeutic drugs for treating retinoid-induced sensory hypersensitivity.

  11. Retinoid receptor signaling and autophagy in acute promyelocytic leukemia

    Science.gov (United States)

    Orfali, Nina; McKenna, Sharon L.; Cahill, Mary R.; Gudas, Lorraine J.; Mongan, Nigel P.

    2014-01-01

    Retinoids are a family of signaling molecules derived from Vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. PMID:24694321

  12. Retinoid metabolism is altered in human and mouse cicatricial alopecia

    Science.gov (United States)

    Everts, Helen B.; Silva, Kathleen A.; Montgomery, Shalise; Suo, Liye; Menser, Monica; Valet, Amy S.; King, Lloyd E.; Ong, David E; Sundberg, John P.

    2012-01-01

    C57BL/6 mice develop dermatitis and scarring alopecia resembling human cicatricial alopecias (CA), particularly the central centrifugal cicatricial alopecia (CCCA) type. To evaluate the role of retinoids in CA, expression of retinoid metabolism components were examined in these mice with mild, moderate, or severe CA compared to hair cycle matched mice with no disease. Two feeding studies were performed with dams fed either NIH 31 diet (study 1) or AIN93G diet (study 2). Adult mice were fed AIN93M diet with 4 (recommended), 28, or 56 IU vitamin A/g diet. Feeding the AIN93M diet to adults increased CA frequency over NIH 31 fed mice. Increased follicular dystrophy was seen in study 1 and increased dermal scars in study 2 in mice fed the 28 IU diet. These results indicate that retinoid metabolism is altered in CA in C57BL/6J mice that require precise levels of dietary vitamin A. Human patients with CCCA, pseudopelade (end stage scarring), and controls with no alopecia were also studied. Many retinoid metabolism proteins were increased in mild CCCA, but were undetectable in pseudopelade. Studies to determine if these dietary alterations in retinoid metabolism seen in C57BL/6J mice are also involved in different types of human CA are needed. PMID:23096705

  13. Retinoid receptor signaling and autophagy in acute promyelocytic leukemia.

    LENUS (Irish Health Repository)

    Orfali, Nina

    2014-05-15

    Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies.

  14. Retinoid-mediated regulation of mood: possible cellular mechanisms.

    Science.gov (United States)

    O'Reilly, Kally; Bailey, Sarah J; Lane, Michelle A

    2008-03-01

    Vitamin A and its derivatives, the retinoids, have long been studied for their ability to alter central nervous system (CNS) development. Increasingly, it is recognized that sufficient levels of retinoids may also be required for adult CNS function. However, excess dietary vitamin A, due to the consumption of supplements or foods rich in vitamin A, has been reported to induce psychosis. In addition, 13-cis-retinoic acid (13-cis-RA, isotretinoin), the active ingredient in the acne treatment Accutane, has been reported to cause adverse psychiatric events, including depression and suicidal ideation. Nevertheless, epidemiological studies have reported no consistent link between Accutane use and clinical depression in humans. Using an animal model, we have recently shown that 13-cis-RA induces an increase in depression-related behavior. Impairments in spatial learning and memory have also been demonstrated following 13-cis-RA treatment in mice. This review focuses on the behavioral and possible cellular effects of retinoid deficiency or excess in the adult brain in relation to altered mood. Specifically, we discuss the effect of retinoids on depression-related behaviors and whether norepinephrinergic, dopaminergic, or serotonergic neurotransmitter systems may be impaired. In addition, we consider the evidence that adult neurogenesis, a process implicated in the pathophysiology of depression, is reduced by retinoid signaling. We suggest that 13-cis-RA treatment may induce depression-related behaviors by decreasing adult neurogenesis and/or altering the expression of components of serotonergic neurotransmitter system, thereby leading to impaired serotonin signaling.

  15. Ziyuglycoside I Inhibits the Proliferation of MDA-MB-231 Breast Carcinoma Cells through Inducing p53-Mediated G2/M Cell Cycle Arrest and Intrinsic/Extrinsic Apoptosis

    Directory of Open Access Journals (Sweden)

    Xue Zhu

    2016-11-01

    Full Text Available Background: Due to the aggressive clinical behavior, poor outcome, and lack of effective specific targeted therapies, triple-negative breast cancer (TNBC has currently been recognized as one of the most malignant types of tumors. In the present study, we investigated the cytotoxic effect of ziyuglycoside I, one of the major components extracted from Chinese anti-tumor herbal Radix Sanguisorbae, on the TNBC cell line MDA-MB-231. Methods: The underlying molecular mechanism of the cytotoxic effect ziyuglycoside I on MDA-MB-231 cells was investigated with cell viability assay, flow cytometric analysis and Western blot. Results: Compared to normal mammary gland Hs 578Bst cells, treatment of ziyuglycoside I resulted in a significant growth inhibitory effect on MDA-MB-231 cells. Ziyuglycoside I induced the G2/M phase arrest and apoptosis of MDA-MB-231 cells in a dose-dependent manner. These effects were found to be partially mediated through the up-regulation of p53 and p21WAF1, elevated Bax/Bcl-2 ratio, and the activation of both intrinsic (mitochondrial-initiated and extrinsic (Fas/FasL-initiated apoptotic pathways. Furthermore, the p53 specific siRNA attenuated these effects. Conclusion: Our study suggested that ziyuglycoside I-triggered MDA-MB-231 cell cycle arrest and apoptosis were probably mediated by p53. This suggests that ziyuglycoside I might be a potential drug candidate for treating TNBC.

  16. Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21(WAF1/CIP1) expression.

    Science.gov (United States)

    Tseng, Tsui-Hwa; Chien, Ming-Hsien; Lin, Wea-Lung; Wen, Yu-Ching; Chow, Jyh-Ming; Chen, Chi-Kuan; Kuo, Tsang-Chih; Lee, Wei-Jiunn

    2017-02-01

    Apigenin (4',5,7-trihydroxyflavone), a flavonoid commonly found in fruits and vegetables, has anticancer properties in various malignant cancer cells. However, the molecular basis of the anticancer effect remains to be elucidated. In this study, we investigated the cellular mechanisms underlying the induction of cell cycle arrest by apigenin. Our results showed that apigenin at the nonapoptotic induction concentration inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in the MDA-MB-231 breast cancer cell line. Immunoblot analysis indicated that apigenin suppressed the expression of cyclin A, cyclin B, and cyclin-dependent kinase-1 (CDK1), which control the G2-to-M phase transition in the cell cycle. In addition, apigenin upregulated p21(WAF1/CIP1) and increased the interaction of p21(WAF1/CIP1) with proliferating cell nuclear antigen (PCNA), which inhibits cell cycle progression. Furthermore, apigenin significantly inhibited histone deacetylase (HDAC) activity and induced histone H3 acetylation. The subsequent chromatin immunoprecipitation (ChIP) assay indicated that apigenin increased acetylation of histone H3 in the p21(WAF1/CIP1) promoter region, resulting in the increase of p21(WAF1/CIP1) transcription. In a tumor xenograft model, apigenin effectively delayed tumor growth. In these apigenin-treated tumors, we also observed reductions in the levels of cyclin A and cyclin B and increases in the levels of p21(WAF1/CIP1) and acetylated histone H3. These findings demonstrate for the first time that apigenin can be used in breast cancer prevention and treatment through epigenetic regulation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 434-444, 2017. © 2016 Wiley Periodicals, Inc.

  17. Synthesis and Biological Evaluation of Retinoid-Chalcones as Inhibitors of Colon Cancer Cell Growth

    Science.gov (United States)

    Based on the observed anticancer activity of chalcones and retinoids, a novel class of retinoid-chalcone hybrids were designed and synthesized. As part of our ongoing studies to discover natural product based anticancer compounds, the retinoid-chalcone hybrids were tested against the colon cancer ce...

  18. Retinoid metabolism (LRAT, REH) in the liver and plasma retinoids of bullfrog, Rana catesbeiana, in relation to agricultural contamination.

    Science.gov (United States)

    Boily, Monique; Thibodeau, Janik; Bisson, Marjolaine

    2009-01-31

    Retinoids have been extensively studied in birds, fish and mammals where their imbalances are associated with adverse effects on growth and reproduction along with decreased embryo survival and deformities. Organochlorine compounds may alter the retinoid system but little is known about the effects of agricultural contaminants on their metabolism. In the Yamaska River project, the retinoid system in bullfrogs is monitored to investigate the possible impact of agricultural contaminants on retinoid homeostasis. Retinoids were measured in liver and plasma of male bullfrogs collected from six locations subject to increasing agricultural activity in the Yamaska River watershed. Bullfrogs living in medium and high agricultural activity areas demonstrated lower hepatic retinyl palmitate and higher hepatic retinol levels when compared to frogs associated with low contaminated sites. Changes in the concentration of hepatic esters could be related to an altered activity of REH or LRAT, enzymes respectively linked to the hydrolysis of retinyl palmitate and the esterification of retinol. A partial characterization and the analysis of liver microsomial REH and LRAT showed significantly higher hydrolysis and lower esterification activities in highly contaminated sites. Enzymatic activities seemed to be influenced by plasma DROH but not by plasma retinol. Bullfrogs from the most contaminated sites showed altered retinoic metabolism that should increase concern for frogs living in intensive agricultural areas.

  19. Off-label uses of retinoids in dermatology

    Directory of Open Access Journals (Sweden)

    Wei Li

    2012-09-01

    Full Text Available Retinoids has been used widely in the topical and systemic treatments of various dermatoses: psoriasis, disorders of keratinization (DOK, keratotic genodermatosis, and severe acne. Moreover, it is also used in the treatment and/or chemoprevention of skin cancer and other neoplasms. Retinoids display key regulatory functions and most dermatologists are familiar with the FDA-approved indication of this medication. Retinoic acid is a potent signaling molecule that is essential for many biological processes, and its levels are tightly regulated by mechanisms that are only partially understood. This article will review these recent findings and attempt to synthesize their meaning to provide a view into the off-label uses of retinoids in dermatology with an emphasis on oral isotretinoin and acitrein.

  20. Activation of P13K/PKB Signaling in Breast Cancer may Inhibit TGFB-Induced G1 Arrest through Changes in p27 Function

    Science.gov (United States)

    2004-10-01

    in Glioblastomas . Cancer Res 2002;gresson. ,62:6764-9. 24. Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell cycle 2002; 1:103...growth factor bets (TGF-P)-induced cell cycle arrest in G I phase is a mechanism that prevents abnormal cell proliferation. Resistance the growth...inhibitory effect of TGF-., often acquired during oncogenesis, may in turn contribute to malignant progression This giant set oui to investigate the

  1. The thyroid hormone receptors modulate the skin response to retinoids.

    Directory of Open Access Journals (Sweden)

    Laura García-Serrano

    Full Text Available Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA in mice.We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced.Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to

  2. Mucocutaneous and systemic toxicity of retinoids: monitoring and management.

    Science.gov (United States)

    Shalita, A R

    1987-01-01

    Oral retinoid therapy is associated with significant mucocutaneous and systemic toxicity similar to that found in hypervitaminosis A. Beside the well-known mucocutaneous adverse effects like cheilitis, xerosis, desquamation, dryness of mucous membranes, more troublesome findings are ocular effects, hair loss or hypergranulation tissue. The most unwanted systemic side effects under both retinoids (isotretinoin and etretinate) are teratogenicity, bone toxicity and serum lipid increments. Careful patient counselling and monitoring will enable the physician to modulate these effects and reduce their impact on patient compliance.

  3. RIG-I is required for the inhibition of measles virus by retinoids.

    Science.gov (United States)

    Soye, Kaitlin J; Trottier, Claire; Richardson, Chris D; Ward, Brian J; Miller, Wilson H

    2011-01-01

    Vitamin A can significantly decrease measles-associated morbidity and mortality. Vitamin A can inhibit the replication of measles virus (MeV) in vitro through an RARα- and type I interferon (IFN)-dependent mechanism. Retinoid-induced gene I (RIG-I) expression is induced by retinoids, activated by MeV RNA and is important for IFN signaling. We hypothesized that RIG-I is central to retinoid-mediated inhibition of MeV in vitro. We demonstrate that RIG-I expression is increased in cells treated with retinoids and infected with MeV. The central role of RIG-I in the retinoid-anti-MeV effect was demonstrated in the Huh-7/7.5 model; the latter cells having non-functional RIG-I. RAR-dependent retinoid signaling was required for the induction of RIG-I by retinoids and MeV. Retinoid signaling was also found to act in combination with IFN to induce high levels of RIG-I expression. RIG-I promoter activation required both retinoids and MeV, as indicated by markers of active chromatin. IRF-1 is known to be regulated by retinoids and MeV, but we found recruitment of IRF-1 to the RIG-I promoter by retinoids alone. Using luciferase expression constructs, we further demonstrated that the IRF-1 response element of RIG-I was required for RIG-I activation by retinoids or IFN. These results reveal that retinoid treatment and MeV infection induces significant RIG-I. RIG-I is required for the retinoid-MeV antiviral response. The induction is dependent on IFN, retinoids and IRF-1.

  4. Phenolic Fractions from Muscadine Grape "Noble" Pomace can Inhibit Breast Cancer Cell MDA-MB-231 Better than those from European Grape "Cabernet Sauvignon" and Induce S-Phase Arrest and Apoptosis.

    Science.gov (United States)

    Luo, Jianming; Wei, Zheng; Zhang, Shengyu; Peng, Xichun; Huang, Yu; Zhang, Yali; Lu, Jiang

    2017-05-01

    Tons of grape pomace which still contained a rich amount of plant polyphenols, is discarded after winemaking. Plant polyphenols have multi-functional activities for human body. In this study, polyphenols of pomaces from Muscadinia rotundifolia "Noble" and Vitis vinifera "Cabernet Sauvignon" were extracted and fractionated, and then they were analyzed with LC-MS and the inhibitory effects on breast cancer cells were compared. The inhibition on MDA-MB-231 cells of fractions from "Noble" was further evaluated. The results showed that polyphenols from 2 grape pomaces could be separated into 3 fractions, and ellagic acid and/or ellagitannins were only detected in fractions from "Noble" pomace. All 3 fractions from "Noble" pomace inhibited MDA-MB-231 better than MCF-7. But fraction 2 from "Cabernet Sauvignon" inhibited MCF-7 better while fraction 1 and fraction 3 inhibited both 2 cells similarly. Moreover, the fractions from "Noble" pomace rather than "Cabernet Sauvignon" can inhibit MDA-MB-231 better. Finally, fractions from "Noble" pomace can induce S-phase arrest and apoptosis on MDA-MB-231. These findings suggested the extracts from grape pomace especially those from "Noble," are potential to be utilized as health beneficial products or even anti-breast cancer agents. © 2017 Institute of Food Technologists®.

  5. RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Sá-Júnior, Paulo Luiz de [Laboratory of Genetics, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Pasqualoto, Kerly Fernanda Mesquita [Biochemistry and Biophysical Laboratory, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Ferreira, Adilson Kleber [Laboratory of Genetics, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Tavares, Maurício Temotheo; Damião, Mariana Celestina Frojuello Costa Bernstorff [Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, Prof. Lineu Prestes Avenue, 580, Postal Code: 05508-000, Sao Paulo (Brazil); Azevedo, Ricardo Alexandre de [Biochemistry and Biophysical Laboratory, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Câmara, Diana Aparecida Dias; Pereira, Alexandre; Madeiro de Souza, Dener [Laboratory of Genetics, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Parise Filho, Roberto, E-mail: roberto.parise@usp.br [Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, Prof. Lineu Prestes Avenue, 580, Postal Code: 05508-000, Sao Paulo (Brazil)

    2013-02-01

    Breast cancer is the world's leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. The use of natural molecular fingerprints as sources for new bioactive chemical entities has proven to be a quite promising and efficient method. Capsaicin, which is the primary pungent compound in red peppers, was reported to selectively inhibit the growth of a variety tumor cell lines. Here, we report for the first time a novel synthetic capsaicin-like analogue, RPF101, which presents a high antitumor activity on MCF-7 cell line, inducing arrest of the cell cycle at the G2/M phase through a disruption of the microtubule network. Furthermore, it causes cellular morphologic changes characteristic of apoptosis and a decrease of Δψm. Molecular modeling studies corroborated the biological findings and suggested that RPF101, besides being a more reactive molecule towards its target, may also present a better pharmacokinetic profile than capsaicin. All these findings support the fact that RPF101 is a promising anticancer agent. -- Highlights: ► We report for the first time that RPF101 possesses anticancer properties. ► RPF101 induces apoptosis of human breast cancer cells. ► RPF 101 decreases mitochondrial potential and induces DNA fragmentation.

  6. Comparison of Two Components of Propolis: Caffeic Acid (CA and Caffeic Acid Phenethyl Ester (CAPE Induce Apoptosis and Cell Cycle Arrest of Breast Cancer Cells MDA-MB-231

    Directory of Open Access Journals (Sweden)

    Agata Kabała-Dzik

    2017-09-01

    Full Text Available Studies show that caffeic acid (CA and caffeic acid phenethyl ester (CAPE are compounds with potent chemopreventive effects. Breast cancer is a common form of aggressive cancer among women worldwide. This study shows a comparison of CA and CAPE activity on triple-negative human caucasian breast adenocarcinoma line cells (MDA-MB-231. MDA-MB-231 cells were treated by CA and CAPE with doses of from 10 to 100 µM, for periods of 24 h and 48 h. Cytotoxicity MTT tests, apoptosis by Annexin V, and cell cycle with Dead Cell Assays were performed. Cytotoxic activity was greater for CAPE compared to CA (both incubation times, same dosage. IC50 values for CAPE were 27.84 µM (24 h and 15.83 µM (48 h and for CA > 10,000 µM (24 h and > 1000 µM (48 h. Polyphenols induced apoptosis, while CAPE (dose dependently, induced a higher apoptotic effect. CAPE also induced cell cycle arrest in S phase (time and dose dependently, CA did it only for 50 and 100 µM. A dose dependent decline was seen for the G0/G1 phase (CAPE, 48 h, as well as elimination of phase G2/M by 100 µM of CAPE (only mild effect for CA. Comparing CA and CAPE activity on MDA-MB-231, CAPE clearly showed better activity for the same dosages and experiment times.

  7. Retinoids, retinoid analogs, and lactoferrin interact and differentially affect cell viability of 2 bovine mammary cell types in vitro.

    Science.gov (United States)

    Wang, Y; Baumrucker, C R

    2010-07-01

    Two bovine mammary cell types (BME-UV1 and MeBo cells) were used to evaluate the effect of natural retinoids, retinoid analogs, and bovine lactoferrin (bLf) on cell viability in vitro. Experiments with Alamar Blue showed a linear relationship between fluorescence and cell viability index. The BME-UV1 cells exhibited twice the metabolic activity but required half the doubling time of the MeBo cells. The BME-UV1 cells were very sensitive to all-trans retinoic acid (atRA) inhibition of cell viability (Pretinoid-induced inhibition of cell viability, depending on the type of bovine mammary cell studied.

  8. What Causes Sudden Cardiac Arrest?

    Science.gov (United States)

    ... Back To Health Topics / Sudden Cardiac Arrest Sudden Cardiac Arrest Also known as Cardiac Arrest , Sudden Cardiac Death ... the condition For People Who Have Survived Sudden Cardiac Arrest If you've already had SCA, you're ...

  9. What Is Sudden Cardiac Arrest?

    Science.gov (United States)

    ... Back To Health Topics / Sudden Cardiac Arrest Sudden Cardiac Arrest Also known as Cardiac Arrest , Sudden Cardiac Death ... the condition For People Who Have Survived Sudden Cardiac Arrest If you've already had SCA, you're ...

  10. Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss.

    Science.gov (United States)

    Clugston, Robin D; Huang, Li-Shin; Blaner, William S

    2015-09-01

    The alcohol-induced depletion of hepatic retinoid stores correlates with the progression of liver injury; however, the mechanisms underlying alcohol's effects have not been fully elucidated. Our goal was to gain a mechanistic understanding of alcohol-induced hepatic retinoid depletion. Wild-type and mutant mice were continuously fed alcohol through Lieber-DeCarli liquid diets, with matched control animals pair fed an isocaloric alcohol-free diet to ensure equal nutrient and calorie intake between groups. A systematic analysis of tissue retinol and retinyl ester levels was performed with HPLC, complemented by gene and protein expression analyses. Our results delineated 2 phases of alcohol-induced depletion of hepatic retinoid. Initially, ∼15% of hepatic retinoid content was mobilized from the liver, causing extrahepatic tissue retinoid levels to increase. Subsequently, there was a precipitous drop in hepatic retinoid content (>60%), without further retinoid accumulation in the periphery. Follow-up studies in mutant mice revealed roles for RBP, CRBP1, and CD36 in retinoid mobilization and extrahepatic retinoid uptake, as well as a role for CYP2E1 in the catabolism of hepatic retinoid. In summary, alcohol has a biphasic effect on hepatic retinoid stores, characterized by an initial phase of rapid mobilization to extrahepatic tissues followed by extensive catabolism within the liver. © FASEB.

  11. Organochlorine contaminant and retinoid levels in blubber of common dolphins (Delphinus delphis) off northwestern Spain

    Energy Technology Data Exchange (ETDEWEB)

    Tornero, Victoria [Department of Animal Biology (Vertebrates), Faculty of Biology, University of Barcelona, Diagonal 645, 08071 Barcelona (Spain)]. E-mail: victoriatornero@ub.edu; Borrell, Assumpcio [Department of Animal Biology (Vertebrates), Faculty of Biology, University of Barcelona, Diagonal 645, 08071 Barcelona (Spain); Aguilar, Alex [Department of Animal Biology (Vertebrates), Faculty of Biology, University of Barcelona, Diagonal 645, 08071 Barcelona (Spain); Forcada, Jaume [Biological Sciences Division, NERC, British Antarctic Survey, High Cross, Madingley Road, Cambridge CB3 0ET (United Kingdom); Lockyer, Christina [Age Dynamics, Huldbergs Alle 42, DK-2800 Kongens, Lyngby (Denmark)

    2006-03-15

    The effect of age, sex, nutritive condition and organochlorine concentration on blubber retinoid concentrations was examined in 74 common dolphins incidentally caught off northwestern Spain. Age and blubber lipid content were strong determinants of the retinoid concentrations in males, while these variables did not account for the variation found in females. Retinoids were positively correlated with organochlorines in males and negatively in females. However, pollution levels were moderate and likely to be below threshold levels above that a toxicological response is to be expected. Thus, a cause-effect relationship between organochlorine and retinoid concentrations could not be properly established, and the observed correlation may be the result of an independent association of the two variables with age. Further research on the influence of the best predictor variables on retinoid dynamics is required to implement the use of retinoids as biomarkers of pollutant exposure in cetaceans. - Organochlorine contaminants and retinoids in common dolphins.

  12. Topical retinoids in acne vulgaris: update on efficacy and safety.

    Science.gov (United States)

    Thielitz, Anja; Gollnick, Harald

    2008-01-01

    Topical retinoids represent a mainstay of acne treatment because they expel mature comedones, reduce microcomedone formation, and exert anti-inflammatory effects. The first-generation retinoid tretinoin (all-trans retinoic acid) and the synthetic third-generation polyaromatics adapalene and tazarotene are approved for acne treatment by the US FDA, whereas topical tretinoin, isotretinoin (13-cis retinoic acid), and adapalene are accredited in Canada and Europe. Topical retinoids have a favorable safety profile distinct from the toxicity of their systemic counterparts. Local adverse effects, including erythema, dryness, itching, and stinging, occur frequently during the early treatment phase. Their impact varies with the vehicle formation, skin type, frequency and mode of application, use of moisturizers, and environmental factors such as sun exposure or temperature. The broad anti-acne activity and safety profile of topical retinoids justifies their use as first-line treatment in most types of non-inflammatory and inflammatory acne. They are also suitable as long-term medications, with no risk of inducing bacterial resistance, for maintenance of remission after cessation of initial combination therapy.

  13. Retinoids regulate gonadotropin action in cultured rat Sertoli cells.

    Science.gov (United States)

    Galdieri, M; Nisticò, L

    1994-01-01

    The effect of retinoids on cultured rat Sertoli cells was studied by evaluation of cAMP and estradiol production after gonadotropin stimulation in the presence or absence of the retinoid. Sertoli cells cultured in the presence of FSH produce a high amount of cAMP and increase their aromatase activity. The addition of retinol alone has no effect on cAMP and estradiol production; however, the presence of retinol in the culture medium exerts an inhibitory effect on Sertoli cell response to FSH stimulation. In particular, FSH-induced cAMP production of rat Sertoli cells was significantly reduced (50-60% decrease) both by retinol and by retinoic acid. This effect was observable during the first ten days of culture and was also evident when Sertoli cells were cultured in the presence of retinol and methylisobutylxanthine, an inhibitor of phosphodiesterase activity. Cholera toxin-stimulated cAMP levels were reduced by retinol, whereas forskolin-induced elevation of cAMP levels was not affected by vitamin treatment. The inhibitory effect of retinoids on FSH-stimulated aromatase activity of Sertoli cells, which is cAMP mediated, was also evident. In conclusion, the present study demonstrates that retinoids modulate FSH action on cultured rat Sertoli cells and decrease cAMP production.

  14. REACTIVITY PROFILE OF CONFORMATIONALLY-FLEXIBLE RETINOID RECEPTOR LIGANDS

    Science.gov (United States)

    Retinoids and associated derivatives represent a class of endogenousr hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of normal vertebrate development. Identification of potential RAR and RXRs ligands is of i...

  15. Psychiatric disorders, acne and systemic retinoids: comparison of risks.

    Science.gov (United States)

    Le Moigne, M; Bulteau, S; Grall-Bronnec, Marie; Gerardin, M; Fournier, Jean-Pascal; Jonville-Bera, A P; Jolliet, Pascale; Dreno, Brigitte; Victorri-Vigneau, C

    2017-09-01

    The link between isotretinoin, treatment of a severe form of acne, and psychiatric disorders remains controversial, as acne itself could explain the occurrence of psychiatric disorders. This study aims at assessing the disproportionality of psychiatric adverse events reported with isotretinoin in the French National PharmacoVigilance Database, compared with other systemic acne treatments and systemic retinoids. Data were extracted from the French National PharmacoVigilance Database for systemic acne treatments, systemic retinoids and drugs used as comparators. Each report was subjected to double-blind analysis by two psychiatric experts. A disproportionality analysis was performed, calculating the number of psychiatric ADRs divided by the total number of notifications for each drug of interest. Concerning acne systemic treatments: all 71 reports of severe psychiatric disorders involved isotretinoin, the highest proportion of mild/moderate psychiatric adverse events was reported with isotretinoin (14.1%). Among systemic retinoids, the highest proportion of severe and mild/moderate psychiatric events occurred with isotretinoin and alitretinoin. Our study raises the hypothesis that psychiatric disorders associated with isotretinoin are related to a class effect of retinoids, as a signal emerges for alitretinoin. Complementary studies are necessary to estimate the risk and further determine at-risk populations.

  16. CASTING A BROAD NETWORK: FISHING FOR MECHANISMS OF RETINOID TERATOGENICITY

    Science.gov (United States)

    This is a short essay that serves to introduce a featured paper for an issue of Toxicological Sciences. The paper being introduced describes a study of mechanisms of retinoid induced abnormal limb development in mice. The paper was notable because the authors used gene expressi...

  17. International Union of Pharmacology. LXIII. Retinoid X Receptors

    National Research Council Canada - National Science Library

    Pierre Germain; Pierre Chambon; Gregor Eichele; Ronald M. Evans; Mitchell A. Lazar; Mark Leid; Angel R. De Lera; Reuben Lotan; David J. Mangelsdorf; Hinrich Gronemeyer

    2006-01-01

    ...) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXR α , RXR β , and RXR γ. RARs bind both all- trans - and 9- cis -RA, whereas only the 9- cis -RA stereoisomer binds to RXRs...

  18. The Expanding Role for Retinoid Signaling in Heart Development

    Directory of Open Access Journals (Sweden)

    Loretta L. Hoover

    2008-01-01

    Full Text Available The importance of retinoid signaling during cardiac development has long been appreciated, but recently has become a rapidly expanding field of research. Experiments performed over 50 years ago showed that too much or too little maternal intake of vitamin A proved detrimental for embryos, resulting in a cadre of predictable cardiac developmental defects. Germline and conditional knockout mice have revealed which molecular players in the vitamin A signaling cascade are potentially responsible for regulating specific developmental events, and many of these molecules have been temporally and spatially characterized. It is evident that intact and controlled retinoid signaling is necessary for each stage of cardiac development to proceed normally, including cardiac lineage determination, heart tube formation, looping, epicardium formation, ventricular maturation, chamber and outflow tract septation, and coronary arteriogenesis. This review summarizes many of the significant milestones in this field and particular attention is given to recently uncovered cross-talk between retinoid signaling and other developmentally significant pathways. It is our hope that this review of the role of retinoid signaling during formation, remodeling, and maturation of the developing heart will serve as a tool for future discoveries.

  19. Retinoid modulation of plasminogen activator production in rat Sertoli cells.

    Science.gov (United States)

    Canipari, R; Galdieri, M

    2000-08-01

    Tissue type (t) and urokinase type (u) plasminogen activators (PAs) have been shown to be secreted by Sertoli cells in the seminiferous tubules in a cyclic fashion and to be dependent upon FSH stimulation or upon the presence of adjacent spermatogenic cells. In the present study we have analyzed the production of PAs by retinoid-treated rat Sertoli cells. In addition, because retinoids modulate the response of Sertoli cells to FSH either potentiating or antagonizing its action, we have investigated a possible modulation of FSH-stimulated PA production. Under basal conditions, Sertoli cells, isolated from prepubertal rats, secrete predominantly uPA. A significant dose-dependent inhibition of uPA activity was observed after treatment with retinol, while no significant effect was detected upon tPA secretion. When Sertoli cells were cultured in the presence of 0.25 microM retinol, a significant inhibition of uPA activity was evident after 16 h of treatment and reached approximately 80% after 48 h of treatment. The analysis of the mRNA levels revealed that retinol induces an inhibition of the steady-state levels of uPA mRNA without affecting those of tPA. Moreover, retinol affected uPA mRNA levels by increasing mRNA turnover. The effect of retinoids on Sertoli cells isolated from older animals was less evident, possibly due to the reduced production of uPA with the increase of age of the donor animals. Our results on the effect of retinoids upon Sertoli cell uPA production reinforce the importance of retinoids in the control of postnatal testis development.

  20. Retinoids, race and the pathogenesis of dengue hemorrhagic fever.

    Science.gov (United States)

    Mawson, Anthony R

    2013-12-01

    Dengue hemorrhagic fever (DHF) is the most significant mosquito-borne viral disease worldwide in terms of illness, mortality and economic cost, but the pathogenesis of DHF is not well understood and there is no specific treatment or vaccine. Based on evidence of liver involvement, it is proposed that dengue virus and retinoids interact to cause cholestatic liver damage, resulting in the spillage of stored retinoids into the circulation and in an endogenous form of hypervitaminosisis A manifested by the signs and symptoms of the disease, including: fever, severe joint and bone pain, capillary leakage, thrombocytopenia, headache, and gastrointestinal symptoms. While retinoids in low concentration are essential for numerous biological functions, they are prooxidant, cytotoxic, mutagenic and teratogenic in higher concentration, especially when unbound to protein, and an endogenous form of vitamin A intoxication is recognized in cholestasis. The model tentatively explains the observations that 1) repeat infections are more severe than initial dengue virus infections; 2) the incidence of denue has increased dramatically worldwide in recent decades; 3) DHF is less prevalent in people of African ancestry than those of other racial backgrounds; and 4) infants are protected from dengue. The retinoid toxicity hypothesis of DHF predicts the co-existence of low serum concentrations of retinol coupled with high concentrations of retinoic acid and an increased percentage of retinyl esters to total vitamin A. Subject to such tests, it may be possible to treat DHF effectively using drugs that target the metabolism and expression of retinoids. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle.

    Science.gov (United States)

    Golczak, Marcin; Kuksa, Vladimir; Maeda, Tadao; Moise, Alexander R; Palczewski, Krzysztof

    2005-06-07

    In vertebrate retinal photoreceptors, photoisomerization of opsin-bound visual chromophore 11-cis-retinal to all-trans-retinal triggers phototransduction events. Regeneration of the chromophore is a critical step in restoring photoreceptors to their dark-adapted state. This regeneration process, called the retinoid cycle, takes place in the photoreceptor outer segments and in the retinal pigmented epithelium (RPE). We have suggested that the regeneration of the chromophore might occur through a retinyl carbocation intermediate. Here, we provide evidence that isomerization is inhibited by positively charged retinoids, which could act as transition state analogs of the isomerization process. We demonstrate that retinylamine (Ret-NH2) potently and selectively inhibits the isomerization step of the retinoid cycle in vitro and in vivo. Ret-NH2 binds a protein(s) in the RPE microsomes, but it does not bind RPE65, a protein implicated in the isomerization reaction. Although Ret-NH2 inhibits the regeneration of visual chromophore in rods and, in turn, severely attenuates rod responses, it has a much smaller effect on cone function in mice. Ret-NH2 interacts only at micromolar concentrations with retinoic acid receptor, does not activate retinoid-X receptor, and is not a substrate for CYP26s, the retinoic acid-metabolizing cytochrome P450 enzymes. Ret-NH2 can be a significant investigational tool to study the mechanism of regeneration of visual chromophore.

  2. Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2012-01-01

    Full Text Available One of the key features of hepatocellular carcinoma (HCC is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR, a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of "clonal deletion and inhibition" therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss "combination chemoprevention" using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.

  3. Metformin Induces Apoptosis and Cell Cycle Arrest Mediated by Oxidative Stress, AMPK and FOXO3a in MCF-7 Breast Cancer Cells

    Science.gov (United States)

    Queiroz, Eveline A. I. F.; Puukila, Stephanie; Eichler, Rosangela; Sampaio, Sandra C.; Forsyth, Heidi L.; Lees, Simon J.; Barbosa, Aneli M.; Dekker, Robert F. H.; Fortes, Zuleica B.; Khaper, Neelam

    2014-01-01

    Recent studies have demonstrated that the anti-diabetic drug, metformin, can exhibit direct antitumoral effects, or can indirectly decrease tumor proliferation by improving insulin sensitivity. Despite these recent advances, the underlying molecular mechanisms involved in decreasing tumor formation are not well understood. In this study, we examined the antiproliferative role and mechanism of action of metformin in MCF-7 cancer cells treated with 10 mM of metformin for 24, 48, and 72 hours. Using BrdU and the MTT assay, it was found that metformin demonstrated an antiproliferative effect in MCF-7 cells that occurred in a time- and concentration- dependent manner. Flow cytometry was used to analyze markers of cell cycle, apoptosis, necrosis and oxidative stress. Exposure to metformin induced cell cycle arrest in G0-G1 phase and increased cell apoptosis and necrosis, which were associated with increased oxidative stress. Gene and protein expression were determined in MCF-7 cells by real time RT-PCR and western blotting, respectively. In MCF-7 cells metformin decreased the activation of IRβ, Akt and ERK1/2, increased p-AMPK, FOXO3a, p27, Bax and cleaved caspase-3, and decreased phosphorylation of p70S6K and Bcl-2 protein expression. Co-treatment with metformin and H2O2 increased oxidative stress which was associated with reduced cell number. In the presence of metformin, treating with SOD and catalase improved cell viability. Treatment with metformin resulted in an increase in p-p38 MAPK, catalase, MnSOD and Cu/Zn SOD protein expression. These results show that metformin has an antiproliferative effect associated with cell cycle arrest and apoptosis, which is mediated by oxidative stress, as well as AMPK and FOXO3a activation. Our study further reinforces the potential benefit of metformin in cancer treatment and provides novel mechanistic insight into its antiproliferative role. PMID:24858012

  4. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Eveline A I F Queiroz

    Full Text Available Recent studies have demonstrated that the anti-diabetic drug, metformin, can exhibit direct antitumoral effects, or can indirectly decrease tumor proliferation by improving insulin sensitivity. Despite these recent advances, the underlying molecular mechanisms involved in decreasing tumor formation are not well understood. In this study, we examined the antiproliferative role and mechanism of action of metformin in MCF-7 cancer cells treated with 10 mM of metformin for 24, 48, and 72 hours. Using BrdU and the MTT assay, it was found that metformin demonstrated an antiproliferative effect in MCF-7 cells that occurred in a time- and concentration-dependent manner. Flow cytometry was used to analyze markers of cell cycle, apoptosis, necrosis and oxidative stress. Exposure to metformin induced cell cycle arrest in G0-G1 phase and increased cell apoptosis and necrosis, which were associated with increased oxidative stress. Gene and protein expression were determined in MCF-7 cells by real time RT-PCR and western blotting, respectively. In MCF-7 cells metformin decreased the activation of IRβ, Akt and ERK1/2, increased p-AMPK, FOXO3a, p27, Bax and cleaved caspase-3, and decreased phosphorylation of p70S6K and Bcl-2 protein expression. Co-treatment with metformin and H2O2 increased oxidative stress which was associated with reduced cell number. In the presence of metformin, treating with SOD and catalase improved cell viability. Treatment with metformin resulted in an increase in p-p38 MAPK, catalase, MnSOD and Cu/Zn SOD protein expression. These results show that metformin has an antiproliferative effect associated with cell cycle arrest and apoptosis, which is mediated by oxidative stress, as well as AMPK and FOXO3a activation. Our study further reinforces the potential benefit of metformin in cancer treatment and provides novel mechanistic insight into its antiproliferative role.

  5. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells.

    Science.gov (United States)

    Queiroz, Eveline A I F; Puukila, Stephanie; Eichler, Rosangela; Sampaio, Sandra C; Forsyth, Heidi L; Lees, Simon J; Barbosa, Aneli M; Dekker, Robert F H; Fortes, Zuleica B; Khaper, Neelam

    2014-01-01

    Recent studies have demonstrated that the anti-diabetic drug, metformin, can exhibit direct antitumoral effects, or can indirectly decrease tumor proliferation by improving insulin sensitivity. Despite these recent advances, the underlying molecular mechanisms involved in decreasing tumor formation are not well understood. In this study, we examined the antiproliferative role and mechanism of action of metformin in MCF-7 cancer cells treated with 10 mM of metformin for 24, 48, and 72 hours. Using BrdU and the MTT assay, it was found that metformin demonstrated an antiproliferative effect in MCF-7 cells that occurred in a time- and concentration-dependent manner. Flow cytometry was used to analyze markers of cell cycle, apoptosis, necrosis and oxidative stress. Exposure to metformin induced cell cycle arrest in G0-G1 phase and increased cell apoptosis and necrosis, which were associated with increased oxidative stress. Gene and protein expression were determined in MCF-7 cells by real time RT-PCR and western blotting, respectively. In MCF-7 cells metformin decreased the activation of IRβ, Akt and ERK1/2, increased p-AMPK, FOXO3a, p27, Bax and cleaved caspase-3, and decreased phosphorylation of p70S6K and Bcl-2 protein expression. Co-treatment with metformin and H2O2 increased oxidative stress which was associated with reduced cell number. In the presence of metformin, treating with SOD and catalase improved cell viability. Treatment with metformin resulted in an increase in p-p38 MAPK, catalase, MnSOD and Cu/Zn SOD protein expression. These results show that metformin has an antiproliferative effect associated with cell cycle arrest and apoptosis, which is mediated by oxidative stress, as well as AMPK and FOXO3a activation. Our study further reinforces the potential benefit of metformin in cancer treatment and provides novel mechanistic insight into its antiproliferative role.

  6. The Dietary Flavonoid Fisetin Causes Cell Cycle Arrest, Caspase-Dependent Apoptosis, and Enhanced Cytotoxicity of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells.

    Science.gov (United States)

    Smith, Matthew L; Murphy, Kaylee; Doucette, Carolyn D; Greenshields, Anna L; Hoskin, David W

    2016-08-01

    Fisetin (3,3',4',7-tetrahydroxyflavone), a flavonoid found in a number of fruits and vegetables, has diverse biological activities, including cytotoxic effects on cancer cells. In this study, we investigated the effect of fisetin on triple-negative breast cancer (TNBC) cells. TNBC has a poorer prognosis than other types of breast cancer and treatment options for this disease are limited. Fisetin inhibited the growth of MDA-MB-468 and MDA-MB-231 TNBC cells, as well as their ability to form colonies, without substantially affecting the growth of non-malignant cells. In addition, fisetin inhibited the growth of estrogen receptor-bearing MCF-7 breast cancer cells and human epidermal growth factor receptor 2-overexpressing SK-BR-3 breast cancer cells. Fisetin inhibited TNBC cell division and induced apoptosis, which was associated with mitochondrial membrane permeabilization and the activation of caspase-9 and caspase-8, as well as the cleavage of poly(ADP-ribose) polymerase-1. Induction of caspase-dependent apoptosis by fisetin was confirmed by reduced killing of TNBC cells in the presence of the pan-caspase inhibitors Z-VAD-FMK and BOC-D-FMK. Decreased phosphorylation of histone H3 at serine 10 in fisetin-treated TNBC cells at G2/M phase of the cell cycle suggested that fisetin-induced apoptosis was the result of Aurora B kinase inhibition. Interestingly, the cytotoxic effect of cisplatin, 5-fluorouracil, and 4-hydroxycyclophosphamide metabolite of cyclophosphamide on TNBC cells was increased in the presence of fisetin. These findings suggest that further investigation of fisetin is warranted for possible use in the management of TNBC. J. Cell. Biochem. 117: 1913-1925, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Targeting ATP7A to increase the sensitivity of neuroblastoma cells to retinoid therapy.

    Science.gov (United States)

    Cheung, B B; Marshall, G M

    2011-09-01

    Following the discovery that defective retinoid signaling directly contributes to tumorigenesis, and, that retinoids have an anti-cancer effect in vitro and in vivo, retinoids have become part of the routine care in children with neuroblastoma at the stage of minimal residual disease. However, many patients still relapse following retinoid therapy, demonstrating the need for more effective retinoids and better assays to predict retinoid sensitivity in cancer cells. Recent evidence suggests that the copper metabolism gene, ATP7A, is retinoid-regulated and an important component of the retinoic acid receptor β (RARβ) anticancer effect in neuroblastoma cells. To highlight and further develop the concept of using ATP7A as a target in retinoid therapy, and combination therapy with copper chelators in neuroblastoma, the current literature and abstracts related to the clinical application of retinoids, the function of ATP7A and the clinical application of copper chelators are summarized. We propose that strategies targeting the copper export protein, ATP7A, in combination therapy with retinoids and copper depletion therapy, may have great therapeutic potential in the clinical treatment of neuroblastoma and other malignancies.

  8. Retinoid-binding proteins: similar protein architectures bind similar ligands via completely different ways.

    Directory of Open Access Journals (Sweden)

    Yu-Ru Zhang

    Full Text Available BACKGROUND: Retinoids are a class of compounds that are chemically related to vitamin A, which is an essential nutrient that plays a key role in vision, cell growth and differentiation. In vivo, retinoids must bind with specific proteins to perform their necessary functions. Plasma retinol-binding protein (RBP and epididymal retinoic acid binding protein (ERABP carry retinoids in bodily fluids, while cellular retinol-binding proteins (CRBPs and cellular retinoic acid-binding proteins (CRABPs carry retinoids within cells. Interestingly, although all of these transport proteins possess similar structures, the modes of binding for the different retinoid ligands with their carrier proteins are different. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we analyzed the various retinoid transport mechanisms using structure and sequence comparisons, binding site analyses and molecular dynamics simulations. Our results show that in the same family of proteins and subcellular location, the orientation of a retinoid molecule within a binding protein is same, whereas when different families of proteins are considered, the orientation of the bound retinoid is completely different. In addition, none of the amino acid residues involved in ligand binding is conserved between the transport proteins. However, for each specific binding protein, the amino acids involved in the ligand binding are conserved. The results of this study allow us to propose a possible transport model for retinoids. CONCLUSIONS/SIGNIFICANCE: Our results reveal the differences in the binding modes between the different retinoid-binding proteins.

  9. Retinoids and nuclear retinoid receptors in white and brown adipose tissues: physiopathologic aspects.

    Science.gov (United States)

    Flajollet, Sébastien; Staels, Bart; Lefebvre, Philippe

    2013-08-01

    Vitamin A, ingested either as retinol or β-carotene from animal- or plant-derived foods respectively, is a nutrient essential for many biological functions such as embryonic development, vision, immune response, tissue remodeling, and metabolism. Its main active metabolite is all trans-retinoic acid (atRA), which regulates gene expression through the activation of α, β, and γ isotypes of the nuclear atRA receptor (RAR). More recently, retinol derivatives were also shown to control the RAR activity, enlightening the interplay between vitamin A metabolism and RAR-mediated transcriptional control. The white and brown adipose tissues regulate the energy homeostasis by providing dynamic fatty acid storing and oxidizing capacities to the organism, in connection with the other fatty acid-consuming tissues. This concerted interorgan response to fatty acid fluxes is orchestrated, in part, by the endocrine activity of the adipose tissue depots. The adipose tissues are also sites for synthesizing and storing vitamin A derivatives, which will act as hormonal cues or intracellularly to regulate essential aspects of adipocyte biology. As agents that prevent adipocyte differentiation hence, expected to decrease fat mass, and inducers of uncoupling protein expression, thus, favoring energy expenditure, retinoids have prompted many investigations to decipher their roles in adipose tissue pathophysiology, which are summarized in this review.

  10. Activation of p53, inhibition of telomerase activity and induction of estrogen receptor beta are associated with the anti-growth effects of combination of ovarian hormones and retinoids in immortalized human mammary epithelial cells

    Directory of Open Access Journals (Sweden)

    Smith-Schneider Sallie

    2005-03-01

    Full Text Available Abstract Background A full-term pregnancy has been associated with reduced risk for developing breast cancer. In rodent models, the protective effect of pregnancy can be mimicked with a defined regimen of estrogen and progesterone combination (E/P. However, the effects of pregnancy levels of E/P in humans and their underlying mechanisms are not fully understood. In this report, we investigated the growth inhibitory effects of pregnancy levels of E/P and both natural and synthetic retinoids in an immortalized human mammary epithelial cell line, 76N TERT cell line. Results We observed that cell growth was modestly inhibited by E/P, 9-cis-retinoic acid (9-cis RA or all-trans-retinoic acid (ATRA, and strongly inhibited by N-(4-hydroxyphenyl retinamide (HPR. The growth inhibitory effects of retinoids were further increased in the presence of E/P, suggesting their effects are additive. In addition, our results showed that both E/P and retinoid treatments resulted in increased RARE and p53 gene activity. We further demonstrated that p53 and p21 protein expression were induced following the E/P and retinoid treatments. Furthermore, we demonstrated that while the telomerase activity was moderately inhibited by E/P, 9-cis RA and ATRA, it was almost completely abolished by HPR treatment. These inhibitions on telomerase activity by retinoids were potentiated by co-treatment with E/P, and correlated well with their observed growth inhibitory effects. Finally, this study provides the first evidence that estrogen receptor beta is up-regulated in response to E/P and retinoid treatments. Conclusion Taken together, our studies show that part of the anti-growth effects of E/P and retinoids is p53 dependent, and involve activation of p53 and subsequent induction of p21 expression. Inhibition of telomerase activity and up-regulation of estrogen receptor beta are also associated with the E/P- and retinoid-mediated growth inhibition. Our studies also demonstrate that

  11. Retinoids in the treatment of glioma: a new perspective

    Directory of Open Access Journals (Sweden)

    Mawson AR

    2012-08-01

    Full Text Available Anthony R MawsonDepartment of Health Policy and Management, School of Health Sciences, College of Public Service, Jackson State University, Jackson, MS, USAAbstract: Primary brain tumors are among the top ten causes of cancer-related deaths in the US. Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors diagnosed in adults each year and are associated with high morbidity and mortality. Despite optimal treatment, the prognosis for patients with gliomas remains poor. The use of retinoids (vitamin A and its congeners in the treatment of certain tumors was originally based on the assumption that these conditions were associated with an underlying deficiency of vitamin A and that supplementation with pharmacological doses would correct the deficiency. Yet the results of retinoid treatment have been only modestly beneficial and usually short-lived. Studies also indicate that vitamin A excess and supplementation have pro-oxidant effects and are associated with increased risks of mortality from cancer and other diseases. The therapeutic role of vitamin A in cancer thus remains uncertain and a new perspective on the facts is needed. The modest and temporary benefits of retinoid treatment could result from a process of feedback inhibition, whereby exogenous retinoid temporarily inhibits the endogenous synthesis of these compounds. In fact, repeated and/or excessive exposure of the tissues to endogenous retinoic acid may contribute to carcinogenesis. Gliomas, in particular, may result from an imbalance in retinoid receptor expression initiated by environmental factors that increase the endogenous production of retinoic acid in glia. At the receptor level, it is proposed that this imbalance is characterized by excessive expression of retinoic acid receptor-α(RARα and reduced expression of retinoic acid receptor-β (RARβ. This suggests a potential new treatment strategy for gliomas, possibly even at a

  12. Long-Distance Retinoid Signaling in the Zebra Finch Brain

    Science.gov (United States)

    Roeske, Tina C.; Scharff, Constance; Olson, Christopher R.; Nshdejan, Arpik; Mello, Claudio V.

    2014-01-01

    All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, is a powerful signaling molecule that regulates large-scale morphogenetic processes during vertebrate embryonic development, but is also involved post-natally in regulating neural plasticity and cognition. In songbirds, it plays an important role in the maturation of learned song. The distribution of the ATRA-synthesizing enzyme, zRalDH, and of ATRA receptors (RARs) have been described, but information on the distribution of other components of the retinoid signaling pathway is still lacking. To address this gap, we have determined the expression patterns of two obligatory RAR co-receptors, the retinoid X receptors (RXR) α and γ, and of the three ATRA-degrading cytochromes CYP26A1, CYP26B1, and CYP26C1. We have also studied the distribution of zRalDH protein using immunohistochemistry, and generated a refined map of ATRA localization, using a modified reporter cell assay to examine entire brain sections. Our results show that (1) ATRA is more broadly distributed in the brain than previously predicted by the spatially restricted distribution of zRalDH transcripts. This could be due to long-range transport of zRalDH enzyme between different nuclei of the song system: Experimental lesions of putative zRalDH peptide source regions diminish ATRA-induced transcription in target regions. (2) Four telencephalic song nuclei express different and specific subsets of retinoid-related receptors and could be targets of retinoid regulation; in the case of the lateral magnocellular nucleus of the anterior nidopallium (lMAN), receptor expression is dynamically regulated in a circadian and age-dependent manner. (3) High-order auditory areas exhibit a complex distribution of transcripts representing ATRA synthesizing and degrading enzymes and could also be a target of retinoid signaling. Together, our survey across multiple connected song nuclei and auditory brain regions underscores the prominent role of

  13. Long-distance retinoid signaling in the zebra finch brain.

    Directory of Open Access Journals (Sweden)

    Tina C Roeske

    Full Text Available All-trans retinoic acid (ATRA, the main active metabolite of vitamin A, is a powerful signaling molecule that regulates large-scale morphogenetic processes during vertebrate embryonic development, but is also involved post-natally in regulating neural plasticity and cognition. In songbirds, it plays an important role in the maturation of learned song. The distribution of the ATRA-synthesizing enzyme, zRalDH, and of ATRA receptors (RARs have been described, but information on the distribution of other components of the retinoid signaling pathway is still lacking. To address this gap, we have determined the expression patterns of two obligatory RAR co-receptors, the retinoid X receptors (RXR α and γ, and of the three ATRA-degrading cytochromes CYP26A1, CYP26B1, and CYP26C1. We have also studied the distribution of zRalDH protein using immunohistochemistry, and generated a refined map of ATRA localization, using a modified reporter cell assay to examine entire brain sections. Our results show that (1 ATRA is more broadly distributed in the brain than previously predicted by the spatially restricted distribution of zRalDH transcripts. This could be due to long-range transport of zRalDH enzyme between different nuclei of the song system: Experimental lesions of putative zRalDH peptide source regions diminish ATRA-induced transcription in target regions. (2 Four telencephalic song nuclei express different and specific subsets of retinoid-related receptors and could be targets of retinoid regulation; in the case of the lateral magnocellular nucleus of the anterior nidopallium (lMAN, receptor expression is dynamically regulated in a circadian and age-dependent manner. (3 High-order auditory areas exhibit a complex distribution of transcripts representing ATRA synthesizing and degrading enzymes and could also be a target of retinoid signaling. Together, our survey across multiple connected song nuclei and auditory brain regions underscores the

  14. Sensitivity of human tumor cells to retinoids or combined treatment with retinoids and ionizing radiation is not dependent on RAR-{beta}2 induction

    Energy Technology Data Exchange (ETDEWEB)

    Blaese, M.A.; Santo-Hoeltje, L.; Peter Rodemann, H. [Section of Radiobiology and Molecular Environmental Research, Eberhard Karls Univ., Tuebingen (Germany)

    2003-06-01

    Purpose: The nuclear retinoic acid receptor beta 2 (RAR-{beta}2) is supposed to be a prognostic marker of retinoid sensitivity in patients after retinoid treatment. Therefore, we investigated the role of RAR-{beta}2 induction with respect to clonogenic survival of different human tumor cells under retinoid treatment alone or in combination with irradiation. Material and Methods: The retinoid responsiveness of seven human tumor cell lines (HTB35, HTB43, SCC4, SCC9, MDA-MB231, HCT116, and CaSki) as well as one normal human skin fibroblast (HSF6) as control cells was analyzed by colony formation assay under retinoid and retinoid/radiation treatment. Basic mRNA levels of all retinoic acid receptors as well as the treatment-dependent modulation of mRNA and protein levels of RAR-{beta} were analyzed by RT-PCR and Western blot analysis under the different treatment conditions. Results: It could be shown that the clonogenic inactivation of tumor cells under retinoid treatment alone or in combination with irradiation was not correlated with the induction of RAR-{beta} on mRNA and protein level, respectively. The control cells (HSF6), however, demonstrated an induction. Conclusion: The responsiveness of human tumor cells to retinoid treatment alone and particularly to combined treatment with irradiation is not necessarily associated with an induction of RAR-{beta}2 as it has been postulated so far. Thus, loss of RAR-{beta} induction in tumors does not seem to be a good prognostic factor for successful retinoid/radiation therapy, since RAR-{beta}-deficient tumors may also present strong retinoid responsiveness. (orig.)

  15. Molecular Biology and Analytical Chemistry Methods Used to Probe the Retinoid Cycle

    Science.gov (United States)

    Golczak, Marcin; Bereta, Grzegorz; Maeda, Akiko; Palczewski, Krzysztof

    2015-01-01

    The retinoid (visual) cycle is a complex enzymatic pathway essential for regeneration of the visual chromophore, 11-cis-retinal, a component of rhodopsin that undergoes activation by light in vertebrate eyes. Pathogenic mutations within genes encoding proteins involved in the retinoid cycle lead to abnormalities in retinoid homeostasis and numerous congenital blinding diseases of humans. Thus, elucidation of disease-specific changes in enzymatic activities and retinoid content of the retina can provide important insights into the mechanisms of disease initiation and progression. Here, we use the protein RPE65 as an example to describe generally applicable methods for determining the stability and enzymatic activity of proteins and their mutants involved in retinoid metabolism. Additionally, we introduce a range of analytical techniques involving high-performance liquid chromatography and mass spectrometry to detect and quantify retinoids and their derivatives in eye extracts. Biochemical protocols combined with advanced mass spectrometry should facilitate fundamental biological studies of vision. PMID:20552432

  16. Single cell analysis in native tissue: Quantification of the retinoid content of hepatic stellate cells

    Science.gov (United States)

    Galler, Kerstin; Requardt, Robert Pascal; Glaser, Uwe; Markwart, Robby; Bocklitz, Thomas; Bauer, Michael; Popp, Jürgen; Neugebauer, Ute

    2016-04-01

    Hepatic stellate cells (HSCs) are retinoid storing cells in the liver: The retinoid content of those cells changes depending on nutrition and stress level. There are also differences with regard to a HSC’s anatomical position in the liver. Up to now, retinoid levels were only accessible from bulk measurements of tissue homogenates or cell extracts. Unfortunately, they do not account for the intercellular variability. Herein, Raman spectroscopy relying on excitation by the minimally destructive wavelength 785 nm is introduced for the assessment of the retinoid state of single HSCs in freshly isolated, unprocessed murine liver lobes. A quantitative estimation of the cellular retinoid content is derived. Implications of the retinoid content on hepatic health state are reported. The Raman-based results are integrated with histological assessments of the tissue samples. This spectroscopic approach enables single cell analysis regarding an important cellular feature in unharmed tissue.

  17. Potential role of retinoids in ovarian physiology and pathogenesis of polycystic ovary syndrome.

    Science.gov (United States)

    Jiang, Yanwen; Li, Chunjin; Chen, Lu; Wang, Fengge; Zhou, Xu

    2017-06-01

    Retinoids (retinol and its derivatives) are required for maintaining vision, immunity, barrier function, reproduction, embryogenesis, cell proliferation and differentiation. Furthermore, retinoid signaling plays a key role in initiating meiosis of germ cells of the mammalian fetal ovary. Recently, studies indicated that precise retinoid level regulation in the ovary provides a molecular control of ovarian development, steroidogenesis and oocyte maturation. Besides, abnormal retinoid signaling may be involved in the pathogenesis of polycystic ovary syndrome (PCOS), one of the most common ovarian endocrinopathies in reproductive-aged women worldwide. This review primarily summarizes recent advancements made in investigating the action of retinoid signaling in ovarian physiology as well as the abnormal retinoid signaling in PCOS. Copyright © 2017. Published by Elsevier B.V.

  18. Molecular biology and analytical chemistry methods used to probe the retinoid cycle.

    Science.gov (United States)

    Golczak, Marcin; Bereta, Grzegorz; Maeda, Akiko; Palczewski, Krzysztof

    2010-01-01

    The retinoid (visual) cycle is a complex enzymatic pathway essential for regeneration of the visual chromophore, 11-cis-retinal, a component of rhodopsin that undergoes activation by light in vertebrate eyes. Pathogenic mutations within genes encoding proteins involved in the retinoid cycle lead to abnormalities in retinoid homeostasis and numerous congenital blinding diseases of humans. Thus, elucidation of disease-specific changes in enzymatic activities and retinoid content of the retina can provide important insights into the mechanisms of disease initiation and progression. Here, we use the protein RPE65 as an example to describe generally applicable methods for determining the stability and enzymatic activity of proteins and their mutants involved in retinoid metabolism. Additionally, we introduce a range of analytical techniques involving high-performance liquid chromatography and mass spectrometry to detect and quantify retinoids and their derivatives in eye extracts. Biochemical protocols combined with advanced mass spectrometry should facilitate fundamental biological studies of vision.

  19. The neurotoxic effects of vitamin A and retinoids

    Directory of Open Access Journals (Sweden)

    MARCOS ROBERTO DE OLIVEIRA

    2015-08-01

    Full Text Available Vitamin A (retinol and its congeners - the retinoids - participate in a panoply of biological events, as for instance cell differentiation, proliferation, survival, and death, necessary to maintain tissue homeostasis. Furthermore, such molecules may be applied as therapeutic agents in the case of some diseases, including dermatological disturbances, immunodeficiency, and cancer (mainly leukemia. In spite of this, there is a growing body of evidences showing that vitamin A doses exceeding the nutritional requirements may lead to negative consequences, including bioenergetics state dysfunction, redox impairment, altered cellular signaling, and cell death or proliferation, depending on the cell type. Neurotoxicity has long been demonstrated as a possible side effect of inadvertent consumption, or even under medical recommendation of vitamin A and retinoids at moderate to high doses. However, the exact mechanism by which such molecules exert a neurotoxic role is not clear yet. In this review, recent data are discussed regarding the molecular findings associated with the vitamin A-related neurotoxicity.

  20. Antibodies to Placental Immunoregulatory Ferritin with Transfer of Polyclonal Lymphocytes Arrest MCF-7 Human Breast Cancer Growth in a Nude Mouse Model

    Directory of Open Access Journals (Sweden)

    Marisa Halpern

    2007-06-01

    Full Text Available The recently cloned human gene named “placental immunoregulatory ferritin” (PLIF is a pregnancyrelated immunomodulator. Recombinant PLIF and its bioactive domain C48 are immune-suppressive and induce pronounced IL-10 production by immune cells. PLIF is expressed in the placenta and breast cancer cells. Blocking PLIF in pregnant mice by anti-C48 antibodies inhibited placental and fetal growth and modulated the cytokine network. It has been revealed that anti-C48 treatment inhibited MCF-7 tumor growth in nude mice. However, this significant effect was observed only in those transfused with human peripheral blood mononuclear cells. Blocking PLIF in tumor-engrafted human immune cell transfused mice resulted in massive infiltration of human CD45+ cells (mainly CD8+ T cells, both intratumorally and in the tumor periphery, and a significant number of caspase-3+ cells. In vitro, antiC48 treatment of MCF-7 tumor cells cocultured with human lymphocytes induced a significant increase in interferon-γ secretion. We conclude that blocking PLIF inhibits breast cancer growth, possibly by an effect on the cytokine network in immune cells and on breakdown of immunosuppression.

  1. Spironolactone and topical retinoids in adult female cyclical acne.

    Science.gov (United States)

    Lessner, Erin; Fisher, Samantha; Kobraei, Katherina; Osleber, Michael; Lessner, Rebecca; Elliott, Lauren; Wesson, Stanton

    2014-02-01

    To access the efficacy of spironolactone and topical retinoids in the treatment of female cyclical acne. A retrospective chart review on 41 female patients age 19-57 years old with cyclical acne was performed. Patients were examined over the course of 2 to 102 months while taking 50 to 200 mg of spironolactone and topical tretinoin 0.025% or adapalene 0.1% cream. All were diagnosed with acne rated mild to severe, prior to treatment, and were started on an initial dose of 50 mg po daily. If significant improvement was not seen within the first 3-6 months, the dose was either held or increased in 25 mg increments every 3 months. Patients on oral and topical antibiotics, as well as patients on photodynamic therapy were excluded from the study. The response to treatment was rated on a 0-4 scale with 0 being no response and 4 corresponding to clear skin. One patient (2.4%) had no response to treatment. This patient was only on 50 mg po daily for only 2 months. Only 5 (12.2%) patients had minimal response to treatment and 9 (22.0%), 12 (29.3%), and 14 (34.1%) had a good, excellent, or clear response respectively. The study showed 26 (63.4%) women on treatment with spironolactone and topical retinoids had an excellent or clear outcome, and 35 (85.4%) were considered to have a good, excellent, or clear response. The addition of spironolactone to topical retinoid treatment suggests a superior response to retinoids alone in clearance of female adult cyclical acne.

  2. Consequences of metal exposure on retinoid metabolism in vertebrates: a review.

    Science.gov (United States)

    Defo, M A; Spear, P A; Couture, P

    2014-02-10

    What we generally refer to as 'vitamin A' is a group of naturally-occurring molecules structurally similar to retinol that are capable of exerting biological activity. These retinoids are essential to diverse physiological functions including vision, immune response, bone mineralization, reproduction, cell differentiation, and growth. As well, some retinoids have antioxidant properties. Independent studies published over the last few decades have revealed that many fish and wildlife populations living in highly polluted environments have altered retinoid status possibly associated with retinoid metabolic or homeostatic mechanisms. Substantial evidence links organic contaminant exposure with changes in retinoid status in animal populations, but only a few detailed studies have been published implicating inorganic contaminants such as metals. This mini-review selectively deals with field and laboratory studies reporting associations between environmental contaminants, especially trace metals, and alterations in retinoid status. Both essential and non-essential trace metals have been reported to affect retinoid status. This review focuses on metabolic imbalances of retinoids in relation to metal contamination and illustrates possible modes of action. The role of retinoids as antioxidants and their potential as biomarkers of metal contamination are discussed. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  3. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids.

    OpenAIRE

    Allenby, G; Bocquel, M T; Saunders, M.; Kazmer, S; Speck, J; Rosenberger, M.; Lovey, A; Kastner, P; Grippo, J F; Chambon, P

    1993-01-01

    The binding of endogenous retinoids and stereoisomers of retinoic acid (RA) to the retinoid nuclear receptors, RA receptor (RARs) and retinoid X receptors (RXRs), was characterized using nucleosol preparations from transiently transfected COS-1 cells. Among several stereoisomers of RA tested, including 7-cis-, 9-cis-, 11-cis-, 13-cis-, and all-trans-RA, only 9-cis-RA effectively competes with 9-cis-[3H]RA binding to the RXRs. Additionally, the endogenous retinoid trans-didehydro-RA (t-ddRA) d...

  4. [Maternal and fetal retinoid assay. Two case reports of isotretinoin (Roaccutane) exposure].

    Science.gov (United States)

    Pons, J C; Ville, Y; Imbert, M C; Thomas, A; Frydman, R; Benifla, J L

    1996-01-01

    We report on 2 women who were treated with retinoids (Roaccutan, isotretinoin) during the first trimester of their pregnancies. Therapeutic abortions were carried out. The interest in these case reports lies in the determination of concentration of isotretinoin and its metabolites (4-oxo-isotretinoin, and tretinoin) in foetal tissues, using high performance liquid chromatography. The findings show the significant transplacental passage of isotretinoin, an accumulation of 4-oxo-isotretinoin in the liver, and a low concentration of retinoids in the brain of these foetuses. Contraception must be used with retinoid treatment and for 4 weeks after retinoid withdrawal.

  5. Fetal tissue dosages of retinoids. Experimental study concerning a case of isotretinoin (Roaccutan) administration and pregnancy.

    Science.gov (United States)

    Benifla, J L; Ville, Y; Imbert, M C; Frydman, R; Thomas, A; Pons, J C

    1995-01-01

    The authors report the case of a women who took retinoids (Roaccutan, isotretinoin) during the first trimester of pregnancy, and a therapeutic abortion was carried out. The interest in this case report lies in the determination of the concentration of isotretinoin and its metabolites (4-oxo-isotretinoin, and tretinoin) in fetal tissues, using high performance liquid chromatography. The findings show the significant transplacental crossing of isotretinoin, an accumulation of 4-oxo-isotretinoin in the liver, and a low concentration of retinoids in the brain of this 4-month-old fetus. The authors emphasize that contraception must be used during retinoid treatment, and 4 weeks after retinoids have been stopped.

  6. CCN5/WISP-2 promotes growth arrest of triple-negative breast cancer cells through accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation.

    Science.gov (United States)

    Haque, I; Banerjee, S; De, A; Maity, G; Sarkar, S; Majumdar, M; Jha, S S; McGragor, D; Banerjee, S K

    2015-06-11

    The matricellular protein CCN5/WISP-2 represents a promising target in triple-negative breast cancer (TNBC) because treatment or induced activation of CCN5 in TNBC cells promotes cell growth arrest at the G0/G1 phase, reduces cell proliferation and delays tumor growth in the xenograft model. Our studies found that the p27(Kip1) tumor suppressor protein is upregulated and relocalized to the nucleus from cytoplasm by CCN5 in these cells and that these two events (upregulation and relocalization of p27(Kip1)) are critical for CCN5-induced growth inhibition of TNBC cells. In the absence of CCN5, p27(Kip1) resides mostly in the cytoplasm, which is associated with the aggressive nature of cancer cells. Mechanistically, CCN5 inhibits Skp2 expression, which seems to stabilize the p27(Kip1) protein in these cells. On the other hand, CCN5 also recruits FOXO3a to mediate the transcriptional regulation of p27(Kip1). The recruitment of FOXO3a is achieved by the induction of its expression and activity through shifting from cytoplasm to the nucleus. Our data indicate that CCN5 blocks PI3K/AKT signaling to dephosphorylate at S318, S253 and Thr32 in FOXO3a for nuclear relocalization and activation of FOXO3a. Moreover, inhibition of α6β1 receptors diminishes CCN5 action on p27(Kip1) in TNBC cells. Collectively, these data suggest that CCN5 effectively inhibits TNBC growth through the accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation, and thus, activation of CCN5 may have the therapeutic potential to kill TNBC.

  7. Co-treatment with retinyl retinoate and a PPARα agonist reduces retinoid dermatitis.

    Science.gov (United States)

    Kim, Bora; Kim, Jin E; Kim, Hyuk; Lee, Joo D; Choi, Kang-Yell; Lee, Seung H

    2012-06-01

    Retinoids have been used for the treatment of skin disorders such as acne, psoriasis, and photoaging. However, despite their beneficial effects, topical retinoids often cause severe local irritation called retinoid dermatitis. We previously developed a novel vitamin A derivative, retinyl retinoate, which induces less irritation and affords excellent tolerance. In this study, we examined whether co-treatment with topical peroxisome proliferator-activated receptor-α (PPARα) agonists (e.g. WY14643) reduce retinoid dermatitis in hairless mouse skin.   The effect of concomitant treatment with a PPARα agonist on retinoid dermatitis in hairless mouse epidermis was evaluated by measuring transepidermal water loss, epidermal histology, and cytokine expression.   Retinyl retinoate induced less severe retinoid dermatitis than retinoic acid. Topical application of a PPARα agonist improved the stratum corneum structure and function, reduced mRNA expression of interleukin (IL)-1α, tumor necrosis factor-α and IL-8, and inhibited ear edema induced by retinoic acid or retinyl retinoate.   Our results indicate that PPARα agonists can potentially be used to improve retinoid dermatitis. We suggest that co-treatment with retinyl retinoate and a PPARα agonist may reduce or prevent detrimental alterations in retinoid-treated skin. © 2012 The International Society of Dermatology.

  8. Working Memory Deficits in Retinoid X receptor [gamma]-Deficient Mice

    Science.gov (United States)

    Wietrzych, Marta; Meziane, Hamid; Sutter, Anne; Ghyselinck, Norbert; Chapman, Paul F.; Chambon, Pierre; Krezel, Wojciech

    2005-01-01

    Retinoid signaling has been recently shown to be required for mnemonic functions in rodents. To dissect the behavioral and molecular mechanisms involved in this requirement, we have analyzed the spatial and recognition working memory in mice carrying null mutations of retinoid receptors RAR[subscript [beta

  9. Abnormal retinoid and TrkB signaling in the prefrontal cortex in mood disorders

    NARCIS (Netherlands)

    Qi, Xin-Rui; Zhao, Juan; Liu, Ji; Fang, Hui; Swaab, Dick F; Zhou, Jiang-Ning

    The prefrontal cortex shows structural and functional alterations in mood disorders. Retinoid signaling, brain-derived neurotrophic factor (BDNF), and its receptor TrkB are reported to be involved in depression. Here, we found that mRNA levels of key elements of retinoid signaling were significantly

  10. The neurobehavioral teratology of retinoids: a 50-year history.

    Science.gov (United States)

    Adams, Jane

    2010-10-01

    This review of the central nervous system (CNS) and behavioral teratology of the retinoids over the last 50 years is a commemorative retrospective organized by decade to show the prominent research focus within each period and the most salient findings. In the 1960s, research focused on the gross CNS malformations associated with exposure and the delineation of dose-response and stage-specific responses in rodent models. Relevant scientific events before and during the 1960s are also discussed to provide the zeitgeist in which the field of neurobehavioral teratology emerged in the 1970s. During this period, studies demonstrated that adverse effects on postnatal behavior could be produced in animals exposed to doses of vitamin A lower than those that were teratogenic or impacted growth. Work during the 1980s showed an overrepresentation of behavioral studies focused on the reliability of screening methods, while the marked effects of human exposure were illustrated in children born to women treated with isotretinoin during pregnancy. The human catastrophe invigorated research during the 1990s, a period when technological advances allowed more elegant examinations of the developing CNS, of biochemical, cellular, and molecular developmental events and regulatory actions, and of the effects of direct genetic manipulations. Likewise, research in the 1990s reflected a reinvigoration of research in neurobehavioral teratology evinced in studies that used animal models to try to better understand human vulnerability. These foci continued in the 2000-2010 period while examinations of the role of retinoids in brain development and lifelong functioning became increasingly sophisticated and broader in scope. This review of the work on retinoids also provides a lens on the more general ontogeny of the field of neurobehavioral teratology. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

  11. SYSTEMIC RETINOIDS IN THE MANAGEMENT OF OF ICHTHYOSES AND RELATED SKIN TYPES

    Science.gov (United States)

    DiGiovanna, John J.; Mauro, Theodora; Milstone, Leonard M.; Schmuth, Matthias; Toro, Jorge

    2013-01-01

    The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid containing treatments have been used since the early Egyptians ~1550BC. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930’s. Early use of high dose vitamin A demonstrated efficacy but, because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types. PMID:23384018

  12. Pittsburgh Police Arrest Data

    Data.gov (United States)

    Allegheny County / City of Pittsburgh / Western PA Regional Data Center — Arrest data contains information on people taken into custody by City of Pittsburgh police officers. More serious crimes such as felony offenses are more likely to...

  13. A conserved retinoid X receptor (RXR) from the mollusk Biomphalaria glabrata transactivates transcription in the presence of retinoids.

    Science.gov (United States)

    Bouton, D; Escriva, H; de Mendonça, R L; Glineur, C; Bertin, B; Noël, C; Robinson-Rechavi, M; de Groot, A; Cornette, J; Laudet, V; Pierce, R J

    2005-04-01

    Retinoid X receptors (RXR) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have been characterized in a wide variety of metazoan phyla. They act as heterodimer partners of other nuclear receptors, and in vertebrates also activate transcription as homodimers in the presence of a ligand, 9-cis retinoic acid. In order to test the hypothesis that retinoic acid signaling pathways involving RXRs are present in the Lophotrochozoa, we have sought to isolate conserved members of this family from the platyhelminth parasite Schistosoma mansoni and its intermediate host, the mollusk Biomphalaria glabrata. Here we report that an RXR ortholog from B. glabrata (BgRXR) is better conserved, compared with mouse RXRalpha, both in the DNA-binding domain (89% identity) and in the ligand-binding domain (LBD) (81% identity), than are arthropod homologs. In EMSA, BgRXR binds to the direct repeat response element DR1 as a homodimer or as a heterodimer with mammalian RARalpha, LXR, FXR or PPARalpha. When transfected alone into mammalian cell lines, BgRXR transactivated transcription of a reporter gene from the Apo-A1 promoter in the presence of 9-cis retinoic acid or DHA. Constructs with the Gal4 DNA binding domain fused to the hinge and LBDs of BgRXR were used to show that ligand-dependent activation of transcription by BgRXR required its intact AF-2 activation domain, and that the LBD can form homodimers. Finally, the binding of 9-cis retinoic acid preferentially protected the LBD of BgRXR from degradation by trypsin in a proteolysis protection assay. Our results show that BgRXR binds and is activated by retinoids and suggest that retinoid signaling pathways are conserved in the Lophotrochozoa. The nucleotide sequence reported in this paper has been submitted to the GenBank/EBI Data Bank with accession no. AY048663.

  14. Synergistic Effects of PPARγ Ligands and Retinoids in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs, which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXRα due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARγ/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRα was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARγ, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRα because the inhibition of RXRα phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.

  15. (111)In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection.

    Science.gov (United States)

    Cai, Zhongli; Chattopadhyay, Niladri; Yang, Kaiyu; Kwon, Yongkyu Luke; Yook, Simmyung; Pignol, Jean-Philippe; Reilly, Raymond M

    2016-12-01

    Gold nanoparticles (AuNP; 30nm) were modified with polyethylene glycol (PEG) chains linked to trastuzumab for binding to HER2-positive breast cancer (BC) cells and diethylenetriaminepentaacetic acid (DTPA) for complexing the Auger electron-emitter, (111)In (trastuzumab-AuNP-(111)In). Our objective was to determine the cytotoxicity of trastuzumab-AuNP-(111)In on HER2-positive BC cells in vitro and evaluate its tumor growth inhibition properties and normal tissue toxicity in vivo following intratumoral (i.t.) injection in mice with s.c. HER2-overexpressing BC xenografts. Binding and internalization of trastuzumab-AuNP-(111)In or non-targeted AuNP-(111)In in SK-BR-3 (1-2×10(6) HER2/cell) and MDA-MB-361 (5×10(5) HER2/cell) human BC cells were studied. The surviving fraction (SF) of SK-BR-3 or MDA-MB-361 cells exposed to trastuzumab-AuNP-(111)In or AuNP-(111)In was determined. DNA double-strand breaks (DSBs) were assayed by probing for γ-H2AX. Tumor growth was monitored over 70days in CD1 athymic mice with s.c. MDA-MB-361 xenografts after i.t. injection of 10MBq (0.7mg; 2.6×10(12) AuNP) of trastuzumab-AuNP-(111)In and normal tissue toxicity was assessed by monitoring body weight, complete blood cell (CBC) counts and serum alanine aminotransferase (ALT) and creatinine (Cr). Trastuzumab-AuNP-(111)In was specifically bound by SK-BR-3 and MDA-MB-361 cells. Trastuzumab-AuNP-(111)In was more efficiently internalized than AuNP-(111)In and localized to a peri-nuclear region. The SF fraction of SK-BR-3 cells was reduced by 1.8-fold by treatment with 3nM (7MBq/mL) of trastuzumab-AuNP-(111)In. The SF of MDA-MB-361 cells was reduced by 3.7-fold at 14.4nM (33.6MBq/mL). In comparison, non-targeted AuNP-(111)In at these concentrations reduced the SF of SK-BR-3 or MDA-MB-361 cells by 1.2-fold (P=0.03) and 1.7-fold (Ptrastuzumab-AuNP-(111)In compared to AuNP-(111)In, but unlabeled trastuzumab-AuNP did not increase DNA DSBs. Local i.t. injection of trastuzumab-AuNP-(111)In in CD1

  16. Retinoids and motor neuron disease: Potential role in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Riancho, Javier; Berciano, Maria T; Ruiz-Soto, Maria; Berciano, Jose; Landreth, Gary; Lafarga, Miguel

    2016-01-15

    Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscular atrophy and unfortunately it does not have an effective treatment. Although a small proportion of ALS cases have a familiar origin, the vast majority of them are thought to have a sporadic origin. Although the pathogenesis of ALS has not been fully elucidated, various disorders in different cellular functions such as gene expression, protein metabolism, axonal transport and glial cell disorders have been linked to MN degeneration. Among them, proteostasis is one of the best studied. Retinoids are vitamin A-derived substances that play a crucial role in embryogenesis, development, programmed cell death and other cellular functions. Retinoid agonists behave as transcription factors throughout the activation of the nuclear retinoid receptors. Several reports in the literature suggest that retinoids are involved in proteostasis regulation, by modulating its two major pathways, the ubiquitin-proteasome system and the autophagy-lysosome response. Additionally, there are some evidences for a role of retinoids themselves, in ALS pathogenesis. In this review, we discuss the importance of proteostasis disruption as a trigger for MN degeneration and the capability of retinoids to modulate it, as well as the potential therapeutic role of retinoids as a new therapy in ALS. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Retinoid X receptor α and retinoids are key regulators in apoptosis of trophoblasts of patients with recurrent miscarriages.

    Science.gov (United States)

    Pestka, A; Toth, B; Kuhn, C; Hofmann, S; Wiest, I; Wypior, G; Friese, K; Jeschke, U

    2011-10-01

    The retinoid X receptor α (RXRα) is a nuclear hormone receptor that is able to bind other nuclear receptors in a heterodimeric complex, thereby activating gene transcription. Recently, we identified enhanced expression of RXRα in extravillous trophoblasts (EVT) and villous trophoblasts (VT) of miscarried placentas. In addition, an increased number of apoptotic EVT was present in miscarried placentas. In this study, on the basis of immunocytochemical analysis, western blots, and quantitative real-time reverse transcription PCR, we could demonstrate a reduced expression of RXRα in choriocarcinoma cell lines and in human VTs after stimulation with the retinoids 9-cis-retinoic acid and all-trans-retinoic acid and the prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2). Furthermore, a simultaneous expression of RXRα and the apoptotic marker M30 CytoDEATH in EVT of miscarried placentas from the first trimester was shown. In EVT of control placentas from legal termination of pregnancies, no co-expression of RXRα and M30 could be detected. A likely conclusion is that RXRα plays an important role in the induction of apoptosis. Downregulation of RXRα, as observed in the tested choriocarcinoma cells and trophoblasts, might serve as a protection against apoptosis and miscarriage. In conclusion, RXRα represents a potential target in the treatment of recurrent miscarriages.

  18. Simultaneous quantification of various retinoids by high performance liquid chromatography: its relevance to alcohol research.

    Science.gov (United States)

    Yokoyama, H; Matsumoto, M; Shiraishi, H; Ishii, H

    2000-04-01

    We established a high performance liquid chromatography system that allowed simultaneous quantification of various retinoids. We applied the retinoids to a high performance liquid chromatography system with a silica gel absorption column. Samples were separated by the system with a binary multistep gradient with two kinds of solvent that contained n-Hexan, 2-propanol, and glacial acetic acid in different ratios. Each retinoid was detected at a wavelength of 350 nm. This condition allowed separation of 13-cis-retinoic acid, 9-cis-retinoic acid, all-trans-retinoic acid, 13-cis-retinol, all-trans-retinol, all-trans-4-oxo-retinoic acid, and 13-cis-4-oxo-retinoic acid as distinct single peaks. Each retinoid was also analyzed separately and its retention time determined. To ascertain the reliability of this system for retinoid quantification, retinoids at various concentrations were applied to the system. We observed the linearities between the concentration and area under the curve of the peak for each retinoid by linear least-squares regression analysis up to 2.5 ng/ml for all retinoic acids and up to 5 ng/ml for all retinols. There was no significant scattering in tests of within-day reproducibility or day-to-day reproducibility. Using this system, we examined effects of light exposure on isomerization of retinoids. When retinoids were exposed to room light for 2 hr, the amounts of all but 13-cis-retinol changed significantly. In particular, the amounts of all-trans-retinoic acid and 9-cis-retinoic acid were reduced by 40% and 60%, respectively. The HPLC system established in this study should be useful for studying the oxidation pathway of retinol to retinoic acid. A light-shielded condition is required when particular retinoic acids are analyzed.

  19. Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina*

    Science.gov (United States)

    Golczak, Marcin; Maeda, Akiko; Bereta, Grzegorz; Maeda, Tadao; Kiser, Philip D.; Hunzelmann, Silke; von Lintig, Johannes; Blaner, William S.; Palczewski, Krzysztof

    2008-01-01

    In vertebrate retinal photoreceptors, the absorption of light by rhodopsin leads to photoisomerization of 11-cis-retinal to its all-trans isomer. To sustain vision, a metabolic system evolved that recycles all-trans-retinal back to 11-cis-retinal. The importance of this visual (retinoid) cycle is underscored by the fact that mutations in genes encoding visual cycle components induce a wide spectrum of diseases characterized by abnormal levels of specific retinoid cycle intermediates. In addition, intense illumination can produce retinoid cycle by-products that are toxic to the retina. Thus, inhibition of the retinoid cycle has therapeutic potential in physiological and pathological states. Four classes of inhibitors that include retinoid and nonretinoid compounds have been identified. We investigated the modes of action of these inhibitors by using purified visual cycle components and in vivo systems. We report that retinylamine was the most potent and specific inhibitor of the retinoid cycle among the tested compounds and that it targets the retinoid isomerase, RPE65. Hydrophobic primary amines like farnesylamine also showed inhibitory potency but a short duration of action, probably due to rapid metabolism. These compounds also are reactive nucleophiles with potentially high cellular toxicity. We also evaluated the role of a specific protein-mediated mechanism on retinoid cycle inhibitor uptake by the eye. Our results show that retinylamine is transported to and taken up by the eye by retinol-binding protein-independent and retinoic acid-responsive gene product 6-independent mechanisms. Finally, we provide evidence for a crucial role of lecithin: retinol acyltransferase activity in mediating tissue specific absorption and long lasting therapeutic effects of retinoid-based visual cycle inhibitors. PMID:18195010

  20. Metabolic basis of visual cycle inhibition by retinoid and nonretinoid compounds in the vertebrate retina.

    Science.gov (United States)

    Golczak, Marcin; Maeda, Akiko; Bereta, Grzegorz; Maeda, Tadao; Kiser, Philip D; Hunzelmann, Silke; von Lintig, Johannes; Blaner, William S; Palczewski, Krzysztof

    2008-04-11

    In vertebrate retinal photoreceptors, the absorption of light by rhodopsin leads to photoisomerization of 11-cis-retinal to its all-trans isomer. To sustain vision, a metabolic system evolved that recycles all-trans-retinal back to 11-cis-retinal. The importance of this visual (retinoid) cycle is underscored by the fact that mutations in genes encoding visual cycle components induce a wide spectrum of diseases characterized by abnormal levels of specific retinoid cycle intermediates. In addition, intense illumination can produce retinoid cycle by-products that are toxic to the retina. Thus, inhibition of the retinoid cycle has therapeutic potential in physiological and pathological states. Four classes of inhibitors that include retinoid and nonretinoid compounds have been identified. We investigated the modes of action of these inhibitors by using purified visual cycle components and in vivo systems. We report that retinylamine was the most potent and specific inhibitor of the retinoid cycle among the tested compounds and that it targets the retinoid isomerase, RPE65. Hydrophobic primary amines like farnesylamine also showed inhibitory potency but a short duration of action, probably due to rapid metabolism. These compounds also are reactive nucleophiles with potentially high cellular toxicity. We also evaluated the role of a specific protein-mediated mechanism on retinoid cycle inhibitor uptake by the eye. Our results show that retinylamine is transported to and taken up by the eye by retinol-binding protein-independent and retinoic acid-responsive gene product 6-independent mechanisms. Finally, we provide evidence for a crucial role of lecithin: retinol acyltransferase activity in mediating tissue specific absorption and long lasting therapeutic effects of retinoid-based visual cycle inhibitors.

  1. Benzo[a]pyrene sensitizes MCF7 breast cancer cells to induction of G1 arrest by the natural flavonoid eupatorin-5-methyl ether, via activation of cell signaling proteins and CYP1-mediated metabolism.

    Science.gov (United States)

    Androutsopoulos, Vasilis P; Tsatsakis, Aristeidis M

    2014-10-15

    Eupatorin-5-methyl ether (E5M) is a flavone containing 4 methoxy groups that is present in plants with medicinal activity, whereas luteolin (L) is a polyhydroxylated flavone commonly encountered in dietary products. In the present study we investigated the interaction of the two flavonoids with cytochrome P450 CYP1 enzymes in breast cancer MCF7 cells. Both compounds induced a dose dependent increase in CYP1A1 and CYP1B1 mRNA levels, as well as in EROD activity, a marker of CYP1 enzyme activity. Induction of cytochrome P450 CYP1 expression by E5M was accompanied by translocation of the ligand-activated transcription factor AhR to the nucleus, as demonstrated by confocal immunofluoresence. More importantly, although E5M was less active than L in inhibiting proliferation of MCF7 cells, when the cells were pretreated with the CYP1 inducer Benzo[a]pyrene (BaP) the potency of E5M was augmented. HPLC and LC-MS analysis revealed that E5M was metabolized to a major conversion product assigned E5M1 resulting from one step demethylation reaction in MCF7 cells whereas L metabolism by recombinant CYP1A1 did not reveal any metabolites. E5M1 production in BaP-induced MCF7 cells was attenuated in the presence of the CYP1A1 inhibitor α-napthoflavone. E5M further induced a dose dependent increase in the cell signaling proteins p21, JNK and p-JNK in MCF7 cells. This effect was enhanced in BaP pretreated cells and was associated with G1 arrest and a small percentage of apoptosis (3.5%). E5M antiproliferative effect in BaP pretreated cells was attenuated in the presence of the CYP1A1 inhibitor α-napthoflavone, as demonstrated by Western blotting and FACS analysis. Taken together the results demonstrate that BaP sensitizes MCF7 cells to E5M antiproliferative activity via enhanced induction of p21, JNK and p-JNK that in turn results by cytochrome P450 CYP1-mediated conversion to the metabolite E5M1. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Runway Arrested Landing Site (RALS)

    Data.gov (United States)

    Federal Laboratory Consortium — The Runway Arrested Landing Site includes an underground complex located on a Mod 2, Mod 3, and Mod 3+ arresting gear and are located under the runway and accurately...

  3. Uteroplacental Insufficiency Alters the Retinoid Pathway and Lung Development in Newborn Rats

    National Research Council Canada - National Science Library

    Huang, Liang-Ti; Chou, Hsiu-Chu; Lin, Chun-Mao; Chen, Chung-Ming

    2016-01-01

    ...) signaling pathway modulates pre- and postnatal lung development. This study was conducted to test our hypothesis that uteroplacental insufficiency alters the elements of the retinoid pathway in developing lungs. Methods...

  4. Uteroplacental Insufficiency Alters the Retinoid Pathway and Lung Development in Newborn Rats

    Directory of Open Access Journals (Sweden)

    Liang-Ti Huang

    2016-12-01

    Conclusion: Uteroplacental insufficiency causes defective alveolarization and transient increases in RAR-β expression in the lungs of newborn rats. The retinoid pathway may be one of the probable pathways mediating lung abnormalities caused by uteroplacental insufficiency.

  5. CHRONIC RETINOID EXPOSURE IN RANA PIPIENS AND XENOPUS LAEVIS: LIFE-STAGE SPECIFIC SENSITIVITY

    Science.gov (United States)

    Recently, high frequencies of malformations have been reported in amphibians across the United States. It has been suggested that the malformations may be the result of xenobiotic disruption of retinoid signaling...

  6. INHIBITION OF RETINOID ACTIVITY BY COMPONENTS OF A PAPER MILL EFFLUENT

    Science.gov (United States)

    A cell line stably transfected with reporter genes activated by retinoic acid was used to test a paper mill effluent for the presence of retinoids or components that interfere with retinoic acid-stimulated gene transcription.

  7. The Acyclic Retinoid Peretinoin Inhibits Hepatitis C Virus Replication and Infectious Virus Release in Vitro

    Science.gov (United States)

    Shimakami, Tetsuro; Honda, Masao; Shirasaki, Takayoshi; Takabatake, Riuta; Liu, Fanwei; Murai, Kazuhisa; Shiomoto, Takayuki; Funaki, Masaya; Yamane, Daisuke; Murakami, Seishi; Lemon, Stanley M.; Kaneko, Shuichi

    2014-04-01

    Clinical studies suggest that the oral acyclic retinoid Peretinoin may reduce the recurrence of hepatocellular carcinoma (HCC) following surgical ablation of primary tumours. Since hepatitis C virus (HCV) infection is a major cause of HCC, we assessed whether Peretinoin and other retinoids have any effect on HCV infection. For this purpose, we measured the effects of several retinoids on the replication of genotype 1a, 1b, and 2a HCV in vitro. Peretinoin inhibited RNA replication for all genotypes and showed the strongest antiviral effect among the retinoids tested. Furthermore, it reduced infectious virus release by 80-90% without affecting virus assembly. These effects could be due to reduced signalling from lipid droplets, triglyceride abundance, and the expression of mature sterol regulatory element-binding protein 1c and fatty acid synthase. These negative effects of Peretinoin on HCV infection may be beneficial in addition to its potential for HCC chemoprevention in HCV-infected patients.

  8. How Is Sudden Cardiac Arrest Treated?

    Science.gov (United States)

    ... Back To Health Topics / Sudden Cardiac Arrest Sudden Cardiac Arrest Also known as Cardiac Arrest , Sudden Cardiac Death ... the condition For People Who Have Survived Sudden Cardiac Arrest If you've already had SCA, you're ...

  9. How Is Sudden Cardiac Arrest Diagnosed?

    Science.gov (United States)

    ... Back To Health Topics / Sudden Cardiac Arrest Sudden Cardiac Arrest Also known as Cardiac Arrest , Sudden Cardiac Death ... the condition For People Who Have Survived Sudden Cardiac Arrest If you've already had SCA, you're ...

  10. The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells.

    Science.gov (United States)

    Whitworth, Jenny M; Londoño-Joshi, Angelina I; Sellers, Jeffrey C; Oliver, Patsy J; Muccio, Donald D; Atigadda, Venkatram R; Straughn, J Michael; Buchsbaum, Donald J

    2012-04-01

    Retinoids are important modulators of cell growth, differentiation, and proliferation. 9cUAB30, 9cUAB124, and 9cUAB130 are three novel retinoid compounds that show cytotoxic effects in other malignancies. We evaluated these novel retinoids in combination with chemotherapy against ovarian cancer stem cells (CSCs) in vitro and in an ex vivo model. A2780 cells were plated in 96-well plates and treated with retinoid, carboplatin, or combination therapy. Cell viability was evaluated using ATPLite assay. The A2780 cell line was also analyzed for CSCs by evaluating ALDH activity using flow cytometry. A2780 cells treated ex vivo with retinoids and chemotherapy were injected into the flank of athymic nude mice in order to evaluate subsequent tumor initiating capacity. A2780 cells were sensitive to treatment with retinoids and carboplatin. The best treatment resulted from the combination of retinoid 9cUAB130 and carboplatin. Untreated A2780 cells demonstrated ALDH activity in 3.3% of the cell population. Carboplatin treatment enriched ALDH activity to 27.3%, while 9cUAB130±carboplatin maintained the ALDH positive levels similar to untreated controls (2.3% and 6.7%, respectively). Similar results were found in tumorsphere-forming conditions. Flank injections of ex vivo treated A2780 cells resulted in 4/4 mice developing tumors at 40 days in the untreated group, while 0/4 tumors developed in the 9cUAB130 and carboplatin treated group. Combination treatment with carboplatin and retinoids reduced cell-viability, reduced CSC marker expression, and inhibited tumorigenicity, making it a more effective treatment when compared with carboplatin alone. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Aldo-keto reductases in retinoid metabolism: search for substrate specificity and inhibitor selectivity.

    Science.gov (United States)

    Porté, Sergio; Xavier Ruiz, F; Giménez, Joan; Molist, Iago; Alvarez, Susana; Domínguez, Marta; Alvarez, Rosana; de Lera, Angel R; Parés, Xavier; Farrés, Jaume

    2013-02-25

    Biological activity of natural retinoids requires the oxidation of retinol to retinoic acid (RA) and its binding to specific nuclear receptors in target tissues. The first step of this pathway, the reversible oxidoreduction of retinol to retinaldehyde, is essential to control RA levels. The enzymes of retinol oxidation are NAD-dependent dehydrogenases of the cytosolic medium-chain (MDR) and the membrane-bound short-chain (SDR) dehydrogenases/reductases. Retinaldehyde reduction can be performed by SDR and aldo-keto reductases (AKR), while its oxidation to RA is carried out by aldehyde dehydrogenases (ALDH). In contrast to SDR, AKR and ALDH are cytosolic. A common property of these enzymes is that they only use free retinoid, but not retinoid bound to cellular retinol binding protein (CRBP). The relative contribution of each enzyme type in retinoid metabolism is discussed in terms of the different subcellular localization, topology of membrane-bound enzymes, kinetic constants, binding affinity of CRBP for retinol and retinaldehyde, and partition of retinoid pools between membranes and cytoplasm. The development of selective inhibitors for AKR enzymes 1B1 and 1B10, of clinical relevance in diabetes and cancer, granted the investigation of some structure-activity relationships. Kinetics with the 4-methyl derivatives of retinaldehyde isomers was performed to identify structural features for substrate specificity. Hydrophilic derivatives were better substrates than the more hydrophobic compounds. We also explored the inhibitory properties of some synthetic retinoids, known for binding to retinoic acid receptors (RAR) and retinoid X receptors (RXR). Consistent with its substrate specificity towards retinaldehyde, AKR1B10 was more effectively inhibited by synthetic retinoids than AKR1B1. A RARβ/γ agonist (UVI2008) inhibited AKR1B10 with the highest potency and selectivity, and docking simulations predicted that its carboxyl group binds to the anion-binding pocket

  12. The role of interphotoreceptor retinoid-binding protein on the translocation of visual retinoids and function of cone photoreceptors.

    Science.gov (United States)

    Jin, Minghao; Li, Songhua; Nusinowitz, Steven; Lloyd, Marcia; Hu, Jane; Radu, Roxana A; Bok, Dean; Travis, Gabriel H

    2009-02-04

    The first event in light perception is absorption of a photon by the retinaldehyde chromophore of an opsin pigment in a rod or cone photoreceptor cell. This induces isomerization of the chromophore, rendering the bleached pigment insensitive to light. Restoration of light sensitivity requires chemical reisomerization of retinaldehyde via a multistep enzyme pathway, called the visual cycle, in cells of the retinal pigment epithelium (RPE). Interphotoreceptor retinoid-binding protein (IRBP) is present in the extracellular space between photoreceptors and the RPE. IRBP is known to bind visual retinoids. Previous studies on irbp(-/-) mice suggested that IRBP plays an insignificant role in opsin-pigment regeneration. However, the mice in these studies were uncontrolled for a severe mutation in the rpe65 gene. Rpe65 catalyzes the rate-limiting step in the visual cycle. Here, we examined the phenotype in irbp(-/-) mice homozygous for the wild-type (Leu450) rpe65 gene. We show that lack of IRBP causes delayed transfer of newly synthesized chromophore from RPE to photoreceptors. Removal of bleached chromophore from photoreceptors is also delayed in irbp(-/-) retinas after light exposure. It was previously shown that rods degenerate in irbp(-/-) mice. Here, we show that cones and rods degenerate at similar rates. However, cones are more affected functionally and show greater reductions in outer segment length than rods in irbp(-/-) mice. The disproportionate reductions in cone function and outer-segment length appear to result from mistrafficking of cone opsins due to impaired delivery of retinaldehyde chromophore, which functions as a chaperone for cone opsins but not rhodopsin.

  13. Retinoid signaling is necessary for, and promotes long-term memory formation following operant conditioning.

    Science.gov (United States)

    Rothwell, Cailin M; Spencer, Gaynor E

    2014-10-01

    Retinoic acid, a metabolite of vitamin A, is proposed to play an important role in vertebrate learning and memory, as well as hippocampal-dependent synaptic plasticity. However, it has not yet been determined whether retinoic acid plays a similar role in learning and memory in invertebrates. In this study, we report that retinoid signaling in the mollusc Lymnaea stagnalis, is required for long-term memory formation following operant conditioning of its aerial respiratory behaviour. Animals were exposed to inhibitors of the RALDH enzyme (which synthesizes retinoic acid), or various retinoid receptor antagonists. Following exposure to these inhibitors, neither learning nor intermediate-term memory (lasting 2 h) was affected, but long-term memory formation (tested at either 24 or 72 h) was inhibited. We next demonstrated that various retinoid receptor agonists promoted long-term memory formation. Using a training paradigm shown only to produce intermediate-term memory (lasting 2 h, but not 24 h) we found that exposure of animals to synthetic retinoids promoted memory formation that lasted up to 30 h. These findings suggest that the role of retinoids in memory formation is ancient in origin, and that retinoid signaling is also important for the formation of implicit memories, in addition to its previously demonstrated role in hippocampal-dependent memories. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. LRAT overexpression diminishes intracellular levels of biologically active retinoids and reduces retinoid antitumor efficacy in the murine melanoma B16F10 cell line.

    Science.gov (United States)

    Amann, Philipp M; Czaja, Katharina; Bazhin, Alexandr V; Rühl, Ralph; Eichmüller, Stefan B; Merk, Hans F; Baron, Jens M

    2015-01-01

    Vitamin A (all- trans -retinol, ATRol) serves as a precursor for all- trans -retinoic acid (ATRA), a ligand for the retinoic acid receptor (RAR), representing a potent regulator for many physiological processes. While murine melanoma cells are highly sensitive to retinoid treatment, human melanoma cells have developed still unidentified mechanisms that mediate cellular retinoid resistance. One of the key retinoid metabolizing enzymes is lecithin retinol acyltransferase (LRAT), which catalyzes the transformation of ATRol into inactive retinyl esters. LRAT is highly expressed in human melanoma cells. The aim of this study was to identify the mechanisms in retinol metabolism that are responsible for cellular retinoid sensitivity in the murine melanoma cell line B16F10. mRNA expression analysis, cell viability assessment and determination of intracellular retinoid levels using HPLC analysis of a generated LRAT-overexpressing B16F10 cell line compared to the control B16F10 cell line. We found that the murine retinoid-sensitive B16F10 cell line does not express the enzyme LRAT. LRAT overexpression decreased the antiproliferative effects of retinoid treatment in these melanoma cells. The RAR-regulated enzyme Cyp26a1 showed a significantly lower expression in LRAT-overexpressing B16F10 cells. Cyp26a1 expression was restored after ATRA incubation. HPLC analysis revealed that the level of inactive retinyl ester increased after ATRol treatment, and levels of the substrate ATRol and biologically active ATRA significantly decreased in LRAT-overexpressing murine melanoma. Consistently with this, levels of 4-oxoretinoic acid, an ATRA metabolite and Cyp26a1 product, were also decreased in LRAT-overexpressing cells. Our results revealed a direct link between LRAT expression and regulation of ATRA levels indicating that the absence of LRAT-catalyzed retinol esterification is important for mediating retinoid sensitivity in murine melanoma cells. Thus, our data suggest that LRAT

  15. Induction of retinoic acid receptor β mediates growth inhibition in retinoid resistant human colon carcinoma cells

    OpenAIRE

    Nicke, B; Riecken, E; Rosewicz, S

    1999-01-01

    BACKGROUND—The molecular mechanisms underlying the differential sensitivity of human colon carcinoma cells to retinoid mediated growth inhibition are poorly understood.
AIM—To identify the intracellular mechanisms responsible for resistance against retinoid mediated growth inhibition in human colon carcinoma cells.
METHODS—Anchorage independent growth of the human colon carcinoma cell lines HT29 and LoVo was determined by a human tumour clonogenic assay. Retinoid receptor expression was evalu...

  16. Retinoic acid protects human breast cancer cells against etoposide-induced apoptosis by NF-kappaB-dependent but cIAP2-independent mechanisms

    Directory of Open Access Journals (Sweden)

    Gronemeyer Hinrich

    2010-01-01

    Full Text Available Abstract Background Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. These ligands can determine the ultimate fate of target cells by stimulating or repressing gene expression directly, or indirectly through crosstalking with other signal transducers. Results Using different breast cancer cell models, we show here that depending on the cellular context retinoids can signal either towards cell death or cell survival. Indeed, retinoids can induce the expression of pro-apoptotic (i.e. TRAIL, TNF-Related Apoptosis-Inducing Ligand, Apo2L/TNFSF10 and anti-apoptotic (i.e. cIAP2, inhibitor of apoptosis protein-2 genes. Promoter mapping, gel retardation and chromatin immunoprecipitation assays revealed that retinoids induce the expression of this gene mainly through crosstalk with NF-kappaB. Supporting this crosstalk, the activation of NF-kappaB by retinoids in T47D cells antagonizes the apoptosis triggered by the chemotherapeutic drugs etoposide, camptothecin or doxorubicin. Notably apoptosis induced by death ligands (i.e. TRAIL or antiFAS is not antagonized by retinoids. That knockdown of cIAP2 expression by small interfering RNA does not alter the inhibition of etoposide-induced apoptosis by retinoids in T47D cells reveals that stimulation of cIAP2 expression is not the cause of their anti-apoptotic action. However, ectopic overexpression of a NF-kappaB repressor increases apoptosis by retinoids moderately and abrogates almost completely the retinoid-dependent inhibition of etoposide-induced apoptosis. Our data exclude cIAP2 and suggest that retinoids target other regulator(s of the NF-kappaB signaling pathway to induce resistance to etoposide on certain breast cancer cells. Conclusions This study shows an important role for the NF-kappaB pathway in retinoic acid signaling and retinoic acid-mediated resistance to

  17. Differential and isomer-specific modulation of vitamin A transport and the catalytic activities of the RBP receptor by retinoids.

    Science.gov (United States)

    Kawaguchi, Riki; Zhong, Ming; Kassai, Miki; Ter-Stepanian, Mariam; Sun, Hui

    2013-08-01

    Retinoids are vitamin A derivatives with diverse biological functions. Both natural and artificial retinoids have been used as therapeutic reagents to treat human diseases, but not all retinoid actions are understood mechanistically. Plasma retinol binding protein (RBP) is the principal and specific carrier of vitamin A in the blood. STRA6 is the membrane receptor for RBP that mediates cellular vitamin A uptake. The effects of retinoids or related compounds on the receptor's vitamin A uptake activity and its catalytic activities are not well understood. In this study, we dissected the membrane receptor-mediated vitamin A uptake mechanism using various retinoids. We show that a subset of retinoids strongly stimulates STRA6-mediated vitamin A release from holo-RBP. STRA6 also catalyzes the exchange of retinol in RBP with certain retinoids. The effect of retinoids on STRA6 is highly isomer-specific. This study provides unique insights into the RBP receptor's mechanism and reveals that the vitamin A transport machinery can be a target of retinoid-based drugs.

  18. Retinoid production using metabolically engineered Escherichia coli with a two-phase culture system.

    Science.gov (United States)

    Jang, Hui-Jeong; Yoon, Sang-Hwal; Ryu, Hee-Kyung; Kim, Jung-Hun; Wang, Chong-Long; Kim, Jae-Yean; Oh, Deok-Kun; Kim, Seon-Won

    2011-07-29

    Retinoids are lipophilic isoprenoids composed of a cyclic group and a linear chain with a hydrophilic end group. These compounds include retinol, retinal, retinoic acid, retinyl esters, and various derivatives of these structures. Retinoids are used as cosmetic agents and effective pharmaceuticals for skin diseases. Retinal, an immediate precursor of retinoids, is derived by β-carotene 15,15'-mono(di)oxygenase (BCM(D)O) from β-carotene, which is synthesized from the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Retinoids are chemically unstable and biologically degraded via retinoic acid. Although extensive studies have been performed on the microbial production of carotenoids, retinoid production using microbial metabolic engineering has not been reported. Here, we report retinoid production using engineered Escherichia coli that express exogenous BCM(D)O and the mevalonate (MVA) pathway for the building blocks synthesis in combination with a two-phase culture system using a dodecane overlay. Among the BCM(D)O tested in E. coli, the synthetic retinoid synthesis protein (SR), based on bacteriorhodopsin-related protein-like homolog (Blh) of the uncultured marine bacteria 66A03, showed the highest β-carotene cleavage activity with no residual intracellular β-carotene. By introducing the exogenous MVA pathway, 8.7 mg/L of retinal was produced, which is 4-fold higher production than that of augmenting the MEP pathway (dxs overexpression). There was a large gap between retinal production and β-carotene consumption using the exogenous MVA pathway; therefore, the retinal derivatives were analyzed. The derivatives, except for retinoic acid, that formed were identified, and the levels of retinal, retinol, and retinyl acetate were measured. Amounts as high as 95 mg/L retinoids were obtained from engineered E. coli DH5α harboring the synthetic SR gene and the exogenous MVA pathway in addition to dxs overexpression, which

  19. Retinoid production using metabolically engineered Escherichia coli with a two-phase culture system

    Directory of Open Access Journals (Sweden)

    Kim Jae-Yean

    2011-07-01

    Full Text Available Abstract Background Retinoids are lipophilic isoprenoids composed of a cyclic group and a linear chain with a hydrophilic end group. These compounds include retinol, retinal, retinoic acid, retinyl esters, and various derivatives of these structures. Retinoids are used as cosmetic agents and effective pharmaceuticals for skin diseases. Retinal, an immediate precursor of retinoids, is derived by β-carotene 15,15'-mono(dioxygenase (BCM(DO from β-carotene, which is synthesized from the isoprenoid building blocks isopentenyl diphosphate (IPP and dimethylallyl diphosphate (DMAPP. Retinoids are chemically unstable and biologically degraded via retinoic acid. Although extensive studies have been performed on the microbial production of carotenoids, retinoid production using microbial metabolic engineering has not been reported. Here, we report retinoid production using engineered Escherichia coli that express exogenous BCM(DO and the mevalonate (MVA pathway for the building blocks synthesis in combination with a two-phase culture system using a dodecane overlay. Results Among the BCM(DO tested in E. coli, the synthetic retinoid synthesis protein (SR, based on bacteriorhodopsin-related protein-like homolog (Blh of the uncultured marine bacteria 66A03, showed the highest β-carotene cleavage activity with no residual intracellular β-carotene. By introducing the exogenous MVA pathway, 8.7 mg/L of retinal was produced, which is 4-fold higher production than that of augmenting the MEP pathway (dxs overexpression. There was a large gap between retinal production and β-carotene consumption using the exogenous MVA pathway; therefore, the retinal derivatives were analyzed. The derivatives, except for retinoic acid, that formed were identified, and the levels of retinal, retinol, and retinyl acetate were measured. Amounts as high as 95 mg/L retinoids were obtained from engineered E. coli DH5α harboring the synthetic SR gene and the exogenous MVA pathway in

  20. Evolution of Retinoid and Steroid Signaling: Vertebrate Diversification from an Amphioxus Perspective

    Science.gov (United States)

    Albalat, Ricard; Brunet, Frédéric; Laudet, Vincent; Schubert, Michael

    2011-01-01

    Although the physiological relevance of retinoids and steroids in vertebrates is very well established, the origin and evolution of the genetic machineries implicated in their metabolic pathways is still very poorly understood. We investigated the evolution of these genetic networks by conducting an exhaustive survey of components of the retinoid and steroid pathways in the genome of the invertebrate chordate amphioxus (Branchiostoma floridae). Due to its phylogenetic position at the base of chordates, amphioxus is a very useful model to identify and study chordate versus vertebrate innovations, both on a morphological and a genomic level. We have characterized more than 220 amphioxus genes evolutionarily related to vertebrate components of the retinoid and steroid pathways and found that, globally, amphioxus has orthologs of most of the vertebrate components of these two pathways, with some very important exceptions. For example, we failed to identify a vertebrate-like machinery for retinoid storage, transport, and delivery in amphioxus and were also unable to characterize components of the adrenal steroid pathway in this invertebrate chordate. The absence of these genes from the amphioxus genome suggests that both an elaboration and a refinement of the retinoid and steroid pathways took place at the base of the vertebrate lineage. In stark contrast, we also identified massive amplifications in some amphioxus gene families, most extensively in the short-chain dehydrogenase/reductase superfamily, which, based on phylogenetic and genomic linkage analyses, were likely the result of duplications specific to the amphioxus lineage. In sum, this detailed characterization of genes implicated in retinoid and steroid signaling in amphioxus allows us not only to reconstruct an outline of these pathways in the ancestral chordate but also to discuss functional innovations in retinoid homeostasis and steroid-dependent regulation in both cephalochordate and vertebrate evolution

  1. Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro

    OpenAIRE

    Widschwendter, M.; Widschwendter, A; Welte, T.; Daxenbichler, G.; Zeimet, A. G.; Bergant, A; Berger, J.(Institut für Experimentelle Kernphysik, Karlsruhe, Germany); Peyrat, J-P; Michel, S.; Doppler, W; Marth, C.

    1999-01-01

    Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans- and 9-cis-retinoic acid, as well as the re...

  2. Retinoids for preventing the progression of cervical intra-epithelial neoplasia.

    Science.gov (United States)

    Helm, C William; Lorenz, Douglas J; Meyer, Nicholas J; Rising, William W R; Wulff, Judith L

    2013-06-06

    Invasive cervical carcinoma is preceded by a precancerous phase, cervical intra-epithelial neoplasia (CIN), which can be detected on cervical smears and confirmed by colposcopy and biopsy. Moderate and severe cases of intra-epithelial neoplasia (CIN2 and CIN3) are treated mainly with surgery to prevent progression to invasive carcinoma. Medical methods of preventing the progression or inducing the regression of CIN are needed. Retinoids are potent modulators of epithelial cell growth and differentiation that may have potential for the treatment of CIN. To ascertain whether retinoids can cause regression or prevent progression of CIN. We searched the Cochrane Gynaecological Cancer Review Group's Specialised Register and Non-Trials Database, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2010), and MEDLINE and EMBASE (July 2010).For the 2013 update, the searches were re-run as follows: CENTRAL, Issue 3, 2013; MEDLINE, April, Week 2, 2013; and EMBASE, Week 16, 2013. Randomized controlled trials (RCTs) and non-RCTs of retinoids for treating CIN in women. Two review authors independently assessed trial quality and extracted data from the trials. Adverse effects information was also collected from the trials. Five RCTs comparing the efficacy of four different retinoids were identified. Two studies examined the effects on CIN2 and CIN3 of the retinoids N-(4-hydroxyphenyl)retinamide (fenretinide) and 9-cis-retinoic acid (aliretinoin) given orally. Two examined the effect of all-trans-retinoic acid administered topically to the cervix. The fifth study investigated the use of 13-cis-retinoic acid (isotretinoin) given orally to human immunodeficiency virus (HIV)-positive participants with CIN1 and condyloma.Four studies reported no significant effect of retinoids on the progression to higher grades of CIN, and the fifth did not report data on progression. In all studies retinoids had no significant effect on regression of CIN3. Two studies reported

  3. Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance.

    Science.gov (United States)

    Duffy, David J; Krstic, Aleksandar; Halasz, Melinda; Schwarzl, Thomas; Konietzny, Anja; Iljin, Kristiina; Higgins, Desmond G; Kolch, Walter

    2017-02-10

    Retinoid therapy is widely employed in clinical oncology to differentiate malignant cells into their more benign counterparts. However, certain high-risk cohorts, such as patients with MYCN-amplified neuroblastoma, are innately resistant to retinoid therapy. Therefore, we employed a precision medicine approach to globally profile the retinoid signalling response and to determine how an excess of cellular MYCN antagonises these signalling events to prevent differentiation and confer resistance. We applied RNA sequencing (RNA-seq) and interaction proteomics coupled with network-based systems level analysis to identify targetable vulnerabilities of MYCN-mediated retinoid resistance. We altered MYCN expression levels in a MYCN-inducible neuroblastoma cell line to facilitate or block retinoic acid (RA)-mediated neuronal differentiation. The relevance of differentially expressed genes and transcriptional regulators for neuroblastoma outcome were then confirmed using existing patient microarray datasets. We determined the signalling networks through which RA mediates neuroblastoma differentiation and the inhibitory perturbations to these networks upon MYCN overexpression. We revealed opposing regulation of RA and MYCN on a number of differentiation-relevant genes, including LMO4, CYP26A1, ASCL1, RET, FZD7 and DKK1. Furthermore, we revealed a broad network of transcriptional regulators involved in regulating retinoid responsiveness, such as Neurotrophin, PI3K, Wnt and MAPK, and epigenetic signalling. Of these regulators, we functionally confirmed that MYCN-driven inhibition of transforming growth factor beta (TGF-β) signalling is a vulnerable node of the MYCN network and that multiple levels of cross-talk exist between MYCN and TGF-β. Co-targeting of the retinoic acid and TGF-β pathways, through RA and kartogenin (KGN; a TGF-β signalling activating small molecule) combination treatment, induced the loss of viability of MYCN-amplified retinoid-resistant neuroblastoma

  4. Registry of Unexplained Cardiac Arrest

    Science.gov (United States)

    2016-05-16

    Cardiac Arrest; Long QT Syndrome; Brugada Syndrome; Catecholaminergi Polymorphic Ventricular Tachycardia; Idiopathic VentricularFibrillation; Early Repolarization Syndrome; Arrhythmogenic Right Ventricular Cardiomyopathy

  5. Retinoids in the chemoprevention of non-melanoma skin cancers: why, when and how.

    Science.gov (United States)

    Bettoli, Vincenzo; Zauli, Stefania; Virgili, Anna

    2013-06-01

    The chemoprevention refers to the use of various types of chemical agents for preventing carcinogenic progression. Systemic retinoids are the most studied chemopreventive agents due to their capacity to regulate cell proliferation and their demonstrated efficacy in several clinical studies. The aim of the authors was to give precise indications regarding the use of the systemic retinoid in the chemoprevention of non-melanoma skin cancer (NMSC). The authors reviewed the literature found through a search to MEDLINE (from 2001 to December 2011). Both acitretin and isotretinoin are effective for the prevention of NMSC. Isotretinoin is preferred in xeroderma pigmentosum and nevoid basal cell carcinoma syndrome, whereas acitretin is more used in transplant recipients, psoriasis and severe sun damage. Despite numerous studies of the literature concerning retinoids in chemoprevention of NMSC, precise details of the type of retinoid to use, dosage and the duration of this preventive treatment and how to manage side effects in the case of long-lasting treatment are still not uniform and comparable. Moreover, neither guidelines nor approval by Food and Drug Administration exist to regulate the use of retinoids in chemoprevention.

  6. Understand Your Risk for Cardiac Arrest

    Science.gov (United States)

    ... Thromboembolism Aortic Aneurysm More Understand Your Risk for Cardiac Arrest Updated:Mar 10,2017 Cardiac arrest may be ... arrest. This content was last reviewed March 2017. Cardiac Arrest • Home • About Cardiac Arrest • Understand Your Risk for ...

  7. ECPR for Refractory Out-Of-Hospital Cardiac Arrest

    Science.gov (United States)

    2017-05-17

    Cardiac Arrest; Heart Arrest; Sudden Cardiac Arrest; Cardiopulmonary Arrest; Death, Sudden, Cardiac; Cardiopulmonary Resuscitation; CPR; Extracorporeal Cardiopulmonary Resuscitation; Extracorporeal Membrane Oxygenation

  8. Regulation of retinoid-mediated signaling involved in skin homeostasis by RAR and RXR agonists/antagonists in mouse skin.

    Science.gov (United States)

    Gericke, Janine; Ittensohn, Jan; Mihály, Johanna; Alvarez, Susana; Alvarez, Rosana; Töröcsik, Dániel; de Lera, Angel R; Rühl, Ralph

    2013-01-01

    Endogenous retinoids like all-trans retinoic acid (ATRA) play important roles in skin homeostasis and skin-based immune responses. Moreover, retinoid signaling was found to be dysregulated in various skin diseases. The present study used topical application of selective agonists and antagonists for retinoic acid receptors (RARs) α and γ and retinoid-X receptors (RXRs) for two weeks on mouse skin in order to determine the role of retinoid receptor subtypes in the gene regulation in skin. We observed pronounced epidermal hyperproliferation upon application of ATRA and synthetic agonists for RARγ and RXR. ATRA and the RARγ agonist further increased retinoid target gene expression (Rbp1, Crabp2, Krt4, Cyp26a1, Cyp26b1) and the chemokines Ccl17 and Ccl22. In contrast, a RARα agonist strongly decreased the expression of ATRA-synthesis enzymes, of retinoid target genes, markers of skin homeostasis, and various cytokines in the skin, thereby markedly resembling the expression profile induced by RXR and RAR antagonists. Our results indicate that RARα and RARγ subtypes possess different roles in the skin and may be of relevance for the auto-regulation of endogenous retinoid signaling in skin. We suggest that dysregulated retinoid signaling in the skin mediated by RXR, RARα and/or RARγ may promote skin-based inflammation and dysregulation of skin barrier properties.

  9. Changes in the skeleton after long-term treatment with retinoids

    Energy Technology Data Exchange (ETDEWEB)

    Montag, M.; Reiser, M.; Hamm, H.; Traupe, H.; Vogt, H.J.

    1988-07-01

    The synthetic retinoids, the vitamin-A-derivatives ethretinate and isotretinoin, have substantially enlarged the therapeutic arsenal in dermatology. They are primarily used in severe cases of acne and cornification disorders. In the majority of cases, long-term treatment is necessary. Certain side effects in the skeletal system can occur, e.g., osteoporosis, premature epiphyseal closure, and changes similar to DISH (diffuse idiopathic skeletal hyperostosis). We discuss the reports in the literature and our own observations in 31 patients treated at the Westphalian Wilhelms University in Muenster, as well as at the Technical University in Munich. In 3 out of 31 patients treated by retinoids on a long-term basis, skeletal changes were found radiologically as a result of the retinoid medication.

  10. Structure-activity relationship study on benzoic acid part of diphenylamine-based retinoids.

    Science.gov (United States)

    Ohta, Kiminori; Kawachi, Emiko; Shudo, Koichi; Kagechika, Hiroyuki

    2013-01-01

    Based on structure-activity relationship studies of the benzoic acid part of diphenylamine-based retinoids, the potent RXR agonist 4 was derivatized to obtain retinoid agonists, synergists, and an antagonist. Cinnamic acid derivatives 5 and phenylpropionic acid derivatives 6 showed retinoid agonistic and synergistic activities, respectively. The difference of the activities is considered to be due to differences in the flexibility of the carboxylic acid-containing substituent on the diphenylamine skeleton. Compound 7, bearing a methyl group at the meta position to the carboxyl group, was an antagonist, dose-dependently inhibiting HL-60 cell differentiation induced by 3.3 × 10(-10)M Am80. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Dowling Oration delivered at the Royal College of Physicians, London, Friday 5 June 1998. Retinoids: renaissance and reformation.

    Science.gov (United States)

    Griffiths, C E

    1999-07-01

    There is confusion as to the cutaneous signs of ageing. For the most part the features of photoageing, namely actinic lentigines and wrinkling, are misinterpreted as features of ageing. Wrinkling is associated with a loss of collagens from the papillary dermis resulting from imperfect remodelling of the dermal extracellular matrix following sun exposure. Retinoids are either derivatives of vitamin A or synthetic ligands of nuclear retinoid receptors. Retinoid receptors, notably retinoic acid receptor gamma and retinoid X receptor alpha are present in human skin. Topically applied all-trans retinoic acid can repair and probably prevent photoageing of the skin by modulation of collagen synthesis in the dermis. There is emerging evidence that intrinsic ageing of the skin is also amenable to reversal by topical retinoids.

  12. Comparison of extraction phases for a two-phase culture of a recombinant E. coli producing retinoids.

    Science.gov (United States)

    Jang, Hui-Jeong; Ha, Bo-Kyung; Kim, Jin-Woong; Jung, Kyung-Hwa; Ahn, Jiyoon; Yoon, Sang-Hwal; Kim, Seon-Won

    2014-03-01

    To prevent degradation of intracellular retinoids through in situ extraction from the cells, a two-phase culture system was performed. Several organic solvents, including n-alkanes, mineral oils and cosmetic raw materials, were applied as the extraction phase. Of the n-alkanes, n-decane had the highest retinoid production as 134 mg/l after 72 h. For mineral oil, light and heavy mineral oil gave retinoid productions of 158 and 174 mg/l after 96 h, respectively. Of other materials, isopropyl myristate gave the highest retinoid production of 181 mg/l. These results indicate that many types of oils can be applied for retinoid production, and optimization of the in situ extraction process will lead to further improve of economical production for the industrial purpose.

  13. Cardiac arrest – cardiopulmonary resuscitation

    Directory of Open Access Journals (Sweden)

    Basri Lenjani

    2014-01-01

    Conclusions: All survivors from cardiac arrest have received appropriate medical assistance within 10 min from attack, which implies that if cardiac arrest occurs near an institution health care (with an opportunity to provide the emergent health care the rate of survival is higher.

  14. An appraisal of oral retinoids in the treatment of pachyonychia congenita.

    Science.gov (United States)

    Gruber, Robert; Edlinger, Michael; Kaspar, Roger L; Hansen, C David; Leachman, Sancy; Milstone, Leonard M; Smith, Frances J D; Sidoroff, Alexis; Fritsch, Peter O; Schmuth, Matthias

    2012-06-01

    Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16, or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Available studies assessing oral retinoid treatment for PC are limited to a few case reports. We sought to assess overall effectiveness, adverse effects, and patient perspective in patients with PC receiving oral retinoids. In a questionnaire-based retrospective cross-sectional survey of 30 patient with PC assessing oral retinoids (10-50 mg/d for 1-240 months), we determined the clinical score, satisfaction score, visual analog pain scale, and adverse effects. In 50% of patients there was thinning of hyperkeratoses (average improvement 1.6 on a scale from -3 to +3) (95% confidence interval 1.2-1.9, P retinoid treatment was 2 or greater in 50% of the patients (mean 4.5 on a scale of 1-10). Although 33% reported decreased and 27% increased plantar pain with treatment, 40% did not notice any pain change. All patients experienced adverse effects, and 83% reported to have discontinued medication. Risk/benefit analysis favored lower retinoid doses (≤25 mg/d) over a longer time period (>5 months), compared with higher doses (>25 mg/d) for a shorter time (≤5 months). The retrospective, cross-sectional study design is prone to a recall bias. Oral retinoids are effective in some patients with PC. However, many patients discontinued medication because adverse effects outweighed the benefits. Careful dose titration is warranted in patients informed about potential adverse effects. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  15. Pathways of retinoid synthesis in mouse macrophages and bone marrow cells.

    Science.gov (United States)

    Niu, Haixia; Hadwiger, Gayla; Fujiwara, Hideji; Welch, John S

    2016-06-01

    In vivo pathways of natural retinoid metabolism and elimination have not been well characterized in primary myeloid cells, even though retinoids and retinoid receptors have been strongly implicated in regulating myeloid maturation. With the use of a upstream activation sequence-GFP reporter transgene and retrovirally expressed Gal4-retinoic acid receptor α in primary mouse bone marrow cells, we identified 2 distinct enzymatic pathways used by mouse myeloid cells ex vivo to synthesize retinoic acid receptor α ligands from free vitamin A metabolites (retinyl acetate, retinol, and retinal). Bulk Kit(+) bone marrow progenitor cells use diethylaminobenzaldehyde-sensitive enzymes, whereas bone marrow-derived macrophages use diethylaminobenzaldehyde-insensitive enzymes to synthesize natural retinoic acid receptor α-activating retinoids (all-trans retinoic acid). Bone marrow-derived macrophages do not express the diethylaminobenzaldehyde-sensitive enzymes Aldh1a1, Aldh1a2, or Aldh1a3 but instead, express Aldh3b1, which we found is capable of diethylaminobenzaldehyde-insensitive synthesis of all trans-retinoic acid. However, under steady-state and stimulated conditions in vivo, diverse bone marrow cells and peritoneal macrophages showed no evidence of intracellular retinoic acid receptor α-activating retinoids, despite expression of these enzymes and a vitamin A-sufficient diet, suggesting that the enzymatic conversion of retinal is not the rate-limiting step in the synthesis of intracellular retinoic acid receptor α-activating retinoids in myeloid bone marrow cells and that retinoic acid receptor α remains in an unliganded configuration during adult hematopoiesis. © Society for Leukocyte Biology.

  16. Cardiac Arrest: MedlinePlus Health Topic

    Science.gov (United States)

    ... and Blood Institute Start Here About Cardiac Arrest (American Heart Association) Sudden Cardiac Arrest (Texas Heart Institute) Also in ... Blood Institute) Understand Your Risk for Cardiac Arrest (American Heart Association) Warning Signs of Heart Attack, Stroke and Cardiac ...

  17. Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.

    Science.gov (United States)

    Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

    2017-03-01

    Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.

  18. Metoclopramide-induced cardiac arrest

    Directory of Open Access Journals (Sweden)

    Martha M. Rumore

    2011-11-01

    Full Text Available The authors report a case of cardiac arrest in a patient receiving intravenous (IV metoclopramide and review the pertinent literature. A 62-year-old morbidly obese female admitted for a gastric sleeve procedure, developed cardiac arrest within one minute of receiving metoclopramide 10 mg via slow intravenous (IV injection. Bradycardia at 4 beats/min immediately appeared, progressing rapidly to asystole. Chest compressions restored vital function. Electrocardiogram (ECG revealed ST depression indicative of myocardial injury. Following intubation, the patient was transferred to the intensive care unit. Various cardiac dysrrhythmias including supraventricular tachycardia (SVT associated with hypertension and atrial fibrillation occurred. Following IV esmolol and metoprolol, the patient reverted to normal sinus rhythm. Repeat ECGs revealed ST depression resolution without pre-admission changes. Metoclopramide is a non-specific dopamine receptor antagonist. Seven cases of cardiac arrest and one of sinus arrest with metoclopramide were found in the literature. The metoclopramide prescribing information does not list precautions or adverse drug reactions (ADRs related to cardiac arrest. The reaction is not dose related but may relate to the IV administration route. Coronary artery disease was the sole risk factor identified. According to Naranjo, the association was possible. Other reports of cardiac arrest, severe bradycardia, and SVT were reviewed. In one case, five separate IV doses of 10 mg metoclopramide were immediately followed by asystole repeatedly. The mechanism(s underlying metoclopramide’s cardiac arrest-inducing effects is unknown. Structural similarities to procainamide may play a role. In view of eight previous cases of cardiac arrest from metoclopramide having been reported, further elucidation of this ADR and patient monitoring is needed. Our report should alert clinicians to monitor patients and remain diligent in surveillance and

  19. Retinoids enhance glucocorticoid-induced apoptosis of T cells by facilitating glucocorticoid receptor-mediated transcription

    Science.gov (United States)

    Tóth, K; Sarang, Z; Scholtz, B; Brázda, P; Ghyselinck, N; Chambon, P; Fésüs, L; Szondy, Z

    2011-01-01

    Glucocorticoid-induced apoptosis of thymocytes is one of the first recognized forms of programmed cell death. It was shown to require gene activation induced by the glucocorticoid receptor (GR) translocated into the nucleus following ligand binding. In addition, the necessity of the glucocorticoid-induced, but transcription-independent phosphorylation of phosphatidylinositol-specific phospholipase C (PI-PLC) has also been shown. Here we report that retinoic acids, physiological ligands for the nuclear retinoid receptors, enhance glucocorticoid-induced death of mouse thymocytes both in vitro and in vivo. The effect is mediated by retinoic acid receptor (RAR) alpha/retinoid X receptor (RXR) heterodimers, and occurs when both RARα and RXR are ligated by retinoic acids. We show that the ligated RARα/RXR interacts with the ligated GR, resulting in an enhanced transcriptional activity of the GR. The mechanism through which this interaction promotes GR-mediated transcription does not require DNA binding of the retinoid receptors and does not alter the phosphorylation status of Ser232, known to regulate the transcriptional activity of GR. Phosphorylation of PI-PLC was not affected. Besides thymocytes, retinoids also promoted glucocorticoid-induced apoptosis of various T-cell lines, suggesting that they could be used in the therapy of glucocorticoid-sensitive T-cell malignancies. PMID:21072052

  20. Retinoid level dynamics during gonad recycling in the limpet Patella vulgata.

    Science.gov (United States)

    Gesto, M; Ruivo, R; Páscoa, I; André, A; Castro, L F C; Santos, M M

    2016-01-01

    Germ cell commitment and meiosis initiation are among the multitude of physiological roles of retinoic acid (RA) in vertebrates. Acting via receptor-mediated transcription, RA induces the expression of meiotic factors, triggering meiosis. Contrasting with vertebrates, invertebrate RA metabolism is scarcely understood. Still, some physiological processes appear to be conserved. Here we set to evaluate the role of retinoids in the gonad maturation process of the marine gastropod Patella vulgata. We found that retinoid concentration in gonadal tissue, namely RA, varies between breeding and resting specimens, with maxima attained in the latter. Additionally, we isolated and quantified the expression of both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR) in gonads. In view of the stability of retinoid receptor expression, we suggest that the balance of RA levels operates through the enzymatic control of synthetic and catabolic processes. Overall, the reported data are supportive for a developmental role of RA during gonadal maturation in P. vulgata, which should be addressed in other protostome lineages. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Toxcast Chemical and Bioactivity Profiles for In Vitro Targets in the Retinoid Signaling System (SOT)

    Science.gov (United States)

    A predictive model for prenatal developmental toxicity using ToxCast Phase I showed the RAR assay set to be the strongest weighting factor (Sipes et al. 2011). Retinoid signaling mediates growth and differentiation of the embryo. ToxCast has 6 reporter assays for trans-activation...

  2. Retinoids irreversibly inhibit in vitro growth of Epstein-Barr virus-immortalized B lymphocytes.

    Science.gov (United States)

    Pomponi, F; Cariati, R; Zancai, P; De Paoli, P; Rizzo, S; Tedeschi, R M; Pivetta, B; De Vita, S; Boiocchi, M; Dolcetti, R

    1996-10-15

    Natural and synthetic retinoids have proved to be effective in the treatment and prevention of various human cancers. In the present study, we investigated the effect of retinoids on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines (LCLs), since these cells closely resemble those that give rise to EBV-related lymphoproliferative disorders in the immunosuppressed host. All six compounds tested inhibited LCL proliferation with no significant direct cytotoxicity, but 9-cis-retinoic acid (RA), 13-cis-RA, and all-trans-RA (ATRA) were markedly more efficacious than Ro40-8757, Ro13-6298, and etretinate. The antiproliferative action of the three most effective compounds was confirmed in a large panel of LCLs, thus appearing as a generalized phenomenon in these cells. LCL growth was irreversibly inhibited even after 2 days of treatment at drug concentrations corresponding to therapeutically achievable plasma levels. Retinoid-treated cells showed a marked downregulation of CD71 and a decreased S-phase compartment with a parallel accumulation in Gzero/ G1 phases. These cell cycle perturbations were associated with the upregulation of p27 Kip1, a nuclear protein that controls entrance and progression through the cell cycle by inhibiting several cyclin/cyclin-dependent kinase complexes. Unlike what is observed in other systems, the antiproliferative effect exerted by retinoids on LCLs was not due to the acquisition of a terminally differentiated status. In fact, retinoid-induced modifications of cell morphology, phenotype (downregulation of CD19, HLA-DR, and s-Ig, and increased expression of CD38 and c-Ig), and IgM production were late events, highly heterogeneous, and often slightly relevant, being therefore only partially indicative of a drug-related differentiative process. Moreover, EBV-encoded EBV nuclear antigen-2 and latent membrane protein-1 proteins were inconstantly downregulated by retinoids, indicating that their growth-inhibitory effect is not mediated

  3. An airline cardiac arrest program

    National Research Council Canada - National Science Library

    O'Rourke, M F; Donaldson, E; Geddes, J S

    1997-01-01

    ...) available for use on airline passengers with cardiac arrest. AEDs were installed on international Qantas aircraft and at major terminals, selected crew were trained in their use, and all crew members were trained in cardiopulmonary resuscitation...

  4. Xanthophyll supplementation regulates carotenoid and retinoid metabolism in hens and chicks.

    Science.gov (United States)

    Gao, Yu-Yun; Ji, Jun; Jin, Ling; Sun, Bao-Li; Xu, Li-Hui; Wang, Chang-Kang; Bi, Ying-Zuo

    2016-03-01

    This study investigated the effects of xanthophylls (containing 40% lutein and 60% zeaxanthin; Juyuan Biochemical Co., Ltd., GuangZhou, China) on gene expression associated with carotenoid cleavage enzymes (β-carotene 15, 15'-monooxygenase, BCMO1; and β-carotene 9', 10'-dioxygenase, BCDO2) and retinoid metabolism (lecithin:retinol acyl transferase (LRAT) and STRA6) of breeding hens and chicks. In experiment 1, 432 hens were divided into 3 groups and fed diets supplemented with zero (as the control group), 20, or 40 mg/kg xanthophyll. The liver, duodenum, jejunum, and ileum were sampled at d 35 of the trial. Results showed that 40 mg/kg xanthophyll supplementation increased BCDO2 mRNA in the liver, duodenum, and jejunum; LRAT mRNA in the jejunum; and STRA6 mRNA in the liver, while it decreased LRAT mRNA in the liver. Experiment 2 was a 2 × 2 factorial design. Male chicks hatched from a zero or 40 mg/kg xanthophyll diet of hens were fed a diet containing either zero or 40 mg/kg xanthophylls. The liver, duodenum, jejunum, and ileum were sampled at zero, 7, 14, and 21 d after hatching. Results showed that in ovo xanthophyll modulated carotenoid and retinoid metabolism mainly within one wk after hatching. The maternal effects gradually vanished and dietary effects began to work one to 2 wk after hatching. Dietary xanthophyll regulated carotenoid and retinoid metabolism mainly from 2 wk onward. The xanthophyll regulation of carotenoid and retinoid metabolism also revealed strong tissue specificity. In conclusion, xanthophyll supplementation could modulate carotenoid and retinoid metabolism in different tissues of hens and chicks. © 2015 Poultry Science Association Inc.

  5. Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

    Energy Technology Data Exchange (ETDEWEB)

    Whelan, Jarrett T.; Wang, Lei; Chen, Jianming; Metts, Meagan E.; Nasser, Taj A.; McGoldrick, Liam J. [Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States); Bridges, Lance C., E-mail: bridgesl@ecu.edu [Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States); East Carolina Diabetes and Obesity Institute, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States)

    2014-11-28

    Highlights: • Transcription and translation are required for retinoid-induced lymphocyte adhesion. • RAR activation is sufficient to induced lymphocyte cell adhesion. • Vitamin D derivatives inhibit RAR-prompted lymphocyte adhesion. • Adhesion occurs through a novel binding site within ADAM disintegrin domains. • RARα is a key nuclear receptor for retinoid-dependent lymphocyte cell adhesion. - Abstract: Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH){sub 2}D{sub 3}, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-α receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion.

  6. Quantification of retinoid concentrations in human serum and brain tumor tissues.

    Science.gov (United States)

    Ali, Ramadan; Campos, Benito; Dyckhoff, Gerhard; Haefeli, Walter E; Herold-Mende, Christel; Burhenne, Jürgen

    2012-05-06

    Retinoic acid signaling is essential for central nervous system (CNS) differentiation and appears to be impaired in tumors. Thus far, there are no established methods to quantify relevant retinoids (all-trans-retinoic acid, 9-cis-retinoic acid, 13-cis retinoic acid, and retinol) in human brain tumors. We developed a single step extraction and quantification procedure for polar and apolar retinoids in normal tissue, lipid-rich brain tumor tissues, and serum. This quantification procedure is based on high performance liquid chromatography (HPLC) with diode-array detection (DAD) using all-trans-acitretin as an internal standard and extraction by liquid-liquid partition with ethyl acetate and borate buffer at pH 9. Recovery with this extraction procedure was higher than earlier (two-step) liquid-liquid extraction procedures based on hexane, NaOH, and HCl. The overall quantification procedure was validated according to Food and Drug Administration (FDA) guidelines and fulfilled all criteria of accuracy, precision, selectivity, recovery, and stability. The overall method accuracy varied between -5.6% and +5.4% for serum and -3.8% and +6.2% for tissues, and overall precision ranged from 3.1% to 6.9% for serum and 2.1% to 8.3% for tissues (%CV batch-to-batch). The lower limit of quantification for all compounds in tumor tissue (and serum) was 3.9 ng g(-1) (ng mL(-1)). Using this assay, photodegradation of the retinoids was evaluated and endogenous polar and apolar retinoids were quantified in sera and brain tumor tissues of patients and compared with serum and tonsil tissue concentrations of controls. It may thus serve as a suitable method for the characterization of retinoid uptake and metabolism in the respective compartments. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Impact of LCA-Associated E14L LRAT Mutation on Protein Stability and Retinoid Homeostasis.

    Science.gov (United States)

    Chelstowska, Sylwia; Widjaja-Adhi, Made Airanthi K; Silvaroli, Josie A; Golczak, Marcin

    2017-08-29

    Vitamin A (all-trans-retinol) is metabolized to the visual chromophore (11-cis-retinal) in the eyes and to all-trans-retinoic acid, a hormone like compound, in most tissues. A key enzyme in retinoid metabolism is lecithin:retinol acyltransferase (LRAT), which catalyzes the esterification of vitamin A. The importance of LRAT is indicated by pathogenic missense and nonsense mutations, which cause devastating blinding diseases. Retinoid-based chromophore replacement therapy has been proposed as treatment for these types of blindness based on studies in LRAT null mice. Here, we analyzed the structural and biochemical basis for retinal pathology caused by mutations in the human LRAT gene. Most LRAT missense mutations associated with retinal degeneration are localized within the catalytic domain, whereas E14L substitution is localized in an N-terminal α-helix, which has been implicated in interaction with the phospholipid bilayer. To elucidate the biochemical consequences of this mutation, we determined LRAT(E14L)'s enzymatic properties, protein stability, and impact on ocular retinoid metabolism. Bicistronic expression of LRAT(E14L) and enhanced green fluorescence protein revealed instability and accelerated proteosomal degradation of this mutant isoform. Surprisingly, instability of LRAT(E14L) did not abrogate the production of the visual chromophore in a cell-based assay. Instead, expression of LRAT(E14L) led to a rapid increase in cellular levels of retinoic acid upon retinoid supplementation. Thus, our study unveils the potential role of retinoic acid in the pathology of a degenerative retinal disease with important implications for the use of retinoid-based therapeutics in affected patients.

  8. Intra-arrest hypothermia during cardiac arrest: a systematic review

    Science.gov (United States)

    2012-01-01

    Introduction Therapeutic hypothermia is largely used to protect the brain following return of spontaneous circulation (ROSC) after cardiac arrest (CA), but it is unclear whether we should start therapeutic hypothermia earlier, that is, before ROSC. Methods We performed a systematic search of PubMed, EMBASE, CINAHL, the Cochrane Library and Ovid/Medline databases using "arrest" OR "cardiac arrest" OR "heart arrest" AND "hypothermia" OR "therapeutic hypothermia" OR "cooling" as keywords. Only studies using intra-arrest therapeutic hypothermia (IATH) were selected for this review. Three authors independently assessed the validity of included studies and extracted data regarding characteristics of the studied cohort (animal or human) and the main outcomes related to the use of IATH: Mortality, neurological status and cardiac function (particularly, rate of ROSC). Results A total of 23 animal studies (level of evidence (LOE) 5) and five human studies, including one randomized controlled trial (LOE 1), one retrospective and one prospective controlled study (LOE 3), and two prospective studies without a control group (LOE 4), were identified. IATH improved survival and neurological outcomes when compared to normothermia and/or hypothermia after ROSC. IATH was also associated with improved ROSC rates and with improved cardiac function, including better left ventricular function, and reduced myocardial infarct size, when compared to normothermia. Conclusions IATH improves survival and neurological outcome when compared to normothermia and/or conventional hypothermia in experimental models of CA. Clinical data on the efficacy of IATH remain limited. PMID:22397519

  9. STORED RETINOIDS IN POPULATIONS OF AN ESTUARINE FISH, FUNDULUS HETERCLITUS, INDIGENOUS TO PCB-CONTAMINATED AND REFERENCE SITES

    Science.gov (United States)

    Concentrations of retinoids, derivatives of vitamin A, were measured in populations of the nonmigratory estuarine fish Fundulus heteroclitus, indigenous to a reference site and a site highly contaminated with polychlorinated biphenyls (PCBs) to address the hypothesis that contami...

  10. Loss of FGF-dependent mesoderm identity and rise of endogenous retinoid signalling determine cessation of body axis elongation.

    Science.gov (United States)

    Olivera-Martinez, Isabel; Harada, Hidekiyo; Halley, Pamela A; Storey, Kate G

    2012-01-01

    The endogenous mechanism that determines vertebrate body length is unknown but must involve loss of chordo-neural-hinge (CNH)/axial stem cells and mesoderm progenitors in the tailbud. In early embryos, Fibroblast growth factor (FGF) maintains a cell pool that progressively generates the body and differentiation onset is driven by retinoid repression of FGF signalling. This raises the possibility that FGF maintains key tailbud cell populations and that rising retinoid activity underlies cessation of body axis elongation. Here we show that sudden loss of the mesodermal gene (Brachyury) from CNH and the mesoderm progenitor domain correlates with FGF signalling decline in the late chick tailbud. This is accompanied by expansion of neural gene expression and a similar change in cell fate markers is apparent in the human tailbud. Fate mapping of chick tailbud further revealed that spread of neural gene expression results from continued ingression of CNH-derived cells into the position of the mesoderm progenitor domain. Using gain and loss of function approaches in vitro and in vivo, we then show that attenuation of FGF/Erk signalling mediates this loss of Brachyury upstream of Wnt signalling, while high-level FGF maintains Brachyury and can induce ectopic CNH-like cell foci. We further demonstrate a rise in endogenous retinoid signalling in the tailbud and show that here FGF no longer opposes retinoid synthesis and activity. Furthermore, reduction of retinoid signalling at late stages elevated FGF activity and ectopically maintained mesodermal gene expression, implicating endogenous retinoid signalling in loss of mesoderm identity. Finally, axis termination is concluded by local cell death, which is reduced by blocking retinoid signalling, but involves an FGFR-independent mechanism. We propose that cessation of body elongation involves loss of FGF-dependent mesoderm identity in late stage tailbud and provide evidence that rising endogenous retinoid activity mediates this

  11. Characterization of Breast Cancer Cell Death Induced by Interferons and Retinoids

    Science.gov (United States)

    1999-07-01

    subjected to chromatography on the indicated column. was monitored by the sulforhodamine B assay (60). The GRIM- The presence or absence of the proteins...and stained with sulforhodamine B and absorbance of bound dye was quantified with a plate reader. Each data point is the mean ± standard error (SE) of...acid (TCA) and were transcription and translation before being cloned into pCXN2 (data not present- stained with 0.4% sulforhodamine B (Sigma) in 1

  12. Differential arrest and adhesion of tumor cells and microbeads in the microvasculature.

    Science.gov (United States)

    Guo, Peng; Cai, Bin; Lei, Ming; Liu, Yang; Fu, Bingmei M

    2014-06-01

    To investigate the mechanical mechanisms behind tumor cell arrest in the microvasculature, we injected fluorescently labeled human breast carcinoma cells or similarly sized rigid beads into the systemic circulation of a rat. Their arrest patterns in the microvasculature of mesentery were recorded and quantified. We found that 93% of rigid beads were arrested either at arteriole-capillary intersections or in capillaries. Only 3% were at the capillary-postcapillary venule intersections and in postcapillary venules. In contrast, most of the flexible tumor cells were either entrapped in capillaries or arrested at capillary or postcapillary venule-postcapillary venule intersections and in postcapillary venules. Only 12% of tumor cells were arrested at the arteriole-capillary intersections. The differential arrest and adhesion of tumor cells and microbeads in the microvasculature was confirmed by a χ(2) test (p < 0.001). These results demonstrate that mechanical trapping was responsible for almost all the arrest of beads and half the arrest of tumor cells. Based on the measured geometry and blood flow velocities at the intersections, we also performed a numerical simulation using commercial software (ANSYS CFX 12.01) to depict the detailed distribution profiles of the velocity, shear rate, and vorticity at the intersections where tumor cells preferred to arrest and adhere. Simulation results reveal the presence of localized vorticity and shear rate regions at the turning points of the microvessel intersections, implying that hemodynamic factors play an important role in tumor cell arrest in the microcirculation. Our study helps elucidate long-debated issues related to the dominant factors in early-stage tumor hematogenous metastasis.

  13. Problems of house arrest application

    Directory of Open Access Journals (Sweden)

    Mikhail Vladimirovich Kolesnikov

    2015-06-01

    Full Text Available Objective to determine the position of house arrest in the system of preventive measures and to identify the main problems of criminal procedural regulation that prevent its broader use during the preliminary investigation and trial. Methods dialectical approach to the analysis of social phenomena allowing to view them in static and dynamic aspect evolutionarysynergetic paradigm providing the opportunity to explore the phenomenon under investigation with respect to the system subordinate and coordinating relationships within the system. Dialectical approach and the evolutionarysynergetic paradigm determined the choice of specific methods of research historical comparative law comparative formallegal statistical. Results the problems arising with application of house arrest are grouped by author depending on the structure of the provisions of Article 107 of the CriminalProcedural Code of the Russian Federation. The first group of problems includes the determination of the location of the accused suspect under house arrest and the scope of the legal restrictions imposed. The second group includes the establishment of terms of house arrest and their subsequent renewal or change of the preventive measure. The third group is the identification of persons to which the house arrest will be the best preventive measure. The results of the study allow to make proposals to change the current wording of Art. 107 of the CriminalProcedural Code of Russia. Scientific novelty a comprehensive study of current state of the normativelegal regulation of house arrest in the context of its practical application. Practical value the main provisions and conclusions of the article can be used in scientific and pedagogical activity when considering questions about the nature of preventive measures related to the restraint of personal liberty of the accused. nbsp

  14. Docking simulations suggest that all- trans retinoic acid could bind to retinoid X receptors

    Science.gov (United States)

    Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

    2015-10-01

    Retinoid X receptors (RXRs) are ligand-controlled transcription factors which heterodimerize with other nuclear receptors to regulate gene transcriptions associated with crucial biological events. 9- cis retinoic acid (9cRA), which transactivates RXRs, is believed to be an endogenous RXR ligand. All- trans retinoic acid (ATRA) is a natural ligand for retinoic acid receptors (RARs), which heterodimerize with RXRs. Although the concentration of 9cRA in tissues is very low, ATRA is relatively abundant and some reports show that ATRA activates RXRs. We computationally studied the possibility of ATRA binding to RXRs using two different docking methods with our developed programs to assess the binding affinities of naturally occurring retinoids. The simulations showed good correlations to the reported binding affinities of these molecules for RXRs and RARs.

  15. Uteroplacental Insufficiency Alters the Retinoid Pathway and Lung Development in Newborn Rats

    OpenAIRE

    Huang, Liang-Ti; Chou, Hsiu-Chu; Lin, Chun-Mao; Chen, Chung-Ming

    2016-01-01

    Intrauterine growth retardation (IUGR) is associated with reduced lung function during infancy and perhaps throughout adulthood. The retinoic acid (RA) signaling pathway modulates pre- and postnatal lung development. This study was conducted to test our hypothesis that uteroplacental insufficiency alters the elements of the retinoid pathway in developing lungs. Methods: On Gestation Day 18, either uteroplacental insufficiency was induced through bilateral uterine vessel ligation (IUGR grou...

  16. RhoA Controls Retinoid Signaling by ROCK Dependent Regulation of Retinol Metabolism

    DEFF Research Database (Denmark)

    García-Mariscal, Alberto; Peyrollier, Karine; Basse, Astrid

    2017-01-01

    The ubiquitously expressed small GTPase RhoA is essential for embryonic development and mutated in different cancers. Functionally, it is well described as a regulator of the actin cytoskeleton, but its role in gene regulation is less understood. Using primary mouse keratinocytes with a deletion ......A-null keratinocytes. These data reveal an unexpected link between the cytoskeletal regulator RhoA and retinoid signalling and uncover a novel pathway by which RhoA regulates gene expression....

  17. Retinoid levels influence enterohemorrhagic Escherichia coli infection and Shiga toxin 2 susceptibility in mice.

    Science.gov (United States)

    Cabrera, Gabriel; Fernández-Brando, Romina J; Abrey-Recalde, María Jimena; Baschkier, Ariela; Pinto, Alipio; Goldstein, Jorge; Zotta, Elsa; Meiss, Roberto; Rivas, Marta; Palermo, Marina S

    2014-09-01

    Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that produces Shiga toxin (Stx) and causes hemorrhagic colitis. Under some circumstances, Stx produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome. Although retinoids like vitamin A (VA) and retinoic acid (RA) are beneficial to gut integrity and the immune system, the effect of VA supplementation on gastrointestinal infections of different etiologies has been controversial. Thus, the aim of this work was to study the influence of different VA status on the outcome of an EHEC intestinal infection in mice. We report that VA deficiency worsened the intestinal damage during EHEC infection but simultaneously improved survival. Since death is associated mainly with Stx toxicity, Stx was intravenously inoculated to analyze whether retinoid levels affect Stx susceptibility. Interestingly, while VA-deficient (VA-D) mice were resistant to a lethal dose of Stx2, RA-supplemented mice were more susceptible to it. Given that peripheral blood polymorphonuclear cells (PMNs) are known to potentiate Stx2 toxicity, we studied the influence of retinoid levels on the absolute number and function of PMNs. We found that VA-D mice had decreased PMN numbers and a diminished capacity to produce reactive oxygen species, while RA supplementation had the opposite effect. These results are in line with the well-known function of retinoids in maintaining the homeostasis of the gut but support the idea that they have a proinflammatory effect by acting, in part, on the PMN population. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  18. Plasma levels of retinoids, carotenoids and tocopherols in patients with mild obstructive sleep apnoea

    Science.gov (United States)

    Day, Regina M.; Matus, Ismael A.; Suzuki, Yuichiro J.; Yeum, Kyung-Jin; Qin, Jian; Park, Ah-Mee; Jain, Vivek; Kuru, Tunay; Tang, Guangwen

    2009-01-01

    Background and objective OSA is associated with increased incidence of cardiovascular diseases. Pathogenic mechanisms of vascular diseases include thickened vascular walls due to the increased number of smooth muscle cells (SMC). Retinoic acid (RA) suppresses the growth of SMC, and reduced retinoid levels are associated with vascular diseases. Oxidant signalling promotes SMC growth, thus antioxidant levels may also influence the development of cardiovascular diseases. The present study tested the hypothesis that plasmas from OSA patients contain altered levels of retinoids, carotenoids and tocopherols. Methods Plasma samples were taken before and after sleep from patients with OSA (mostly mild) without known cardiovascular diseases and from control subjects. Levels of retinoids, carotenoids and tocopherols were measured using sensitive gas chromatograph-mass spectrometry and high pressure liquid chromatography methods and total antioxidant capacity was assessed fluorometrically. Results Results showed that plasmas from patients with OSA had significantly lower retinyl palmitate and 9-cis RA compared with control subjects, while levels of retinol, all-trans RA and 13-cis RA were indifferent. All-trans β-carotene and 9-cis β-carotene were also lower in OSA patients. Levels of all-trans RA and 13-cis RA in OSA patients were reduced after sleep compared with before sleep. OSA patients showed significantly higher δ-tocopherol compared with controls. Treatment of cultured human vascular SMC with post-sleep OSA patient plasmas promoted cell growth, but not in controls. Conclusions Mild OSA exhibits altered levels of specific retinoids, carotenoids and tocopherols, which may be markers and/or mediators for the increased susceptibility of patients to vascular diseases. PMID:19761534

  19. Retinoid levels influence enterohemorrhagic Escherichia coli infection and shiga toxin susceptibility in mice

    OpenAIRE

    Cabrera, Gabriel Gustavo; Fernández Brando, Romina Jimena; Abrey Recalde, Maria Jimena; Baschkier, Ariela; Vasconcelos Esteves Pinto, Alipio; Goldstein Raij, Jorge; Zotta, Elsa; Meiss, Roberto; Rivas, Marta; Palermo, Marina Sandra

    2017-01-01

    Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that produces Shiga toxin (Stx) and causes hemorrhagic colitis. Under some circumstances, Stx produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome. Although retinoids like vitamin A (VA) and retinoic acid (RA) are beneficial to gut integrity and the immune system, the effect of VA supplementation on gastrointestinal infecti...

  20. [The influence of retinoids on the regeneration of an open osteal wound].

    Science.gov (United States)

    Semenov, F V; Leonov, G K

    The objective of the present study was to elucidate the influence of retinoid-based pharmaceutical products on the process of regeneration of the tissues surrounding an open osteal wound under the experimental conditions. The experiments were carried out using 20 'Sovetskaya shinshilla' rabbits (12 males and 8 females). The animals with the modelled open osteal wound underwent daily treatment by the placement of the dressings impregnated with a mixture of dioxo-methyltetrahydropyrimidine and chloramphenicol ointments supplemented by 0.05% retinoic acid (1:1:1). The rabbits of the control group were treated using the dressings impregnated only with a mixture of dioxo-methyltetrahydropyrimidine and chloramphenicol ointments containing no retinoic acid. The study has demonstrated that the application of the retinoid-based medications for the treatment of the open osteal wound resulted in the well apparent positive dynamics of the wound process in comparison with that in the control animals. It is concluded that the data obtained give evidence that retinoid-based preparations can be used as an adjuvant treatment for the acceleration and promotion of the wound healing process in the trepanation cavity following sanation surgery on the middle ear.

  1. Crystal structure of native RPE65, the retinoid isomerase of the visual cycle

    Energy Technology Data Exchange (ETDEWEB)

    Kiser, Philip D.; Golczak, Marcin; Lodowski, David T.; Chance, Mark R.; Palczewski, Krzysztof; (WRU-MED)

    2009-12-01

    Vertebrate vision is maintained by the retinoid (visual) cycle, a complex enzymatic pathway that operates in the retina to regenerate the visual chromophore, 11-cis-retinal. A key enzyme in this pathway is the microsomal membrane protein RPE65. This enzyme catalyzes the conversion of all-trans-retinyl esters to 11-cis-retinol in the retinal pigment epithelium (RPE). Mutations in RPE65 are known to be responsible for a subset of cases of the most common form of childhood blindness, Leber congenital amaurosis (LCA). Although retinoid isomerase activity has been attributed to RPE65, its catalytic mechanism remains a matter of debate. Also, the manner in which RPE65 binds to membranes and extracts retinoid substrates is unclear. To gain insight into these questions, we determined the crystal structure of native bovine RPE65 at 2.14-{angstrom} resolution. The structural, biophysical, and biochemical data presented here provide the framework needed for an in-depth understanding of the mechanism of catalytic isomerization and membrane association, in addition to the role mutations that cause LCA have in disrupting protein function.

  2. Peretinoin, an Acyclic Retinoid, Inhibits Hepatitis B Virus Replication by Suppressing Sphingosine Metabolic Pathway In Vitro

    Directory of Open Access Journals (Sweden)

    Kazuhisa Murai

    2018-01-01

    Full Text Available Hepatocellular carcinoma (HCC frequently develops from hepatitis C virus (HCV and hepatitis B virus (HBV infection. We previously reported that peretinoin, an acyclic retinoid, inhibits HCV replication. This study aimed to examine the influence of peretinoin on the HBV lifecycle. HBV-DNA and covalently closed circular DNA (cccDNA were evaluated by a qPCR method in HepG2.2.15 cells. Peretinoin significantly reduced the levels of intracellular HBV-DNA, nuclear cccDNA, and HBV transcript at a concentration that did not induce cytotoxicity. Conversely, other retinoids, such as 9-cis, 13-cis retinoic acid (RA, and all-trans-retinoic acid (ATRA, had no effect or rather increased HBV replication. Mechanistically, although peretinoin increased the expression of HBV-related transcription factors, as observed for other retinoids, peretinoin enhanced the binding of histone deacetylase 1 (HDAC1 to cccDNA in the nucleus and negatively regulated HBV transcription. Moreover, peretinoin significantly inhibited the expression of SPHK1, a potential inhibitor of HDAC activity, and might be involved in hepatic inflammation, fibrosis, and HCC. SPHK1 overexpression in cells cancelled the inhibition of HBV replication induced by peretinoin. This indicates that peretinoin activates HDAC1 and thereby suppresses HBV replication by inhibiting the sphingosine metabolic pathway. Therefore, peretinoin may be a novel therapeutic agent for HBV replication and chemoprevention against HCC.

  3. Sudden Cardiac Arrest (SCA) Risk Assessment

    Science.gov (United States)

    ... Specialist Share Twitter Facebook SCA Risk Assessment Sudden Cardiac Arrest (SCA) occurs abruptly and without warning, and two- ... and health conditions. Start Risk Assessment The Sudden Cardiac Arrest (SCA) Risk Assessment Tool is supported in part ...

  4. DUI Arrests and Academic Attrition

    Science.gov (United States)

    Thompson, Kevin M.; Richardson, Katie

    2008-01-01

    A sobering 2002 study reported that over 2 million college students drove under the influence of alcohol (DUI) in 1999. Among those driving while intoxicated, approximately 1.7% or roughly 34,000 students reported being arrested on DUI charges. Regrettably, a significant proportion of the 1,400 college student deaths and 500,000 injuries are…

  5. Application of synthetic photostable retinoids induces novel limb and facial phenotypes during chick embryogenesis in vivo.

    Science.gov (United States)

    Lopez-Real, R E; Budge, J J R; Marder, T B; Whiting, A; Hunt, P N; Przyborski, S A

    2014-04-01

    We have recently developed a range of synthetic retinoid analogues which include the compounds EC23 and EC19. They are stable on exposure to light and are predicted to be resistant to the normal metabolic processes involved in the inactivation of retinoids in vivo. Based on the position of the terminal carboxylic acid groups in the compounds we suggest that EC23 is a structural analogue of all-trans retinoic acid (ATRA), and EC19 is an analogue of 13-cis retinoic acid. Their effects on the differentiation of pluripotent stem cells has been previously described in vitro and are consistent with this hypothesis. We present herein the first description of the effects of these molecules in vivo. Retinoids were applied to the anterior limb buds of chicken embryos in ovo via ion-exchange beads. We found that retinoid EC23 produces effects on the wing digits similar to ATRA, but does so at two orders of magnitude lower concentration. When larger quantities of EC23 are applied, a novel phenotype is obtained involving production of multiple digit 1s on the anterior limb. This corresponds to differential effects of ATRA and EC23 on sonic hedgehog (shh) expression in the developing limb bud. With EC23 application we also find digit 1 phenotypes similar to thumb duplications described in the clinical literature. EC23 and ATRA are shown to have effects on the entire proximal-distal axis of the limb, including hitherto undescribed effects on the scapula. This includes suppression of expression of the scapula marker Pax1. EC23 also produces effects similar to those of ATRA on the developing face, producing reductions of the upper beak at concentrations two orders of magnitude lower than ATRA. In contrast, EC19, which is structurally very similar to EC23, has novel, less severe effects on the face and rarely alters limb development. EC19 and ATRA are effective at similar concentrations. These results further demonstrate the ability of retinoids to influence embryonic development

  6. An airline cardiac arrest program.

    Science.gov (United States)

    O'Rourke, M F; Donaldson, E; Geddes, J S

    1997-11-04

    As many as 1000 lives are lost annually from cardiac arrest in commercial aircraft. Ventricular fibrillation (VF), the most common mechanism, can be treated effectively only with prompt defibrillation, whereas the current policy of most airlines is to continue cardiopulmonary resuscitation pending aircraft diversion. The objective of this study was to assess the impact of making semiautomatic external defibrillators (AEDs) available for use on airline passengers with cardiac arrest. AEDs were installed on international Qantas aircraft and at major terminals, selected crew were trained in their use, and all crew members were trained in cardiopulmonary resuscitation. Supervision was provided by medical volunteers or (remotely) by airline physicians. During a 64-month period, AEDs were used on 109 occasions: 63 times for monitoring an acutely ill passenger and 46 times for cardiac arrest. Twenty-seven episodes of cardiac arrest occurred in aircraft, often (11 of 27 [41%]) unwitnessed, and they were usually (21 of 27 [78%]) associated with asystole or pulseless idioventricular rhythm. All 19 arrests in terminals were witnessed; VF was present in 17 (89%). Overall, defibrillation was initially successful in 21 of 23 cases (91%). Long-term survival from VF was achieved in 26% (2 of 6 in aircraft and 4 of 17 in terminals). The ability to monitor cardiac rhythm aided decisions on diversion, which was avoided in most passengers with asystole or idioventricular rhythm. AEDs in aircraft and terminals, with appropriate crew training, are helpful in the management of cardiac emergencies. Survival from VF is practicable and is comparable with the most effective prehospital ambulance emergency services. Costly aircraft diversions can be avoided in clearly futile situations, enhancing the cost-effectiveness of the program.

  7. Cardiac arrest: resuscitation and reperfusion.

    Science.gov (United States)

    Patil, Kaustubha D; Halperin, Henry R; Becker, Lance B

    2015-06-05

    The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and

  8. Who Is at Risk for Sudden Cardiac Arrest?

    Science.gov (United States)

    ... Back To Health Topics / Sudden Cardiac Arrest Sudden Cardiac Arrest Also known as Cardiac Arrest , Sudden Cardiac Death ... the condition For People Who Have Survived Sudden Cardiac Arrest If you've already had SCA, you're ...

  9. How Can Death Due to Sudden Cardiac Arrest Be Prevented?

    Science.gov (United States)

    ... Back To Health Topics / Sudden Cardiac Arrest Sudden Cardiac Arrest Also known as Cardiac Arrest , Sudden Cardiac Death ... the condition For People Who Have Survived Sudden Cardiac Arrest If you've already had SCA, you're ...

  10. Police Response to Mandatory Arrest Laws.

    Science.gov (United States)

    Mignon, Sylvia I.; Holmes, William M.

    1995-01-01

    Examines how police officers in 24 departments have responded to mandatory arrest statutes in 861 cases of domestic violence. Arrests of offenders, especially those violating restraining orders, increased. Arrest was affected by victim injury, use of a weapon, use of alcohol, and presence of a witness. Police training was crucial to implementation…

  11. Cellular and molecular determinants of all-trans retinoic acid sensitivity in breast cancer: Luminal phenotype and RARα expression

    Science.gov (United States)

    Centritto, Floriana; Paroni, Gabriela; Bolis, Marco; Garattini, Silvio Ken; Kurosaki, Mami; Barzago, Maria Monica; Zanetti, Adriana; Fisher, James Neil; Scott, Mark Francis; Pattini, Linda; Lupi, Monica; Ubezio, Paolo; Piccotti, Francesca; Zambelli, Alberto; Rizzo, Paola; Gianni', Maurizio; Fratelli, Maddalena; Terao, Mineko; Garattini, Enrico

    2015-01-01

    Forty-two cell lines recapitulating mammary carcinoma heterogeneity were profiled for all-trans retinoic acid (ATRA) sensitivity. Luminal and ER+ (estrogen-receptor-positive) cell lines are generally sensitive to ATRA, while refractoriness/low sensitivity is associated with a Basal phenotype and HER2 positivity. Indeed, only 2 Basal cell lines (MDA-MB157 and HCC-1599) are highly sensitive to the retinoid. Sensitivity of HCC-1599 cells is confirmed in xenotransplanted mice. Short-term tissue-slice cultures of surgical samples validate the cell-line results and support the concept that a high proportion of Luminal/ER+ carcinomas are ATRA sensitive, while triple-negative (Basal) and HER2-positive tumors tend to be retinoid resistant. Pathway-oriented analysis of the constitutive gene-expression profiles in the cell lines identifies RARα as the member of the retinoid pathway directly associated with a Luminal phenotype, estrogen positivity and ATRA sensitivity. RARα3 is the major transcript in ATRA-sensitive cells and tumors. Studies in selected cell lines with agonists/antagonists confirm that RARα is the principal mediator of ATRA responsiveness. RARα over-expression sensitizes retinoid-resistant MDA-MB453 cells to ATRA anti-proliferative action. Conversely, silencing of RARα in retinoid-sensitive SKBR3 cells abrogates ATRA responsiveness. All this is paralleled by similar effects on ATRA-dependent inhibition of cell motility, indicating that RARα may mediate also ATRA anti-metastatic effects. We define gene sets of predictive potential which are associated with ATRA sensitivity in breast cancer cell lines and validate them in short-term tissue cultures of Luminal/ER+ and triple-negative tumors. In these last models, we determine the perturbations in the transcriptomic profiles afforded by ATRA. The study provides fundamental information for the development of retinoid-based therapeutic strategies aimed at the stratified treatment of breast cancer subtypes

  12. [Abnormal expression of genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer].

    Science.gov (United States)

    Kuznetsova, E S; Zinovieva, O L; Oparina, N Yu; Prokofjeva, M M; Spirin, P V; Favorskaya, I A; Zborovskaya, I B; Lisitsyn, N A; Prassolov, V S; Mashkova, T D

    2016-01-01

    Retinoids are signaling molecules that control a wide variety of cellular processes and possess antitumor activity. This work presents a comprehensive description of changes in the expression of 23 genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer tumors compared to adjacent normal tissues obtained using RT-PCR. Even at early stages of malignant transformation, a significant decrease in ADH1B, ADH3, RDHL, and RALDH1 mRNA levels was observed in 82, 79, 73, and 64% of tumor specimens, respectively, and a considerable increase in AKR1B10 mRNA content was observed in 80% of tumors. Dramatic changes in the levels of these mRNAs can impair the synthesis of all-trans retinoic acid, a key natural regulatory retinoid. Apart from that, it was found that mRNA levels of nuclear retinoid receptor genes RXRγ, RARα, RXRα, and gene RDH11 were significantly decreased in 80, 67, 57, and 66% of tumor specimens, respectively. Thus, neoplastic transformation of lung tissue cells is accompanied with deregulated expression of key genes of retinoid metabolism and function.

  13. Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Streb

    2011-04-01

    Full Text Available Retinoids are used clinically to treat a number of hyper-proliferative disorders and have been shown in experimental animals to attenuate vascular occlusive diseases, presumably through nuclear receptors bound to retinoic acid response elements (RARE located in target genes. Here, we show that natural or synthetic retinoids rapidly induce mRNA and protein expression of a specific isoform of A-Kinase Anchoring Protein 12 (AKAP12β in cultured smooth muscle cells (SMC as well as the intact vessel wall. Expression kinetics and actinomycin D studies indicate Akap12β is a retinoid-induced, immediate-early gene. Akap12β promoter analyses reveal a conserved RARE mildly induced with atRA in a region that exhibits hyper-acetylation. Immunofluorescence microscopy and protein kinase A (PKA regulatory subunit overlay assays in SMC suggest a physical association between AKAP12β and PKA following retinoid treatment. Consistent with its designation as a tumor suppressor, inducible expression of AKAP12β attenuates SMC growth in vitro. Further, immunohistochemistry studies establish marked decreases in AKAP12 expression in experimentally-injured vessels of mice as well as atheromatous lesions in humans. Collectively, these results demonstrate a novel role for retinoids in the induction of an AKAP tumor suppressor that blocks vascular SMC growth thus providing new molecular insight into how retiniods may exert their anti-proliferative effects in the injured vessel wall.

  14. Hepatic retinoid levels in seven fish species (teleosts) from a tropical coastal lagoon receiving effluents from iron-ore mining and processing

    NARCIS (Netherlands)

    Alves Pereira Wilken, A.; van Hattum, A.G.M.; Brouwer, A.

    2012-01-01

    The present study was undertaken to investigate the possible effects of Fe and trace element exposure on hepatic levels of retinoids in seven fish species. Concentrations of retinoids were measured in fish collected from a coastal lagoon in Brazil that receives effluents from an iron-ore mining and

  15. Importance of Membrane Structural Integrity for RPE65 Retinoid Isomerization Activity

    Energy Technology Data Exchange (ETDEWEB)

    Golczak, Marcin; Kiser, Philip D.; Lodowski, David T.; Maeda, Akiko; Palczewski, Krzysztof (Case Western)

    2010-04-05

    Regeneration of visual chromophore in the vertebrate visual cycle involves the retinal pigment epithelium-specific protein RPE65, the key enzyme catalyzing the cleavage and isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol. Although RPE65 has no predicted membrane spanning domains, this protein predominantly associates with microsomal fractions isolated from bovine retinal pigment epithelium (RPE). We have re-examined the nature of RPE65 interactions with native microsomal membranes by using extraction and phase separation experiments. We observe that hydrophobic interactions are the dominant forces that promote RPE65 association with these membranes. These results are consistent with the crystallographic model of RPE65, which features a large lipophilic surface that surrounds the entrance to the catalytic site of this enzyme and likely interacts with the hydrophobic core of the endoplasmic reticulum membrane. Moreover, we report a critical role for phospholipid membranes in preserving the retinoid isomerization activity and physical properties of RPE65. Isomerase activity measured in bovine RPE was highly sensitive to phospholipase A{sup 2} treatment, but the observed decline in 11-cis-retinol production did not directly reflect inhibition by products of lipid hydrolysis. Instead, a direct correlation between the kinetics of phospholipid hydrolysis and retinoid isomerization suggests that the lipid membrane structure is critical for RPE65 enzymatic activity. We also provide evidence that RPE65 operates in a multiprotein complex with retinol dehydrogenase 5 and retinal G protein-coupled receptor in RPE microsomes. Modifications in the phospholipid environment affecting interactions with these protein components may be responsible for the alterations in retinoid metabolism observed in phospholipid-depleted RPE microsomes. Thus, our results indicate that the enzymatic activity of native RPE65 strongly depends on its membrane binding and

  16. Incidence of apoptosis after retinoids and insulin-like growth factor-I (IGF-I) supplementation during goat in vitro embryo production.

    Science.gov (United States)

    Conceição, Juliana C Z; Moura, Marcelo T; Ferreira-Silva, José C; Cantanhêde, Ludymila F; Chaves, Ricardo M; Lima, Paulo F; Oliveira, Marcos A L

    2016-12-01

    The addition of growth factors and vitamins enhances goat embryonic development in vitro. However, few attempts have been reported trying to identify supplementation regimens for oocyte maturation or embryo culture with additive properties. The present report was aimed to evaluate if retinoids [0.3 μM retinyl acetate (RAc) and 0.5 μM 9-cis-retinoic acid (RA)] supplementation during goat oocyte maturation and retinoids and/or 50 ng mL-1 IGF-I during embryo culture synergically enhanced embryonic development while diminishing the incidence of apoptosis. All combinations of RAc and RA treatment produced blastocysts with similar efficiencies, while IGF-I enhanced embryos yields irrespectively of retinoid addition. Moreover, retinoids and IGF-I supplementation showed similar caspase activity or DNA fragmentation indexes in blastocysts. In conclusion, supplementation with retinoids and IGF-I during goat embryo culture enhances blastocysts development without synergic reduction of apoptosis.

  17. Retinoid Uptake, Processing, and Secretion in Human iPS-RPE Support the Visual Cycle

    Science.gov (United States)

    Muñiz, Alberto; Greene, Whitney A.; Plamper, Mark L.; Choi, Jae Hyek; Johnson, Anthony J.; Tsin, Andrew T.; Wang, Heuy-Ching

    2014-01-01

    Purpose. Retinal pigmented epithelium derived from human induced pluripotent stem (iPS) cells (iPS-RPE) may be a source of cells for transplantation. For this reason, it is essential to determine the functional competence of iPS-RPE. One key role of the RPE is uptake and processing of retinoids via the visual cycle. The purpose of this study is to investigate the expression of visual cycle proteins and the functional ability of the visual cycle in iPS-RPE. Methods. iPS-RPE was derived from human iPS cells. Immunocytochemistry, RT-PCR, and Western blot analysis were used to detect expression of RPE genes lecithin-retinol acyl transferase (LRAT), RPE65, cellular retinaldehyde-binding protein (CRALBP), and pigment epithelium–derived factor (PEDF). All-trans retinol was delivered to cultured cells or whole cell homogenate to assess the ability of the iPS-RPE to process retinoids. Results. Cultured iPS-RPE expresses visual cycle genes LRAT, CRALBP, and RPE65. After incubation with all-trans retinol, iPS-RPE synthesized up to 2942 ± 551 pmol/mg protein all-trans retinyl esters. Inhibition of LRAT with N-ethylmaleimide (NEM) prevented retinyl ester synthesis. Significantly, after incubation with all-trans retinol, iPS-RPE released 188 ± 88 pmol/mg protein 11-cis retinaldehyde into the culture media. Conclusions. iPS-RPE develops classic RPE characteristics and maintains expression of visual cycle proteins. The results of this study confirm that iPS-RPE possesses the machinery to process retinoids for support of visual pigment regeneration. Inhibition of all-trans retinyl ester accumulation by NEM confirms LRAT is active in iPS-RPE. Finally, the detection of 11-cis retinaldehyde in the culture medium demonstrates the cells' ability to process retinoids through the visual cycle. This study demonstrates expression of key visual cycle machinery and complete visual cycle activity in iPS-RPE. PMID:24255038

  18. Retinoid uptake, processing, and secretion in human iPS-RPE support the visual cycle.

    Science.gov (United States)

    Muñiz, Alberto; Greene, Whitney A; Plamper, Mark L; Choi, Jae Hyek; Johnson, Anthony J; Tsin, Andrew T; Wang, Heuy-Ching

    2014-01-09

    Retinal pigmented epithelium derived from human induced pluripotent stem (iPS) cells (iPS-RPE) may be a source of cells for transplantation. For this reason, it is essential to determine the functional competence of iPS-RPE. One key role of the RPE is uptake and processing of retinoids via the visual cycle. The purpose of this study is to investigate the expression of visual cycle proteins and the functional ability of the visual cycle in iPS-RPE. iPS-RPE was derived from human iPS cells. Immunocytochemistry, RT-PCR, and Western blot analysis were used to detect expression of RPE genes lecithin-retinol acyl transferase (LRAT), RPE65, cellular retinaldehyde-binding protein (CRALBP), and pigment epithelium-derived factor (PEDF). All-trans retinol was delivered to cultured cells or whole cell homogenate to assess the ability of the iPS-RPE to process retinoids. Cultured iPS-RPE expresses visual cycle genes LRAT, CRALBP, and RPE65. After incubation with all-trans retinol, iPS-RPE synthesized up to 2942 ± 551 pmol/mg protein all-trans retinyl esters. Inhibition of LRAT with N-ethylmaleimide (NEM) prevented retinyl ester synthesis. Significantly, after incubation with all-trans retinol, iPS-RPE released 188 ± 88 pmol/mg protein 11-cis retinaldehyde into the culture media. iPS-RPE develops classic RPE characteristics and maintains expression of visual cycle proteins. The results of this study confirm that iPS-RPE possesses the machinery to process retinoids for support of visual pigment regeneration. Inhibition of all-trans retinyl ester accumulation by NEM confirms LRAT is active in iPS-RPE. Finally, the detection of 11-cis retinaldehyde in the culture medium demonstrates the cells' ability to process retinoids through the visual cycle. This study demonstrates expression of key visual cycle machinery and complete visual cycle activity in iPS-RPE.

  19. Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression.

    Science.gov (United States)

    Virtanen, M; Gedde-Dahl, T; Mörk, N J; Leigh, I; Bowden, P E; Vahlquist, A

    2001-01-01

    Dominant-negative mutations in the KRT1 and KRT10 genes cause epidermolytic hyperkeratosis, a rare form of ichthyosis sometimes associated with palmoplantar keratoderma. Although there is no permanent cure, some patients improve on retinoid therapy. More knowledge is needed, however, about the mechanism of action of retinoids and the genotypic/phenotypic correlations in this disease. Thirteen patients from 10 families with generalized disease and 2 sporadic patients with nevoid lesions were studied, probably representing most of the patients in Sweden and Norway. All patients, except one nevoid case, were known to have KRT1 or KRT10 mutations. Those with mutated keratin 1 (K1) invariably had associated keratoderma (n=6). In contrast, only 1 of 7 patients with K10 mutations had this problem (p = 0.0047). Five out of 6 patients with KRT10 mutations benefited from treatment with oral acitretin (5-25mg/day) or topical tretinoin/tazarotene, but none of the patients with KRT1 mutations derived any benefit. Quantitative analysis of K1 and K10 mRNA in skin biopsies obtained before and after retinoid therapy (n=8) showed no consistent down-regulation of mutated keratin that would explain the therapeutic outcome. Instead, the mRNA expression of K2e (a normal constituent of the upper epidermis) diminished especially in nonresponders. In contrast, K4 mRNA and protein (marker of retinoid bioactivity in normal epidermis) increased in almost all retinoid-treated patients. In conclusion, our study confirms a strong association between KRT1 mutations and palmoplantar keratoderma. Retinoid therapy is particularly effective in patients with KRT10 mutations possibly because they are less vulnerable to a down-regulation of K2e, potentially functioning as a substitute for the mutated protein in patients with KRT1 mutations.

  20. Breast lump

    Science.gov (United States)

    ... removed with surgery. Breast infections are treated with antibiotics. If you are diagnosed with breast cancer , you will discuss your options carefully and thoroughly with your provider. Alternative Names Breast mass Images Female breast Breast lumps ...

  1. Breast lift

    Science.gov (United States)

    Mastopexy; Breast lift with reduction; Breast lift with augmentation ... enlargement with implants) when they have a breast lift. ... it for medical reasons. Women usually have breast lifts to lift sagging, loose breasts. Pregnancy, breastfeeding, and ...

  2. The biochemical and structural basis for trans-to-cis isomerization of retinoids in the chemistry of vision

    Science.gov (United States)

    von Lintig, Johannes; Kiser, Philip D.; Golczak, Marcin; Palczewski, Krzysztof

    2010-01-01

    Recently, much progress has been made in elucidating the chemistry and metabolism of retinoids and carotenoids as well as the structures of processing proteins related to vision. Because carotenoids and their retinoid metabolites are isoprenoids, only a limited number of chemical transformations are possible and just a few of these naturally occur. Although there is an intriguing evolutionary conservation of the key components involved in chromophore production and recycling, these genes also have adapted to the specific requirements of both insect and vertebrate vision. These ancestral footprints in animal genomes bear witness to the common origin of the chemistry of vision and will further stimulate research across evolutionary boundaries. PMID:20188572

  3. Out-of-hospital cardiac arrest

    DEFF Research Database (Denmark)

    Sondergaard, Kathrine B; Hansen, Steen Moller; Pallisgaard, Jannik L

    2018-01-01

    : We used data from the nationwide Danish Cardiac Arrest Registry and the Danish AED Network to identify out-of-hospital cardiac arrests and route distances to nearest accessible registered AED during 2008-2013. The association between route distance and bystander defibrillation was described using...... restricted cubic spline logistic regression. RESULTS: We included 6,971 out-of-hospital cardiac arrest cases. The proportion of arrests according to distance in meters (≤100, 101-200, >200) to the nearest accessible AED was: 4.6% (n=320), 5.3% (n=370), and 90.1% (n=6,281), respectively. For cardiac arrests......meters route distance from cardiac arrest to nearest accessible AED whereas the probability of bystander defibrillation was low for all distances in residential areas....

  4. Regulation of retinoid receptors by retinoic acid and axonal contact in Schwann cells.

    Directory of Open Access Journals (Sweden)

    Maria-Jesus Latasa

    Full Text Available BACKGROUND: Schwann cells (SCs are the cell type responsible for the formation of the myelin sheath in the peripheral nervous system (PNS. As retinoic acid (RA and other retinoids have a profound effect as regulators of the myelination program, we sought to investigate how their nuclear receptors levels were regulated in this cell type. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, by using Schwann cells primary cultures from neonatal Wistar rat pups, as well as myelinating cocultures of Schwann cells with embryonic rat dorsal root ganglion sensory neurons, we have found that sustained expression of RXR-γ depends on the continuous presence of a labile activator, while axonal contact mimickers produced an increase in RXR-γ mRNA and protein levels, increment that could be prevented by RA. The upregulation by axonal contact mimickers and the transcriptional downregulation by RA were dependent on de novo protein synthesis and did not involve changes in mRNA stability. On the other hand, RAR-β mRNA levels were only slightly modulated by axonal contact mimickers, while RA produced a strong transcriptional upregulation that was independent of de novo protein synthesis without changes in mRNA stability. CONCLUSIONS/SIGNIFICANCE: All together, our results show that retinoid receptors are regulated in a complex manner in Schwann cells, suggesting that they could have a prominent role as regulators of Schwann cell physiology.

  5. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

    Science.gov (United States)

    van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

    2014-04-01

    The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

  6. Molecular Mechanisms of Retinoid Receptors in Diabetes-Induced Cardiac Remodeling

    Directory of Open Access Journals (Sweden)

    Jing Pan

    2014-06-01

    Full Text Available Diabetic cardiomyopathy (DCM, a significant contributor to morbidity and mortality in diabetic patients, is characterized by ventricular dysfunction, in the absence of coronary atherosclerosis and hypertension. There is no specific therapeutic strategy to effectively treat patients with DCM, due to a lack of a mechanistic understanding of the disease process. Retinoic acid, the active metabolite of vitamin A, is involved in a wide range of biological processes, through binding and activation of nuclear receptors: retinoic acid receptors (RAR and retinoid X receptors (RXR. RAR/RXR-mediated signaling has been implicated in the regulation of glucose and lipid metabolism. Recently, it has been reported that activation of RAR/RXR has an important role in preventing the development of diabetic cardiomyopathy, through improving cardiac insulin resistance, inhibition of intracellular oxidative stress, NF-κB-mediated inflammatory responses and the renin-angiotensin system. Moreover, downregulated RAR/RXR signaling has been demonstrated in diabetic myocardium, suggesting that impaired RAR/RXR signaling may be a trigger to accelerate diabetes-induced development of DCM. Understanding the molecular mechanisms of retinoid receptors in the regulation of cardiac metabolism and remodeling under diabetic conditions is important in providing the impetus for generating novel therapeutic approaches for the prevention and treatment of diabetes-induced cardiac complications and heart failure.

  7. Impact of retinal disease-associated RPE65 mutations on retinoid isomerization.

    Science.gov (United States)

    Bereta, Grzegorz; Kiser, Philip D; Golczak, Marcin; Sun, Wenyu; Heon, Elise; Saperstein, David A; Palczewski, Krzysztof

    2008-09-16

    Pathogenic mutations in the RPE65 gene are associated with a spectrum of congenital blinding diseases in humans. We evaluated changes in the promoter region, coding regions, and exon/intron junctions of the RPE65 gene by direct sequencing of DNA from 36 patients affected with Leber's congenital amaurosis (LCA), 62 with autosomal recessive retinitis pigmentosa (arRP), and 21 with autosomal dominant/recessive cone-rod dystrophies (CORD). Fifteen different variants were found, of which 6 were novel. Interesting was Gly244Val, a novel mutation close to the catalytic center. To assess the role of this mutation in RPE65 inactivation, we performed detailed biochemical studies of the mutant along with a structural analysis of the 244 amino acid position with respect to amino acids known to be important for RPE65-dependent retinoid isomerization. Bicistronic plasmid expression of the RPE65 Gly244Val mutant and enhanced green fluorescent protein (EGFP) allowed us to document both its instability in cultured cells by cell sorting and immunoblotting methodology and its loss of RPE65-dependent isomerase activity by enzymatic assays. Further insights into the structural requirements for retinoid isomerization by RPE65 were obtained by using the carotenoid oxygenase (ACO) from Synechocystis (PDB accession code 2BIW ) as a structural template to construct a RPE65 homology model and locating all known inactivating mutations including Gly244Val within this model.

  8. Impact of Retinal Disease-Associated RPE65 Mutations on Retinoid Isomerization†

    Science.gov (United States)

    Bereta, Grzegorz; Kiser, Philip D.; Golczak, Marcin; Sun, Wenyu; Heon, Elise; Saperstein, David A.; Palczewski, Krzysztof

    2008-01-01

    Pathogenic mutations in the RPE65 gene are associated with a spectrum of congenital blinding diseases in humans. We evaluated changes in the promoter region, coding regions, and exon/intron junctions of the RPE65 gene by direct sequencing of DNA from 36 patients affected with Leber's congenital amaurosis (LCA), 62 with autosomal recessive retinitis pigmentosa (arRP), and 21 with autosomal dominant/recessive cone-rod dystrophies (CORD). Fifteen different variants were found, of which 6 were novel. Interesting was Gly244Val, a novel mutation close to the catalytic center. To assess the role of this mutation in RPE65 inactivation, we performed detailed biochemical studies of the mutant along with a structural analysis of the 244 amino acid position with respect to amino acids known to be important for RPE65-dependent retinoid isomerization. Bicistronic plasmid expression of the RPE65 Gly244Val mutant and enhanced green fluorescent protein (EGFP) allowed us to document both its instability in cultured cells by cell sorting and immunoblotting methodology and its loss of RPE65-dependent isomerase activity by enzymatic assays. Further insights into the structural requirements for retinoid isomerization by RPE65 were obtained by using the carotenoid oxygenase (ACO) from Synechocystis (PDB accession code 2BIW) as a structural template to construct a RPE65 homology model and locating all known inactivating mutations including Gly244Val within this model. PMID:18722466

  9. Correlation between precancerous bronchial metaplasia and cigarette consumption, and preliminary results of retinoid treatment.

    Science.gov (United States)

    Mathe, G; Gouveia, J; Hercend, T; Gros, F; Dorval, T; Hazon, J; Misset, J L; Schwarzenberg, L; Ribaud, P; Lemaigre, G; Santelli, G; Reizenstein, P; Homasson, J P; Gaillard, J P; Angebault, M; Bonniot, J P; Lededente, A; Marsac, J; Parrot, R; Pretet, S; Gaget, H

    1982-01-01

    Vitamin A and its derivatives, so-called retinoids, can prevent squamous metaplasia induced not only by vitamin A deficiency but also by carcinogenic hydrocarbons. An aromatic retinoid, such as ET1, has been shown to prevent chemically induced papillomas in mice and to amplify certain immunologic reactions. Heavy smokers, 106 volunteers, were submitted to fibrobronchoscopy with bronchial biopsies. An index of metaplasia (IM) was calculated on the basis of microscopical examination of a total of 9,633 sections of 1,010 biopsies. Despite the subjectivity of the estimates of cigarette consumption, this was significantly (P less than 0.02) and positively correlated to the IM. Eighty-five percent of the women had a low IM as compared to only 42% of the men (P less than 0.01), although there was no significant difference in the reported cigarette consumption. Fifty-two subjects had an IM greater than 15% and were given 25 mg ET1 orally daily for 6 months. The bronchoscopy was repeated in 30 patients following completion of the 6-month treatment. The IM was significantly (P less than 0.01) reduced after treatment.

  10. Keratoacanthoma centrifugum marginatum: unresponsive to oral retinoid and successfully treated with wide local excision.

    Directory of Open Access Journals (Sweden)

    Kapildev Das

    2010-01-01

    Full Text Available We describe a case of a 65-year-old male presenting with a large plaque with a rolled-out interrupted margin, atrophic center, and island of normal skin over the left arm. It grew peripherally with central healing, and there was a history of recurrence after inadequate excision. Investigations ruled out other clin­ical mimickers; namely, squamous cell carcinoma, lupus vulgaris, botryomycosis, and blastomycosis-like pyoderma. Histopathological sections showed irregularly shaped craters filled with keratin and epithelial pearl but no evidence of granuloma or cellular atypia. Clinico­pathological correlation proved the lesion to be keratoacanthoma centrifugum marginatum (KCM, a rare variant of keratoacanthoma, which spreads centrifugally, attains a huge size, and never involutes spontaneously. Treatment of KCM has been a problem always and, in our case, systemic retinoid (acitretin for three months proved ineffective. The patient also had a history of recurrence following surgical intervention previously, necessitating wide excision to achieve complete clearance of tumor cells. Hence, after failure of retinoid therapy, the decision of excision with a 1-centimeter margin was taken and the large defect was closed by a split thickness skin graft. The graft uptake was satisfactory, and the patient is being followed-up presently and shows no signs of recurrence after six months, highlighting wide local excision as a useful treatment option.

  11. Prediction of cardiac arrest recurrence using ensemble classifiers

    Indian Academy of Sciences (India)

    Inability of a heart to contract effectually or its failure to contract prevents blood from circulating efficiently, causing circulatory arrest or cardiac arrest or cardiopulmonary arrest. The unexpected cardiac arrest is medically referred to as sudden cardiac arrest (SCA). Poor survival rate of patients with SCA is one of themost ...

  12. Breast Pain

    Science.gov (United States)

    ... result in the development of breast cysts. Breast trauma, prior breast surgery or other factors localized to the breast can lead to breast pain. Breast pain may also start outside the breast — in the chest wall, muscles, joints or heart, for example — and ...

  13. Lipocalin-type Prostaglandin D Synthase (β-Trace) Is a Newly Recognized Type of Retinoid Transporter

    National Research Council Canada - National Science Library

    Toshiki Tanaka; Yoshihiro Urade; Hiromi Kimura; Naomi Eguchi; Akemi Nishikawa; Osamu Hayaishi

    1997-01-01

    ... of the UV absorption spectra of retinoids. We found that the enzyme binds all- trans - or 9- cis -retinoic acid and all- trans - or 13- cis -retinal, but not all- trans -retinol, with affinities ( K d of 70–80 n m...

  14. Gestational and lactational exposure to the polychlorinated biphenyl mixture Aroclor 1254 modulates retinoid homeostasis in rat offspring.

    Science.gov (United States)

    Esteban, Javier; Elabbas, Lubna E; Borg, Daniel; Herlin, Maria; Åkesson, Agneta; Barber, Xavier; Hamscher, Gerd; Nau, Heinz; Bowers, Wayne J; Nakai, Jamie S; Viluksela, Matti; Håkansson, Helen

    2014-08-17

    Polychlorinated biphenyls (PCBs) induce a broad spectrum of biochemical and toxic effects in mammals including alterations of the vital retinoid (vitamin A) system. The aim of this study was to characterize alterations of tissue retinoid levels in rat offspring and their dams following gestational and lactational exposure to the PCB mixture Aroclor 1254 (A1254) and to assess the interrelationship of these changes with other established sensitive biochemical and toxicological endpoints. Sprague-Dawley rat dams were exposed orally to 0 or 15 mg/kg body weight/day of A1254 from gestational day 1 to postnatal day (PND) 23. Livers, kidneys and serum were collected from the offspring on PNDs 35, 77 and 350. Tissue and serum retinoid levels, hepatic cytochrome P450 (CYP) enzymes and serum thyroid hormones were analyzed. A multivariate regression between A1254 treatment, hepatic retinoid levels, hepatic CYP enzymes activities, thyroid hormone levels and body/liver weights was performed using an orthogonal partial least-squares (PLS) analysis. The contribution of dioxin-like (DL) components of A1254 to the observed effects was also estimated using the toxic equivalency (TEQ) concept. In both male and female offspring short-term alterations in tissue retinoid levels occurred at PND35, i.e. decreased levels of hepatic retinol and retinoic acid (RA) metabolite 9-cis-4-oxo-13,14-dihydro-RA with concurrent increases in hepatic and renal all-trans-RA levels. Long-term changes consisted of decreased hepatic retinyl palmitate and increased renal retinol levels that were apparent until PND350. Retinoid system alterations were associated with altered CYP enzyme activities and serum thyroid hormone levels as well as body and liver weights in both offspring and dams. The estimated DL activity was within an order of magnitude of the theoretical TEQ for different endpoints, indicating significant involvement of DL congeners in the observed effects. This study shows that tissue retinoid

  15. Fibroadenoma - breast

    Science.gov (United States)

    ... fibroadenoma; Breast lump - noncancerous; Breast lump - benign References Hacker NF, Friedlander ML. Breast disease: a gynecologic perspective. In: Hacker NF, Gambone JC, Hobel CJ, eds. Hacker and ...

  16. 10 CFR 1047.4 - Arrest authority.

    Science.gov (United States)

    2010-01-01

    ... OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS General Provisions § 1047.4 Arrest authority. (a) Under the Act, the authority of a DOE protective force... badges, identification cards, other insignia—18 U.S.C. 701—(pertains to the manufacture, sale, and...

  17. Psychopathology in Women Arrested for Domestic Violence

    Science.gov (United States)

    Stuart, Gregory L.; Moore, Todd M.; Gordon, Kristina Coop; Ramsey, Susan E.; Kahler, Christopher W.

    2006-01-01

    This study examined the prevalence of psychopathology among women arrested for violence and whether the experience of intimate partner violence (IPV) was associated with Axis I psychopathology. Women who were arrested for domestic violence perpetration and court referred to violence intervention programs (N=103) completed measures of IPV…

  18. Requirement of retinoids for the expression of CD38 on human hematopoietic progenitors in vitro.

    Science.gov (United States)

    Muench, M O; Bárcena, A; Ohkubo, T; Harrison, M R

    1999-01-01

    Cells expressing high levels of CD34 and little or no CD38 comprise a primitive compartment of progenitors, thought to include hematopoietic stem cells. In this study we sought to determine the feasibility of using CD34 and CD38 as markers of hematopoietic differentiation in vitro, using retinoids to induce the expression of CD38. The effects over time of culture, sera and retinoids on the expression of CD34 and CD38 were determined using a base-medium lacking serum. Two early progenitor populations, isolated by FACS from human fetal liver, were studied: CD38(-)CD34(++) and CD38(+)CD34(++) cells. Additionally, HL-60 cells were adapted to grow in serum-deprived medium to study factors that control CD38 expression. Colony forming cell (CFC) assays and short-term expansion cultures were used to measure the effects of all-trans-retinoic acid (ATRA) oil the growth of fetal progenitors. Fetal progenitors and HL-60 cells grown under serum-deprived conditions exhibited almost no CD38 expression. However, CD34 expression was observed on fetal progenitors and declined slowly over time. Addition of FBS or human serum restored CD38 expression to cultured cells, but at levels below those found on progenitors in vivo. Addition of ATRA or 9-cis-retinoic acid (9CRA) to cultures of fetal progenitors or HL-60 cells, resulted in a time- and dose-dependent increase in CD38 expression, ATRA being the more potent of the two retinoids. However, ATRA inhibited colony formation, reduced the expansion of CFC and accelerated the loss of CD34 expression at doses required for the induction of CD38 expression. ATRA-induced CD38 expression on cells to levels comparable to those found on progenitors in vivo. ATRA also inhibited the growth of early progenitors, which was partly due to ATRA accelerating the differentiation of the progenitors. These findings indicate that CD34 and CD38 expression may be followed as markers of hematopoietic differentiation in vitro, but at the cost of culture

  19. Distribution, teratogenicity, and embryonic delivered dose of retinoid Ro 23-9223.

    Science.gov (United States)

    Willhite, C C; Lovey, A; Eckhoff, C

    2000-04-15

    Ro 23-9223 is a highly lipophilic aromatic retinoid with antiproliferative and sebum supressive effects in preclinical disease models of acne. To investigate the relation between Ro 23-9223 developmental toxicity, drug distribution, and transplacental transfer, groups of pregnant hamsters were given oral doses of 50-500 mg/kg Ro 23-9223 on days 8 and 9 of gestation. The teratogenic phenotype induced at doses greater than 125 mg/kg per day was similar to that found after exposure to doses of 13-cis-retinoic acid (isotretinoin, Accutane) greater than 37.5 mg/kg per day. Oral bioavailability of Ro 23-9223 was very low compared to 13-cis-retinoic acid. The highest concentrations of Ro 23-9223 were found in maternal liver, lung, adipose tissue, cardiac muscle, and placenta, whereas only little of the compound crossed the blood-brain barrier. Based on embryo AUC, Ro 23-9223 had a 30- to 50-fold greater embryo:maternal concentration ratio than 13-cis-retinoic acid plus its bioactive metabolites following similar doses of the two retinoids. In preclinical pharmacology studies, oral doses of Ro 23-9223 (5 mg/kg per day) and 13-cis-retinoic acid (10 mg/kg per day) produced comparable gland size reductions in the hamster ear sebaceous gland reduction assay. Under these conditions, Ro 23-9223 plasma AUC was 40 times smaller than that of 13-cis-retinoic acid plus its bioactive metabolites. Assuming that the near linear dose-exposure relationship of Ro 23-9223 extends beyond the dose range of this study, embryo AUCs of Ro 23-9223 and 13-cis-retinoic acid (plus metabolites) would be near identical following pharmacologically equivalent doses. A comparison of embryo retinoid AUCs suggests a 4-fold lower teratogenic potency of Ro 23-9223 compared to with 13-cis-retinoic acid. Despite high embryo levels in hamsters, the data suggest an improved therapeutic index for Ro 23-9223 compared with 13-cis-retinoic acid in a preclinical acne disease model. Copyright 2000 Academic Press.

  20. RORα, a Potential Tumor Suppressor and Therapeutic Target of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jun Du

    2012-11-01

    Full Text Available The function of the nuclear receptor (NR in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORα, one member of the retinoid orphan nuclear receptor (ROR subfamily of orphan receptors, regulates various cellular and pathological activities. RORα is commonly down-regulated and/or hypoactivated in breast cancer compared to normal mammary tissue. Expression of RORα suppresses malignant phenotypes in breast cancer cells, in vitro and in vivo. Activity of RORα can be categorized into the canonical and non-canonical nuclear receptor pathways, which in turn regulate various breast cancer cellular function, including cell proliferation, apoptosis and invasion. This information suggests that RORα is a potent tumor suppressor and a potential therapeutic target for breast cancer.

  1. Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) regulates glucocorticoid action in adipocytes.

    Science.gov (United States)

    Emont, Margo P; Mantis, Stelios; Kahn, Jonathan H; Landeche, Michael; Han, Xuan; Sargis, Robert M; Cohen, Ronald N

    2015-05-15

    Local modulation of glucocorticoid action in adipocytes regulates adiposity and systemic insulin sensitivity. However, the specific cofactors that mediate glucocorticoid receptor (GR) action in adipocytes remain unclear. Here we show that the silencing mediator of retinoid and thyroid hormone receptors (SMRT) is recruited to GR in adipocytes and regulates ligand-dependent GR function. Decreased SMRT expression in adipocytes in vivo increases expression of glucocorticoid-responsive genes. Moreover, adipocytes with decreased SMRT expression exhibit altered glucocorticoid regulation of lipolysis. We conclude that SMRT regulates the metabolic functions of GR in adipocytes in vivo. Modulation of GR-SMRT interactions in adipocytes represents a novel approach to control the local degree of glucocorticoid action and thus influence adipocyte metabolic function. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Electro-Absorption Spectroscopy and Semi-Empirical Molecular Orbital Calculations of Polar Retinoid Analogues

    Science.gov (United States)

    Hashimoto, Hideki; Hattori, Kingo; Yamada, Takashi; Kobayashi, Takayoshi

    2001-08-01

    Nonlinear polarizabilities of a series of polar retinoid analogues were determined experimentally by means of electro-absorption (Stark) spectroscopy. The dependence of the magnitude of nonlinear polarizabilities on polyene chain-lengths as well as on the strength of electron-accepting groups was systematically compared. Semi-empirical molecular orbital calculations using AM1 Hamiltonian (MNDO-AM1 method) could quantitatively predict the second (β) and the third (γ) order nonlinear polarizabilities of the present set of molecules except for the γ value of C20BDCInd. The real and imaginary parts of χ(3)(-ω0,0,ω) spectra were calculated in order to account the figure of merit of the third-order nonlinear optical material.

  3. NADPH-d activity in rat thymus after the application of retinoid acid

    Directory of Open Access Journals (Sweden)

    F. Dorko

    2012-02-01

    Full Text Available The aim of this work was to determine the localization of nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d activity as the marker for synthesis of nitric oxide synthase (NOS in the rat thymus after the application of retinoid acid (RA on 1st, 7th, 14th and 21st days of gestation. The given results can build the basis for understanding of the role of NOS in rat thymus. NADPH-d positive cells were represented with dark-blue color and were localized on corticomedullar junction of the thymus. These cells were of different intensity of coloring and were shaped in oval, circle or irregular forms. NADPH-d positive nerve fibers were observed in perivascular topography. They were marked more strongly in the case of control group. The result of application of RA to gravid rats was that the birth weights of newborn rats and their thymuses were smaller, but without statistically significance.

  4. Cheilitis in acne vulgaris patients with no previous use of systemic retinoid products.

    Science.gov (United States)

    Balighi, Kamran; Daneshpazhooh, Maryam; Lajevardi, Vahideh; Talebi, Shahin; Azizpour, Arghavan

    2017-08-01

    Isotretinoin is commonly used in the treatment of acne vulgaris. While one of the more common side-effects is cheilitis, we have observed an increased incidence of cheilitis prior to the commencement of systemic isotretinoin. The aim of this study was to assess the prevalence of cheilitis among acne vulgaris patients. A non-interventional cross-sectional study of patients with acne vulgaris. Patients with previous use of systemic retinoids were excluded. The patients were examined for signs and symptoms of cheilitis. Of a total of 400 patients, 134 (34%) had evidence of cheilitis at initial presentation. Two-thirds (63%) were female (P acne excorie, compared with only 8% of patients with no signs of cheilitis. Our findings suggest that cheilitis is quite common among acne vulgaris patients even before treatment with isotretinoin. © 2016 The Australasian College of Dermatologists.

  5. NADPH-d activity in rat thymus after the application of retinoid acid.

    Science.gov (United States)

    Dorko, F; Spakovská, T; Lovasová, K; Patlevič, P; Kluchová, D

    2012-02-08

    The aim of this work was to determine the localization of nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d) activity as the marker for synthesis of nitric oxide synthase (NOS) in the rat thymus after the application of retinoid acid (RA) on 1st, 7th, 14th and 21st days of gestation. The given results can build the basis for understanding of the role of NOS in rat thymus. NADPH-d positive cells were represented with dark-blue color and were localized on corticomedullar junction of the thymus. These cells were of different intensity of coloring and were shaped in oval, circle or irregular forms. NADPH-d positive nerve fibers were observed in perivascular topography. They were marked more strongly in the case of control group. The result of application of RA to gravid rats was that the birth weights of newborn rats and their thymuses were smaller, but without statistically significance.

  6. Systemic retinoids for chemoprevention of non-melanoma skin cancer in high-risk patients.

    Science.gov (United States)

    Marquez, Christina; Bair, Sarah M; Smithberger, Erica; Cherpelis, Basil S; Glass, L Frank

    2010-07-01

    Patients at high risk for the development of multiple non-melanoma skin cancers, especially those receiving immunosuppressive medications following solid organ transplantation, are candidates for chemoprophylaxis. In patients where photo-protection and topical medications are insufficient to prevent the growth of new cancers, there is considerable evidence that oral retinoids, including vitamin A, and synthetics such as isotretinoin, etretinate and acitretin are efficacious in this regard. This manuscript is a review of the literature regarding the use of these agents for chemoprophylaxis of non-melanoma skin cancer. Also included is anecdotal evidence that bexarotene, a rexinoid, may be as effective as acitretin in terms of chemoprevention, with a comparable side effects at doses recommended for chemoprophylaxis.

  7. The Regulation of JAB1 and Its Role in Breast Cancer

    National Research Council Canada - National Science Library

    Johnson, Terry J

    2007-01-01

    ...) JAB1 overexpression confers resistance to Herceptin in breast cancer cell lines SKBR3 and BT474, and inhibition of JAB1 increased the efficacy of Herceptin mediated G1 arrest and p27 accumulation...

  8. The Role of RB in the Therapeutic Response of Breast Cancer

    National Research Council Canada - National Science Library

    Bosco, Emily E

    2005-01-01

    The retinoblastoma tumor suppressor protein (RB) participates in the growth regulation of breast cancer cells by controlling G-S phase progression and mediating cell cycle arrest in response to anti-mitogenic signaling...

  9. Uteroplacental Insufficiency Alters the Retinoid Pathway and Lung Development in Newborn Rats.

    Science.gov (United States)

    Huang, Liang-Ti; Chou, Hsiu-Chu; Lin, Chun-Mao; Chen, Chung-Ming

    2016-12-01

    Intrauterine growth retardation (IUGR) is associated with reduced lung function during infancy and perhaps throughout adulthood. The retinoic acid (RA) signaling pathway modulates pre- and postnatal lung development. This study was conducted to test our hypothesis that uteroplacental insufficiency alters the elements of the retinoid pathway in developing lungs. On Gestation Day 18, either uteroplacental insufficiency was induced through bilateral uterine vessel ligation (IUGR group) or sham surgery (control group) was performed. Lung tissues from the offspring were examined through Western blotting, immunohistochemistry, and morphometry on Postnatal Day 3 and Postnatal Day 7. Compared with control rats, the IUGR rats exhibited significantly lower body weights on Postnatal Day 3 and Postnatal Day 7 and significantly lower lung weights on Postnatal Day 3. Uteroplacental insufficiency significantly increased RA receptor (RAR)-β protein expression on Postnatal Day 3. The expression of RAR-α, RAR-γ, cellular RA-binding protein-1, and cellular RA-binding protein-2 between the control and IUGR rats was comparable on Postnatal Day 3 and Postnatal Day 7. Compared with the control rats, the IUGR rats exhibited a significantly higher volume fraction of alveolar airspace on Postnatal Day 3 and Postnatal Day 7 and a significantly lower volume fraction of alveolar walls on Postnatal Day 3. Uteroplacental insufficiency causes defective alveolarization and transient increases in RAR-β expression in the lungs of newborn rats. The retinoid pathway may be one of the probable pathways mediating lung abnormalities caused by uteroplacental insufficiency. Copyright © 2016. Published by Elsevier B.V.

  10. Integrating protein structures and precomputed genealogies in the Magnum database: Examples with cellular retinoid binding proteins

    Directory of Open Access Journals (Sweden)

    Bradley Michael E

    2006-02-01

    Full Text Available Abstract Background When accurate models for the divergent evolution of protein sequences are integrated with complementary biological information, such as folded protein structures, analyses of the combined data often lead to new hypotheses about molecular physiology. This represents an excellent example of how bioinformatics can be used to guide experimental research. However, progress in this direction has been slowed by the lack of a publicly available resource suitable for general use. Results The precomputed Magnum database offers a solution to this problem for ca. 1,800 full-length protein families with at least one crystal structure. The Magnum deliverables include 1 multiple sequence alignments, 2 mapping of alignment sites to crystal structure sites, 3 phylogenetic trees, 4 inferred ancestral sequences at internal tree nodes, and 5 amino acid replacements along tree branches. Comprehensive evaluations revealed that the automated procedures used to construct Magnum produced accurate models of how proteins divergently evolve, or genealogies, and correctly integrated these with the structural data. To demonstrate Magnum's capabilities, we asked for amino acid replacements requiring three nucleotide substitutions, located at internal protein structure sites, and occurring on short phylogenetic tree branches. In the cellular retinoid binding protein family a site that potentially modulates ligand binding affinity was discovered. Recruitment of cellular retinol binding protein to function as a lens crystallin in the diurnal gecko afforded another opportunity to showcase the predictive value of a browsable database containing branch replacement patterns integrated with protein structures. Conclusion We integrated two areas of protein science, evolution and structure, on a large scale and created a precomputed database, known as Magnum, which is the first freely available resource of its kind. Magnum provides evolutionary and structural

  11. Fatty acid transport protein 1 regulates retinoid metabolism and photoreceptor development in mouse retina

    Science.gov (United States)

    Cubizolle, Aurélie; Guillou, Laurent; Mollereau, Bertrand; Hamel, Christian P.

    2017-01-01

    In retinal pigment epithelium (RPE), RPE65 catalyzes the isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol in the visual cycle and controls the rhodopsin regeneration rate. However, the mechanisms by which these processes are regulated are still unclear. Fatty Acid Transport Protein 1 (FATP1) is involved in fatty acid uptake and lipid metabolism in a variety of cell types. FATP1 co-localizes with RPE65 in RPE and inhibits its isomerase activity in vitro. Here, we further investigated the role of FATP1 in the visual cycle using transgenic mice that overexpress human FATP1 specifically in the RPE (hFATP1TG mice). The mice displayed no delay in the kinetics of regeneration of the visual chromophore 11-cis-retinal after photobleaching and had no defects in light sensitivity. However, the total retinoid content was higher in the hFATP1TG mice than in wild type mice, and the transgenic mice also displayed an age-related accumulation (up to 40%) of all-trans-retinal and retinyl esters that was not observed in control mice. Consistent with these results, hFATP1TG mice were more susceptible to light-induced photoreceptor degeneration. hFATP1 overexpression also induced an ~3.5-fold increase in retinosome autofluorescence, as measured by two-photon microscopy. Interestingly, hFATP1TG retina contained ~25% more photoreceptor cells and ~35% longer outer segments than wild type mice, revealing a non-cell-autonomous effect of hFATP1 expressed in the RPE. These data are the first to show that FATP1-mediated fatty acid uptake in the RPE controls both retinoid metabolism in the outer retina and photoreceptor development. PMID:28672005

  12. HPMA copolymer-based polymer conjugates for the delivery and controlled release of retinoids.

    Science.gov (United States)

    Lidický, O; Šírová, M; Etrych, T

    2016-10-20

    In this paper, we describe the synthesis, physicochemical characterization, drug release kinetics and preliminary biological evaluation of several N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer-retinoid conjugates designed for solid tumor immunotherapy. The conjugates are supposed to inhibit the immunosuppressive activity of myeloid-derived suppressor cells (MDSC) accumulated in the solid tumor microenvironment. All-trans retinoic acid (ATRA) was derivatized to hydrazide (AtrHy) and then attached to the polymer backbone via a spacer that is stable at the normal pH of blood (7.4) and hydrolytically degradable in mildly acidic environments (e.g. in endosomes or lysosomes, pH~5.0-6.5). Polymer-AtrHy conjugates were designed to achieve prolonged blood circulation and release of the immunomodulator intracellularly or extracellularly in solid tumor tissue. Three types of polymer precursors, differing in the structure of the keto acid-containing side chains, were synthesized. A linkage susceptible to hydrolytic cleavage was formed by the conjugation reaction of the carbonyl group-terminated side chains of the polymer precursors with the hydrazide group of a drug derivative. In vitro incubation of the conjugates in buffers resulted in much faster release of the drugs or their derivatives from the polymer at pH 5.0 than at pH 7.4, with the rate depending on the detailed structure of the spacer. Both the AtrHy derivative and its polymer conjugates showed the ability to induce the differentiation of retinoid-responsive HL-60 cells, thus demonstrating the required biological activity.

  13. Myocardial Dysfunction and Shock after Cardiac Arrest

    Science.gov (United States)

    Jentzer, Jacob C.; Chonde, Meshe D.; Dezfulian, Cameron

    2015-01-01

    Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies. PMID:26421284

  14. Extracorporeal membrane oxygenation for refractory cardiac arrest

    Directory of Open Access Journals (Sweden)

    Steven A Conrad

    2017-01-01

    Full Text Available Extracorporeal cardiopulmonary resuscitation (ECPR is the use of rapid deployment venoarterial (VA extracorporeal membrane oxygenation to support systemic circulation and vital organ perfusion in patients in refractory cardiac arrest not responding to conventional cardiopulmonary resuscitation (CPR. Although prospective controlled studies are lacking, observational studies suggest improved outcomes compared with conventional CPR when ECPR is instituted within 30-60 min following cardiac arrest. Adult and pediatric patients with witnessed in-hospital and out-of-hospital cardiac arrest and good quality CPR, failure of at least 15 min of conventional resuscitation, and a potentially reversible cause for arrest are candidates. Percutaneous cannulation where feasible is rapid and can be performed by nonsurgeons (emergency physicians, intensivists, cardiologists, and interventional radiologists. Modern extracorporeal systems are easy to prime and manage and are technically easy to manage with proper training and experience. ECPR can be deployed in the emergency department for out-of-hospital arrest or in various inpatient units for in-hospital arrest. ECPR should be considered for patients with refractory cardiac arrest in hospitals with an existing extracorporeal life support program, able to provide rapid deployment of support, and with resources to provide postresuscitation evaluation and management.

  15. Chromosomal Aneuploidies and Early Embryonic Developmental Arrest

    Directory of Open Access Journals (Sweden)

    Maria Maurer

    2015-07-01

    Full Text Available Background: Selecting the best embryo for transfer, with the highest chance of achieving a vital pregnancy, is a major goal in current in vitro fertilization (IVF technology. The high rate of embryonic developmental arrest during IVF treatment is one of the limitations in achieving this goal. Chromosomal abnormalities are possibly linked with chromosomal arrest and selection against abnormal fertilization products. The objective of this study was to evaluate the frequency and type of chromosomal abnormalities in preimplantation embryos with developmental arrest. Materials and Methods: This cohort study included blastomeres of embryos with early developmental arrest that were biopsied and analyzed by fluorescence in-situ hybridization (FISH with probes for chromosomes 13, 16, 18, 21 and 22. Forty-five couples undergoing IVF treatment were included, and 119 arrested embryos were biopsied. All probes were obtained from the Kinderwunsch Zentrum, Linz, Austria, between August 2009 and August 2011. Results: Of these embryos, 31.6% were normal for all chromosomes tested, and 68.4% were abnormal. Eleven embryos were uniformly aneuploid, 20 were polyploid, 3 were haploid, 11 displayed mosaicism and 22 embryos exhibited chaotic chromosomal complement. Conclusion: Nearly 70% of arrested embryos exhibit chromosomal errors, making chromosomal abnormalities a major cause of embryonic arrest and may be a further explanation for the high developmental failure rates during culture of the embryos in the IVF setting.

  16. Chromosomal locations and modes of action of genes of the retinoid (vitamin A) system support their involvement in the etiology of schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Goodman, A.B. [Columbia Univ. School of Public Health, New York, NY (United States)

    1995-08-14

    Vitamin A (retinoid), an essential nutrient for fetal and subsequent mammalian development, is involved in gene expression, cell differentiation, proliferation, migration, and death. Retinoic acid (RA) the morphogenic derivative of vitamin A is highly teratogenic. In humans retinoid excess or deficit can result in brain anomalies and psychosis. This review discusses chromosomal loci of genes that control the retinoid cascade in relation to some candidate genes in schizophrenia. The paper relates the knowledge about the transport, delivery, and action of retinoids to what is presently known about the pathology of schizophrenia, with particular reference to the dopamine hypothesis, neurotransmitters, the glutamate hypothesis, neurotransmitters, the glutamate hypothesis, retinitis pigmentosa, dermatologic disorders, and craniofacial anomalies. 201 refs., 1 tab.

  17. Retinoid and carotenoid status in serum and liver among patients at high-risk for liver cancer.

    Science.gov (United States)

    Kataria, Yachana; Deaton, Ryan J; Enk, Erika; Jin, Ming; Petrauskaite, Milita; Dong, Linlin; Goldenberg, Joseph R; Cotler, Scott J; Jensen, Donald M; van Breemen, Richard B; Gann, Peter H

    2016-02-29

    Approximately 2.7 million Americans are chronically infected with hepatitis C virus (HCV). HCV patients with cirrhosis form the largest group of persons at high risk for hepatocellular carcinoma (HCC). Increased oxidative stress is regarded as a major mechanism of HCV-related liver disease progression. Deficiencies in retinoid and carotenoid antioxidants may represent a major modifiable risk factor for disease progression. This study aims to identify key predictors of serum antioxidant levels in patients with HCV, to examine the relationship between retinoid/carotenoid concentrations in serum and hepatic tissue, to quantify the association between systemic measures of oxidative stress and antioxidant status, and to examine the relationship between retinoids and stellate cell activation. Patients undergoing liver biopsy (n = 69) provided fasting blood, fresh tissue, urine and completed a diet history questionnaire. Serum and questionnaire data from healthy volunteers (n = 11), normal liver tissue from public repositories and patients without liver disease (n = 11) were also collected. Urinary isoprostanes, serum and tissue retinoid concentrations were obtained by UHPLC-MS-MS. Immunohistochemistry for αSMA was performed on FFPE sections and subsequently quantified via digital image analysis. Associations between urinary isoprostanes, αSMA levels, and retinoids were assessed using Spearman correlation coefficients and non-parametric tests were utilized to test differences among disease severity groups. There was a significant inverse association between serum retinol, lycopene, and RBP4 concentrations with fibrosis stage. Serum β-carotene and lycopene were strongly associated with their respective tissue concentrations. There was a weak downward trend of tissue retinyl palmitate with increasing fibrosis stage. Tissue retinyl palmitate was inversely and significantly correlated with hepatic αSMA expression, a marker for hepatic stellate cell activation (r = -0

  18. In utero and lactational exposure to a mixture of environmental contaminants detected in Canadian Arctic human populations alters retinoid levels in rat offspring with low margins of exposure.

    Science.gov (United States)

    Elabbas, Lubna E; Esteban, Javier; Barber, Xavier; Hamscher, Gerd; Nau, Heinz; Bowers, Wayne J; Nakai, Jamie S; Herlin, Maria; Åkesson, Agneta; Viluksela, Matti; Borg, Daniel; Håkansson, Helen

    2014-01-01

    Arctic inhabitants are highly exposed to persistent organic pollutants (POP), which may produce adverse health effects. This study characterized alterations in tissue retinoid (vitamin A) levels in rat offspring and their dams following in utero and lactational exposure to the Northern Contaminant Mixture (NCM), a mixture of 27 contaminants including polychlorinated biphenyls (PCB), organochlorine (OC) pesticides, and methylmercury (MeHg), present in maternal blood of the Canadian Arctic Inuit population. Further, effect levels for retinoid system alterations and other endpoints were compared to the Arctic Inuit population exposure and their interrelationships were assessed. Sprague-Dawley rat dams were dosed with NCM from gestational day 1 to postnatal day (PND) 23. Livers, kidneys and serum were obtained from offspring on PND35, PND77, and PND350 and their dams on PND30 for analysis of tissue retinoid levels, hepatic cytochrome P-450 (CYP) enzymes, and serum thyroid hormones. Benchmark doses were established for all endpoints, and a partial least-squares regression analysis was performed for NCM treatment, hepatic retinoid levels, CYP enzyme induction, and thyroid hormone levels, as well as body and liver weights. Hepatic retinoid levels were sensitive endpoints, with the most pronounced effects at PND35 though still apparent at PND350. The effects on tissue retinoid levels and changes in CYP enzyme activities, body and liver weights, and thyroid hormone levels were associated and likely driven by dioxin-like compounds in the mixture. Low margins of exposure were observed for all retinoid endpoints at PND35. These findings are important for health risk assessment of Canadian Arctic populations and further support the use of retinoid system analyses in testing of endocrine-system-modulating compounds.

  19. Preventing and arresting coronary atherosclerosis.

    Science.gov (United States)

    Roberts, W C

    1995-09-01

    The good news about coronary atherosclerosis is that it takes an awful lot of plaque before symptoms of myocardial ischemia occur. The bad news is that despite the need for large quantities of plaque for symptoms to occur, nevertheless nearly half of us in the United States eventually have the necessary quantity. Atherosclerosis is infrequently hereditary in origin. Most of us get atherosclerosis because we consume too much fat, cholesterol, and calories. The consequence is an elevated ( > 150 mg/dl) serum total cholesterol level, and the higher the number is above 150, the greater is the quantity of plaque deposited in our arteries. If the serum total cholesterol level can be prevented from rising to more than 150 mg/dl, plaques are not laid down; if elevated levels are lowered to 150 mg/dl, further plaque does not form, and parts of those present may vanish. A fruit-vegetarian-starch diet is necessary as a rule to achieve the 150 mg/dl level in most adults. Lipid-lowering drugs are required in the patients with familial hypercholesterolemia and in most patients with atherosclerotic events. The best news about atherosclerosis is that it can be prevented in those without the hereditary form, and it can be arrested by lowering elevated serum total (and LDL) cholesterol to the 150 mg/dl level.

  20. Pituitary specific retinoid-X receptor ligand interactions with thyroid hormone receptor signaling revealed by high throughput reporter and endogenous gene responses.

    Science.gov (United States)

    Mengeling, Brenda J; Furlow, J David

    2015-10-01

    Disruption of thyroid hormone (TH) signaling can compromise vital processes both during development and in the adult. We previously reported on high-throughput screening experiments for man-made TH disruptors using a stably integrated line of rat pituitary cells, GH3.TRE-Luc, in which a thyroid hormone receptor (TR) response element drives luciferase (Luc) expression. In these experiments, several retinoid/rexinoid compounds activated the reporter. Here we show that all-trans and 13-cis retinoic acid appear to function through the heterodimer partners of TRs, retinoid-X receptors (RXRs), as RXR antagonists abrogated retinoid-induced activation. The retinoids also induced known endogenous TR target genes, showing good correlation with Luc activity. Synthetic RXR-specific agonists significantly activated all tested TR target genes, but interestingly, retinoid/rexinoid activation was more consistent between genes than the extent of T3-induced activation. In contrast, the retinoids neither activated the Luc reporter construct in transient transfection assays in the human hepatocarcinoma cell line HuH7, nor two of the same T3-induced genes examined in pituitary cells. These data demonstrate the suitability and sensitivity of GH3.TRE-Luc cells for screening chemical compound libraries for TH disruption and suggest that the extent of disruption can vary on a cell type and gene-specific bases, including an underappreciated contribution by RXRs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. β-Carotene and its cleavage enzyme β-carotene-15,15′-oxygenase (CMOI) affect retinoid metabolism in developing tissues

    Science.gov (United States)

    Kim, Youn-Kyung; Wassef, Lesley; Chung, Stacey; Jiang, Hongfeng; Wyss, Adrian; Blaner, William S.; Quadro, Loredana

    2011-01-01

    The mammalian embryo relies on maternal circulating retinoids (vitamin A derivatives) for development. β-Carotene is the major human dietary provitamin A. β-Carotene-15,15′-oxygenase (CMOI) has been proposed as the main enzyme generating retinoid from β-carotene in vivo. CMOI is expressed in embryonic tissues, suggesting that β-carotene provides retinoids locally during development. We performed loss of CMOI function studies in mice lacking retinol-binding protein (RBP), an established model of embryonic vitamin A deficiency (VAD). We show that, unexpectedly, lack of CMOI in the developing tissues further exacerbates the severity of VAD and thus the embryonic malformations of RBP−/− mice. Since β-carotene was not present in any of the mouse diets, we unveiled a novel action of CMOI independent from its β-carotene cleavage activity. We also show for the first time that CMOI exerts an additional function on retinoid metabolism by influencing retinyl ester formation via modulation of lecithin:retinol acyltransferase (LRAT) activity, at least in developing tissues. Finally, we demonstrate unequivocally that β-carotene can serve as an alternative vitamin A source for the in situ synthesis of retinoids in developing tissues by the action of CMOI.—Kim, Y.-K., Wassef, L., Chung, S., Jiang, H., Wyss, A., Blaner, W. S., Quadro, L. β-Carotene and its cleavage enzyme β-carotene-15,15′-oxygenase (CMOI) affect retinoid metabolism in developing tissues. PMID:21285397

  2. Sex Disparities in Arrest Outcomes for Domestic Violence

    Science.gov (United States)

    Hamilton, Melissa; Worthen, Meredith G. F.

    2011-01-01

    Domestic violence arrests have been historically focused on protecting women and children from abusive men. Arrest patterns continue to reflect this bias with more men arrested for domestic violence compared to women. Such potential gender variations in arrest patterns pave the way to the investigation of disparities by sex of the offender in…

  3. Determination of retinoids in human serum, tocopherol and retinyl acetate in pharmaceuticals by RP-LC with electrochemical detection.

    Science.gov (United States)

    Wang, L H; Wang, J F

    2001-07-01

    A liquid chromatography with a electrochemical detector method has been developed of the quantitative measurement for the three retinoids in human serum (13-cis and all-trans retinoic acid and retinol), as well as tocopherol acetate, retinyl acetate and retinol in pharmaceuticals. The detection cell consisted of a glassy carbon electrode held at 1.0 V versus an Ag/AgCl reference electrode. The maximum electrochemical signal was obtained with a supporting electrolyte containing 92% methanol 0.1 M acetate buffer (pH 4.72) as the mobile phase. The quantification limits are 0.5, 0.2, 0.4, 0.5, 0.8 and 0.8 ng for tocopherol acetate, all-trans-RA, 13-cis-RA, retinol, retinal and retinyl acetate, respectively. The electrooxidation process is applied for the simultaneous quantitative determination of retinoids in human serum. Comparison with results obtained from HPLC-UV shows agreement.

  4. Distinct populations of hepatic stellate cells in the mouse liver have different capacities for retinoid and lipid storage.

    Directory of Open Access Journals (Sweden)

    Diana N D'Ambrosio

    Full Text Available Hepatic stellate cell (HSC lipid droplets are specialized organelles for the storage of retinoid, accounting for 50-60% of all retinoid present in the body. When HSCs activate, retinyl ester levels progressively decrease and the lipid droplets are lost. The objective of this study was to determine if the HSC population in a healthy, uninjured liver demonstrates heterogeneity in its capacity for retinoid and lipid storage in lipid droplets. To this end, we utilized two methods of HSC isolation, which leverage distinct properties of these cells, including their vitamin A content and collagen expression. HSCs were isolated either from wild type (WT mice in the C57BL/6 genetic background by flotation in a Nycodenz density gradient, followed by fluorescence activated cell sorting (FACS based on vitamin A autofluorescence, or from collagen-green fluorescent protein (GFP mice by FACS based on GFP expression from a GFP transgene driven by the collagen I promoter. We show that GFP-HSCs have: (i increased expression of typical markers of HSC activation; (ii decreased retinyl ester levels, accompanied by reduced expression of the enzyme needed for hepatic retinyl ester synthesis (LRAT; (iii decreased triglyceride levels; (iv increased expression of genes associated with lipid catabolism; and (v an increase in expression of the retinoid-catabolizing cytochrome, CYP2S1.Our observations suggest that the HSC population in a healthy, uninjured liver is heterogeneous. One subset of the total HSC population, which expresses early markers of HSC activation, may be "primed" and ready for rapid response to acute liver injury.

  5. Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression

    Directory of Open Access Journals (Sweden)

    Pugazhenthi Umarani

    2009-03-01

    Full Text Available Abstract Background Metastatic melanoma has a high mortality rate and suboptimal therapeutic options. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid × receptor selective agonist, and thiazolidinediones (TZD, PPARγ selective ligands, as novel treatments. Results Mouse xenograft models with human melanoma cell lines [A375(DRO or M14(5–16] were treated for 4 weeks with daily vehicle, RXR agonist (rexinoid, LGD1069, 30 mg/kg/d, PPARγ agonist (TZD, rosiglitazone, 10 mg/kg/d or combination. A375(DRO tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect. M14(5–16 tumors only responded to LGD1069 100 mg/kg/day. A375(DRO sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARγ expression but preserved RXR expression. shRNA knockdown of PPARγ or RXRγ attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO cells. Rexinoid (LGD1069 and retinoid (TTNPB treatment of M14(5–16 cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRγ resulted in a decreased response to either ligand. Conclusion A375 (DRO melanoma cell growth is inhibited by rexinoid and TZD treatment, and this response is dependent on RXR and PPARγ receptor expression. M14 (5–16 melanoma cell growth is inhibited by rexinoid and retinoid treatment, and this response is dependent on RXR expression. These findings may help guide molecular-based treatment strategies in melanoma and provide insight for mechanisms of resistance to nuclear receptor targeted therapies in certain cancers.

  6. The action of a dietary retinoid on gene expression and cancer induction in electron-irradiated rat skin

    Energy Technology Data Exchange (ETDEWEB)

    Burns, F.J.; Chen, S.; Xu, G.; Wu, F.; Tang, M.S. [New York Univ., NY (United States). School of Medicine

    2002-12-01

    Current models of radiation carcinogenesis generally assume that the DNA is damaged in a variety of ways by the radiation and that subsequent cell divisions contribute to the conversion of the damage to heritable mutations. Cancer may seem complex and intractable, but its complexity provides multiple opportunities for preventive interventions. Mitotic inhibitors are among the strongest cancer preventive agents, not only slowing the growth rate of preneoplasias but also increasing the fidelity of DNA repair processes. Ionizing radiation, including electrons, is a strong inducer of cancer in rat skin, and dietary retinoids have shown potent cancer preventive activity in the same system. A non-toxic dietary dose of retinyl acetate altered gene expression levels 24 hours after electron irradiation of rat skin. Of the 8740 genes on an Affymetrix rat expression array, the radiation significantly (5 fold or higher) altered 188, while the retinoid altered 231, including 16 radiation-altered genes that were reversely altered. While radiation strongly affected the expression of stress response, immune/inflammation and nucleic acid metabolism genes, the retinoid most strongly affected proliferation-related genes, including some significant reversals, such as, keratin 14, retinol binding protein, and calcium binding proteins. These results point to reversal of proliferation-relevant genes as a likely basis for the anti-radiogenic effects of dietary retinyl acetate. (author)

  7. Molecular Anti-inflammatory Mechanisms of Retinoids and Carotenoids in Alzheimer's Disease: a Review of Current Evidence.

    Science.gov (United States)

    Mohammadzadeh Honarvar, Niyaz; Saedisomeolia, Ahmad; Abdolahi, Mina; Shayeganrad, Amir; Taheri Sangsari, Gholamreza; Hassanzadeh Rad, Babak; Muench, Gerald

    2017-03-01

    Alzheimer's disease (AD) is considered as one of the most prevalent neurodegenerative disorders characterized by progressive loss of mental function and ability to learn. AD is a multifactorial disorder. Various hypotheses are suggested for the pathophysiology of AD including "Aβ hypothesis," "tau hypothesis," and "cholinergic hypothesis." Recently, it has been demonstrated that neuroinflammation is involved in the pathogenesis of AD. Neuroinflammation causes synaptic dysfunction and neuronal death within the brain. Excessive production of pro-inflammatory mediators induces Aβ peptide production/accumulation and hyperphosphorylated tau generating inflammatory molecules and cytokines. These inflammatory molecules disrupt blood-brain barrier integrity and increase the production of Aβ42 oligomers. Retinoids and carotenoids are potent antioxidants and anti-inflammatory agents having neuroprotective properties. They are able to prevent disease progression through several mechanisms such as suppression of Aβ peptide production/accumulation, oxidative stress, and pro-inflammatory mediator's secretion as well as improvement of cognitive performance. These observations, therefore, confirm the neuroprotective role of retinoids and carotenoids through multiple pathways. Therefore, the administration of these nutrients is considered as a promising approach to the prevention and/or treatment of AD in the future. The aim of this review is to present existing evidences regarding the beneficial effects of retinoids and carotenoids on AD's risk and outcomes, seeking the mechanism of their action.

  8. Retinoids, 585-nm laser, and carbon dioxide laser: a numeric comparison of neocollagen formation in photoaged hairless mouse skin.

    Science.gov (United States)

    Lee, C J; Park, J H; Ciesielski, T E; Thomson, J G; Persing, J A

    2008-11-01

    A variety of new methods for treating photoaging have been recently introduced. There has been increasing interest in comparing the relative efficacy of multiple methods for photoaging. However, the efficacy of a single method is difficult to assess from the data reported in the literature. Photoaged hairless mice were randomly divided into seven treatment groups: control, retinoids (tretinoin and adapalene), lasers (585 nm and CO(2)), and combination groups (585 nm + adapalene and CO(2 )+ adapalene). Biopsies were taken from the treated regions, and the results were analyzed based on the repair zone. The repair zones of the various methods for photoaging were compared. Retinoids produced a wider repair zone than the control condition. The 585-nm and CO(2) laser resurfacing produced a result equivalent to that of the control condition. A combination of these lasers with adapalene produced a wider repair zone than the lasers alone, but the combination produced a result equivalent to that of adapalene alone. Retinoids are potent stimuli for neocollagen formation. The 585-nm or CO(2) laser alone did not induce more neocollagen than the control condition. In addition, no synergistic effect was observed with the combination treatments. The repair zone of the combination treatment is mainly attributable to adapalene.

  9. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

    Science.gov (United States)

    Cideciyan, Artur V.; Aleman, Tomas S.; Boye, Sanford L.; Schwartz, Sharon B.; Kaushal, Shalesh; Roman, Alejandro J.; Pang, Ji-jing; Sumaroka, Alexander; Windsor, Elizabeth A. M.; Wilson, James M.; Flotte, Terence R.; Fishman, Gerald A.; Heon, Elise; Stone, Edwin M.; Byrne, Barry J.; Jacobson, Samuel G.; Hauswirth, William W.

    2008-01-01

    The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with vision after RPE65 gene therapy. PMID:18809924

  10. [Serum triglycerides and cholesterin in patients with skin diseases during oral treatment with aromatic retinoid (author's transl)].

    Science.gov (United States)

    Gollnick, H; Orfanos, C E

    1981-09-15

    The serum lipid levels were repeatedly controlled in 25 patients with various skin diseases treated orally with retinoid Ro 10-9359 in different doses. In 19 cases serum lipid values before onset of treatment were taken. 6 additional patients were controlled after long-term intake of the drug over 6-8 months. Pathological elevations of triglycerides were seen in 5 patients, in 4 of them 2-12 weeks after onset of oral treatment. All patients with elevated values had additional risk factors: Manifest or asymptomatic diabetes, alcoholic abuse with fatty liver, adipositas, and/or preexisting disorders of lipid metabolism. The observed changes seemed dose-dependent. The values were lowered or returned to normal after dose reduction or after discontinuation of treatment (one case). The cholesterin levels also showed some elevated values during the time of observation, however, there was no clear relation to the administration of the drug and the daily dose. The changes were also seen preferably in patients with risk factors. Controls of serum lipid levels seem, therefore, indicated before and under administration of oral retinoid. In patients with the additional risk factors mentioned above strict indication for oral retinoid therapy is needed and lower doses should be rather administered.

  11. Effects on thyroid hormone and retinoid metabolism in transthyretin-null mice by polychlorinated biphenyl isomers 118 and 114

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, N.; Yonemoto, J.; Takeuchi, Y.; Yokoi, C.; Tohyama, C. [National Inst. for Environmental Studies, Tsukuba (Japan)

    2004-09-15

    Some congeners/isomers of polychlorinated biphenyls (PCBs) and their metabolites are known to disturb thyroid and retinoid metabolism in laboratory animals and humans. Among 209 isomers of PCBs, 12 PCB isomers termed as the coplanar PCBs are grouped into dioxin-like chemicals based on their resemblance of toxic effects and mechanism(s) to dioxins. Mechanism(s) of toxicity by the dioxin-like chemicals have been established to be mediated through aryl hydrocarbon receptor (AhR). The toxic potency of each congener/isomer of dioxin-like chemicals has been evaluated by relative potency to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as the toxic equivalent factor (TEF). Because dioxins in environments are generally distributed as mixtures, the toxic equivalency (TEQ) concept has been adopted to evaluate the health risk of exposure to complex environmental mixtures. TEQ values are calculated by multiplication of the sum of the chemical concentrations by the corresponding TEF values. The present study was undertaken to investigate the effects of two coplanar PCBs, PCB118, highly detected in human tissues and milk (TEF value: 0.0001), and PCB114 (TEF value: 0.0005) on thyroid hormone and retinoid metabolism. Possible involvement of transthyretin (TTR), the principal carrier of thyroid hormone and retinol-binding protein in the rodent, in PCBs-induced disruption of thyroid and retinoid homeostasis was investigated.

  12. All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells

    Science.gov (United States)

    Zanetti, Adriana; Affatato, Roberta; Centritto, Floriana; Fratelli, Maddalena; Kurosaki, Mami; Barzago, Maria Monica; Bolis, Marco; Terao, Mineko; Garattini, Enrico; Paroni, Gabriela

    2015-01-01

    All-trans-retinoic acid (ATRA) is a natural compound proposed for the treatment/chemoprevention of breast cancer. Increasing evidence indicates that aberrant regulation of epithelial-to-mesenchymal transition (EMT) is a determinant of the cancer cell invasive and metastatic behavior. The effects of ATRA on EMT are largely unknown. In HER2-positive SKBR3 and UACC812 cells, showing co-amplification of the ERBB2 and RARA genes, ATRA activates a RARα-dependent epithelial differentiation program. In SKBR3 cells, this causes the formation/reorganization of adherens and tight junctions. Epithelial differentiation and augmented cell-cell contacts underlie the anti-migratory action exerted by the retinoid in cells exposed to the EMT-inducing factors EGF and heregulin-β1. Down-regulation of NOTCH1, an emerging EMT modulator, is involved in the inhibition of motility by ATRA. Indeed, the retinoid blocks NOTCH1 up-regulation by EGF and/or heregulin-β1. Pharmacological inhibition of γ-secretase and NOTCH1 processing also abrogates SKBR3 cell migration. Stimulation of TGFβ contributes to the anti-migratory effect of ATRA. The retinoid switches TGFβ from an EMT-inducing and pro-migratory determinant to an anti-migratory mediator. Inhibition of the NOTCH1 pathway not only plays a role in the anti-migratory action of ATRA; it is relevant also for the anti-proliferative activity of the retinoid in HCC1599 breast cancer cells, which are addicted to NOTCH1 for growth/viability. This effect is enhanced by the combination of ATRA and the γ-secretase inhibitor N-(N-(3,5-difluorophenacetyl)-l-alanyl)-S-phenylglycine t-butyl ester, supporting the concept that the two compounds act at the transcriptional and post-translational levels along the NOTCH1 pathway. PMID:26018078

  13. Waterborne cadmium and nickel impact oxidative stress responses and retinoid metabolism in yellow perch

    Energy Technology Data Exchange (ETDEWEB)

    Defo, Michel A. [Institut national de la recherche scientifique (INRS), Centre Eau Terre Environnement, 490 de la Couronne, Québec, Québec G1K 9A9 (Canada); Bernatchez, Louis [Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, Québec, Québec G1V 0A6 (Canada); Campbell, Peter G.C. [Institut national de la recherche scientifique (INRS), Centre Eau Terre Environnement, 490 de la Couronne, Québec, Québec G1K 9A9 (Canada); Couture, Patrice, E-mail: patrice.couture@ete.inrs.ca [Institut national de la recherche scientifique (INRS), Centre Eau Terre Environnement, 490 de la Couronne, Québec, Québec G1K 9A9 (Canada)

    2014-09-15

    Highlights: • Cd and Ni affected indicators of retinoid metabolism and oxidative stress in fish. • Liver rdh-2 transcription levels increase in fish exposed to waterborne Cd. • Liver REH and LdRAT activities increase with increasing kidney Cd concentration. • Changes at molecular levels do not always mean changes at the functional levels. • Multi-level biological approaches are needed when assessing fish metal toxicology. - Abstract: In this experiment, we studied the transcriptional and functional (enzymatic) responses of yellow perch (Perca flavescens) to metal stress, with a focus on oxidative stress and vitamin A metabolism. Juvenile yellow perch were exposed to two environmentally relevant concentrations of waterborne cadmium (Cd) and nickel (Ni) for a period of 6 weeks. Kidney Cd and Ni bioaccumulation significantly increased with increasing metal exposure. The major retinoid metabolites analyzed in liver and muscle decreased with metal exposure except at high Cd exposure where no variation was reported in liver. A decrease in free plasma dehydroretinol was also observed with metal exposure. In the liver of Cd-exposed fish, both epidermal retinol dehydrogenase 2 transcription level and corresponding enzyme activities retinyl ester hydrolase and lecithin dehydroretinyl acyl transferase increased. In contrast, muscle epidermal retinol dehydrogenase 2 transcription level decreased with Cd exposure. Among antioxidant defences, liver transcription levels of catalase, microsomal glutathione-S-transferase-3 and glucose-6-phosphate dehydrogenase were generally enhanced in Cd-exposed fish and this up-regulation was accompanied by an increase in the activities of corresponding enzymes, except for microsomal glutathione-S-transferase. No consistent pattern in antioxidant defence responses was observed between molecular and biochemical response when fish were exposed to Ni, suggesting a non-synchronous response of antioxidant defence in fish exposed to

  14. Cardiac arrest leadership: in need of resuscitation?

    Science.gov (United States)

    Robinson, Philip S; Shall, Emma; Rakhit, Roby

    2016-12-01

    Leadership skills directly correlate with the quality of technical performance of cardiopulmonary resuscitation (CPR) and clinical outcomes. Despite an improved focus on non-technical skills in CPR training, the leadership of cardiac arrests is often variable. To assess the perceptions of leadership and team working among members of a cardiac arrest team and to evaluate future training needs. Cross-sectional survey of 102 members of a cardiac arrest team at an Acute Hospital Trust in the UK with 892 inpatient beds. Responses sought from doctors, nurses and healthcare assistants to 12 rated statements and 4 dichotomous questions. Of 102 responses, 81 (79%) were from doctors and 21 (21%) from nurses. Among specialist registrars 90% agreed or strongly agreed that there was clear leadership at all arrests compared with between 28% and 49% of nurses and junior doctors respectively. Routine omission of key leadership tasks was reported by as many as 80% of junior doctors and 50% of nurses. Almost half of respondents reported non-adherence with Advanced Life Support (ALS) guidelines. Among junior members of the team, 36% felt confident to lead an arrest and 75% would welcome further dedicated cardiac arrest leadership training. Leadership training is integrated into the ALS (Resus Council, UK) qualification. However, this paper found that in spite of this training; standards of leadership are variable. The findings suggest a pressing need for further dedicated cardiac arrest leadership training with a focus on improving key leadership tasks such as role assignment, team briefing and debriefing. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Arrested coalescence of viscoelastic droplets: polydisperse doublets.

    Science.gov (United States)

    Dahiya, Prerna; Caggioni, Marco; Spicer, Patrick T

    2016-07-28

    Arrested droplet coalescence produces stable anisotropic shapes and is a key mechanism for microstructure development in foods, petroleum and pharmaceutical formulations. Past work has examined the dynamic elastic arrest of coalescing monodisperse droplet doublets and developed a simple model of doublet strain as a function of physical variables. Although the work describes experimental data well, it is limited to describing same-size droplets. A new model incorporating a generalized description of doublet shape is developed to describe polydisperse doublet formation in more realistic emulsion systems. Polydisperse doublets are shown to arrest at lower strains than monodisperse doublets as a result of the smaller contribution of surface area in a given pair. Larger droplet size ratios have lower relative degrees of strain because coalescence is arrested at an earlier stage than in more monodisperse cases. Experimental observations of polydisperse doublet formation indicate that the model under-predicts arrest strains at low solid levels and small droplet sizes. The discrepancy is hypothesized to be the result of nonlinear elastic deformation at high strains.This article is part of the themed issue 'Soft interfacial materials: from fundamentals to formulation'. © 2016 The Author(s).

  16. Arrested larval development in cattle nematodes.

    Science.gov (United States)

    Armour, J; Duncan, M

    1987-06-01

    Most economically important cattle nematodes are able to arrest their larval development within the host - entering a period of dormancy or hypobiosis. Arrested larvae have a low death rate, and large numbers can accumulate in infected cattle during the grazing season. Because of this, outbreaks of disease caused by such nematodes can occur at times when recent infection with the parasites could not have occurred, for example during winter in temperature northern climates when cattle are normally housed. The capacity to arrest is a heritable trait. It is seen as an adaptation by the parasite to avoid further development to its free-living stages during times when the climate is unsuitable for free-living survival. But levels of arrestment can vary markedly in different regions, in different cattle, and under different management regimes. Climatic factors, previous conditioning, host immune status, and farm management all seem to affect arrestment levels. In this article, James Armour and Mary Duncan review the biological basis of the phenomenon, and discuss the apparently conflicting views on how it is controlled.

  17. Vitamin D Receptor, Retinoid X Receptor, Ki-67, Survivin, and Ezrin Expression in Canine Osteosarcoma

    Directory of Open Access Journals (Sweden)

    John Davies

    2012-01-01

    Full Text Available Canine osteosarcoma (OS is an aggressive malignant bone tumor. Prognosis is primarily determined by clinical parameters. Vitamin D has been postulated as a novel therapeutic option for many malignancies. Upon activation, vitamin D receptors (VDRs combine with retinoid receptor (RXR forming a heterodimer initiating a cascade of events. Vitamin D's antineoplastic activity and its mechanism of action in OS remain to be clearly established. Expression of VDR, RXR, Ki-67, survivin, and ezrin was studied in 33 archived, canine OS specimens. VDR, RXR, survivin, and ezrin were expressed in the majority of cases. There was no statistically significant difference in VDR expression in relationship with tumor grade, type, or locations or animal breed, age, and/or sex. No significant association (p=0.316 between tumor grade and Ki-67 expression was found; in particular, no difference in Ki-67 expression between grades 2 and 3 OSs was found, while a negative correlation was noted between Ki-67 and VDR expression (ρ=−0.466, a positive correlation between survivin and RXR expression was found (p=0.374. A significant relationship exists between VDR and RXR expression in OSs and proliferative/apoptosis markers. These results establish a foundation for elucidating mechanisms by which vitamin D induces antineoplastic activity in OS.

  18. Temperature-sensitive retinoid isomerase activity of RPE65 mutants associated with Leber Congenital Amaurosis.

    Science.gov (United States)

    Li, Songhua; Hu, Jane; Jin, Robin J; Aiyar, Ashok; Jacobson, Samuel G; Bok, Dean; Jin, Minghao

    2015-08-01

    RPE65 is a membrane-associated retinoid isomerase involved in the visual cycle responsible for sustaining vision. Many mutations in the human RPE65 gene are associated with distinct forms of retinal degenerative diseases. The pathogenic mechanisms for most of these mutations remain poorly understood. Here, we show that three Leber congenital amaurosis -associated RPE65 mutants (R91W, Y249C and R515W) undergo rapid proteasomal degradation mediated by the 26 S proteasome non-ATPase regulatory subunit 13 (PSMD13) in cultured human retinal pigment epithelium (RPE) cells. These mutant proteins formed cytosolic inclusion bodies or high molecular weight complexes via disulfide bonds. The mutations are mapped on non-active sites but severely reduced isomerase activity of RPE65. At 30°C, however, the enzymatic function and membrane-association of the mutant RPE65s are significantly rescued possibly due to proper folding. In addition, PSMD13 displayed a drastically decreased effect on degradation of the mutant proteins in the cells grown at 30°C. These results suggest that PSMD13 plays a critical role in regulating pathogenicity of the mutations and the molecular basis for the PSMD13-mediated rapid degradation and loss of function of the mutants is misfolding of RPE65. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  19. Levels of binding proteins for retinoids in cultured Sertoli cells: effect of medium composition.

    Science.gov (United States)

    Galdieri, M; Piantedosi, R; Blaner, W S

    1989-05-10

    The levels of cellular retinol-binding protein (CRBP) and cellular retinoic acid-binding protein (CRABP) have been measured in Sertoli cells maintained under different cultural conditions. Sertoli cells were isolated from prepubertal rats and cultured in a chemically defined medium without or with follicle-stimulating hormone (FSH), insulin, retinol or testosterone added individually or in combinations. The additions were made at the beginning of the culture or 24 h before the cells were subjected to determinations of CRBP and CRABP by radioimmunoassay. No differences were observed either after 1 or 4 days of treatment. The results obtained indicated that the levels of the two retinoid-binding proteins were unchanged in Sertoli cells in response to hormone and/or retinol administration. To rule out the possibility that the Sertoli cells used in our study were unresponsive to the hormones, lactate production by the cells cultured in the presence of FSH or insulin was measured. The amount of lactate produced under hormonal stimulation was significantly higher than the amount produced in absence of the hormones, thus indicating the ability of our Sertoli cells to respond to the hormonal stimulation.

  20. Photocurrent Response of Photoreceptive Devices Using a Retinoid Immobilized in a Chitosan Gel Film

    Science.gov (United States)

    Tsuchida, Yosuke; Hidaka, Akira; Mitachi, Seiko

    2010-12-01

    In order to realize a biophotonic device with biomimetic functions, we focus on the retinal in human eyes. A photoreceptive device was prepared using all-trans retinal immobilized in a gel film chitosan. This device was prepared with either indium tin oxide (ITO)-coated glass and gold-coated glass electrodes (ITO-Au), or using ITO electrodes for both ends (ITO-ITO). Each device was irradiated with 365 nm ultraviolet light for 20 s intervals at an applied voltage of 4 V. The photocurrent response was synchronized to the ON-OFF states of the ultraviolet light and was about 16 times higher for an ITO-ITO device than for an ITO-Au device. We searched for the optimum applied voltage because the ITO-ITO devices deteriorated on the second day at 4 V and found that 3 V produced a photocurrent response in both pre- and post-regenerated devices. Further ITO-ITO devices using three kinds of retinoids (all-trans retinal, all-trans retinoic acid, and all-trans retinol) were prepared. Photocurrent responses measured by a similar method persisted for 331 days using retinal, 313 days using retinoic acid, and 59 days using retinol. Furthermore, the photocurrent response was also observed in post-regenerated gel films of these ITO-ITO devices. These photoreceptive devices could be applied to bio-functional optical sensing or to future visual information processing devices.

  1. Identification of a naturally occurring retinoid X receptor agonist from Brazilian green propolis.

    Science.gov (United States)

    Nakashima, Ken-Ichi; Murakami, Tohru; Tanabe, Hiroki; Inoue, Makoto

    2014-10-01

    Brazilian green propolis (BGP), a resinous substance produced from Baccharis dracunculifolia by Africanized honey bees (Apis mellifera), is used as a folk medicine. Our present study explores the retinoid X receptor (RXR) agonistic activity of BGP and the identification of an RXR agonist in its extract. RXRα agonistic activity was evaluated using a luciferase reporter gene assay. Isolation of the RXRα agonist from the ethanolic extract of BGP was performed using successive silica gel and a reversed phase column chromatography. The interaction between the isolated RXRα agonist and RXRα protein was predicted by a receptor-ligand docking simulation. The nuclear receptor (NR) cofactor assay was used to estimate whether the isolated RXRα agonist bound to various NRs, including RXRs and peroxisome proliferator-activated receptors (PPARs). We further examined its effect on adipogenesis in 3T3-L1 fibroblasts. We identified drupanin as an RXRα agonist with an EC50 value of 4.8 ± 1.0 μM. Drupanin activated three RXR subtypes by a similar amount and activated PPARγ moderately. Additionally, drupanin induced adipogenesis and elevated aP2 mRNA levels in 3T3-L1 fibroblasts. Drupanin, a component of BGP, is a novel RXR agonist with slight PPARγ agonistic activity. This study revealed for the first time that BGP activates RXR and drupanin is an RXR agonist in its extract. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Retinoid X Receptor α-Dependent HBV Minichromosome Remodeling and Viral Replication.

    Science.gov (United States)

    Zhang, Yan; He, Song; Guo, Jin-Jun; Peng, Hong; Fan, Jia-Hao; Li, Qing-Ling

    2017-01-01

    The HBV covalently closed circular DNA (cccDNA) is organized into a minichromosome in the nuclei of infected hepatocytes through interactions with histone and nonhistone proteins. Retinoid X receptor α (RXRα), a liver-enriched nuclear receptor, participates in regulation of HBV replication and transcription through modulation of HBV enhancer 1 and core promoter activity. This study investigated RXRα involvement in HBV cccDNA epigenetic modifications. Quantitative cccDNA chromatin immunoprecipitation (ChIP) was applied to study the recruitment of RXRα, histones, and chromatin-modifying enzymes to HBV minichromosome in HepG2 cells after transfection of the linear HBV genome. RXRα Was found to directly bind to HBV cccDNA; recruitment of RXRα to HBV mini-chromosome paralleled HBV replication, histone recruitment, and histone acetylation in HBVcccDNA. Moreover, RXRα overexpression or knock-down significantly increased or impaired the recruitment of the p300 acetyltransferase to cccDNAminichromosome. Our results confirmed the regulation of RXRα on HBV replication in vitro and demonstrated the modulation of RXRα on HBV cccDNA epigenetics. These findings provide a profound theoretical and experimental basis for late-model antiviral treatment acting on the HBV cccDNA and minichromosome.

  3. Structure-activity relationships of retinoids in hamster tracheal organ culture.

    Science.gov (United States)

    Newton, D L; Henderson, W R; Sporn, M B

    1980-10-01

    Structure-activity relationships are summarized for 87 retinoids, using reversal of keratinization in the hamster tracheal organ culture system to measure biological activity. Classes of compounds evaluated include all-trans-retinoic acid and its esters, ring-modified analogs of all-trans-retinoic acid and its esters, side-chain-modified analogs of all-trans-retinoic acid and its esters, analogs in which both ring and side chain have been modified, all-trans-retinol and derivatives, all-trans-retinyl amine derivatives, all-trans-retinal derivatives, all-trans-retinoic acid amides, 13-cis-retinoic acid and derivatives, and 5,6-epoxyretinoids. the activity of many synthetic amide derivatives of all-trans- or 13-cis-retinoic acid approaches that of the parent compounds. No metabolite of all-trans- or 13-cis-retinoic acid has yet been identified which has greater activity than the parent compounds in this assay. New synthetic derivatives with a gem-dimethyl group at position 4 in the cyclohexenyl ring and two aromatic rings in the side chain have activity equal to or greater than that of all-trans- or 13-cis-retinoic acid, with some activity detectable in the 10(-11) M range.

  4. Effects of vitamin A deficiency in the postnatal mouse heart: role of hepatic retinoid stores.

    Science.gov (United States)

    Asson-Batres, Mary Ann; Ryzhov, Sergey; Tikhomirov, Oleg; Duarte, Christine W; Congdon, Clare Bates; Lessard, Craig R; McFarland, Samuel; Rochette-Egly, Cecile; Tran, Truc-Linh; Galindo, Cristi L; Favreau-Lessard, Amanda J; Sawyer, Douglas B

    2016-06-01

    To determine whether hepatic depletion of vitamin A (VA) stores has an effect on the postnatal heart, studies were carried out with mice lacking liver retinyl ester stores fed either a VA-sufficient (LRVAS) or VA-deficient (LRVAD) diet (to deplete circulating retinol and extrahepatic stores of retinyl esters). There were no observable differences in the weights or gross morphology of hearts from LRVAS or LRVAD mice relative to sex-matched, age-matched, and genetically matched wild-type (WT) controls fed the VAS diet (WTVAS), but changes in the transcription of functionally relevant genes were consistent with a state of VAD in LRVAS and LRVAD ventricles. In silico analysis revealed that 58/67 differentially expressed transcripts identified in a microarray screen are products of genes that have DNA retinoic acid response elements. Flow cytometric analysis revealed a significant and cell-specific increase in the number of proliferating Sca-1 cardiac progenitor cells in LRVAS animals relative to WTVAS controls. Before myocardial infarction, LRVAS and WTVAS mice had similar cardiac systolic function and structure, as measured by echocardiography, but, unexpectedly, repeat echocardiography demonstrated that LRVAS mice had less adverse remodeling by 1 wk after myocardial infarction. Overall, the results demonstrate that the adult heart is responsive to retinoids, and, most notably, reducing hepatic VA stores (while maintaining circulating levels of VA) impacts ventricular gene expression profiles, progenitor cell numbers, and response to injury. Copyright © 2016 the American Physiological Society.

  5. Retinoid X receptor gene expression and protein content in tissues of the rock shell Thais clavigera

    Energy Technology Data Exchange (ETDEWEB)

    Horiguchi, Toshihiro [Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506 (Japan)], E-mail: thorigu@nies.go.jp; Nishikawa, Tomohiro [Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506 (Japan); Ohta, Yasuhiko [Department of Veterinary Science, Faculty of Agriculture, Tottori University, 4-101 Koyamacho-Minami, Tottori 680-8553 (Japan); Shiraishi, Hiroaki; Morita, Masatoshi [Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506 (Japan)

    2007-10-15

    To elucidate the role of retinoid X receptor (RXR) in the development of imposex caused by organotin compounds in gastropod molluscs, we investigated RXR gene expression and RXR protein content in various tissues of male and female wild rock shells (Thais clavigera). Quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry with a commercial antibody against human RXR {alpha} revealed that RXR gene expression was significantly higher in the penises of males and imposex-exhibiting females than in the penis-forming areas of normal females (P < 0.01 and P < 0.05, respectively). Western blotting demonstrated that the antibody could detect rock shell RXR and showed that the male penis had the highest content of RXR protein among the analyzed tissues of males and normal females. Immunohistochemical staining revealed nuclear localization of RXR protein in the epithelial and smooth muscle cells of the vas deferens and in the interstitial or connective tissues and epidermis of the penis in males and imposex-exhibiting females. RXR could be involved in the mechanism of induction of male-type genitalia (penis and vas deferens) by organotin compounds in female rock shells.

  6. Establishment of a myeloid cell line, YM711, characterized by retinoid resistance.

    Science.gov (United States)

    Sumimoto, Y; Maeda, Y; Naiki, Y; Sono, H; Miyatake, J I; Sakaguchi, M; Matsuda, M; Kanamaru, A

    2000-10-01

    A myeloid cell line (YM711) was established by transfecting exogenous PML/RARalpha cDNA into peripheral blood stem cells. The cells were positive for CD33, CD34, CD38, CD13, CD14, and CD11b. Cytochemical examination revealed YM711 cells to be positive for peroxidase, alpha-naphtyl butyrate esterase, and acid phosphatase as well. Karyotypic analysis showed them to be nearly tetraploid (92 XXYY). Reverse-transcription polymerase chain reaction showed that, although PML/RARalpha mRNA was detected in YM711, these cells could not be differentiated by all-trans retinoic acid (ATRA). We therefore designated the YM711 cell line as being ATRA resistant. Because YM711 expressed multi drug resistance 1 (MDR-1) mRNA and p-glycoprotein cell surface protein, we assessed whether verapamil and ATRA would induce the differentiation of YM711 cells; they did not. An increased expression of cellular retinoic acid-binding protein (CRABP)-II was also detected on YM711 cells compared with that of HL-60. These results suggest that high level of expression of CRABP-II may contribute to be the mechanism of ATRA resistance. This cell line may be useful in evaluating the mechanism of resistance to retinoid.

  7. Are retinoids potential therapeutic agents in disorders of social cognition including autism?

    Science.gov (United States)

    Ebstein, Richard P; Mankuta, David; Yirmiya, Nurit; Malavasi, Fabio

    2011-06-06

    Increasing evidence suggests that the nonapeptide, oxytocin (OT), helps shape social and affiliative behaviors not only in lower mammals but also in humans. Recently, an essential mediator of brain OT release has been discovered, ADP-ribosyl cyclase and/or CD38. We have subsequently shown that polymorphisms across the CD38 gene are associated with autism spectrum disorders (ASD). Notably, CD38 expression in lymphoblastoid cells (LBC) is reduced in cell lines derived from ASD subjects compared to parental cell lines. Intriguingly, a correlation was observed between CD38 expression and measures of social function in ASD. Finally, we have shown that all-trans retinoic acid (ATRA), a known inducer of CD38 transcription, can rescue low CD38 expressing LBC lines derived from ASD subjects and restore normal levels of transcription of this ectoenzyme providing 'proof of principle' in a peripheral model that retinoids are potential therapeutic agents in ASD. Copyright © 2011 Federation of European Biochemical Societies. All rights reserved.

  8. Breast Diseases

    Science.gov (United States)

    Most women experience breast changes at some time. Your age, hormone levels, and medicines you take may cause lumps, bumps, and discharges (fluids that are not breast milk). If you have a breast lump, pain, ...

  9. Miller Fisher syndrome with sinus arrest

    Directory of Open Access Journals (Sweden)

    Nobuko Shiraiwa

    2017-08-01

    Full Text Available Dysautonomia in Guillain-Barre syndrome (GBS rarely causes serious cardiovascular complications, such as sinus arrest. Miller Fisher syndrome (MFS is recognized as a variant of GBS. There have been few reports regarding the association between MFS and dysautonomia. We describe a case of a 68-year-old man with ophthalmoplegia, bulbar palsy, truncal ataxia, and areflexia. He was diagnosed with MFS because he exhibited the classical clinical triad and had elevated serum anti- GQ1b immunoglobulin G levels. A magnetic resonance imaging scan of his head was normal. His 24-hour Holter recording showed sinus arrest. He was treated with intravenous immunoglobulin, whereupon his symptoms gradually improved. This included the sinus arrest, which was considered a symptom of dysautonomia in MFS. Therefore, clinicians should be mindful of dysautonomia not only in GBS patients, but also in cases of MFS.

  10. Dietary Natural Products for Prevention and Treatment of Breast Cancer.

    Science.gov (United States)

    Li, Ya; Li, Sha; Meng, Xiao; Gan, Ren-You; Zhang, Jiao-Jiao; Li, Hua-Bin

    2017-07-08

    Breast cancer is the most common cancer among females worldwide. Several epidemiological studies suggested the inverse correlation between the intake of vegetables and fruits and the incidence of breast cancer. Substantial experimental studies indicated that many dietary natural products could affect the development and progression of breast cancer, such as soy, pomegranate, mangosteen, citrus fruits, apple, grape, mango, cruciferous vegetables, ginger, garlic, black cumin, edible macro-fungi, and cereals. Their anti-breast cancer effects involve various mechanisms of action, such as downregulating ER-α expression and activity, inhibiting proliferation, migration, metastasis and angiogenesis of breast tumor cells, inducing apoptosis and cell cycle arrest, and sensitizing breast tumor cells to radiotherapy and chemotherapy. This review summarizes the potential role of dietary natural products and their major bioactive components in prevention and treatment of breast cancer, and special attention was paid to the mechanisms of action.

  11. Dietary Natural Products for Prevention and Treatment of Breast Cancer

    Science.gov (United States)

    Li, Ya; Li, Sha; Meng, Xiao; Zhang, Jiao-Jiao

    2017-01-01

    Breast cancer is the most common cancer among females worldwide. Several epidemiological studies suggested the inverse correlation between the intake of vegetables and fruits and the incidence of breast cancer. Substantial experimental studies indicated that many dietary natural products could affect the development and progression of breast cancer, such as soy, pomegranate, mangosteen, citrus fruits, apple, grape, mango, cruciferous vegetables, ginger, garlic, black cumin, edible macro-fungi, and cereals. Their anti-breast cancer effects involve various mechanisms of action, such as downregulating ER-α expression and activity, inhibiting proliferation, migration, metastasis and angiogenesis of breast tumor cells, inducing apoptosis and cell cycle arrest, and sensitizing breast tumor cells to radiotherapy and chemotherapy. This review summarizes the potential role of dietary natural products and their major bioactive components in prevention and treatment of breast cancer, and special attention was paid to the mechanisms of action. PMID:28698459

  12. Assessment of the efficacy and safety of a combination of 2 topical retinoids (RetinSphere) in maintaining post-treatment response of acne to oral isotretinoin.

    Science.gov (United States)

    Truchuelo, M T; Jiménez, N; Mavura, D; Jaén, P

    2015-03-01

    The high rate of relapse of acne lesions following oral isotretinoin treatment is a common problem which remains unsolved. To avoid or minimize relapses, topical retinoids have been used for many years as maintenance treatment. However, adverse effects frequently occur. To determine the efficacy and safety of a new retinoid combination (Retinsphere technology) in maintaining post-treatment response to oral isotretinoin. Prospective, randomized, double-blind and vehicle-controlled study of 30 patients with acne previously treated with isotretinoin. Treatment with the retinoid combination was applied to one side of the face and vehicle was applied to the other, once daily, for 3 months. Standardized photographs were taken using RBX technology at baseline, 1.5 months and 3 months. The primary efficacy endpoint was the appearance of relapse on the treated side compared to the vehicle-treated side. Other endpoints included lesion count, investigator-reported improvement, patient-reported improvement, impact on quality-of-life, and side effects. Although the majority of patients did not reach the total target dose of oral isotretinoin, the relapse rate was significantly lower on the retinoid-treated side compared to the vehicle-treated side. Likewise, improved lesion count and excellent tolerance were observed. This new retinoid combination (Retinsphere technology) were effective and safe as maintenance therapy after post-treatment response to oral isotretinoin in patients with acne. Copyright © 2014 Elsevier España, S.L.U. and AEDV. All rights reserved.

  13. Pharmaceutical and nutraceutical approaches for preventing liver carcinogenesis: chemoprevention of hepatocellular carcinoma using acyclic retinoid and branched-chain amino acids.

    Science.gov (United States)

    Shimizu, Masahito; Shirakami, Yohei; Hanai, Tatsunori; Imai, Kenji; Suetsugu, Atsushi; Takai, Koji; Shiraki, Makoto; Moriwaki, Hisataka

    2014-01-01

    The poor prognosis for patients with hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, more effective strategies need to be urgently developed for the chemoprevention of this malignancy. The malfunction of retinoid X receptor α, a retinoid receptor, due to phosphorylation by Ras/mitogen-activated protein kinase is closely associated with liver carcinogenesis and may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, can prevent HCC development by inhibiting retinoid X receptor α phosphorylation and improve the prognosis for this malignancy. Supplementation with branched-chain amino acids (BCAA), which are used to improve protein malnutrition in patients with liver cirrhosis, can also reduce the risk of HCC in obese cirrhotic patients. In experimental studies, both ACR and BCAA exert suppressive effects on HCC development and the growth of HCC cells. In particular, combined treatment with ACR and BCAA cooperatively inhibits the growth of HCC cells. Furthermore, ACR and BCAA inhibit liver tumorigenesis associated with obesity and diabetes, both of which are critical risk factors for HCC development. These findings suggest that pharmaceutical and nutraceutical approaches using ACR and BCAA may be promising strategies for preventing HCC and improving the prognosis of this malignancy. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Lycopene-derived bioactive retinoic acid receptors/retinoid-X receptors-activating metabolites may be relevant for lycopene's anti-cancer potential.

    Science.gov (United States)

    Aydemir, Gamze; Kasiri, Yasamin; Birta, Eszter; Béke, Gabriella; Garcia, Ada L; Bartók, Emőke-Márta; Rühl, Ralph

    2013-05-01

    Dietary consumption of tomato products and especially the red tomato pigment lycopene has been associated with lower risk of cancer. New evidence is emerging toward metabolic pathways mediating the anti-cancer activities of lycopene. In this review, we explore associations between tomatoes and lycopene intake and cancer and relate this to the metabolic activation pathways of lycopene via carotene oxygenases and further carotenoid/retinoid-metabolizing enzymes to apo-lycopenoids. Several of these apo-lycopenoids have already been identified but up to date no direct connection between lycopene metabolism and apo-lycopenoids mediated receptor activation pathways has been established. Retinoic acid receptors/retinoid-X receptors activation pathways in particular, may be mediated via lycopene metabolites that are related to retinoic acids. Various studies have shown an association between lower concentration of insulin-like growth factor-1 upon lycopene treatment, cancer incidences, and retinoid-mediated signaling. In this review, we interrelate tomato/lycopene ingestion and cancer incidence, with metabolic activation of lycopene and retinoid-mediated signaling. The aim is to discuss a potential mechanism to explain lycopene related anti-cancer activities by modulation of insulin-like growth factor-1 concentrations via lycopene metabolite activation of retinoid-mediated signaling. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Association between a Hospital’s Rate of Cardiac Arrest Incidence and Cardiac Arrest Survival

    Science.gov (United States)

    Chen, Lena M.; Nallamothu, Brahmajee K.; Spertus, John A.; Li, Yan; Chan, Paul S.

    2014-01-01

    Context National efforts to measure hospital performance for cardiac arrest have focused on case survival, with the hope of improving survival after cardiac arrest. However, it is plausible that hospitals with high case-survival rates do a poor job of preventing cardiac arrests in the first place. Objective To describe the association between inpatient cardiac arrest incidence and survival rates. Design, Setting, and Patients Within a large, national registry, we identified hospitals with at least 50 adult in-hospital cardiac arrest cases between January 1, 2000 and November 30, 2009. We used multivariable hierarchical regression to evaluate the correlation between a hospital’s cardiac arrest incidence rate and its case-survival rate after adjusting for patient and hospital characteristics. Main Outcome Measure The correlation between a hospital’s incidence rate and case-survival rate for cardiac arrest. Results Of 102,153 cases at 358 hospitals, the median hospital cardiac arrest incidence rate was 4.02 per 1000 admissions (IQR: 2.95 to 5.65 per 1000 admissions), and the median hospital case-survival rate was 18.8% (IQR: 14.5% to 22.6%). In crude analyses, hospitals with higher case-survival rates also had lower cardiac arrest incidence (correlation of -0.16; P=0.003). This relationship persisted after adjusting for patient characteristics (correlation of -0.15; P=0.004). After adjusting for potential mediators of this relationship (i.e., hospital characteristics), the relationship between incidence and case-survival was attenuated (correlation of -0.07; P=0.18). The one modifiable hospital factor that most attenuated this relationship was a hospital’s nurse-to-bed ratio (correlation of -0.12; P=0.03). Conclusions Hospitals with exceptional rates of survival for in-hospital cardiac arrest are also better at preventing cardiac arrests, even after adjusting for patient case-mix. This relationship is partially mediated by measured hospital attributes

  16. Chemoprevention of breast cancer in the older patient.

    Science.gov (United States)

    Minton, S E

    2000-02-01

    serum lipids and incidence of osteoporotic bone fractures. The development of SERMs results from an understanding of novel mechanisms of ER modulation and allows targeting for favorable effects in specific tissues. The challenge is to develop an ideal SERM that is effective in preventing breast cancer and does not increase the risk of endometrial cancer, while providing beneficial estrogenic effects on serum lipids and bone mineral density changes. Estrogen receptor-mediated intracellular processes are complex. There are at least two different types of estrogen receptors. The alpha receptors predominate in the breast and uterus, and the beta receptors predominate in the bone and blood vessels. Many proteins also interact with these receptors as co-activators or co-repressors. Transcription-activating factors modulate the effects of estrogen on its target genes. Future prevention strategies may use a combined targeted approach to inhibit ER-mediated cancer progression pathways. The retinoids are under investigation in prevention studies for a multitude of cancers, because they have been shown to inhibit cellular proliferation and to induce cellular differentiation. The retinoid 4HPR was selected for use in breast cancer prevention studies because of its low toxicity profile and prevention efficacy in preclinical studies. It is now being used in combination with tamoxifin in a phase II breast cancer prevention trial. Multiple surrogate endpoint biomarkers are being measured before and after treatment, including measurement of serum IGF-I levels. Future directions in breast cancer prevention include the development of more potent hormonal therapies that completely inhibit ER-mediated cancer progression and, ultimately, multitargeted therapies involving agents that work synergistically.

  17. Warning Signs of Heart Attack, Stroke and Cardiac Arrest

    Science.gov (United States)

    ... Heart Attack WARNING SIGNS OF HEART ATTACK, STROKE & CARDIAC ARREST HEART ATTACK WARNING SIGNS CHEST DISCOMFORT Most heart ... to the hospital immediately. Learn more about stroke CARDIAC ARREST WARNING SIGNS SUDDEN LOSS OF RESPONSIVENESS No response ...

  18. Heart Attack or Sudden Cardiac Arrest: How Are They Different?

    Science.gov (United States)

    ... Thromboembolism Aortic Aneurysm More Heart Attack or Sudden Cardiac Arrest: How Are They Different? Updated:Sep 19,2016 ... flow to the heart is blocked, and sudden cardiac arrest is when the heart malfunctions and suddenly stops ...

  19. Activation of Retinoid X Receptor increases dopamine cell survival in models for Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Bergsland Maria

    2009-12-01

    Full Text Available Abstract Background Parkinson's disease (PD is caused by degeneration of dopamine (DA neurons in the ventral midbrain (vMB and results in severely disturbed regulation of movement. The disease inflicts considerable suffering for the affected and their families. Today, the opportunities for pharmacological treatment are meager and new technologies are needed. Previous studies have indicated that activation of the nuclear receptor Retinoid X Receptor (RXR provides trophic support for DA neurons. Detailed investigations of these neurotrophic effects have been hampered by the lack of readily available DA neurons in vitro. The aim of this study was to further describe the potential neurotrophic actions of RXR ligands and, for this and future purposes, develop a suitable in vitro-platform using mouse embryonic stem cells (mESCs. Results We studied the potential neurotrophic effects of the RXR ligand LG100268 (LG268 and the RXR-Nurr1 ligand XCT0139508 (XCT in neuronal cultures derived from rat primary vMB and mESCs. RXR ligands protect DA neurons from stress, such as that induced by the PD-modeling toxin 6-hydroxy dopamine (6-OHDA and hypoxia, but not from stress induced by oxidative hydrogen peroxide (H2O2 or the excitotoxic agent kainic acid (KA. The neurotrophic effect is selective for DA neurons. DA neurons from rat primary vMB and mESCs behaved similarly, but the mESC-derived cultures contained a much higher fraction of DA cells and thus provided more accessible experimental conditions. Conclusions RXR ligands rescue DA neurons from degeneration caused by the PD simulating 6-OHDA as well as hypoxia. Thus, RXR is a novel promising target for PD research. mESC-derived DA cells provide a valid and accessible in vitro-platform for studying PD inducing toxins and potential trophic agents.

  20. Imposex induction is mediated through the Retinoid X Receptor signalling pathway in the neogastropod Nucella lapillus.

    Science.gov (United States)

    Castro, L Filipe C; Lima, D; Machado, A; Melo, C; Hiromori, Y; Nishikawa, J; Nakanishi, T; Reis-Henriques, M A; Santos, M M

    2007-11-15

    The imposex phenomenon in female prosobranch gastropods provides one of the best documented examples of endocrine disruption in wildlife. While many field studies have demonstrated the negative impact of tributyltin (TBT) upon female gastropods, the mechanism(s) underlying imposex development has not yet been fully clarified. Over the years several hypotheses have been raised to determine the biochemical and molecular determinants of this process. Nevertheless, the interplay between the different suggested pathways (neuroendocrine, steroid and retinoid) is still unknown. Hence, through a combination of exposure experiments, we show that the 9-cis-retinoic acid (9cisRA), the proposed natural ligand of the retinoic X receptor (RXR), induces imposex in females of Nucella lapillus to the same degree as tributyltin, when administered at similar concentrations (1 microg/g body weight). Methoprene acid, a selective ligand for RXR, also induces imposex, albeit to a lower degree than that of the positive control. In contrast, testosterone significantly induced imposex, but had no effect on female penis induction, while the neuropeptide APGWamide had no effect on imposex development. These results clearly demonstrate that imposex induction in N. lapillus is mediated through the modulation of the RXR signalling pathways. In addition to the effects reported in female dogwhelks, both TBT and RA significantly increased male penis length, thus suggesting that TBT may also impact male secondary sex organs through the RXR signalling pathways. As a step for future studies, we have cloned the orthologue of N. lapillus RXR and provide experimental evidence that it binds 9cisRA. Finally, the basal expression level of RXR in several tissues of N. lapillus was determined through real-time PCR, thus showing that RXR is ubiquitously expressed in mollusc tissues, with the highest expression levels being recorded in female and male gonads. The mechanistic impacts of the overall findings to

  1. Breast pain

    Science.gov (United States)

    ... the level of of hormones during menstruation or pregnancy often cause breast pain. Some swelling and tenderness just before your period is normal. Some women who have pain in one or both breasts may fear breast cancer . However, breast pain is not a common symptom ...

  2. Respiratory arrest after retrobulbar anaesthesia | Ashaye | West ...

    African Journals Online (AJOL)

    This is a report of a patient who developed respiratory arrest some minutes after retrobulbar block was given for ocular anesthesia before cataract extraction. She was managed by artificial ventilation and haemodynamic support without any cardiac or neurological sequelae. This report highlights this rare but fatal ...

  3. Cerebral dysplastic vascular malformation: a developmental arrest

    Energy Technology Data Exchange (ETDEWEB)

    Wortzman, G.; Sima, A.A.F.; Morley, T.P.

    1983-08-01

    A cryptic malformation of the brain was found to represent an arrest in vascular development. Microscopy showed plump endothelium of blood vessels, which did not have a normal lumen and consisted of solid cords of cells. The microscopic, angiographic, and computed tomographic appearance of this anomaly are discussed and compared with cavernous angiomas, arteriovenous malformations, and venous angiomas.

  4. Sudden cardiac arrest risk in young athletes

    African Journals Online (AJOL)

    Underlying cardiac abnormalities are the main cause of unexpected death in athletes on field. These abnormalities have been associated with a previous history of syncope, a family history of sudden cardiac arrest (SCA), cardiac murmur, a history of over-exhaustion post exercise and ventricular tachyarrhythmia during ...

  5. 32 CFR 935.122 - Arrests.

    Science.gov (United States)

    2010-07-01

    ..., without a warrant, for any crime (including a petty offense) that is committed in his presence. (b) Any... this part or commits a crime that is not a violation of this part, in his presence, or that he... to enter any building, vehicle, or aircraft to execute a warrant of arrest, force an entry after...

  6. Broad-spectrum antiviral activity including human immunodeficiency and hepatitis C viruses mediated by a novel retinoid thiosemicarbazone derivative.

    Science.gov (United States)

    Kesel, Andreas J

    2011-05-01

    Aromatic aldehyde-derived thiosemicarbazones 4-6, the S-substituted modified thiosemicarbazones 7/8, and a vitamin A-derived (retinoid) thiosemicarbazone derivative 12 were investigated as inhibitors of human hepatitis C virus (HCV) subgenomic RNA replicon Huh7 ET (luc-ubi-neo/ET) replication. Compounds 4-6 and 12 were found to be potent suppressors of HCV RNA replicon replication. The trifluoromethoxy-substituted thiosemicarbazone 6 and the retinoid thiosemicarbazone derivative 12 were even superior in selectivity to the included reference agent recombinant human alpha-interferon-2b, showing potencies in the nanomolar range of concentration. In addition, compounds 5, 6, 8 and 12 were tested as inhibitors of cytopathic effect (CPE) induced by human varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV). Compounds 4-6, 8 and 12 were additionally examined as inhibitors of CPE induced by cowpox virus and vaccinia virus. Thiosemicarbazone 4 was inhibitory on cowpox and vaccinia virus replication comparable in potency and selectivity to the reference agent cidofovir. Retinoid thiosemicarbazone derivative 12 was active as micromolar inhibitor of VZV, HCMV, and, in addition, human immunodeficiency virus type 1 (HIV-1) replication. These results indicate that thiosemicarbazone derivatives are appropriate lead structures to be evaluated in targeted antiviral therapies for hepatitis C (STAT-C), and that the vitamin A-related thiosemicarbazone derivative 12 emerges as a broad-spectrum antiviral agent, co-suppressing the multiplication of important RNA and DNA viruses. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  7. Cross-linked matrix rigidity and soluble retinoids synergize in nuclear lamina regulation of stem cell differentiation.

    Science.gov (United States)

    Ivanovska, Irena L; Swift, Joe; Spinler, Kyle; Dingal, Dave; Cho, Sangkyun; Discher, Dennis E

    2017-07-07

    Synergistic cues from extracellular matrix and soluble factors are often obscure in differentiation. Here the rigidity of cross-linked collagen synergizes with retinoids in the osteogenesis of human marrow mesenchymal stem cells (MSCs). Collagen nanofilms serve as a model matrix that MSCs can easily deform unless the film is enzymatically cross-linked, which promotes the spreading of cells and the stiffening of nuclei as both actomyosin assembly and nucleoskeletal lamin-A increase. Expression of lamin-A is known to be controlled by retinoic acid receptor (RAR) transcription factors, but soft matrix prevents any response to any retinoids. Rigid matrix is needed to induce rapid nuclear accumulation of the RARG isoform and for RARG-specific antagonist to increase or maintain expression of lamin-A as well as for RARG-agonist to repress expression. A progerin allele of lamin-A is regulated in the same manner in iPSC-derived MSCs. Rigid matrices are further required for eventual expression of osteogenic markers, and RARG-antagonist strongly drives lamin-A-dependent osteogenesis on rigid substrates, with pretreated xenografts calcifying in vivo to a similar extent as native bone. Proteomics-detected targets of mechanosensitive lamin-A and retinoids underscore the convergent synergy of insoluble and soluble cues in differentiation. © 2017 Ivanovska et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  8. Retinoic acid mediates long-paced oscillations in retinoid receptor activity: evidence for a potential role for RIP140.

    Directory of Open Access Journals (Sweden)

    Kelly C Heim

    Full Text Available Mechanisms that underlie oscillatory transcriptional activity of nuclear receptors (NRs are incompletely understood. Evidence exists for rapid, cyclic recruitment of coregulatory complexes upon activation of nuclear receptors. RIP140 is a NR coregulator that represses the transactivation of agonist-bound nuclear receptors. Previously, we showed that RIP140 is inducible by all-trans retinoic acid (RA and mediates limiting, negative-feedback regulation of retinoid signaling.Here we report that in the continued presence of RA, long-paced oscillations of retinoic acid receptor (RAR activity occur with a period ranging from 24 to 35 hours. Endogenous expression of RIP140 and other RA-target genes also oscillate in the presence of RA. Cyclic retinoid receptor transactivation is ablated by constitutive overexpression of RIP140. Further, depletion of RIP140 disrupts cyclic expression of the RA target gene HOXA5. Evidence is provided that RIP140 may limit RAR signaling in a selective, non-redundant manner in contrast to the classic NR coregulators NCoR1 and SRC1 that are not RA-inducible, do not cycle, and may be partially redundant in limiting RAR activity. Finally, evidence is provided that RIP140 can repress and be induced by other nuclear receptors in a manner that suggests potential participation in other NR oscillations.We provide evidence for novel, long-paced oscillatory retinoid receptor activity and hypothesize that this may be paced in part, by RIP140. Oscillatory NR activity may be involved in mediating hormone actions of physiological and pathological importance.

  9. Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Simon, D.; Krausch, M.; Segering, J.; Roeher, H.D. [Department of Surgery, Heinrich-Heine-University, Duesseldorf (Germany); Koerber, C.; Reiners, C. [Department of Nuclear Medicine, University of Wuerzburg (Germany); Groth, P. [Department of Nuclear Medicine, University of Rostock (Germany); Goerges, R. [Department of Nuclear Medicine, University of Essen (Germany); Gruenwald, F. [Department of Nuclear Medicine, Johann-Wolfgang-Goethe University, Frankfurt (Germany); Mueller-Gaertner, H.W. [Department of Nuclear Medicine, Heinrich-Heine-University, Duesseldorf (Germany); Schmutzler, C.; Koehrle, J. [Department of Molecular Internal Medicine, University of Wuerzburg (Germany)

    2002-06-01

    Differentiated thyroid cancer is a malignant tumour that has a fairly good prognosis, with patients surviving for many years. Multimodal therapy with surgery, radioiodine therapy and TSH suppressive medication is of proven efficacy. However, loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer, paralleled by an increase in tumour grading and loss of thyroid-specific functions (thyrotropin receptor, iodine accumulation). Such tumours may no longer be amenable to standard treatment protocols, including TSH suppression and radioiodide therapy. Retinoic acids have been shown to exert re-differentiating effects on thyrocytes in various experimental studies and case reports, and it was on this basis that this pilot study was initiated. Patients with advanced thyroid cancer and without the therapeutic options of operation or radioiodide therapy were treated with 13-cis-retinoic acid at a dosage of 1.5 mg/kg body weight daily over 5 weeks. Parameters for assessment of the therapeutic effect were serum thyroglobulin (TG) levels, radioiodine uptake, and tumour size prior to and after retinoid treatment. Fifty patients were evaluated for response, classified as reduction in tumour size and TG levels, stable disease or disease progression. Thirteen patients showed a clear increase in radioiodine uptake, and eight a mild increase. TG levels were unchanged or decreased in 20 patients. Tumour size was assessable in 37 patients; tumour regression was observed in six, and there was no change in 22. In total, a response was seen in 19 patients (38%). Response to retinoid therapy did not always correlate with increased radioiodine uptake, so other direct antiproliferative effects have to be assumed. The encouraging results of the study and the low rate of side-effects with good tolerability of retinoids warrant further studies with altered inclusion criteria and employment of other redifferentiating drugs or combinations of agents

  10. Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration

    Directory of Open Access Journals (Sweden)

    Lourdes Sánchez-Sevilla

    2016-10-01

    Full Text Available Abstract Background The pre-treatment with α-tocopherol inhibits progression of rat liver proliferation induced by partial hepatectomy (PH, by decreasing and/or desynchronizing cyclin D1 expression and activation into the nucleus, activation and nuclear translocation of STAT-1 and -3 proteins and altering retinoid metabolism. Interactions between retinoic acid and polyamines have been reported in the PH-induced rat liver regeneration. Therefore, we evaluated the effect of low dosage of α-tocopherol on PH-induced changes in polyamine metabolism. Methods This study evaluated the participation of polyamine synthesis and metabolism during α-tocopherol-induced inhibition of rat liver regeneration. In PH-rats (Wistar treated with α-tocopherol and putrescine, parameters indicative of cell proliferation, lipid peroxidation, ornithine decarboxylase expression (ODC, and polyamine levels, were determined. Results Pre-treatment with α-tocopherol to PH-animals exerted an antioxidant effect, shifting earlier the increased ODC activity and expression, temporally affecting polyamine synthesis and ornithine metabolism. Whereas administration of putrescine induced minor changes in PH-rats, the concomitant treatment actually counteracted most of adverse actions exerted by α-tocopherol on the remnant liver, restituting its proliferative potential, without changing its antioxidant effect. Putrescine administration to these rats was also associated with lower ODC expression and activity in the proliferating liver, but the temporally shifting in the amount of liver polyamines induced by α-tocopherol, was also “synchronized” by the putrescine administration. The latter is supported by the fact that a close relationship was observed between fluctuations of polyamines and retinoids. Conclusions Putrescine counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring liver proliferative potential and restituting the decreased

  11. Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration.

    Science.gov (United States)

    Sánchez-Sevilla, Lourdes; Mendieta-Condado, Edgar; Hernández-Muñoz, Rolando

    2016-10-26

    The pre-treatment with α-tocopherol inhibits progression of rat liver proliferation induced by partial hepatectomy (PH), by decreasing and/or desynchronizing cyclin D1 expression and activation into the nucleus, activation and nuclear translocation of STAT-1 and -3 proteins and altering retinoid metabolism. Interactions between retinoic acid and polyamines have been reported in the PH-induced rat liver regeneration. Therefore, we evaluated the effect of low dosage of α-tocopherol on PH-induced changes in polyamine metabolism. This study evaluated the participation of polyamine synthesis and metabolism during α-tocopherol-induced inhibition of rat liver regeneration. In PH-rats (Wistar) treated with α-tocopherol and putrescine, parameters indicative of cell proliferation, lipid peroxidation, ornithine decarboxylase expression (ODC), and polyamine levels, were determined. Pre-treatment with α-tocopherol to PH-animals exerted an antioxidant effect, shifting earlier the increased ODC activity and expression, temporally affecting polyamine synthesis and ornithine metabolism. Whereas administration of putrescine induced minor changes in PH-rats, the concomitant treatment actually counteracted most of adverse actions exerted by α-tocopherol on the remnant liver, restituting its proliferative potential, without changing its antioxidant effect. Putrescine administration to these rats was also associated with lower ODC expression and activity in the proliferating liver, but the temporally shifting in the amount of liver polyamines induced by α-tocopherol, was also "synchronized" by the putrescine administration. The latter is supported by the fact that a close relationship was observed between fluctuations of polyamines and retinoids. Putrescine counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring liver proliferative potential and restituting the decreased retinoid levels induced by α-tocopherol. Therefore interactions

  12. Non-invasive short-term assessment of retinoids effects on human skin in vivo using multiphoton microscopy.

    Science.gov (United States)

    Tancrède-Bohin, E; Baldeweck, T; Decencière, E; Brizion, S; Victorin, S; Parent, N; Faugere, J; Souverain, L; Bagot, M; Pena, A-M

    2015-04-01

    The occlusive patch test developed for assessing topical retinoids activity in human skin has been extended as a short-term screening protocol for anti-ageing agents. In this model, biopsies are performed at the end of the occlusion period for morphological and immuno-histochemistry analysis. Multiphoton microscopy is a recent non-invasive imaging technique that combined with image processing tools allows the in vivo quantification of human skin modifications. To validate with gold standards of anti-ageing that are retinoids, the relevance of multiphoton microscopy for kinetic and quantitative assessment in this model. Twenty women, aged 50-65 years, were enrolled. Retinol 0.3% (RO) and Retinoic acid 0.025% (RA) were applied to the dorsal photo-damaged side of their forearm under occlusive patches for 12 days. A patch alone was applied to a third area as control. Evaluation was performed at day D0, D12 (end of treatment), D18 and D32 using multiphoton microscopy. Epidermal thickness, normalized area of the dermal-epidermal junction (DEJ) and melanin density were estimated using 3D image processing tools. Main significant results are: Epidermal thickening at D12, D18 and D32 with RO and at D12, D18 with RA vs. baseline and vs. Increased DEJ undulation at D32 with RO and at D12 with RA vs. baseline and vs. Decreased melanin content with RO (at D12 and D18 vs. baseline and at D32 vs. baseline and vs. control) and with RA (at D12 vs. baseline). This study shows that multiphoton microscopy associated to specific 3D image processing tools allows cutaneous effects induced by topical retinoids in this in vivo model to be non-invasively detected, quantified and followed over time. This innovative approach could be applied to the evaluation of other active compounds. © 2014 European Academy of Dermatology and Venereology.

  13. Fall arrest characteristics of a scissor lift.

    Science.gov (United States)

    Harris, James R; Powers, John R; Pan, Christopher S; Boehler, Brad

    2010-06-01

    Census of Fatal Occupational Injuries (CFOI) data indicate 306 aerial lift fatalities between 1992-2003. Seventy-eight of these fatalities specifically involved scissor lifts. Members of standards committees have requested that NIOSH conduct research to determine the effects of safety-control practices related to using fall-protection systems for scissor lifts. This research examined the structural and dynamic stability of a scissor lift subjected to fall arrest forces. This was accomplished by conducting drop tests from a scissor lift. Anchorage locations evaluated included manufacturer-supplied anchorage points on the scissor lift platform as well as mid-rail and top-rail locations. Preliminary drop tests determined that a 2400 lb maximum arrest force (MAF) could be generated by dropping 169 lb through a fall height of 36" using Nystron rope as a lanyard. The scissor lift maintained structural and dynamic stability for all drop tests when fully extended and on an incline. Anchoring a fall arrest system to either the mid-rail or top-rail is not a recommended practice by the scissor lift manufacturer. Anchor points are provided on the platform floor of the scissor lift for this purpose. However, our results demonstrate that the mid-rail and top-rail absorb substantial energy from an arrested fall and may have potential as appropriate anchorage points. Employers and workers should consider implementing fall arrest systems when using scissor lifts as part of their overall risk mitigation plan for fall injury prevention. (c) 2010 National Safety Council. Published by Elsevier Ltd. All rights reserved.

  14. An Audit Of Perioperative Cardiac Arrest At Lagos University ...

    African Journals Online (AJOL)

    Objective: Intraoperative cardiac arrests are not uncommon and are related to both surgical and anaesthetic factors. This study aimed to examine the factors which predispose to a periopeartive cardiac arrest, to assess the appropriateness of therapy and the outcome. Materials and Methods: All perioperative cardiac arrests ...

  15. 32 CFR 935.125 - Citation in place of arrest.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Citation in place of arrest. 935.125 Section 935... INSULAR REGULATIONS WAKE ISLAND CODE Peace Officers § 935.125 Citation in place of arrest. In any case in which a peace officer may make an arrest without a warrant, he may issue and serve a citation if he...

  16. Transient Central Diabetes Insipidus and Marked Hypernatremia following Cardiorespiratory Arrest

    Directory of Open Access Journals (Sweden)

    Sahar H. Koubar

    2017-01-01

    Full Text Available Central Diabetes Insipidus is often an overlooked complication of cardiopulmonary arrest and anoxic brain injury. We report a case of transient Central Diabetes Insipidus (CDI following cardiopulmonary arrest. It developed 4 days after the arrest resulting in polyuria and marked hypernatremia of 199 mM. The latter was exacerbated by replacing the hypotonic urine by isotonic saline.

  17. Surge arresters - Part 5: Selection and application recommendations

    CERN Document Server

    International Electrotechnical Commission. Geneva

    2000-01-01

    Provides recommendations for the selection and application of surge arresters to be used in three-phase systems with nominal voltages above 1kV. It applies to non-linear resistor type gapped surge arresters as defined in IEC 60099-1 and to gapless metal-oxide surge arresters as defined in IEC 60099-4.

  18. Location of cardiac arrest and impact of pre-arrest chronic disease and medication use on survival

    DEFF Research Database (Denmark)

    Granfeldt, Asger; Wissenberg, Mads; Hansen, Steen Møller

    2017-01-01

    INTRODUCTION: Cardiac arrest in a private location is associated with a higher mortality when compared to public location. Past studies have not accounted for pre-arrest factors such as chronic disease and medication. AIM: To investigate whether the association between cardiac arrest in a private...... location and a higher mortality can be explained by differences in chronic diseases and medication. METHODS: We identified 27,771 out-of-hospital cardiac arrest patients ≥18 years old from the Danish Cardiac Arrest Registry (2001-2012). Using National Registries, we identified pre-arrest chronic disease...... and medication. To investigate the importance of cardiac arrest related factors and chronic disease and medication use we performed adjusted Cox regression analyses during day 0-7 and day 8-365 following cardiac arrest to calculate hazard ratios (HR) for death. RESULTS: Day 0-7: Un-adjusted HR for death day 0...

  19. The 20-hydroxyecdysone-induced signalling pathway in G2/M arrest of Plodia interpunctella imaginal wing cells.

    Science.gov (United States)

    Siaussat, David; Bozzolan, Françoise; Porcheron, Patrick; Debernard, Stéphane

    2008-05-01

    The mechanisms involved in the control of cellular proliferation by the steroid hormone 20-hydroxyecdysone (20E) in insects are not known. We dissected the 20E signalling pathway responsible for G2/M arrest of imaginal cells from the IAL-PID2 cells of the Indian meal moth Plodia interpunctella. We first used a 5'-3' RACE-based strategy to clone a 4479bp cDNA encoding a putative P. interpunctella HR3 transcription factor named PiHR3. The deduced amino acid sequence of PiHR3 was highly similar to those of HR3 proteins from other lepidopterans, e.g. Manduca sexta and Bombyx mori. Using double-stranded RNA-mediated interference (dsRNAi), we then succeeded in blocking the ability of 20E to induce the expression of PiEcR-B1, PiUSP-2 and PiHR3 genes that encode the P. interpunctella ecdysone receptor B1-isoform, Ultraspiracle-2 isoform, the insect homologue of the vertebrate retinoid X receptor, and the HR3 transcription factor. We showed that inhibiting the 20E induction of PiEcR-B1, PiUSP-2 and PiHR3 mRNAs prevented the decreased expression of B cyclin and consequently the G2/M arrest of IAL-PID2 cells. Using this functional approach, we revealed the participation of EcR, USP and HR3 in a 20E signalling pathway that controls the proliferation of imaginal cells by regulating the expression of B cyclin.

  20. Arrest History and Intimate Partner Violence Perpetration in a Sample of Men and Women Arrested for Domestic Violence

    OpenAIRE

    Shorey, Ryan C.; Ninnemann, Andrew; Elmquist, Joanna; Labrecque, Lindsay; Zucosky, Heather; Febres, Jeniimarie; Brasfield, Hope; Temple, Jeff R.; Stuart, Gregory L.

    2012-01-01

    Intimate partner violence (IPV) is a serious and prevalent problem throughout the United States. Currently, individuals arrested for domestic violence are often court mandated to batterer intervention programs (BIPs). However, little is known about the arrest histories of these individuals, especially women. The current study examined the arrest histories of men (n = 303) and women (n = 82) arrested for domestic violence and court-referred to BIPs. Results demonstrated that over 30% of the en...

  1. An association between snowfall and ED presentation of cardiac arrest.

    Science.gov (United States)

    Spitalnic, S J; Jagminas, L; Cox, J

    1996-10-01

    Studies from several cities have reported increased cardiovascular mortality associated with snowfall; whether this weather also results in increased emergency department (ED) presentation of cardiac arrests is not known. A retrospective review was conducted of cardiac arrest patients presenting to a New England ED during the months of October through May, from 1991 to 1994. Comparing daily frequency of cardiac arrest patients with climactic data, a 27% increase was observed in the frequency of cardiac arrest presentation to the ED on days with snowfall (P = .0004). ED physicians and staff should anticipate an increased frequency of cardiac arrest patients on days with snowfall.

  2. Summer Undergraduate Training Program in Breast Cancer Research

    Science.gov (United States)

    2006-05-01

    Pharmacy), Prof. Jo Davisson Steve Kaverman (Purdue University School of Pharmacy), Prof. David J. Riese Jack Laney (Florida State University Chemistry...breast-cancer cells with the gene for the mutant and observed growth arrest of the cells. Kyle Hodges. This summer I worked in the V. Jo Davisson lab

  3. AP-2γ Induces p21 Expression, Arrests Cell Cycle, Inhibits the Tumor Growth of Human Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Hualei Li

    2006-07-01

    Full Text Available Activating enhancer-binding protein 2γ (AP-2γ is a member of the developmentally regulated AP-2 transcription factor family that regulates the expression of many downstream genes. Whereas the effects of AP-2α overexpression on cell growth are fairly well established, the cellular effects of AP-2γ overexpression are less well studied. Our new findings show that AP-2γ significantly upregulates p21 mRNA and proteins, inhibits cell growth, decreases clonogenic survival. Cell cycle analysis revealed that forced AP-2γ expression induced G1-phase arrest, decreased DNA synthesis, decreased the fraction of cells in S phase. AP-2γ expression also led to cyclin D1 repression, decreased Rb phosphorylation, decreased E2F activity in breast carcinoma cells. AP-2γ binding to the p21 promoter was observed in vivo, the absence of growth inhibition in response to AP-2γ expression in p21 (-/- cells demonstrated that p21 caused, at least in part, AP-2-induced cell cycle arrest. Finally, the tumor growth of human breast carcinoma cells in vivo was inhibited by the expression of AP-2γ relative to empty vector-infected cells, suggesting that AP-2γ acts as a tumor suppressor. In summary, expression of either AP-2γ or AP-2α inhibited breast carcinoma cell growth; thus, these genes may be therapeutic targets for breast cancer.

  4. Effect of Am-80, A Novel Retinoid Derivative, On Contact Hypersensitivity Caused by Repeated Applications of Hapten in Mice

    Directory of Open Access Journals (Sweden)

    Satoru Niwa

    2000-01-01

    Full Text Available Some retinoids show an anti-inflammatory action through regulation of transcription of various genes. In the present study, the inhibitory effect of 4-((5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-2-naphthyl carbamoyl benzoic acid (Am-80, a synthetic retinoid, on mouse contact hypersensitivity provoked by repeated applications of 2,4-dinitrofluorobenzene (DNFB to the ear was investigated. Five-fold applications of DNFB on ears once per week elicited severe contact dermatitis with marked infiltration of inflammatory cells and elevation of anti-dinitrophenyl (DNP-IgE antibody in the serum. The Am-80 significantly inhibited ear swelling in a dose-dependent manner. In the histopathologic study, infiltration of inflammatory cells was clearly decreased by Am-80. However, Am-80 did not affect the production of DNP-specific IgE antibody both at the transcriptional and post-transcriptional levels. The effects of Am-80 on the transcriptional level of cytokines, interferon (IFN-γ, interleukin (IL-1 and IL-4 in cervical lymph nodes were investigated. Marked elevation of mRNA for all cytokines was observed and Am-80 potently inhibited the expression of IFN-γ mRNA, but not IL-1 and IL-4 mRNA. These findings indicated that Am-80 may inhibit the contact dermatitis at the post-sensitization phase by inhibiting IFN-γ production at the transcriptional level in mice.

  5. Diet, Stem Cells, and Breast Cancer Prevention

    Science.gov (United States)

    2011-01-01

    abrogated by small interfering RNA to PTEN, indicating PTEN-dependence. Using FACS analysis , we showed that GEN induced cell cycle arrest at G0-G1 phase...isolated from WT (PND 100) and Tg (PND75) mice. The percentage of mammary SCs was quantified by Fluorescence activated cell sorting analysis of...fruits and vegetables in breast cancer prevention due to their phytochemical components, yet mechanisms underlying their presumed anti-tumor activities

  6. Out-of-Hospital Cardiac Arrest in Denmark

    DEFF Research Database (Denmark)

    Wissenberg Jørgensen, Mads

    BACK COVER TEXT Cardiac arrest is an emergency medical condition characterized by the cessation of cardiac mechanical activity; without immediate and decisive treatment, a victim’s chances of survival are minimal. Out-of-hospital cardiac arrest is a particular arrest subgroup that poses additional...... challenges, due to the victim’s physical location, which brings an inherent risk of delay (or altogether absence) of recognition and treatment of cardiac arrest. A low frequency of bystander cardiopulmonary resuscitation and low 30-day survival after out-of-hospital cardiac arrest were identified nearly ten...... in patient survival following out-of hospital cardiac arrest; utilizing the Danish nationwide registries, we sought to answer these questions. Moreover, in order to further improve understanding and target future national strategies for cardiac arrest management, we examined whether there were sex- and age...

  7. Antagonist effect of triptolide on AKT activation by truncated retinoid X receptor-alpha.

    Directory of Open Access Journals (Sweden)

    Na Lu

    Full Text Available BACKGROUND: Retinoid X receptor-alpha (RXRα is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXRα resulted in production of a truncated product, tRXRα, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K/AKT pathway. However, how the tRXRα-mediated signaling pathway in cancer cells is regulated remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: We screened a natural product library for tRXRα targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXRα-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXRα expression levels, demonstrating that tRXRα serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXRα degradation and inhibits tRXRα-dependent AKT activity without affecting the full-length RXRα. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXRα degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXRα interaction with p85α leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXRα mediation. We finally show that targeting tRXRα by triptolide strongly activates TNFα death signaling and enhances the anticancer activity of other chemotherapies. CONCLUSIONS/SIGNIFICANCE: Our results identify triptolide as a new xenobiotic regulator of the tRXRα-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most

  8. The effect of acyclic retinoid on the metabolomic profiles of hepatocytes and hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Xian-Yang Qin

    Full Text Available BACKGROUND/PURPOSE: Acyclic retinoid (ACR is a promising chemopreventive agent for hepatocellular carcinoma (HCC that selectively inhibits the growth of HCC cells (JHH7 but not normal hepatic cells (Hc. To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS-based metabolome analyses in JHH7 and Hc cells after treatment with ACR. METHODOLOGY/PRINCIPAL FINDINGS: NMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5'-triphosphate (ATP, the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells. Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4, a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively. CONCLUSIONS/SIGNIFICANCE: The results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways

  9. A case report: arresting dental caries.

    Science.gov (United States)

    Milgrom, P; Rothen, M; Spadafora, A; Skaret, E

    2001-01-01

    To arrest dental caries in the dentin in a patient that had been refractory to other attempts at caries control. Repeated applications of fluoride varnish (5%, Duraflor, Pharmascience Laboratories, Montreal) in the clinic every three months along with two daily two-minute rinses with sodium fluoride at home. Results over five years are presented. None of the lesions identified five years earlier had been restored. The teeth were monitored with frequent bitewing radiographs and clinical exams; the interproximal decay appears inactive clinically. This present case report shows that fluoride varnish may be a good addition to preventive therapy for arresting caries in adult patients in general practice. Surgical intervention may be avoided in patients whose risk has shifted to a lower level.

  10. [Cardiorespiratory arrest at the age of 30].

    Science.gov (United States)

    Porlier, Magali; Porlier, Ludovic; Lefort, Hugues

    The cardiovascular risk of women is specific and polymorphous. Delays in treatment in women are evident and caused by multiple social and anthropological factors as well as changes to lifestyle habits which are becoming similar to those of men. Young women thereby have a higher risk of sudden death than the rest of the female and general population. A nurse who experienced cardiorespiratory arrest at the age of 30 shares her story. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Dental Calculus Arrest of Dental Caries.

    Science.gov (United States)

    Keyes, Paul H; Rams, Thomas E

    An inverse relationship between dental calculus mineralization and dental caries demineralization on teeth has been noted in some studies. Dental calculus may even form superficial layers over existing dental caries and arrest their progression, but this phenomenon has been only rarely documented and infrequently considered in the field of Cariology. To further assess the occurrence of dental calculus arrest of dental caries, this study evaluated a large number of extracted human teeth for the presence and location of dental caries, dental calculus, and dental plaque biofilms. A total of 1,200 teeth were preserved in 10% buffered formal saline, and viewed while moist by a single experienced examiner using a research stereomicroscope at 15-25× magnification. Representative teeth were sectioned and photographed, and their dental plaque biofilms subjected to gram-stain examination with light microscopy at 100× magnification. Dental calculus was observed on 1,140 (95%) of the extracted human teeth, and no dental carious lesions were found underlying dental calculus-covered surfaces on 1,139 of these teeth. However, dental calculus arrest of dental caries was found on one (0.54%) of 187 evaluated teeth that presented with unrestored proximal enamel caries. On the distal surface of a maxillary premolar tooth, dental calculus mineralization filled the outer surface cavitation of an incipient dental caries lesion. The dental calculus-covered carious lesion extended only slightly into enamel, and exhibited a brown pigmentation characteristic of inactive or arrested dental caries. In contrast, the tooth's mesial surface, without a superficial layer of dental calculus, had a large carious lesion going through enamel and deep into dentin. These observations further document the potential protective effects of dental calculus mineralization against dental caries.

  12. Breast Gangrene

    Directory of Open Access Journals (Sweden)

    Husasin Irfan

    2011-08-01

    Full Text Available Abstract Background Breast gangrene is rare in surgical practice. Gangrene of breast can be idiopathic or secondary to some causative factor. Antibiotics and debridement are used for management. Acute inflammatory infiltrate, severe necrosis of breast tissue, necrotizing arteritis, and venous thrombosis is observed on histopathology. The aim of was to study patients who had breast gangrene. Methods A prospective study of 10 patients who had breast gangrene over a period of 6 years were analyzed Results All the patients in the study group were female. Total of 10 patients were encountered who had breast gangrene. Six patients presented with breast gangrene on the right breast whereas four had on left breast. Out of 10 patients, three had breast abscess after teeth bite followed by gangrene, one had iatrogenic trauma by needle aspiration of erythematous area of breast under septic conditions. Four had history of application of belladonna on cutaneous breast abscess and had then gangrene. All were lactating female. Amongst the rest two were elderly, one of which was a diabetic who had gangrene of breast and had no application of belladonna. All except one had debridement under cover of broad spectrum antibiotics. Three patients had grafting to cover the raw area. Conclusion Breast gangrene occurs rarely. Etiology is variable and mutifactorial. Teeth bite while lactation and the iatrogenic trauma by needle aspiration of breast abscess under unsterlised conditions could be causative. Uncontrolled diabetes can be one more causative factor for the breast gangrene. Belladonna application as a topical agent could be inciting factor. Sometimes gangrene of breast can be idiopathic. Treatment is antibiotics and debridement.

  13. Arrest History and Intimate Partner Violence Perpetration in a Sample of Men and Women Arrested for Domestic Violence.

    Science.gov (United States)

    Shorey, Ryan C; Ninnemann, Andrew; Elmquist, Joanna; Labrecque, Lindsay; Zucosky, Heather; Febres, Jeniimarie; Brasfield, Hope; Temple, Jeff R; Stuart, Gregory L

    2012-01-01

    Intimate partner violence (IPV) is a serious and prevalent problem throughout the United States. Currently, individuals arrested for domestic violence are often court mandated to batterer intervention programs (BIPs). However, little is known about the arrest histories of these individuals, especially women. The current study examined the arrest histories of men ( n = 303) and women ( n = 82) arrested for domestic violence and court-referred to BIPs. Results demonstrated that over 30% of the entire sample had been previously arrested for a non-violent offense, and over 25% of the participants had been previously arrested for a violent offense other than domestic violence. Moreover, men were arrested significantly more frequently for violence-related and non-violent offenses than their female counterparts. In addition, men were more likely than women to have consumed binge-levels of alcohol prior to the offense that led to their most recent arrest and court-referral to a BIP. Lastly, arrest history was positively associated with physical and psychological aggression perpetration against an intimate partner for men only, such that more previous arrests were associated with more frequent aggression. These results provide evidence that many men and women arrested for domestic violence have engaged in a number of diverse criminal acts during their lifetimes, suggesting that BIPs may need to address general criminal behavior.

  14. Duration of oral tetracycline-class antibiotic therapy and use of topical retinoids for the treatment of acne among general practitioners (GP): A retrospective cohort study.

    Science.gov (United States)

    Barbieri, John S; Hoffstad, Ole; Margolis, David J

    2016-12-01

    Guidelines recommend limiting the duration of oral antibiotic therapy in acne to 3 to 6 months and prescribing concomitant topical retinoids for all patients. We sought to evaluate the duration of therapy with oral tetracyclines and the use of topical retinoids among patients with acne treated primarily by general practitioners in the United Kingdom. We conducted a retrospective cohort study using the Health Improvement Network database. The mean duration of therapy was 175.1 days. Of antibiotic courses, 62% were not associated with a topical retinoid; 29% exceeded 6 months in duration. If all regions were to achieve uses similar to the region with the shortest mean duration of therapy, approximately 3.3 million antibiotic days per year could be avoided in the United Kingdom. The Health Improvement Network does not include information on acne severity and clinical outcomes. Prescribing behavior for oral antibiotics in the treatment of acne among general practitioners is not aligned with current guideline recommendations. Increasing the use of topical retinoids and considering alternative agents to oral antibiotics when appropriate represent opportunities to reduce antibiotic exposure and associated complications such as antibiotic resistance and to improve outcomes in patients treated for acne. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  15. Plant-mediated silencing of the fatty acid- and retinoid-binding Pp-far-1 gene can reduce development of the root lesion nematode, Pratylenchus penetrans

    Science.gov (United States)

    Pratylenchus penetrans is one of the most important plant-parasitic nematodes and can act as a limiting factor of important agricultural, horticultural and industrial crops. Fatty acid- and retinoid- (FAR) binding proteins are unique to nematodes. The cDNA corresponding to a putative P. penetrans FA...

  16. Retinoid metabolism and all-trans retinoic acid-induced growth inhibition in head and neck squamous cell carcinoma cell lines

    NARCIS (Netherlands)

    Braakhuis, B.J.M.; Klaassen, I.; Leede, B.M. van der; Cloos, J.; Brakenhoff, R.H.; Copper, M.P.; Teerlink, T.; Hendriks, H.F.J.; Saag, P.T. van der; Snow, G.B.

    1997-01-01

    Retinoids can reverse potentially premalignant lesions and prevent second primary tumours in patients with head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been reported that acquired resistance to all-trans retinoic acid (RA) in leukaemia is associated with decreased plasma peak

  17. RXR antagonism induces G0 /G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21(Cip1) pathway in adipocytes.

    Science.gov (United States)

    Nakatsuka, Atsuko; Wada, Jun; Hida, Kazuyuki; Hida, Aya; Eguchi, Jun; Teshigawara, Sanae; Murakami, Kazutoshi; Kanzaki, Motoko; Inoue, Kentaro; Terami, Takahiro; Katayama, Akihiro; Ogawa, Daisuke; Kagechika, Hiroyuki; Makino, Hirofumi

    2012-04-01

    The peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G0/G1 cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G0 + G1 ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G0 /G1 cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G0/G1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  18. Breast Tomosynthesis

    Science.gov (United States)

    ... cancers when they are most curable and breast-conservation therapies are available. See the Mammography page for ... special platform and gradually compressed with a clear plastic paddle. Breast compression is necessary during tomosynthesis imaging ...

  19. Breast Exam

    Science.gov (United States)

    ... 210:314. Mac Bride MB, et al. The evolution of the breast self-examination to breast awareness. ... of these materials may be reprinted for noncommercial personal use only. "Mayo," "Mayo Clinic," "MayoClinic.org," "Mayo ...

  20. Breast cancer

    Science.gov (United States)

    ... help you not feel alone. Outlook (Prognosis) New, improved treatments are helping people with breast cancer live ... carcinoma in situ Patient Instructions Breast radiation - discharge Chemotherapy - what to ask your doctor Lymphedema - self-care ...

  1. Breast Cancer

    Science.gov (United States)

    Breast cancer affects one in eight women during their lives. No one knows why some women get breast cancer, but there are many risk factors. Risks that ... who have family members with breast or ovarian cancer may wish to be tested for the genes. ...

  2. Tissue- and sex-specific effects of β-carotene 15,15' oxygenase (BCO1) on retinoid and lipid metabolism in adult and developing mice.

    Science.gov (United States)

    Kim, Youn-Kyung; Zuccaro, Michael V; Costabile, Brianna K; Rodas, Rebeka; Quadro, Loredana

    2015-04-15

    In mammals, β-carotene-15,15'-oxygenase (BCO1) is the main enzyme that cleaves β-carotene, the most abundant vitamin A precursor, to generate retinoids (vitamin A derivatives), both in adult and developing tissues. We previously reported that, in addition to this function, BCO1 can also influence the synthesis of retinyl esters, the storage form of retinoids, in the mouse embryo at mid-gestation. Indeed, lack of embryonic BCO1 impaired both lecithin-dependent and acyl CoA-dependent retinol esterification, mediated by lecithin:retinol acyltransferase (LRAT) and acyl CoA:retinol acyltransferase (ARAT), respectively. Furthermore, embryonic BCO1 also influenced the ester pools of cholesterol and diacylglycerol. In this report, we gained novel insights into this alternative function of BCO1 by investigating whether BCO1 influenced embryonic retinoid and lipid metabolism in a tissue-dependent manner. To this end, livers and brains from wild-type and BCO1-/- embryos at mid-gestation were analyzed for retinoid and lipid content, as well as gene expression levels. We also asked whether or not the role of BCO1 as a regulator of lecithin- and acyl CoA-dependent retinol esterification was exclusively restricted to the developing tissues. Thus, a survey of retinol and retinyl ester levels in adult tissues of wild-type, BCO1-/-, LRAT-/- and LRAT-/-BCO1-/- mice was performed. We showed that the absence of BCO1 affects embryonic retinoid and lipid homeostasis in a tissue-specific manner and that retinyl ester formation is also influenced by BCO1 in a few adult tissues (pancreas, lung, heart and adipose) in a sex-dependent manner. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. A case of thyroid storm with cardiac arrest

    Directory of Open Access Journals (Sweden)

    Nakashima Y

    2014-05-01

    Full Text Available Yutaka Nakashima,1 Tsuneaki Kenzaka,2 Masanobu Okayama,3 Eiji Kajii31Department for Support of Rural Medicine, Yamaguchi Grand Medical Center, 2Division of General Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan; 3Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke, JapanAbstract: A 23-year-old man became unconscious while jogging. He immediately received basic life support from a bystander and was transported to our hospital. On arrival, his spontaneous circulation had returned from a state of ventricular fibrillation and pulseless electrical activity. Following admission, hyperthyroidism led to a suspicion of thyroid storm, which was then diagnosed as a possible cause of the cardiac arrest. Although hyperthyroidism-induced cardiac arrest including ventricular fibrillation is rare, it should be considered when diagnosing the cause of treatable cardiac arrest.Keywords: hyperthyroidism, ventricular fibrillation, treatable cardiac arrest, cardiac arrest, cardiopulmonary arrest

  4. Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA

    Energy Technology Data Exchange (ETDEWEB)

    Lou, Xiaohua; Toresson, Gudrun; Benod, Cindy; Suh, Ji Ho; Philips, Kevin J; Webb, Paul; Gustafsson, Jan-Ake [Karolinska; (Houston)

    2014-03-11

    Nuclear receptors (NRs) are conditional transcription factors with common multidomain organization that bind diverse DNA elements. How DNA sequences influence NR conformation is poorly understood. Here we report the crystal structure of the human retinoid X receptor α–liver X receptor β (RXRα–LXRβ) heterodimer on its cognate element, an AGGTCA direct repeat spaced by 4 nt. The complex has an extended X-shaped arrangement, with DNA- and ligand-binding domains crossed, in contrast to the parallel domain arrangement of other NRs that bind an AGGTCA direct repeat spaced by 1 nt. The LXRβ core binds DNA via canonical contacts and auxiliary DNA contacts that enhance affinity for the response element. Comparisons of RXRα–LXRβs in the crystal asymmetric unit and with previous NR structures reveal flexibility in NR organization and suggest a role for RXRα in adaptation of heterodimeric complexes to DNA.

  5. Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.

    Science.gov (United States)

    Desphande, Anil; Xia, Gang; Boerma, LeeAnn J; Vines, Kimberly K; Atigadda, Venkatram R; Lobo-Ruppert, Susan; Grubbs, Clinton J; Moeinpour, Fariba L; Smith, Craig D; Christov, Konstantin; Brouillette, Wayne J; Muccio, Donald D

    2014-01-01

    (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Occurrence of xenobiotic ligands for retinoid X receptors and thyroid hormone receptors in the aquatic environment of Taiwan.

    Science.gov (United States)

    Chen, Chien-Hsun; Chou, Pei-Hsin; Kawanishi, Masanobu; Yagi, Takashi

    2014-08-30

    Various synthetic compounds are frequently discharged into the environment via human activities. Among them, certain contaminants may disrupt normal physiological functions of wildlife and humans via interactions with nuclear receptors. To protect human health and the environment, it is important to detect environmental ligands for human nuclear receptors. In this study, yeast-based reporter gene assays were used to investigate the occurrence of xenobiotic ligands for retinoid X receptors (RXR) and thyroid hormone receptors (TR) in the aquatic environment of Taiwan. Experimental results revealed that RXR agonist/antagonist activity was detected in river water and sediment samples. In particular, high RXR agonist/antagonist activity was found in the samples collected near river mouths. Additionally, few samples also elicited significant TR antagonist activity. Our findings show that the aquatic environment of Taiwan was contaminated with RXR and TR ligands. Further study is necessary to identify these xenobiotic RXR and TR agonists and antagonists. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Roles of Retinoids and Retinoic Acid Receptors in the Regulation of Hematopoietic Stem Cell Self-Renewal and Differentiation

    Directory of Open Access Journals (Sweden)

    Louise E. Purton

    2007-01-01

    Full Text Available Multipotent hematopoietic stem cells (HSCs sustain blood cell production throughout an individual's lifespan through complex processes ultimately leading to fates of self-renewal, differentiation or cell death decisions. A fine balance between these decisions in vivo allows for the size of the HSC pool to be maintained. While many key factors involved in regulating HSC/progenitor cell differentiation and cell death are known, the critical regulators of HSC self-renewal are largely unknown. In recent years, however, a number of studies describing methods of increasing or decreasing the numbers of HSCs in a given population have emerged. Of major interest here are the emerging roles of retinoids in the regulation of HSCs.

  8. Interrater variability of EEG interpretation in comatose cardiac arrest patients

    DEFF Research Database (Denmark)

    Westhall, Erik; Rosén, Ingmar; Rossetti, Andrea O

    2015-01-01

    of cardiac arrest patients included in the Target Temperature Management trial. The main objective was to evaluate if malignant EEG-patterns could reliably be identified. METHODS: Full-length EEGs from 103 comatose cardiac arrest patients were interpreted by four EEG-specialists with different nationalities...... in an international context with high reliability. SIGNIFICANCE: The establishment of strict criteria with high transferability between interpreters will increase the usefulness of routine EEG to assess neurological prognosis after cardiac arrest....

  9. Predictors for outcome among cardiac arrest patients

    DEFF Research Database (Denmark)

    Wibrandt-Johansen, Ida Maria; Norsted, Kristine; Schmidt, Henrik

    2015-01-01

    BackgroundIn the past decade, early treatment of cardiac arrest (CA) victims has been improved in several ways, leading to more optimistic over all prognoses. However, the global survival rate after out-of-hospital CA (OHCA) is still not more than 5-10%. With a better knowledge of the predictors...... circulation (ROSC).ResultsThe overall mortality was 44% and a favorable neurological outcome was seen among 52%. Strong predictors for survival and favorable neurological outcome were ventricular tachycardia/ventricular fibrillation (VT/VF) as initial rhythm, cardiac etiology and time to ROSC¿... rhythm of VT/VF and a cardiac etiology were the strongest....

  10. Growth arrest specific protein (GAS) 6

    DEFF Research Database (Denmark)

    Haase, T N; Rasmussen, Morten; Jaksch, C A M

    2013-01-01

    Aims/hypothesis Maternal low-protein (LP) diet during gestation results in a reduced beta cell mass in the offspring at birth and this may hamper the ability to adapt to high-energy food and sedentary lifestyle later in life. To investigate the biology behind the LP-offspring phenotype, this study...... using RNA microarray and quantitative PCR. The role of a differentially expressed gene, growth arrest specific protein 6 (GAS6), was evaluated in vitro using neonatal rat islets. Results The mRNA level of Gas6, known to be mitogenic in other tissues, was reduced in LP offspring. The mRNA content of Mafa...

  11. Use of the Retinoid Pregnancy Prevention Program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate.

    Science.gov (United States)

    Pastuszak, A; Koren, G; Rieder, M J

    1994-01-01

    We sought to describe demographic characteristics of and pattern of contraception use by Canadian women prescribed synthetic retinoids who voluntarily contacted the Motherisk Program in Toronto and to describe the degree of use of the Pregnancy Prevention Program (PPP) for retinoids. Prospectively gathered intake data from isotretinoin-exposed women was statistically compared to that from matched controls selected from our database. Intake data is qualitatively reported for etretinate-exposed women. We included women who voluntarily contacted the Motherisk Program from November 1, 1988, to January 30, 1991, for counseling about reproductive risks of isotretinoin or etretinate. Primary outcome parameters were maternal age, race, marital status, socioeconomic status; gravity, parity, previous miscarriages and elective abortions, maternal tobacco and ethanol exposure, contraception use, and use of PPP (educational components used, patient recollection of warnings). The 26 isotretinoin-exposed women were younger than controls (25.2 [SD 6.7] years vs 28.9 [SD 5.1] years, P = 0.03), tended to be adolescent (30.8% vs. 3.8%, P = 0.014) and sought counselling later in gestation (10.1 [SD 8] weeks vs. 6 [SD 4.2] weeks, P = 0.01). Twenty (77%) knew the drug was teratogenic, yet 10 (38.5%) used no contraception, 6 (23.1%) experienced method failure, and 2 (8%) stopped contraception during isotretinoin therapy. In conclusion, although cognizant of the teratogenicity of isotretinoin, more than one-third of the women in this study used no birth control or experienced contraception failure. In this same group, however, compliance with contraception use appeared to increase in those who saw more of the PPP.

  12. Retinoid x receptor gamma is implicated in docosahexaenoic acid modulation of despair behaviors and working memory in mice.

    Science.gov (United States)

    Wietrzych-Schindler, Marta; Szyszka-Niagolov, Monika; Ohta, Kiminori; Endo, Yasuyuki; Pérez, Efrén; de Lera, Angel R; Chambon, Pierre; Krezel, Wojciech

    2011-04-15

    Omega-3 polyunsaturated fatty acids, including docosahexaenoic acid (DHA), have antidepressant and promnemonic functions. The mechanisms of such activities are still elusive and may involve retinoid X receptors (RXRs), transcription factors known to bind DHA in vitro. Promnemonic and antidespair activities of acute DHA treatment were tested in BALBcByJ mice using spontaneous alternation and forced swim test, respectively. The involvement of retinoid receptors in such DHA activities was investigated using RXR and/or retinoic acid receptor (RAR) agonists to mimic DHA activities or a synthetic pan-RXR antagonist to block them. Involvement of RXR isotypes was analyzed using the same tasks and delayed nonmatch to place for working memory in RXRγ knockout mice. Docosahexaenoic acid decreased despair behavior and improved working memory in BALBcByJ mice. Such effects were suppressed by co-treatment with BR1211, a pan-RXR antagonist, whereas a pan-RXR agonist, UVI2108, mimicked DHA activities. Retinoic acid (RA), a natural ligand of RXRs, also reduced despair behavior and improved working memory and such activities did not require activation of RARs, as RA effects were abolished by co-treatment with BR1211 and they were not reproduced by TTNPB, a pan-RAR agonist. The RXRγ knockout mice displayed increased despair and deficits in working memory, which were insensitive to DHA and pan-RXR agonist treatments, whereas DHA or UVI2108 reversed these deficits in RXRγ heterozygous mice. Our data suggest that RXRs are a converging point in mediating DHA and RA modulations of despair behavior and working memory and that RXRγ is the predominant RXR isotype in these regulations. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  13. Sublingual Microcirculation is Impaired in Post-cardiac Arrest Patients

    DEFF Research Database (Denmark)

    G. Omar, Yasser; Massey, Michael; Wiuff Andersen, Lars

    2013-01-01

    the microcirculation flow index (MFI) at 6 and 24h in the cardiac arrest patients, and within 6h of emergency department admission in the sepsis and control patients. RESULTS: We evaluated 30 post-cardiac arrest patients, 16 severe sepsis/septic shock patients, and 9 healthy control patients. Sublingual...... markers in the post-cardiac arrest state. METHODS: We prospectively evaluated the sublingual microcirculation in post-cardiac arrest patients, severe sepsis/septic shock patients, and healthy control patients using Sidestream Darkfield microscopy. Microcirculatory flow was assessed using...

  14. Breast Reconstruction After Mastectomy

    Science.gov (United States)

    ... Cancers Breast Cancer Screening Research Breast Reconstruction After Mastectomy On This Page What is breast reconstruction? How ... are some new developments in breast reconstruction after mastectomy? What is breast reconstruction? Many women who have ...

  15. Breast reconstruction - implants

    Science.gov (United States)

    Breast implants surgery; Mastectomy - breast reconstruction with implants; Breast cancer - breast reconstruction with implants ... to make reconstruction easier. If you will have breast reconstruction later, your surgeon will remove enough skin ...

  16. Breast Cancer Treatment

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Treatment (PDQ®)–Patient Version General Information About Breast Cancer Go to Health Professional Version Key Points Breast ...

  17. Stages of Breast Cancer

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Treatment (PDQ®)–Patient Version General Information About Breast Cancer Go to Health Professional Version Key Points Breast ...

  18. Breast Cancer Prevention

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Prevention (PDQ®)–Patient Version What is prevention? Go ... from starting. Risk-reducing surgery . General Information About Breast Cancer Key Points Breast cancer is a disease in ...

  19. Breast cancer screening

    Science.gov (United States)

    Mammogram - breast cancer screening; Breast exam - breast cancer screening; MRI - breast cancer screening ... is performed to screen women to detect early breast cancer when it is more likely to be cured. ...

  20. Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Fournier, Marcia V.; Fata, Jimmie E.; Martin, Katherine J.; Yaswen, Paul; Bissell, Mina J.

    2009-06-03

    PTEN is a dual function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two non-malignant human mammary epithelial cell lines (HMECs) that form polarized, growth-arrested structures (acini) when cultured in 3-dimensional laminin-rich extracellular matrix gels (3D lrECM). As acini begin to form, PTEN accumulates in both the cytoplasm, and at cell-cell contacts where it colocalizes with E-cadherin/{beta}-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in SKBR3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in 3D lrECM indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus appears to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells.

  1. Rice hull extracts inhibit proliferation of MCF-7 cells with G₁ cell cycle arrest in parallel with their antioxidant activity.

    Science.gov (United States)

    Chung, Nam-Jin; Choi, Ki-Choon; Lee, Seung-Ah; Baek, Jin-A; Lee, Jeong-Chae

    2015-03-01

    Rice (Oryza sativa L.) has been a major dietary staple worldwide for centuries. Growing interest in the beneficial effects of antioxidants has inspired investigation of rice hulls as an attractive source of chemopreventive compounds for breast cancer intervention. We prepared methanol extracts from rice hulls of three Korean bred cultivars (japonica), Ilpum, Heugjinju, and Jeogjinju, and one japonica weedy rice, WD-3. We examined the antiproliferative potential of the hull extracts on MCF-7 human breast cancer cells and the related mechanisms thereof. Hull extracts inhibited proliferation of the cells and mediated G0/G1 phase arrest by suppressing cyclins and cyclin-dependent kinases, where WD-3 extract showed the most potent. Blockage of p21 expression by small interfering RNA transfection attenuated G1 phase arrest induced by WD-3 extract. The WD-3 extract exhibited greater antioxidant potential and total phenolic compounds, compared with other rice hulls. Gas chromatography-mass spectrometry analysis for the F4 fractioned from WD-3 extract revealed that cinnamic acid derivatives were the major active constituents. The F4 fraction most potently inhibited proliferation of MCF-7 cells than WD-3 extract through the suppression of cell cycle regulatory factors. Collectively, our results suggest that the pigmented rice hulls possess greater antioxidant and chemopreventive activity against breast cancer than the other rice cultivars tested, demonstrating that WD-3 rice hulls are an attractive source of chemopreventive bioactive compounds.

  2. New Approaches to Chemoprevention of Breast Cancer

    National Research Council Canada - National Science Library

    Sporn, Michael

    1997-01-01

    Triterpenoids, natural products related to steroids and retinoids, represent an important class of new structures for drug discovery, with potential applications in many fields of medicine, particularly cancer...

  3. Ophiobolin O Isolated from Aspergillus ustus Induces G1 Arrest of MCF-7 Cells through Interaction with AKT/GSK3β/Cyclin D1 Signaling

    Directory of Open Access Journals (Sweden)

    Cuiting Lv

    2015-01-01

    Full Text Available Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.

  4. Profiling of the transcriptional response to all-trans retinoic acid in breast cancer cells reveals RARE-independent mechanisms of gene expression.

    Science.gov (United States)

    Coyle, Krysta Mila; Maxwell, Selena; Thomas, Margaret Lois; Marcato, Paola

    2017-11-30

    Retinoids, derivatives of vitamin A, are key physiological molecules with regulatory effects on cell differentiation, proliferation and apoptosis. As a result, they are of interest for cancer therapy. Specifically, models of breast cancer have varied responses to manipulations of retinoid signaling. This study characterizes the transcriptional response of MDA-MB-231 and MDA-MB-468 breast cancer cells to retinaldehyde dehydrogenase 1A3 (ALDH1A3) and all-trans retinoic acid (atRA). We demonstrate limited overlap between ALDH1A3-induced gene expression and atRA-induced gene expression in both cell lines, suggesting that the function of ALDH1A3 in breast cancer progression extends beyond its role as a retinaldehyde dehydrogenase. Our data reveals divergent transcriptional responses to atRA, which are largely independent of genomic retinoic acid response elements (RAREs) and consistent with the opposing responses of MDA-MB-231 and MDA-MB-468 to in vivo atRA treatment. We identify transcription factors associated with each gene set. Manipulation of the IRF1 transcription factor demonstrates that it is the level of atRA-inducible and epigenetically regulated transcription factors that determine expression of target genes (e.g. CTSS, cathepsin S). This study provides a paradigm for complex responses of breast cancer models to atRA treatment, and illustrates the need to characterize RARE-independent responses to atRA in a variety of models.

  5. Involvement of Different networks in mammary gland involution after the pregnancy/lactation cycle: Implications in breast cancer.

    Science.gov (United States)

    Zaragozá, Rosa; García-Trevijano, Elena R; Lluch, Ana; Ribas, Gloria; Viña, Juan R

    2015-04-01

    Early pregnancy is associated with a reduction in a woman's lifetime risk for breast cancer. However, different studies have demonstrated an increase in breast cancer risk in the years immediately following pregnancy. Early and long-term risk is even higher if the mother age is above 35 years at the time of first parity. The proinflammatory microenvironment within the mammary gland after pregnancy renders an "ideal niche" for oncogenic events. Signaling pathways involved in programmed cell death and tissue remodeling during involution are also activated in breast cancer. Herein, the major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGFβ), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, are important regulatory nodes for signaling amplification after weaning. Indeed, during involution, p65/p300 target genes such as MMP9, Capn1, and Capn2 are upregulated. Elevated expression and activities of these proteases in breast cancer have been extensively documented. The role of these proteases during mammary gland involution is further discussed. MMPs, calpains, and cathepsins exert their effect by modification of the extracellular matrix and intracellular proteins. Calpains, activated in the mammary gland during involution, cleave several proteins located in cell membrane, lysosomes, mitochondria, and nuclei favoring cell death. Besides, during this period, Capn1 is most probably involved in the modulation of preadipocyte differentiation through chromatin remodeling. Calpains can be implicated in cell anchoring loss, providing a proper microenvironment for tumor growth. A better understanding of the role of any of these proteases in tumorigenesis may

  6. 29 CFR 1915.159 - Personal fall arrest systems (PFAS).

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Personal fall arrest systems (PFAS). 1915.159 Section 1915... Protective Equipment (PPE) § 1915.159 Personal fall arrest systems (PFAS). The criteria of this section apply to PFAS and their use. Effective January 1, 1998, body belts and non-locking snaphooks are not...

  7. Cardiac arrest during anesthesia at a University Hospital in Nigeria ...

    African Journals Online (AJOL)

    Background: We assessed the incidence and outcomes of cardiac arrest during anesthesia in the operating room at our university hospital. A previous study on intraoperative cardiac arrests covered a period from 1994-1998 and since then; anesthetic personnel, equipment, and workload have increased remarkably.

  8. Thiamine as a neuroprotective agent after cardiac arrest.

    Science.gov (United States)

    Ikeda, Kohei; Liu, Xiaowen; Kida, Kotaro; Marutani, Eizo; Hirai, Shuichi; Sakaguchi, Masahiro; Andersen, Lars W; Bagchi, Aranya; Cocchi, Michael N; Berg, Katherine M; Ichinose, Fumito; Donnino, Michael W

    2016-08-01

    Reduction of pyruvate dehydrogenase (PDH) activity in the brain is associated with neurological deficits in animals resuscitated from cardiac arrest. Thiamine is an essential co-factor of PDH. The objective of this study was to examine whether administration of thiamine improves outcomes after cardiac arrest in mice. Secondarily, we aimed to characterize the impact of cardiac arrest on PDH activity in mice and humans. Animal study: Adult mice were subjected to cardiac arrest whereupon cardiopulmonary resuscitation was performed. Thiamine or vehicle was administered 2min before resuscitation and daily thereafter. Mortality, neurological outcome, and metabolic markers were evaluated. Human study: In a convenience sample of post-cardiac arrest patients, we measured serial PDH activity from peripheral blood mononuclear cells and compared them to healthy controls. Animal study: Mice treated with thiamine had increased 10-day survival (48% versus 17%, Pcardiac arrest patients had lower PDH activity in mononuclear cells than did healthy volunteers (estimated difference: -5.8O.D./min/mg protein, Pcardiac arrest improved neurological outcome and 10-day survival in mice. PDH activity was markedly depressed in post-cardiac arrest patients suggesting that this pathway may represent a therapeutic target. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Cooling the crisis: Therapeutic hypothermia after sickle cardiac arrest

    NARCIS (Netherlands)

    Metske, Hennie A.; Postema, Pieter G.; Biemond, Bart J.; Bouman, Catherine S. C.

    2012-01-01

    Objective: The management of patients with sickle-cell disease and cardiac arrest presents special challenges. Mild therapeutic hypothermia may improve survival and neurologic outcome after cardiac arrest, however, it may also precipitate sickling in patients with sickle-cell disease. Rigorous

  10. Performance of Surge Arrester Installation to Enhance Protection

    Directory of Open Access Journals (Sweden)

    Mbunwe Muncho Josephine

    2017-01-01

    Full Text Available The effects of abnormal voltages on power system equipment and appliances in the home have raise concern as most of the equipments are very expensive. Each piece of electrical equipment in an electrical system needs to be protected from surges. To prevent damage to electrical equipment, surge protection considerations are paramount to a well designed electrical system. Lightning discharges are able to damage electric and electronic devices that usually have a low protection level and these are influenced by current or voltage pulses with a relatively low energy, which are induced by lightning currents. This calls for proper designed and configuration of surge arresters for protection on the particular appliances. A more efficient non-linear surge arrester, metal oxide varistor (MOV, should be introduced to handle these surges. This paper shows the selection of arresters laying more emphasis on the arresters for residential areas. In addition, application and installation of the arrester will be determined by the selected arrester. This paper selects the lowest rated surge arrester as it provides insulation when the system is under stress. It also selected station class and distribution class of arresters as they act as an open circuit under normal system operation and to bring the system back to its normal operation mode as the transient voltage is suppressed. Thus, reduces the risk of damage, which the protection measures can be characterized, by the reduction value of the economic loss to an acceptable level.

  11. Resuscitation, prolonged cardiac arrest, and an automated chest compression device

    DEFF Research Database (Denmark)

    Risom, Martin; Jørgensen, Henrik; Rasmussen, Lars S

    2010-01-01

    The European Resuscitation Council's 2005 guidelines for cardiopulmonary resuscitation (CPR) emphasize the delivery of uninterrupted chest compressions of adequate depth during cardiac arrest.......The European Resuscitation Council's 2005 guidelines for cardiopulmonary resuscitation (CPR) emphasize the delivery of uninterrupted chest compressions of adequate depth during cardiac arrest....

  12. Alterations in Cerebral Blood Flow after Resuscitation from Cardiac Arrest

    Directory of Open Access Journals (Sweden)

    Bistra Iordanova

    2017-08-01

    Full Text Available Greater than 50% of patients successfully resuscitated from cardiac arrest have evidence of neurological disability. Numerous studies in children and adults, as well as in animal models have demonstrated that cerebral blood flow (CBF is impaired after cardiac arrest. Stages of cerebral perfusion post-resuscitation include early hyperemia, followed by hypoperfusion, and finally either resolution of normal blood flow or protracted hyperemia. At the level of the microcirculation the blood flow is heterogeneous, with areas of no flow, low flow, and increased flow. CBF directed therapies in animal models of cardiac arrest improved neurological outcome, and therefore, the alterations in CBF after cardiac arrest likely contribute to the development of hypoxic ischemic encephalopathy. Current intensive care after cardiac arrest is centered upon maintaining systemic oxygenation, normal blood pressure values for age, maintaining general homeostasis, and avoiding hyperthermia. Assessment of CBF and oxygenation is not routinely performed after cardiac arrest. Currently available and underutilized techniques to assess cerebral perfusion include transcranial doppler, near-infrared spectroscopy, and arterial spin labeling magnetic resonance imaging. Limited clinical studies established the role of CBF and oxygenation monitoring in prognostication after cardiac arrest and few studies suggest that guiding critical care post-resuscitation to mean arterial pressures above the minimal autoregulatory range might improve outcome. Important knowledge gaps thus remain in cerebral monitoring and CBF and oxygen goal-directed therapies post-resuscitation from cardiac arrest.

  13. Exercise-related cardiac cardiac rehabilitation arrest In

    African Journals Online (AJOL)

    most important being myocardial infarction and cardiac arrest. (CA).1,2. 'Normal' ... myocardial infarction and CA in cardiac rehabilitation pro- ..... The acute risk of. Strenuous exercise.JAMA 1980; 244: 1799-1801. 5. Siscovick DS, Weiss NS, Fletcber RH et al. The incidence of primary cardiac arrest during vigorous exercise.

  14. Cardiac arrest during anesthesia at a University Hospital in Nigeria

    African Journals Online (AJOL)

    2013-03-07

    Mar 7, 2013 ... Background: We assessed the incidence and outcomes of cardiac arrest during anesthesia in the operating room at our university hospital. A previous study on intraoperative cardiac arrests covered a period from 1994-1998 and since then; anesthetic personnel, equipment, and workload have increased ...

  15. Efficacy of silver diamine fluoride for Arresting Caries Treatment.

    NARCIS (Netherlands)

    Yee, R.; Holmgren, C.J.; Mulder, J.; Lama, D.; Walker, D.; Palenstein Helderman, W.H. van

    2009-01-01

    Arresting Caries Treatment (ACT) has been proposed to manage untreated dental caries in children. This prospective randomized clinical trial investigated the caries-arresting effectiveness of a single spot application of: (1) 38% silver diamine fluoride (SDF) with tannic acid as a reducing agent;

  16. Location of cardiac arrest and impact of pre-arrest chronic disease and medication use on survival.

    Science.gov (United States)

    Granfeldt, Asger; Wissenberg, Mads; Hansen, Steen Møller; Lippert, Freddy K; Torp-Pedersen, Christian; Christensen, Erika Frischknecht; Christiansen, Christian Fynbo

    2017-05-01

    Cardiac arrest in a private location is associated with a higher mortality when compared to public location. Past studies have not accounted for pre-arrest factors such as chronic disease and medication. To investigate whether the association between cardiac arrest in a private location and a higher mortality can be explained by differences in chronic diseases and medication. We identified 27,771 out-of-hospital cardiac arrest patients ≥18 years old from the Danish Cardiac Arrest Registry (2001-2012). Using National Registries, we identified pre-arrest chronic disease and medication. To investigate the importance of cardiac arrest related factors and chronic disease and medication use we performed adjusted Cox regression analyses during day 0-7 and day 8-365 following cardiac arrest to calculate hazard ratios (HR) for death. Day 0-7: Un-adjusted HR for death day 0-7 was 1.21 (95%CI:1.18-1.25) in private compared to public location. When including cardiac arrest related factors HR for death was 1.09 (95%CI:1.06-1.12). Adding chronic disease and medication to the analysis changed HR for death to 1.08 (95%CI:1.05-1.12). 8-365 day: The un-adjusted HR for death day 8-365 was 1.70 (95% CI: 1.43-2.02) in private compared to public location. When including cardiac arrest related factors the HR decreased to 1.39 (95% CI: 1.14-1.68). Adding chronic disease and medication to the analysis changed HR for death to 1.27 (95% CI:1.04-1.54). The higher mortality following cardiac arrest in a private location is partly explained by a higher prevalence of chronic disease and medication use in patients surviving until day 8. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Serum tau and neurological outcome in cardiac arrest

    DEFF Research Database (Denmark)

    Mattsson, Niklas; Zetterberg, Henrik; Nielsen, Niklas

    2017-01-01

    OBJECTIVE: To test serum tau as a predictor of neurological outcome after cardiac arrest. METHODS: We measured the neuronal protein tau in serum at 24, 48, and 72 h after cardiac arrest in 689 patients in the prospective international Target Temperature Management trial. The main outcome was poor...... neurological outcome, defined as Cerebral Performance Category 3-5 at 6 months. RESULTS: Increased tau was associated with poor outcome at 6 months after cardiac arrest (median 38.5 [IQR 5.7-245] ng/L in poor versus 1.5 [0.7-2.4] ng/L in good outcome, for tau at 72 h, p... and 36°C targeted temperature after cardiac arrest. INTERPRETATION: Serum tau is a promising novel biomarker for prediction of neurological outcome in patients with cardiac arrest. It may be significantly better than serum NSE, which is recommended in guidelines and currently used in clinical practice...

  18. Characterization of mitochondrial injury after cardiac arrest (COMICA).

    Science.gov (United States)

    Donnino, Michael W; Liu, Xiaowen; Andersen, Lars W; Rittenberger, Jon C; Abella, Benjamin S; Gaieski, David F; Ornato, Joseph P; Gazmuri, Raúl J; Grossestreuer, Anne V; Cocchi, Michael N; Abbate, Antonio; Uber, Amy; Clore, John; Peberdy, Mary Anne; Callaway, Clifton W

    2017-04-01

    Mitochondrial injury post-cardiac arrest has been described in pre-clinical settings but the extent to which this injury occurs in humans remains largely unknown. We hypothesized that increased levels of mitochondrial biomarkers would be associated with mortality and neurological morbidity in post-cardiac arrest subjects. We performed a prospective multicenter study of post-cardiac arrest subjects. Inclusion criteria were comatose adults who suffered an out-of-hospital cardiac arrest. Mitochondrial biomarkers were measured at 0, 12, 24, 36 and 48h after return of spontaneous circulation as well as in healthy controls. Out of 111 subjects enrolled, 102 had evaluable samples at 0h. Cardiac arrest subjects had higher baseline cytochrome c levels compared to controls (2.18ng/mL [0.74, 7.74] vs. 0.16ng/mL [0.03, 0.91], pcardiac arrest subjects at baseline compared to the control subjects. There were no differences between survivors and non-survivors for mitochondrial DNA, nuclear DNA, or cell free DNA. Cytochrome c was increased in post- cardiac arrest subjects compared to controls, and in post-cardiac arrest non-survivors compared to survivors. Nuclear DNA and cell free DNA was increased in plasma of post-cardiac arrest subjects. There were no differences in mitochondrial DNA, nuclear DNA, or cell free DNA between survivors and non-survivors. Mitochondrial injury markers showed mixed results in the post-cardiac arrest period. Future research needs to investigate these differences. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Effect of donor cardiac arrest and arrest duration on outcomes of lung transplantation.

    Science.gov (United States)

    Mohite, Prashant N; Zych, Bartlomiej; Sabashnikov, Anton; Popov, Aron-Frederik; Garcia-Saez, Diana; Patil, Nikhil P; Koch, Achim; Zeriouh, Mohamed; Rahmanian, Parwis B; Dhar, Dhruva; Amrani, Mohamed; Bahrami, Toufan; DeRobertis, Fabio; Carby, Martin; Reed, Anna; Simon, Andre R

    2016-04-01

    Limited data are available about lung transplantation (LTx) from donors suffering cardiac arrest (CA) prior to actual donation. A retrospective analysis of LTx performed between January 2007 and September 2012 was done with the focus on CA in donors. The recipients were grouped depending on the history of donor CA and CA duration (downtime) as: No cardiac arrest ("NoCA"), CA downtime less than 20 min ("CA 20"). Early and mid-term outcomes after LTx were compared among the three groups. A total of 237 LTx were performed during the study period. One hundred eighty-eight patients received organs from "NoCA" donors, 25 from "CA 20" donors. There was a trend toward better overall cumulative survival in both CA groups (log rank p = 0.076) whereas the survival in the "CA > 20" group was significantly better than in the "NoCA" group in the subgroup analysis (log rank p = 0.045). Freedom from bronchiolitis obliterans syndrome (BOS) also increased with increase in CA duration, although it did not reach statistical significance. Transplantation of lungs from donors with a history of CA is safe and feasible. Longer duration of cardiac arrest may improve the outcomes after the LTx in terms of survival and freedom from BOS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Cellular retinoic-acid-binding-protein and retinol-binding-protein mRNA expression in the cells of the rat seminiferous tubules and their regulation by retinoids.

    Science.gov (United States)

    Faraonio, R; Galdieri, M; Colantuoni, V

    1993-02-01

    The levels of the mRNA corresponding to the intracellular binding proteins for retinoic acid and retinol (CRABP1 and CRBP1, respectively) were studied in primary cultures of somatic and germ cells of the rat seminiferous tubules. We show that the CRABP1 mRNA is expressed in Sertoli and germ cells and a single molecular species of mRNA is detected. CRBP1 mRNA is detected in Sertoli and peritubular cells. The regulation of the expression of both genes by retinoids was studied in Sertoli cells. CRABP1 mRNA levels are not affected by either retinoic acid or retinol, whereas both compounds positively regulate CRBP1 mRNA synthesis in a dose-dependent manner. A fivefold increase in CRBP1 mRNA levels was observed 32-48 h after addition of either agent. These results demonstrate that in Sertoli cells the expression of CRABP1 is not affected by retinoids, similar to the situation observed in vivo and in other in-vitro cultures. CRBP1-gene expression is, instead, induced and the variations in CRBP1-mRNA levels may regulate the intracellular concentrations of retinoids, as a response to changes in the vitamin-A nutritional status.

  1. Induction of Apoptosis and Cell Cycle Arrest in Human Colorectal Carcinoma by Litchi Seed Extract

    Directory of Open Access Journals (Sweden)

    Chih-Ping Hsu

    2012-01-01

    Full Text Available The Litchi (Litchi chinensis fruit products possess rich amounts of flavanoids and proanthocyanidins. Its pericarp has been shown to inhibit breast and liver cancer cell growth. However, the anticolorectal cancer effect of Litchi seed extract has not yet been reported. In this study, the effects of polyphenol-rich Litchi seed ethanol extract (LCSP on the proliferation, cell cycle, and apoptosis of two colorectal cancer cell lines Colo320DM and SW480 were examined. The results demonstrated that LCSP significantly induced apoptotic cell death in a dose-dependent manner and arrested cell cycle in G2/M in colorectal carcinoma cells. LCSP also suppressed cyclins and elevated the Bax : Bcl-2 ratio and caspase 3 activity. This study provides in vitro evidence that LCSP serves as a potential chemopreventive agent for colorectal cancer.

  2. Experimental investigation of interfacial crack arrest in sandwich beams subjected to fatigue loading using a novel crack arresting device

    DEFF Research Database (Denmark)

    Martakos, G.; Andreasen, J.H.; Berggreen, Christian

    2017-01-01

    A recently proposed face-sheet–core interface crack arresting device is implemented in sandwich beams and tested using the Sandwich Tear Test configuration. Fatigue loading conditions are applied to propagate the crack and determine the effect of the crack stopper on the fatigue growth rate...... and arrest of the crack. Digital image correlation is used through the duration of the fatigue experiment to track the strain evolution as the crack tip advances. The measured strains are related to crack tip propagation, arrest, and re-initiation of the crack. A finite element model is used to calculate...... the energy release rate, mode mixity and to simulate crack propagation and arrest of the crack. Finally, the effectiveness of the crack arresting device is demonstrated on composite sandwich beams subjected to fatigue loading conditions....

  3. Breast Feeding.

    Science.gov (United States)

    International Children's Centre, Paris (France).

    This set of documents consists of English, French, and Spanish translations of four pamphlets on breast-feeding. The pamphlets provide information designed for lay persons, academics and professionals, health personnel and educators, and policy-makers. The contents cover health-related differences between breast and bottle milk; patterns of…

  4. Breast lymphoma

    African Journals Online (AJOL)

    outside the breast. Histological diagnoses of the so-called primary breast lymphomas included 1 case of Hodgkin's disease and 6 of non-Hodgkin's lymphoma (inclUding 2 with T-cell phenotypes). ... adequate specimens; (iI) mammary tissue and lymphomatous infiltrate ... All the patients were female. Their ages ranged from ...

  5. Breast asymmetry and predisposition to breast cancer

    OpenAIRE

    Scutt, D; Lancaster, GA; Manning, JT

    2006-01-01

    INTRODUCTION: It has been shown in our previous work that breast asymmetry is related to several of the known risk factors for breast cancer, and that patients with diagnosed breast cancer have more breast volume asymmetry, as measured from mammograms, than age-matched healthy women. METHODS: In the present study, we compared the breast asymmetry of women who were free of breast disease at time of mammography, but who had subsequently developed breast cancer, with that of age-matched healthy ...

  6. Sudden Cardiac Arrest during Participation in Competitive Sports.

    Science.gov (United States)

    Landry, Cameron H; Allan, Katherine S; Connelly, Kim A; Cunningham, Kris; Morrison, Laurie J; Dorian, Paul

    2017-11-16

    The incidence of sudden cardiac arrest during participation in sports activities remains unknown. Preparticipation screening programs aimed at preventing sudden cardiac arrest during sports activities are thought to be able to identify at-risk athletes; however, the efficacy of these programs remains controversial. We sought to identify all sudden cardiac arrests that occurred during participation in sports activities within a specific region of Canada and to determine their causes. In this retrospective study, we used the Rescu Epistry cardiac arrest database (which contains records of every cardiac arrest attended by paramedics in the network region) to identify all out-of-hospital cardiac arrests that occurred from 2009 through 2014 in persons 12 to 45 years of age during participation in a sport. Cases were adjudicated as sudden cardiac arrest (i.e., having a cardiac cause) or as an event resulting from a noncardiac cause, on the basis of records from multiple sources, including ambulance call reports, autopsy reports, in-hospital data, and records of direct interviews with patients or family members. Over the course of 18.5 million person-years of observation, 74 sudden cardiac arrests occurred during participation in a sport; of these, 16 occurred during competitive sports and 58 occurred during noncompetitive sports. The incidence of sudden cardiac arrest during competitive sports was 0.76 cases per 100,000 athlete-years, with 43.8% of the athletes surviving until they were discharged from the hospital. Among the competitive athletes, two deaths were attributed to hypertrophic cardiomyopathy and none to arrhythmogenic right ventricular cardiomyopathy. Three cases of sudden cardiac arrest that occurred during participation in competitive sports were determined to have been potentially identifiable if the athletes had undergone preparticipation screening. In our study involving persons who had out-of-hospital cardiac arrest, the incidence of sudden cardiac

  7. Fat embolization and fatal cardiac arrest during hip arthroplasty with methylmethacrylate.

    Science.gov (United States)

    Fallon, K M; Fuller, J G; Morley-Forster, P

    2001-01-01

    This case report describes a cardiac arrest during a cemented hip arthroplasty procedure. Hemodynamic instability during methylmethacrylate use in arthroplasty surgery can be explained by fat embolization rather than the inherent toxicity of the monomer. A 78-yr-old woman required a cemented hemiarthroplasty for a pathologic left subcapital fracture. The patient's past medical history included stable angina, diet-controlled type II diabetes and metastatic breast cancer. During the cementing of the canal and insertion of the femoral prosthesis, desaturation, hypotension and cardiac arrest occurred. The patient underwent a successful intraoperative resuscitation and was transferred to the intensive care unit where she subsequently developed disseminated intravascular coagulopathy. The patient died 24 hr later and autopsy confirmed the cause of death as fat embolization. The deleterious cardiovascular effects of methylmethacrylate have been discussed in the literature. However, clinical evidence supports fat embolization during arthroplasty surgery as a greater determinant of hemodynamic compromise. Surgical precautions are paramount in minimizing the sequelae of Bone Implantation Syndrome and anesthetic treatment consists of supportive care.

  8. Cloning and Expression of Ecdysone Receptor and Retinoid X Receptor from Procambarus clarkii: Induction by Eyestalk Ablation

    Directory of Open Access Journals (Sweden)

    Tian-Hao Dai

    2016-10-01

    Full Text Available Ecdysone receptor and retinoid X receptor are key regulators in molting. Here, full length ecdysone receptor (PcEcR and retinoid X receptor (PcRXR cDNAs from Procambarus clarkii were cloned. Full length cDNA of PcEcR has 2500 bp, encoding 576 amino acid proteins, and full length cDNA of PcRXR has 2593 bp, in which a 15 bp and a 204 bp insert/deletion splice variant regions in DNA binding domain and hinge domain were identified. The two splice variant regions in PcRXR result four isoforms: PcRXR1-4, encoding 525, 520, 457 and 452 amino acids respectively. PcEcR was highly expressed in the hepatopancreas and eyestalk and PcRXR was highly expressed in the eyestalk among eight examined tissues. Both PcEcR and PcRXR had induced expression after eyestalk ablation (ESA in the three examined tissues. In muscle, PcEcR and PcRXR were upregulated after ESA, PcEcR reached the highest level on day 3 after ESA and increased 33.5-fold relative to day 0, and PcRXR reached highest the level on day 1 after ESA and increased 2.7-fold relative to day 0. In the hepatopancreas, PcEcR and PcRXR dEcReased continuously after ESA, and the expression levels of PcEcR and PcRXR were only 0.7% and 1.7% on day 7 after ESA relative to day 0, respectively. In the ovaries, PcEcR was upregulated after ESA, reached the highest level on day 3 after ESA, increased 3.0-fold relative to day 0, and the expression level of PcRXR changed insignificantly after ESA (p > 0.05. The different responses of PcEcR and PcRXR after ESA indicates that different tissues play different roles (and coordinates their functions in molting.

  9. Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.

    Directory of Open Access Journals (Sweden)

    Franziska D Weber

    Full Text Available X-linked adrenoleukodystrophy (X-ALD, the most common peroxisomal disorder, is a clinically heterogeneous disease that can manifest as devastating inflammatory cerebral demyelination (CALD leading to death of affected males. Currently, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT. However, HSCT is only effective when performed at an early stage because the inflammation may progress for eighteen months after HSCT. Thus, alternative treatment options able to immediately halt the progression are urgently needed. X-ALD is caused by mutations in the ABCD1 gene, encoding the peroxisomal membrane protein ABCD1, resulting in impaired very long-chain fatty acid metabolism. The related ABCD2 protein is able to functionally compensate for ABCD1-deficiency both in vitro and in vivo. Recently, we demonstrated that of the cell types derived from CD34+ stem cells, predominantly monocytes but not lymphocytes are metabolically impaired in X-ALD. As ABCD2 is virtually not expressed in these cells, we hypothesize that a pharmacological up-regulation of ABCD2 should compensate metabolically and halt the inflammation in CALD. Retinoids are anti-inflammatory compounds known to act on ABCD2. Here, we investigated the capacity of selected retinoids for ABCD2 induction in human monocytes/macrophages. In THP-1 cells, 13-cis-retinoic acid reached the highest, fivefold, increase in ABCD2 expression. To test the efficacy of retinoids in vivo, we analyzed ABCD2 mRNA levels in blood cells isolated from acne patients receiving 13-cis-retinoic acid therapy. In treated acne patients, ABCD2 mRNA levels were comparable to pre-treatment levels in monocytes and lymphocytes. Nevertheless, when primary monocytes were in vitro differentiated into macrophages and treated with 13-cis-retinoic acid, we observed a fourfold induction of ABCD2. However, the level of ABCD2 induction obtained by retinoids alone is probably not of therapeutic relevance

  10. Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Weber, Franziska D; Weinhofer, Isabelle; Einwich, Angelika; Forss-Petter, Sonja; Muneer, Zahid; Maier, Harald; Weber, Willi H A; Berger, Johannes

    2014-01-01

    X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is a clinically heterogeneous disease that can manifest as devastating inflammatory cerebral demyelination (CALD) leading to death of affected males. Currently, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT is only effective when performed at an early stage because the inflammation may progress for eighteen months after HSCT. Thus, alternative treatment options able to immediately halt the progression are urgently needed. X-ALD is caused by mutations in the ABCD1 gene, encoding the peroxisomal membrane protein ABCD1, resulting in impaired very long-chain fatty acid metabolism. The related ABCD2 protein is able to functionally compensate for ABCD1-deficiency both in vitro and in vivo. Recently, we demonstrated that of the cell types derived from CD34+ stem cells, predominantly monocytes but not lymphocytes are metabolically impaired in X-ALD. As ABCD2 is virtually not expressed in these cells, we hypothesize that a pharmacological up-regulation of ABCD2 should compensate metabolically and halt the inflammation in CALD. Retinoids are anti-inflammatory compounds known to act on ABCD2. Here, we investigated the capacity of selected retinoids for ABCD2 induction in human monocytes/macrophages. In THP-1 cells, 13-cis-retinoic acid reached the highest, fivefold, increase in ABCD2 expression. To test the efficacy of retinoids in vivo, we analyzed ABCD2 mRNA levels in blood cells isolated from acne patients receiving 13-cis-retinoic acid therapy. In treated acne patients, ABCD2 mRNA levels were comparable to pre-treatment levels in monocytes and lymphocytes. Nevertheless, when primary monocytes were in vitro differentiated into macrophages and treated with 13-cis-retinoic acid, we observed a fourfold induction of ABCD2. However, the level of ABCD2 induction obtained by retinoids alone is probably not of therapeutic relevance for X-ALD. In

  11. Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands.

    Science.gov (United States)

    Elmazar, M M A; Nau, H

    2004-11-01

    Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21-28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:2-9; Nau and Elmazar 1999, Handbook of experimental pharmacology, vol 139, Retinoids, Springer-Verlag, pp 465-487). The present study was designed to investigate whether these RAR-RXR heterodimer-mediated defects can be also induced by interactions of natural and synthetic ligands for retinoid receptors. A non-teratogenic dose of the natural RXR agonist phytanic acid (100 mg/kg orally) or its precursor phytol (500 mg/kg orally) was coadministered with a synthetic RARalpha-agonist (Am580; 5 mg/kg orally) to NMRI mice on day 8.25 of gestation (GD8.25). Furthermore, a non-teratogenic dose of the synthetic RXR agonist LGD1069 (20 mg/kg orally) was also coadministered with the natural RAR agonist, all- trans-retinoic acid (atRA, 20 mg/kg orally) or its precursor retinol (ROH, 50 mg/kg orally) to NMRI mice on GD8.25. The teratogenic outcome was scored in day-18 fetuses. The incidence of Am580-induced resorptions, spina bifida aperta, micrognathia, anotia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, short and absent tail, fused ribs and fetal weight retardation were potentiated by coadministration of phytanic acid or its precursor phytol. Am580-induced exencephaly and cleft palate, which were not potentiated by coadministration with the synthetic RXR agonists, were also not potentiated by coadministration with either phytanic acid or its precursor phytol. LGD1069 potentiated atRA- and ROH-induced resorption, exencephaly, spina bifida, aperta, ear anotia and microtia, macroglossia, kidney hypoplasia, undescended testis, atresia ani, tail defects and fetal weight retardation, but not cleft palate. These results suggest that synergistic

  12. Epidemiology and management of cardiac arrest: what registries are revealing.

    Science.gov (United States)

    Gräsner, Jan-Thorsten; Bossaert, Leo

    2013-09-01

    Major European institutions report cardiovascular disease (CVD) as the first cause of death in adults, with cardiac arrest and sudden death due to coronary ischaemia as the primary single cause. Global incidence of CVD is decreasing in most European countries, due to prevention, lifestyle and treatment. Mortality of acute coronary events inside the hospital decreases more rapidly than outside the hospital. To improve the mortality of cardiac arrest outside the hospital, reliable epidemiological and process figures are essential: "we can only manage what we can measure". Europe is a patchwork of 47 countries (total population of 830 million), with a 10-fold difference in incidence of coronary heart disease between North and South, East and West, and a 5-fold difference in number of EMS-treated cardiac arrest (range 17-53/1000,000/year). Epidemiology of cardiac arrest should not be calculated as a European average, but it is appropriate to describe the incidence of cardiac arrest, the resuscitation process, and the outcome in each of the European regions, for benchmarking and quality management. Epidemiological reports of cardiac arrest should specify definitions, nominator (number of cases) and denominator (study population). Recently some regional registries in North America, Japan and Europe fulfilled these conditions. The European Registry of Cardiac Arrest (EuReCa) has the potential to achieve these objectives on a pan-European scale. For operational applications, the Utstein definition of "Cardiac arrest" is used which includes the potential of survival. For application in community health, the WHO definition of "sudden death" is frequently used, describing the mode of death. There is considerable overlap between both definitions. But this explains that no single method can provide all information. Integrating data from multiple sources (local, national, multinational registries and surveys, death certificates, post-mortem reports, community statistics, medical

  13. Post-resuscitation care for survivors of cardiac arrest

    Science.gov (United States)

    Mangla, Ashvarya; Daya, Mohamud R.; Gupta, Saurabh

    2014-01-01

    Cardiac arrest can occur following a myriad of clinical conditions. With advancement of medical science and improvements in Emergency Medical Services systems, the rate of return of spontaneous circulation for patients who suffer an out-of-hospital cardiac arrest (OHCA) continues to increase. Managing these patients is challenging and requires a structured approach including stabilization of cardiopulmonary status, early consideration of neuroprotective strategies, identifying and managing the etiology of arrest and initiating treatment to prevent recurrence. This requires a closely coordinated multidisciplinary team effort. In this article, we will review the initial management of survivors of OHCA, highlighting advances and ongoing controversies. PMID:24568821

  14. Crack propagation and arrest of structural steels and pipelines

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Takehiro

    2008-07-01

    Crack arrest of fast running cracks is an important issue for the safety of steel structures. Crack arrest design can prevent fatal damage of large structures by restricting the influence of the incidents. Therefore crack arrest design is important especially for very large structure, where accidents may cause huge economical and social losses. Propagating shear fracture, long running ductile crack propagation in pipelines and brittle crack propagation in heavy thick shipbuilding steels have been investigated. For the propagating shear fracture issue, a new HLP simulation model, applicable to various backfill conditions, including underwater backfill, was developed. The proposed backfill model can be applied to the prediction of the crack arrest of propagating shear fracture under various backfill conditions. The new HLP simulation was successful in estimating full-scale burst tests with various backfill depths. The new HLP simulation for underwater pipelines indicated that propagating shear cracks are easily arrested in offshore pipelines compared to onshore pipeline. The toughness requirement of the line pipe for preventing propagating shear fracture can be significantly smaller in underwater pipelines compared to onshore pipelines. The margin of the underwater pipeline for propagating shear fracture was clarified by the new model developed in this thesis. For brittle crack arrest, an empirical approach for long crack propagation has been conducted. Several large-scale crack arrest tests were carried out in order to investigate the long crack arrestability of heavy-thick shipbuilding steel plates. All plates and their welded joints used in this study satisfied the Charpy toughness requirement for EH-grade shipbuilding steels and welded joints. A brittle crack ran along a welded joint and penetrated through the test plate under a stress exceeding 200MPa, despite the presence of longitudinal stiffeners across the test weld. A brittle crack in a base plate model

  15. Regulation and binding of pregnane X receptor by nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT).

    Science.gov (United States)

    Johnson, David R; Li, Chia-Wei; Chen, Liuh-Yow; Ghosh, Jagadish C; Chen, J Don

    2006-01-01

    The pregnane X receptor (PXR) is an orphan nuclear receptor predominantly expressed in liver and intestine. PXR coordinates hepatic responses to prevent liver injury induced by environmental toxins. PXR activates cytochrome P450 3A4 gene expression upon binding to rifampicin (Rif) and clotrimazole (CTZ) by recruiting transcriptional coactivators. It remains unclear whether and how PXR regulates gene expression in the absence of ligand. In this study, we analyzed interactions between PXR and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) and determined the role of SMRT in regulating PXR activity. We show that SMRT interacts with PXR in glutathione S-transferase pull-down, yeast two-hybrid, and mammalian two-hybrid assays. The interaction is mediated through the ligand-binding domain of PXR and the SMRTs' nuclear receptor-interacting domain 2. The PXR-SMRT interaction is sensitive to species-specific ligands, and Rif causes an exchange of the corepressor SMRT with the p160 coactivator known as receptor-associated coactivator 3 (RAC3). Deletion of the PXR's activation function 2 helix enhances SMRT binding and abolishes ligand-dependent dissociation of SMRT. Coexpression of PXR with SMRT results in colocalization at discrete nuclear foci. Finally, transient transfection assays show that overexpression of SMRT inhibits PXR's transactivation of the Cyp3A4 promoter, whereas silencing of SMRT enhances the reporter expression. Taken together, our results suggest that the corepressor SMRT may bind to and regulate the transcriptional activity of PXR.

  16. The silencing mediator of retinoid and thyroid hormone receptors (SMRT) regulates adipose tissue accumulation and adipocyte insulin sensitivity in vivo.

    Science.gov (United States)

    Sutanto, Maria M; Ferguson, Kelly K; Sakuma, Hiroya; Ye, Honggang; Brady, Matthew J; Cohen, Ronald N

    2010-06-11

    The silencing mediator of retinoid and thyroid hormone receptors (SMRT) serves as a corepressor for nuclear receptors and other factors. Recent evidence suggests that SMRT is an important regulator of metabolism, but its role in adipocyte function in vivo remains unclear. We generated heterozygous SMRT knock-out (SMRT(+/-)) mice to investigate the function of SMRT in the adipocyte and the regulation of adipocyte insulin sensitivity. We show that SMRT(+/-) mice are normal weight on a regular diet, but develop increased adiposity on a high-fat diet (HFD). The mechanisms underlying this phenotype are complex, but appear to be due to a combination of an increased number of smaller subcutaneous adipocytes as well as decreased leptin expression, resulting in greater caloric intake. In addition, adipogenesis of mouse embryonic fibroblasts (MEFs) derived from these mice was increased. However, adipocyte insulin sensitivity, measured by insulin-induced Akt phosphorylation and insulin-mediated suppression of lipolysis, was enhanced in SMRT(+/-) adipocytes. These finding suggest that SMRT regulates leptin expression and limits the ability of fat mass to expand with increased caloric intake, but that SMRT also negatively regulates adipocyte insulin sensitivity.

  17. The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) Regulates Adipose Tissue Accumulation and Adipocyte Insulin Sensitivity in Vivo*

    Science.gov (United States)

    Sutanto, Maria M.; Ferguson, Kelly K.; Sakuma, Hiroya; Ye, Honggang; Brady, Matthew J.; Cohen, Ronald N.

    2010-01-01

    The silencing mediator of retinoid and thyroid hormone receptors (SMRT) serves as a corepressor for nuclear receptors and other factors. Recent evidence suggests that SMRT is an important regulator of metabolism, but its role in adipocyte function in vivo remains unclear. We generated heterozygous SMRT knock-out (SMRT+/−) mice to investigate the function of SMRT in the adipocyte and the regulation of adipocyte insulin sensitivity. We show that SMRT+/− mice are normal weight on a regular diet, but develop increased adiposity on a high-fat diet (HFD). The mechanisms underlying this phenotype are complex, but appear to be due to a combination of an increased number of smaller subcutaneous adipocytes as well as decreased leptin expression, resulting in greater caloric intake. In addition, adipogenesis of mouse embryonic fibroblasts (MEFs) derived from these mice was increased. However, adipocyte insulin sensitivity, measured by insulin-induced Akt phosphorylation and insulin-mediated suppression of lipolysis, was enhanced in SMRT+/− adipocytes. These finding suggest that SMRT regulates leptin expression and limits the ability of fat mass to expand with increased caloric intake, but that SMRT also negatively regulates adipocyte insulin sensitivity. PMID:20371609

  18. Antagonist-perturbation mechanism for activation function-2 fixed motifs: active conformation and docking mode of retinoid X receptor antagonists

    Science.gov (United States)

    Tsuji, Motonori

    2017-06-01

    HX531, which contains a dibenzodiazepine skeleton, is one of the first retinoid X receptor (RXR) antagonists. Functioning via RXR-PPARγ heterodimer, this compound is receiving a lot of attention as a therapeutic drug candidate for diabetic disease controlling differentiation of adipose tissue. However, the active conformation of HX531 for RXRs is not well established. In the present study, quantum mechanics calculations and molecular mechanical docking simulations were carried out to precisely study the docking mode of HX531 with the human RXRα ligand-binding domain, as well as to provide a new approach to drug design using a structure-based perspective. It was suggested that HX531, which has the R configuration for the bent dibenzodiazepine plane together with the equatorial configuration for the N-methyl group attached to the nitrogen atom in the seven-membered diazepine ring, is a typical activation function-2 (AF-2) fixed motif perturbation type antagonist, which destabilizes the formation of AF-2 fixed motifs. On the other hand, the docking simulations supported the experimental result that LG100754 is an RXR homodimer antagonist and an RXR heterodimer agonist.

  19. Evidence of myeloid differentiation in non-M3 acute myeloid leukemia treated with the retinoid X receptor agonist bexarotene.

    Science.gov (United States)

    Tsai, Donald E; Luger, Selina M; Kemner, Allison; Swider, Cezary; Goradia, Ami; Tomczak, Ewa; DiPatri, Doris; Bagg, Adam; Nowell, Peter; Loren, Alison W; Perl, Alexander; Schuster, Stephen; Thompson, James E; Porter, David; Andreadis, Charlambos; Stadtmauer, Edward A; Goldsteini, Steven; Ghalie, Richard; Carroll, Martin

    2007-01-01

    All-trans-retinoic acid has dramatically changed the treatment paradigm for acute promyelocytic leukemia, however, it has no significant activity in non-M3 acute myeloid leukemia (AML). In vitro, bexarotene, a retinoid X receptor agonist inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts from patients. We hypothesized that there may be similar activity in patients with AML. We report on two patients with relapsed or refractory non-M3 AML treated with bexarotene monotherapy. After initiating treatment, both patients showed leukemic differentiation in their peripheral blood and reduction in bone marrow blasts to less than 5%. One patient had a significant improvement in her platelet count with loss of platelet transfusion needs. Differentiation syndrome occurred in one patient and was successfully treated with steroids and discontinuation of bexarotene. These data suggest that bexarotene has clinical activity in non-M3 AML and may be able to induce myeloid differentiation in vivo.

  20. Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma.

    Science.gov (United States)

    El Hajj, Hiba; Khalil, Bariaa; Ghandour, Botheina; Nasr, Rihab; Shahine, Sharif; Ghantous, Akram; Abdel-Samad, Rana; Sinjab, Ansam; Hasegawa, Hideki; Jabbour, Mark; Hall, William W; Zaatari, Ghazi; Dbaibo, Ghassan; Pisano, Claudio; Bazarbachi, Ali; Darwiche, Nadine

    2014-09-25

    Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1-positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL. © 2014 by The American Society of Hematology.

  1. Chromatin Accessibility Mapping Identifies Mediators of Basal Transcription and Retinoid-Induced Repression of OTX2 in Medulloblastoma

    Science.gov (United States)

    Zhang, Monica; Song, Lingyun; Lee, Bum-Kyu; Iyer, Vishwanath R.; Furey, Terrence S.; Crawford, Gregory E.; Yan, Hai; He, Yiping

    2014-01-01

    Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes. PMID:25198066

  2. Imposex development in Nucella lapillus--evidence for the involvement of retinoid X receptor and androgen signalling pathways in vivo.

    Science.gov (United States)

    Stange, Daniela; Sieratowicz, Agnes; Oehlmann, Jörg

    2012-01-15

    Imposex in female gastropods is a widely documented masculinisation phenomenon in response to tributyltin (TBT) exposure. Although it is generally accepted that imposex is a case of endocrine disruption the underlying mechanisms are controversially discussed with aromatase inhibition and retinoid X receptor (RXR) signalling pathways as two conflicting hypotheses. Hence, we performed injection experiments with the marine dogwhelk Nucella lapillus. As expected TBT induced imposex in all test specimens while the natural RXR ligand 9 cis-retinoic acid did not cause significant effects. Additionally, TBT effects were suppressed if the organotin compound was simultaneously injected with an androgen receptor inhibitor (cyproterone acetate) but not if co-administered with the synthetic RXR antagonist HX531. In contrast, the injection of the RXR agonist HX630 resulted in imposex development in nearly 100% females. Therefore, the results provide evidence for the involvement of the RXR and the androgen signalling pathway. Further investigations are necessary to resolve the biochemical mechanism of imposex development. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Jojoba Oil Soft Colloidal Nanocarrier of a Synthetic Retinoid: Preparation, Characterization and Clinical Efficacy in Psoriatic Patients.

    Science.gov (United States)

    Nasr, Maha; Abdel-Hamid, Sameh; Moftah, Noha H; Fadel, Maha; Alyoussef, Abdullah A

    2017-01-01

    Nanotechnology has provided substantial benefits in drug delivery, especially in the treatment of dermatological diseases. Psoriasis is a chronic inflammatory skin disease in which topical delivery of antipsoriatic agents is considered the first line treatment. To investigate whether the encapsulation of the synthetic retinoid tazarotene in a nanocarrier based on jojoba oil would decrease its irritation potential and clinically improve its therapeutic outcome in psoriatic patients. A microemulsion system based on jojoba wax and labrasol/plurol isostearique was prepared and characterized. The selected formula displayed spherical morphology, particle size of 15.49±2.41 nm, polydispersity index of 0.20 ±0.08, negative charge and low viscosity. The microemulsion provided two folds increase in skin deposition of tazarotene, correlating with higher reduction in psoriatic patients PASI scores after treatment (68% reduction in PASI scores versus 8.96% reduction with the marketed gel). No irritation was encountered in patients using microemulsion, with redness and inflammation reported with the marketed gel-treated patients. Jojoba oil microemulsion proved to be advantageous in reducing the irritancy of tazarotene, enhancing its skin deposition and achieving better therapeutic outcome in psoriatic patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Identification of interacting proteins of retinoid-related orphan nuclear receptor gamma in HepG2 cells

    Directory of Open Access Journals (Sweden)

    Ze-Min Huang1,#, Jun Wu2,#, Zheng-Cai Jia1, Yi Tian1, Jun Tang3, Yan Tang1, Ying Wang2, Yu-Zhang Wu1,* & Bing Ni1,*

    2012-06-01

    Full Text Available The retinoid-related orphan nuclear receptor gamma (RORγplays critical roles in regulation of development, immunity andmetabolism. As transcription factor usually forms a proteincomplex to function, thus capturing and dissecting of theRORγ protein complex will be helpful for exploring themechanisms underlying those functions. After construction ofthe recombinant tandem affinity purification (TAP plasmid,pMSCVpuro RORγ-CTAP(SG, the nuclear localization ofRORγ-CTAP(SG fusion protein was verified. Followingisolation of RORγ protein complex by TAP strategy, sevencandidate interacting proteins were identified. Finally, the heatshock protein 90 (HSP90 and receptor-interacting protein 140(RIP140 were confirmed to interplay with RORγ byco-immunoprecipitation. Interference of HSP90 or/and RIP140genes resulted in dramatically decreased expression ofCYP2C8 gene, the RORγ target gene. Data from this studydemonstrate that HSP90 and RIP140 proteins interact withRORγ protein in a complex format and function asco-activators in the RORγ-mediated regulatory processes ofHepG2 cells.

  5. Development of real-time quantitative polymerase chain reaction assays to track treatment response in retinoid resistant acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Jelena V Jovanovic

    2011-10-01

    Full Text Available Molecular detection of minimal residual disease (MRD has become established to assess remission status and guide therapy in patients with PML-RARA+ acute promyelocytic leukemia (APL. However, there are few data on tracking disease response in patients with rarer retinoid resistant subtypes of APL, characterized by PLZF-RARA and STAT5b-RARA. Despite their relative rarity (<1% of APL we identified 6 cases (PLZF-RARA, n=5; STAT5b-RARA, n=1, established the respective breakpoint junction regions and designed real-time quantitative polymerase chain reaction (RQ-PCR assays to detect leukemic transcripts. The relative level of fusion gene expression in diagnostic samples was comparable to that observed in t(15;17-associated APL, affording assay sensitivities of ~1 in 104-105. Serial samples were available from 2 PLZF-RARA APL patients. One showed persistent PCR positivity, predicting subsequent relapse, and remains in CR2, ~11 years post-autograft. The other, achieved molecular remission (CRm with combination chemotherapy, remaining in CR1 at 6 years. The STAT5b-RARA patient failed to achieve CRm following frontline combination chemotherapy and ultimately proceeded to allogeneic transplant on the basis of a steadily rising fusion transcript level. These data highlight the potential of RQ-PCR detection of MRD to facilitate development of more individualized approaches to the management of rarer molecularly-defined subsets of acute leukemia.

  6. Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin

    Science.gov (United States)

    Li, Mei; Messaddeq, Nadia; Teletin, Marius; Pasquali, Jean-Louis; Metzger, Daniel; Chambon, Pierre

    2005-01-01

    To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXRαβep-/- somatic mutants in which both RXRα and RXRβ are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXRαβ-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXRαβ-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies. PMID:16199515

  7. Breast MRI scan

    Science.gov (United States)

    MRI - breast; Magnetic resonance imaging - breast; Breast cancer - MRI; Breast cancer screening - MRI ... radiologist) see some areas more clearly. During the MRI, the person who operates the machine will watch ...

  8. MRI of the Breast

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Magnetic Resonance Imaging (MRI) - Breast Magnetic resonance imaging (MRI) of the breast ... limitations of MRI of the Breast? What is MRI of the Breast? Magnetic resonance imaging (MRI) is ...

  9. Premenstrual breast changes

    Science.gov (United States)

    Premenstrual tenderness and swelling of the breasts; Breast tenderness - premenstrual; Breast swelling - premenstrual ... Symptoms of premenstrual breast tenderness may range from mild to ... most severe just before each menstrual period Improve during ...

  10. Breast reconstruction - natural tissue

    Science.gov (United States)

    ... muscle flap; TRAM; Latissimus muscle flap with a breast implant; DIEP flap; DIEAP flap; Gluteal free flap; Transverse upper gracilis flap; TUG; Mastectomy - breast reconstruction with natural tissue; Breast cancer - breast reconstruction ...

  11. Breast Cancer: Treatment Options

    Science.gov (United States)

    ... Breast Cancer > Breast Cancer: Treatment Options Request Permissions Breast Cancer: Treatment Options Approved by the Cancer.Net Editorial ... as possible. Learn more about palliative care . Recurrent breast cancer If the cancer does return after treatment for ...

  12. Breast pain (image)

    Science.gov (United States)

    ... breast pain is from hormonal fluctuations from menstruation, pregnancy, puberty, menopause, and breastfeeding. Breast pain can also be associated with fibrocystic breast disease, but it is a very unusual symptom of breast cancer.

  13. Drinking and driving and perceptions of arrest risk among California drivers: Relationships with DUI arrests in their city of residence.

    Science.gov (United States)

    MacLeod, Kara E; Karriker-Jaffe, Katherine J; Satariano, William A; Kelley-Baker, Tara; Lacey, John H; Ragland, David R

    2017-08-18

    Addressing drinking and driving remains a challenge in the United States. The present study aims to provide feedback on driving under the influence (DUI) in California by assessing whether drinking and driving behavior is associated with the DUI arrest rates in the city in which the driver lives; whether this is due to perceptions that one can get arrested for this behavior; and whether this differed by those drivers who would be most affected by deterrence efforts (those most likely to drink outside the home). This study consisted of a 2012 roadside survey of 1,147 weekend nighttime drivers in California. City DUI arrest rates for 2009-2011 were used as an indicator of local enforcement efforts. Population average logistic modeling was conducted modeling the odds of perceived high arrest likelihood for DUI and drinking and driving behavior within the past year. As the DUI arrest rates for the city in which the driver lives increased, perceived high risk of DUI arrest increased. There was no significant relationship between either city DUI arrest rates or perceived high risk of DUI arrest with self-reported drinking and driving behavior in the full sample. Among a much smaller sample of those most likely to drink outside the home, self-reported drinking and driving behavior was negatively associated with DUI arrests rates in their city of residence but this was not mediated by perceptions. The results of the present study suggest that perceptions are correlated with one aspect of DUI efforts in one's community. Those who were more likely to drink outside the home could be behaviorally influenced by these efforts.

  14. Efficacy of the dietary histone deacetylase inhibitor butyrate alone or in combination with vitamin A against proliferation of MCF-7 human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Andrade, F.O. [Laboratório de Dieta, Nutrição e Câncer, Departamento de Alimentos e Nutrição Experimental, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP (Brazil); Nagamine, M.K. [Laboratório de Oncologia Experimental, Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); De Conti, A. [Laboratório de Dieta, Nutrição e Câncer, Departamento de Alimentos e Nutrição Experimental, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP (Brazil); Chaible, L.M. [Laboratório de Oncologia Experimental, Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Fontelles, C.C. [Laboratório de Dieta, Nutrição e Câncer, Departamento de Alimentos e Nutrição Experimental, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP (Brazil); Jordão Junior, A.A.; Vannucchi, H. [Divisão de Nutrição, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Dagli, M.L.Z. [Laboratório de Oncologia Experimental, Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Bassoli, B.K.; Moreno, F.S.; Ong, T.P. [Laboratório de Dieta, Nutrição e Câncer, Departamento de Alimentos e Nutrição Experimental, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-06-22

    The combined treatment with histone deacetylase inhibitors (HDACi) and retinoids has been suggested as a potential epigenetic strategy for the control of cancer. In the present study, we investigated the effects of treatment with butyrate, a dietary HDACi, combined with vitamin A on MCF-7 human breast cancer cells. Cell proliferation was evaluated by the crystal violet staining method. MCF-7 cells were plated at 5 x 10{sup 4} cells/mL and treated with butyrate (1 mM) alone or combined with vitamin A (10 µM) for 24 to 120 h. Cell proliferation inhibition was 34, 10 and 46% following treatment with butyrate, vitamin A and their combination, respectively, suggesting that vitamin A potentiated the inhibitory activities of butyrate. Furthermore, exposure to this short-chain fatty acid increased the level of histone H3K9 acetylation by 9.5-fold (Western blot), but not of H4K16, and increased the expression levels of p21{sup WAF1} by 2.7-fold (Western blot) and of RARβ by 2.0-fold (quantitative real-time PCR). Our data show that RARβ may represent a molecular target for butyrate in breast cancer cells. Due to its effectiveness as a dietary HDACi, butyrate should be considered for use in combinatorial strategies with more active retinoids, especially in breast cancers in which RARβ is epigenetically altered.

  15. Cardiac Arrest in Pediatric Patients Receiving Azithromycin.

    Science.gov (United States)

    Valdés, Santiago O; Kim, Jeffrey J; Niu, Mary C; de la Uz, Caridad M; Miyake, Christina Y; Moffett, Brady S

    2017-03-01

    To compare outcomes of pediatric patients treated with azithromycin compared with penicillin or cephalosporin. We hypothesized that azithromycin use would not be associated with increased cardiac mortality in the pediatric population. Retrospective cohort study from the Pediatric Health Information System database between 2008 and 2012. Patients Azithromycin was used in 5039 (6.1%); penicillin or cephalosporin was used in 77 943 (93.9%). Overall prevalence of antibiotic-associated CPR was 0.14%. Patients receiving a macrolide antibiotic had a lower prevalence of CPR compared with patients receiving a penicillin or cephalosporin (0.04% vs 0.14%, P = .04), and there was no difference in mortality. Multivariable analysis did not find an association between macrolide use and CPR. In contrast to recent adult studies, among children hospitalized for community-acquired pneumonia, azithromycin use was not associated with a greater prevalence of cardiac arrest compared with penicillin or cephalosporin use. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Arresting dissolution by interfacial rheology design

    Science.gov (United States)

    Beltramo, Peter J.; Gupta, Manish; Alicke, Alexandra; Liascukiene, Irma; Gunes, Deniz Z.; Baroud, Charles N.; Vermant, Jan

    2017-09-01

    A strategy to halt dissolution of particle-coated air bubbles in water based on interfacial rheology design is presented. Whereas previously a dense monolayer was believed to be required for such an “armored bubble” to resist dissolution, in fact engineering a 2D yield stress interface suffices to achieve such performance at submonolayer particle coverages. We use a suite of interfacial rheology techniques to characterize spherical and ellipsoidal particles at an air-water interface as a function of surface coverage. Bubbles with varying particle coverages are made and their resistance to dissolution evaluated using a microfluidic technique. Whereas a bare bubble only has a single pressure at which a given radius is stable, we find a range of pressures over which bubble dissolution is arrested for armored bubbles. The link between interfacial rheology and macroscopic dissolution of ˜ 100 μm bubbles coated with ˜ 1 μm particles is presented and discussed. The generic design rationale is confirmed by using nonspherical particles, which develop significant yield stress at even lower surface coverages. Hence, it can be applied to successfully inhibit Ostwald ripening in a multitude of foam and emulsion applications.

  17. Polydimethylsiloxane (PDMS) modulates CD38 expression, absorbs retinoic acid and may perturb retinoid signalling.

    Science.gov (United States)

    Futrega, Kathryn; Yu, Jianshi; Jones, Jace W; Kane, Maureen A; Lott, William B; Atkinson, Kerry; Doran, Michael R

    2016-04-21

    Polydimethylsiloxane (PDMS) is the most commonly used material in the manufacture of customized cell culture devices. While there is concern that uncured PDMS oligomers may leach into culture medium and/or hydrophobic molecules may be absorbed into PDMS structures, there is no consensus on how or if PDMS influences cell behaviour. We observed that human umbilical cord blood (CB)-derived CD34(+) cells expanded in standard culture medium on PDMS exhibit reduced CD38 surface expression, relative to cells cultured on tissue culture polystyrene (TCP). All-trans retinoic acid (ATRA) induces CD38 expression, and we reasoned that this hydrophobic molecule might be absorbed by PDMS. Through a series of experiments we demonstrated that ATRA-mediated CD38 expression was attenuated when cultures were maintained on PDMS. Medium pre-incubated on PDMS for extended durations resulted in a time-dependant reduction of ATRA in the medium and increasingly attenuated CD38 expression. This indicated a time-dependent absorption of ATRA into the PDMS. To better understand how PDMS might generally influence cell behaviour, Ingenuity Pathway Analysis (IPA) was used to identify potential upstream regulators. This analysis was performed for differentially expressed genes in primary cells including CD34(+) haematopoietic progenitor cells, mesenchymal stromal cells (MSC), and keratinocytes, and cell lines including prostate cancer epithelial cells (LNCaP), breast cancer epithelial cells (MCF-7), and myeloid leukaemia cells (KG1a). IPA predicted that the most likely common upstream regulator of perturbed pathways was ATRA. We demonstrate here that ATRA is absorbed by PDMS in a time-dependent manner and results in the concomitant reduced expression of CD38 on the cell surface of CB-derived CD34(+) cells.

  18. Epidemiology of Breast Cancer

    OpenAIRE

    南, 優子; ミナミ, ユウコ; MINAMI, Yuko

    2007-01-01

    During recent decades, breast cancer incidence has been increasing in Japan. Epidemiological studies have clarified the trend in breast cancer incidence and identified risk factors for breast cancer. Established risk factors for breast cancer include early age at menarche, late age at first birth, low parity, postmenopausal obesity, family history of breast cancer, and history of benign breast disease. Breast-feeding and physical activity may also be associated with breast cancer risk. Detail...

  19. Cardiac Arrest? Someday, Drones May Come to Your Rescue

    Science.gov (United States)

    ... gov/news/fullstory_166543.html Cardiac Arrest? Someday, Drones May Come to Your Rescue Like something from ... 13, 2017 TUESDAY, June 13, 2017 (HealthDay News) -- Drones have been proposed for some pretty mundane uses, ...

  20. Arrest of cytoplasmic streaming induces algal proliferation in green paramecia.

    Directory of Open Access Journals (Sweden)

    Toshiyuki Takahashi

    Full Text Available A green ciliate Paramecium bursaria, bearing several hundreds of endosymbiotic algae, demonstrates rotational microtubule-based cytoplasmic streaming, in which cytoplasmic granules and endosymbiotic algae flow in a constant direction. However, its physiological significance is still unknown. We investigated physiological roles of cytoplasmic streaming in P. bursaria through host cell cycle using video-microscopy. Here, we found that cytoplasmic streaming was arrested in dividing green paramecia and the endosymbiotic algae proliferated only during the arrest of cytoplasmic streaming. Interestingly, arrest of cytoplasmic streaming with pressure or a microtubule drug also induced proliferation of endosymbiotic algae independently of host cell cycle. Thus, cytoplasmic streaming may control the algal proliferation in P. bursaria. Furthermore, confocal microscopic observation revealed that a division septum was formed in the constricted area of a dividing paramecium, producing arrest of cytoplasmic streaming. This is a first report to suggest that cytoplasmic streaming controls proliferation of eukaryotic cells.

  1. Fewer Heart Failure Patients Dying of Cardiac Arrest

    Science.gov (United States)

    ... https://medlineplus.gov/news/fullstory_167058.html Fewer Heart Failure Patients Dying of Cardiac Arrest Researchers chock it ... 6, 2017 THURSDAY, July 6, 2017 (HealthDay News) -- Heart failure patients are much less likely now to die ...

  2. The outcome of anaesthesia related cardiac arrest in a

    Directory of Open Access Journals (Sweden)

    O.O. Adekola

    2016-07-01

    Conclusion: Anaesthesia related cardiac arrest and mortality were linked to cardiovascular depression from halothane overdose in our institution. The burden can be reduced by improving on establishing standard monitoring in the perioperative period, and a team approach to patients care.

  3. Liver X receptor as a drug target for the treatment of breast cancer.

    Science.gov (United States)

    Wu, Ying; Yu, Dan-Dan; Yan, Da-Li; Hu, Yong; Chen, Dan; Liu, Yun; Zhang, He-da; Yu, Shao-Rong; Cao, Hai-Xia; Feng, Ji-Feng

    2016-06-01

    Liver X receptor (LXR) has been exploited widely as a drug target in breast cancer treatment, and various mechanisms underlying the effects of LXR in this area are well studied. The activated LXR plays important roles in estrogen receptor α (ERα) breast cancer cells, such as reducing cell proliferation and arresting cell cycle progression. Different LXR ligands have diverse effects on the development of breast cancer, such as the inhibitory effect of oxysterol, which can return cells to normocholesterol conditions and target other metabolic genes. Moreover, 27-hydroxycholesterol, a locally produced cholesterol metabolite, reportedly promotes the proliferation of ERα breast cancer cells in vitro and facilitates tumor metastasis with other LXR ligands. Moreover, the expression of LXR also exerts potential effects on immune surveillance, tumor immunity, and tumor microenvironment. These advances in breast cancer research indicate that LXR may be a new therapeutic target to treat the refractory or drug-resistant subtypes of breast cancer.

  4. Ectopic breasts: familial functional axillary breasts and breast cancer arising in an axillary breast.

    Science.gov (United States)

    Osswald, Sandra S; Osswald, Michael B; Elston, Dirk M

    2011-06-01

    Supernumerary breasts and nipples are not uncommon and have familial and syndrome associations. Although usually of only cosmetic concern, hormonal changes and inflammatory or neoplastic conditions that affect primary breast tissue also may occur in areas of ectopic breast tissue. We describe cases of familial functional axillary breasts and primary carcinoma of the breast arising in ectopic axillary breast tissue.

  5. Breast Rash

    Science.gov (United States)

    ... rashes/rash-in-adults. Accessed Dec. 29, 2016. Papadakis MA, et al., eds. Breast disorders. In: Current ... http://www.accessmedicine.com. Accessed Dec. 28, 2016. Papadakis MA, et al., eds. Dermatologic disorders. In: Current ...

  6. Breast Cancer

    Science.gov (United States)

    ... a reduced risk of breast cancer. The Mediterranean diet focuses mostly on plant-based foods, such as fruits and vegetables, whole grains, legumes, and nuts. People who follow the Mediterranean diet choose healthy fats, such as olive oil, over ...

  7. Breast reduction

    Science.gov (United States)

    ... difficulty finding clothes that fit, and low self-confidence. Chronic rashes under your breasts. Unwelcome attention that is making you feel awkward. Inability to participate in sports. Some women may benefit from non-surgical treatments, such as: ...

  8. Dense Breasts

    Science.gov (United States)

    ... also appear white on mammography, they can be hidden by or within dense breast tissue. Other imaging ... understanding of the possible charges you will incur. Web page review process: This Web page is reviewed ...

  9. Breast Cancer

    Science.gov (United States)

    ... disease. It’s estimated that about 10% of breast cancer cases are hereditary (run in the family). In many of these cases, you inherited a gene from your parents that has mutated (changed from ...

  10. Al-Qaeda arrest casts shadow over the LHC

    CERN Document Server

    Dacey, James

    2010-01-01

    "Cern remains on course for the imminent switch-on of the Large Hadron Collider (LHC) despite the media frenzy following the recent arrest of a physicist who had been working at the facility. The researcher in question is a 32-year-old man of Algerian descent who is expected to face trail in France - the country in which he was arrested" (0.5 page)

  11. Impact of donor cardiac arrest on heart transplantation.

    Science.gov (United States)

    Southerland, Kevin W; Castleberry, Anthony W; Williams, Judson B; Daneshmand, Mani A; Ali, Ayyaz A; Milano, Carmelo A

    2013-08-01

    Cardiac transplantation is an effective therapy for patients with end-stage heart failure, but it is still hindered by the lack of donor organs. A history of donor cardiac arrest raises trepidation regarding the possibility of poor post-transplant outcomes. The impact of donor cardiac arrest following successful cardiopulmonary resuscitation on heart transplant outcomes is unknown. Therefore, we sought to evaluate the impact of donor cardiac arrest on orthotropic heart transplantation using the United Network for Organ Sharing database. We performed a secondary longitudinal analysis of all cardiac transplants performed between April 1994 and December 2011 through the United Network for Organ Sharing registry. Multiorgan transplants, repeat transplants, and pediatric recipients were excluded. Survival analyses were performed using Kaplan-Meier methods as well as multivariate adjusted logistic regression and Cox proportional hazard models. A total of 19,980 patients were analyzed. In 856 cases, the donors had histories of cardiac arrest, and in the remaining 19,124 cases, there was no history of donor cardiac arrest. The unadjusted 1-, 5-, and 10-year actuarial survival rates between the arrest and the nonarrest groups were not significantly different. Multivariate logistic regression demonstrated no difference in survival in the donor arrest group at 30 days, 1 year, or 3 years. Furthermore, the adjusted Cox proportional hazard model for cumulative survival also showed no survival difference between the 2 groups. If standard recipient and donor transplantation criteria are met, a history of donor cardiac arrest should not prohibit the potential consideration of an organ for transplantation. Copyright © 2013 Mosby, Inc. All rights reserved.

  12. Heritability of Risk for Sudden Cardiac Arrest in ESRD.

    Science.gov (United States)

    Chan, Kevin E; Newton-Cheh, Christopher; Gusella, James F; Maddux, Franklin W

    2015-11-01

    Patients on dialysis are 20 times more likely to have a cardiac arrest compared with the general population. We considered whether inherited factors associate with cardiac arrest among patients on dialysis. From a sample of 647,457 patients on chronic dialysis, we identified 5117 pairs of patients who came from the same family. These patients were each matched to a control subject from the same population. McNemar's tests were used to compare the risk of cardiac arrest between the familial related and unrelated pairs. Genetically related family members who did not cohabitate had an odds ratio of 1.88 (95% confidence interval [95% CI], 1.25 to 2.84) for cardiac arrest compared with their phenotypically matched unrelated controls. Genetically related family members who lived together in the same environment had an odds ratio of 1.66 (95% CI, 1.20 to 2.28). Spouses, who are genetically unrelated but live together in the same environment, had an odds ratio of 0.95 (95% CI, 0.60 to 1.59) for cardiac arrest. The risk of cardiac arrest in patients on dialysis may be attributable to inherited factors. Additional studies are needed to identify such candidate genes that modify cardiovascular risk in ESRD. Copyright © 2015 by the American Society of Nephrology.

  13. Arrested coalescence of viscoelastic droplets with internal microstructure.

    Science.gov (United States)

    Pawar, Amar B; Caggioni, Marco; Hartel, Richard W; Spicer, Patrick T

    2012-01-01

    There are many new approaches to designing complex anisotropic colloids, often using droplets as templates. However, droplets themselves can be designed to form anisotropic shapes without any external templates. One approach is to arrest binary droplet coalescence at an intermediate stage before a spherical shape is formed. Further shape relaxation of such anisotropic, arrested structures is retarded by droplet elasticity, either interfacial or internal. In this article we study coalescence of structured droplets, containing a network of anisotropic colloids, whose internal elasticity provides a resistance to full shape relaxation and interfacial energy minimization during coalescence. Precise tuning of droplet elasticity arrests coalescence at different stages and leads to various anisotropic shapes, ranging from doublets to ellipsoids. A simple model balancing interfacial and elastic energy is used to explain experimentally observed coalescence arrest in viscoelastic droplets. During coalescence of structured droplets the interfacial energy is continuously reduced while the elastic energy is increased by compression of the internal structure and, when the two processes balance one another, coalescence is arrested. Experimentally we observe that if either interfacial energy or elasticity dominates, total coalescence or total stability of droplets results. The stabilization mechanism is directly analogous to that in a Pickering emulsion, though here the resistance to coalescence is provided via an internal volume-based, rather than surface, structure. This study provides guidelines for designing anisotropic droplets by arrested coalescence but also explains some observations of "partial" coalescence observed in commercial foods like ice cream and whipped cream.

  14. Cardiac arrest due to lymphocytic colitis: a case report

    Directory of Open Access Journals (Sweden)

    Groth Kristian A

    2012-03-01

    Full Text Available Abstract Introduction We present a case of cardiac arrest due to hypokalemia caused by lymphocytic colitis. Case presentation A 69-year-old Caucasian man presented four months prior to a cardiac arrest with watery diarrhea and was diagnosed with lymphocytic colitis. Our patient experienced a witnessed cardiac arrest at his general practitioner's surgery. Two physicians and the emergency medical services resuscitated our patient for one hour and four minutes before arriving at our university hospital. Our patient was defibrillated 16 times due to the recurrence of ventricular tachyarrhythmias. An arterial blood sample revealed a potassium level of 2.0 mmol/L (reference range: 3.5 to 4.6 mmol/L and pH 6.86 (reference range: pH 7.37 to 7.45. As the potassium level was corrected, the propensity for ventricular tachyarrhythmias ceased. Our patient recovered from his cardiac arrest without any neurological deficit. Further tests and examinations revealed no other reason for the cardiac arrest. Conclusion Diarrhea can cause life-threatening situations due to the excretion of potassium, ultimately causing cardiac arrest due to hypokalemia. Physicians treating patients with severe diarrhea should consider monitoring their electrolyte levels.

  15. The neighborhood context of racial and ethnic disparities in arrest.

    Science.gov (United States)

    Kirk, David S

    2008-02-01

    This study assesses the role of social context in explaining racial and ethnic disparities in arrest, with afocus on how distinct neighborhood contexts in which different racial and ethnic groups reside explain variations in criminal outcomes. To do so, I utilize a multilevel, longitudinal research design, combining individual-level data with contextual data from the Project on Human Development in Chicago Neighborhoods (PHDCN). Findings reveal that black youths face multiple layers of disadvantage relative to other racial and ethnic groups, and these layers work to create differences in arrest. At the family level, results show that disadvantages in the form of unstable family structures explain much of the disparities in arrest across race and ethnicity. At the neighborhood level, black youths tend to reside in areas with both significantly higher levels of concentrated poverty than other youths as well as lower levels of collective efficacy than white youths. Variations in neighborhood tolerance of deviance across groups explain little of the arrest disparities, yet tolerance of deviance does influence the frequency with which a crime ultimately ends in an arrest. Even after accounting for relevant demographic, family, and neighborhood-level predictors, substantial residual arrest differences remain between black youths and youths of other racial and ethnic groups.

  16. Respiratory Arrest in an Obese Pregnant Woman with Hyperemesis Gravidarum

    Directory of Open Access Journals (Sweden)

    Ayumi Iwashita

    2015-01-01

    Full Text Available A pregnant, non-Japanese-speaking Peruvian, and, thus, with communication difficulty, suffered hyperemesis gravidarum and had respiratory arrest, requiring cardiopulmonary resuscitation. The obese pregnant woman (prepregnancy weight: 107 kg had vomited and lost 15 kg in bodyweight over appropriately 2 weeks prior to the arrest but had not complained due to communication difficulty, which, together with her obesity, prevented a Japanese obstetrician from noticing her severe condition. 1,000 mL of low potassium fluid plus thiamine was administered. She became unable to stand, suggesting lower-extremity-proximal-muscle weakness, and then respiratory arrest occurred. Hypopotassemia (2.3 mEq/L, pulseless electrical activity, and muscle weakness suggested the presence of severe potassium deficiency, which may have caused respiratory muscle paralysis, leading to the respiratory arrest. Hypercapnea was severer than expected for compensatory hypoventilation, indicating the presence of concomitant severe hypoventilation, which may also have contributed to respiratory arrest. She recovered with electrolyte and volume replacement. Respiratory arrest can occur with hyperemesis gravidarum, and obesity and communication difficulties can prevent the early detection of severe conditions.

  17. Associates of Cardiopulmonary Arrest in the Perihemodialytic Period

    Directory of Open Access Journals (Sweden)

    Jennifer E. Flythe

    2014-01-01

    Full Text Available Cardiopulmonary arrest during and proximate to hemodialysis is rare but highly fatal. Studies have examined peridialytic sudden cardiac event risk factors, but no study has considered associates of cardiopulmonary arrests (fatal and nonfatal events including cardiac and respiratory causes. This study was designed to elucidate patient and procedural factors associated with peridialytic cardiopulmonary arrest. Data for this case-control study were taken from the hemodialysis population at Fresenius Medical Care, North America. 924 in-center cardiopulmonary events (cases and 75,538 controls were identified. Cases and controls were 1 : 5 matched on age, sex, race, and diabetes. Predictors of cardiopulmonary arrest were considered for logistic model inclusion. Missed treatments due to hospitalization, lower body mass, coronary artery disease, heart failure, lower albumin and hemoglobin, lower dialysate potassium, higher serum calcium, greater erythropoietin stimulating agent dose, and normalized protein catabolic rate (J-shaped were associated with peridialytic cardiopulmonary arrest. Of these, lower albumin, hemoglobin, and body mass index; higher erythropoietin stimulating agent dose; and greater missed sessions had the strongest associations with outcome. Patient health markers and procedural factors are associated with peridialytic cardiopulmonary arrest. In addition to optimizing nutritional status, it may be prudent to limit exposure to low dialysate potassium (<2 K bath and to use the lowest effective erythropoietin stimulating agent dose.

  18. Activation of RARα induces autophagy in SKBR3 breast cancer cells and depletion of key autophagy genes enhances ATRA toxicity.

    Science.gov (United States)

    Brigger, D; Schläfli, A M; Garattini, E; Tschan, M P

    2015-08-27

    All-trans retinoic acid (ATRA), a pan-retinoic acid receptor (RAR) agonist, is, along with other retinoids, a promising therapeutic agent for the treatment of a variety of solid tumors. On the one hand, preclinical studies have shown promising anticancer effects of ATRA in breast cancer; on the other hand, resistances occurred. Autophagy is a cellular recycling process that allows the degradation of bulk cellular contents. Tumor cells may take advantage of autophagy to cope with stress caused by anticancer drugs. We therefore wondered if autophagy is activated by ATRA in mammary tumor cells and if modulation of autophagy might be a potential novel treatment strategy. Indeed, ATRA induces autophagic flux in ATRA-sensitive but not in ATRA-resistant human breast cancer cells. Moreover, using different RAR agonists as well as RARα-knockdown breast cancer cells, we demonstrate that autophagy is dependent on RARα activation. Interestingly, inhibition of autophagy in breast cancer cells by either genetic or pharmacological approaches resulted in significantly increased apoptosis under ATRA treatment and attenuated epithelial differentiation. In summary, our findings demonstrate that ATRA-induced autophagy is mediated by RARα in breast cancer cells. Furthermore, inhibition of autophagy results in enhanced apoptosis. This points to a potential novel treatment strategy for a selected group of breast cancer patients where ATRA and autophagy inhibitors are applied simultaneously.

  19. Acute kidney injury after cardiac arrest.

    Science.gov (United States)

    Tujjar, Omar; Mineo, Giulia; Dell'Anna, Antonio; Poyatos-Robles, Belen; Donadello, Katia; Scolletta, Sabino; Vincent, Jean-Louis; Taccone, Fabio Silvio

    2015-04-17

    The aim of this study was to evaluate the incidence and determinants of AKI in a large cohort of cardiac arrest patients. We reviewed all patients admitted, for at least 48 hours, to our Dept. of Intensive Care after CA between January 2008 and October 2012. AKI was defined as oligo-anuria (daily urine output <0.5 ml/kg/h) and/or an increase in serum creatinine (≥0.3 mg/dl from admission value within 48 hours or a 1.5 time from baseline level). Demographics, comorbidities, CA details, and ICU interventions were recorded. Neurological outcome was assessed at 3 months using the Cerebral Performance Category scale (CPC 1-2 = favorable outcome; 3-5 = poor outcome). A total of 199 patients were included, 85 (43%) of whom developed AKI during the ICU stay. Independent predictors of AKI development were older age, chronic renal disease, higher dose of epinephrine, in-hospital CA, presence of shock during the ICU stay, a low creatinine clearance (CrCl) on admission and a high cumulative fluid balance at 48 hours. Patients with AKI had higher hospital mortality (55/85 vs. 57/114, p = 0.04), but AKI was not an independent predictor of poor 3-month neurological outcome. AKI occurred in more than 40% of patients after CA. These patients had more severe hemodynamic impairment and needed more aggressive ICU therapy; however the development of AKI did not influence neurological recovery.

  20. Characterizing cardiopulmonary arrest during interventional radiology procedures.

    Science.gov (United States)

    Rueb, George Richard; Brady, William J; Gilliland, Charles A; Patrie, James T; Saad, Wael E; Sabri, Saher S; Park, Auh W; Stone, James R; Angle, John F

    2013-12-01

    Careful case selection and preparation can prevent most cardiopulmonary arrest (CPA) in the interventional radiology (IR) suite. A series of CPAs was analyzed to provide insight into risk factors for these events. A single-institution CPA database was used to identify all code team activations from January 1, 2005, to May 30, 2011, in the IR department. Medical records were searched for medical history, American Society of Anesthesiologists (ASA) classification, moderate sedation, and outcomes. Procedural data and procedure classification was acquired from the HI-IQ database. There were 36,489 procedures and 23 CPAs during the study period. Of the 23 patients with CPAs, 12 (52%) were male and 11 (48%) female, and average age was 57 years ± 19 (standard deviation). Risk factors included a 56% incidence of diabetes mellitus, 48% incidence of hypertension, and 78% incidence of renal failure. Of the patients with kidney disease, 56% were chronically dialysis-dependent, and an additional 9% were undergoing central venous catheter placement for new hemodialysis. Seventy-eight percent had ASA status of III or greater, and 57% underwent moderate sedation during the procedure. Relative risk of a CPA during dialysis shunt interventions versus arterial interventions was 3.6 (95% confidence interval, 1.0-11.3; P = .045). Eight of 23 (35%) died: one (12%) during resuscitation and seven (88%) after resuscitation (P = .070). The most common comorbidity of patients with CPA in IR was kidney disease, and the most patients who had CPA underwent dialysis access-related procedures. Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.