WorldWideScience

Sample records for aulacomya atra atra

  1. Biomarkers of environmental stress in gills of ribbed mussel Aulacomya atra atra (Nuevo Gulf, Northern Patagonia).

    Science.gov (United States)

    Giarratano, Erica; Gil, Mónica N; Malanga, Gabriela

    2014-09-01

    In this study, we assessed in gills of native ribbed mussels Aulacomya atra atra from three sites within Nuevo Gulf (Northern Patagonia) several biomarkers such as reactive oxygen species (ROS), lipid radicals (LR), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and metallothionein (MT). Furthermore, concentrations of main trace metals (Fe, Al, Zn, Cu, Cd and Pb) were quantified in mussel tissue. Results showed significant induction of SOD, GST, MT and MDA, as well as, higher concentration of Fe, Al and Cd in winter than in summer. The high MDA content measured in mussels from Folías Wreck seemed to be caused by the very high levels of Fe that would come from the corrosion of the vessel. Mussels from the control site Punta Cuevas presented the lowest levels of Cd and the highest of Al in winter. Despite positive correlations were found between Al and GST and MT, no spatial differentiation was detected in those biomarkers. On the other hand, MT was only related to Al been most likely influenced by environmental variables than by the trace metals. It has to be highlighted that the relationship detected among water temperature, nutrients and antioxidant responses in gills is probably related to the fact that this tissue is in direct contact with water and it is sensitive to its fluctuations. Taking into account that mussel gill is a tissue actively proliferating and the first target of contaminants present in water, so that changes in its antioxidant system can provide an earlier warning signal than in other tissues. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Assessment of antioxidant responses and trace metal accumulation by digestive gland of ribbed mussel Aulacomya atra atra from Northern Patagonia.

    Science.gov (United States)

    Giarratano, Erica; Gil, Mónica N; Malanga, Gabriela

    2013-06-01

    Seasonal and spatial variability of trace metal concentrations and of a battery of antioxidant parameters were evaluated in digestive gland of the ribbed mussel Aulacomya atra atra. Fe, Al and Cu accumulated in tissue exhibited maximum values in winter, coinciding partially with the highest labile concentrations of Fe and Cu in sediment. Metals, as other pollutants, are known to influence the oxidative status of organisms and antioxidant enzymes have been often proposed as biomarkers of contaminant effects. Seasonal variations of trace metals did not appear to influence those of biochemical parameters, which generally showed an opposite trend with higher enzymatic activities in summer when trace metal concentrations were lower. Organisms from Punta Cuevas (control site) showed higher induction of reactive oxygen species production than those from both considered impacted sites, suggesting the possibility of some biochemical adaptation in organisms or a higher modulation of environmental and physiological factors on antioxidant responses than levels of trace metals. This study, which is the first in the area in this matter, showed that seasonal variations of potential biomarkers should be incorporated into interpretation of long-term biomonitoring studies in this marine coastal ecosystem. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Naja atra snakebite in Taiwan.

    Science.gov (United States)

    Mao, Yan-Chiao; Liu, Po-Yu; Chiang, Liao-Chun; Lai, Chih-Sheng; Lai, Kuo-Lung; Ho, Cheng-Hsuan; Wang, Te-Huo; Yang, Chen-Chang

    2017-08-23

    Naja atra snakebite is uncommon in Taiwan and causes distinct effects on its victims. Although the Taiwan government produces its own specific antivenom, little information on the management of N. atra snakebite is available. We retrospectively evaluated 183 patients admitted to two medical centers. Of these, 45 were identified as definite cases of N. atra snakebite, 86 as suspected cases, and 52 as clinical cases. Demographic data, symptomatology, and management were compared between these case groups. Symptomatology and management were similar in the three groups. Among the 183 patients, 10 (5.5%) were asymptomatic and nine (4.9%) had transient and partial ptosis or body weakness. The principal effects were local tissue swelling and pain in 173 patients (94.5%), followed by clinically suspected wound infection in 148 (80.9%), skin necrosis in 120 (65.6%), necrotizing soft tissue infection in 77 (42.1%), fever in 59 (32.2%), and gastrointestinal effects in 53 (29%). The median total dose of specific antivenom needed to treat N. atra envenoming was 10 vials. In the envenomed patients, debridement was required in 74 patients (42.8%), fasciotomy/fasciectomy in 46 (26.6%), and finger or toe amputation in seven (4%). The first operation was performed at a median of 3.5 days after the bite. Based on these typical manifestations, clinical diagnosis of N. atra snakebites may be feasible and practical. In contrast to other snakes of Elapidae family, N. atra bite did not cause serious neurological effects. Early surgical consultation should be obtained because half of the patients underwent surgery due to infectious complications. Acute compartment syndrome was the surgical indication in rare cases; however, overestimation of the incidence may have occurred. This syndrome should be confirmed by serial intracompartmental pressure monitoring instead of only physical examination, and a sufficient dose of antivenom should be given prior to surgical decompression.

  4. Pigmentary system of the adult alpine salamander Salamandra atra atra (Laur., 1768).

    Science.gov (United States)

    Trevisan, P; Pederzoli, A; Barozzi, G

    1991-10-01

    The pigmentary system of the skin from adult specimens of the black alpine salamander Salamandra atra atra was investigated by light microscope, electron microscope, and biochemical studies. Results were compared with those obtained in previous study of the subspecies Salamandra atra aurorae. Unlike Salamandra atra aurorae, which presents epidermal xanthophores and iridophores, Salamandra atra atra is completely melanized, presenting only epidermal and dermal melanophores. The melanosomes in both the epidermis and the dermis appear to derive from a multivesicular premelanosome similar to that in the goldfish, and the epidermal melanosomes are smaller than those in the dermis. Premelanosomes with an internal lamellar matrix were not observed. The biochemical results have shown that in the ethanol extracts obtained from the skin in toto and from the melanosomes, pteridines and flavins are always present and are the same as those extracted from the black skin areas of Salamandra atra aurorae.

  5. [Effect of curcumin combined with ATRA on differentiation of ATRA-resistant acute promyelocytic leukemia cells].

    Science.gov (United States)

    Chen, Tang-Yong; Xu, Fen; Kong, Yun-Yuan; Wen, Fang; Xie, Fu-Yuan; Wan, La-Gen; Zhang, Zhang-Lin

    2013-08-01

    In order to investigate the effect of curcumin combined with all-trans retinoid acid (ATRA) on differentiation of ATRA-resistant acute promyelocytic leukemia (APL) cells and its molecular mechanism, the NB4-R1, an ATRA-resistant APL cells, was used as a model, counting of NB4-R1 and cell morphologic observation were performed, the effect of curcumin alone or combined with ATRA on proliferation, differentiation of NB4-R1 cells was detected by flow cytometry (FCM), the change of AKT phosphorylation in cell differentiation was detected by Western blot. The results showed that ATRA had no influence on NB4-R1 cell proliferation, but enhanced the inhibitory effect of curcumin on NB4-R1 cell growth; the curcumin or ATRA alone did not affect NB4-R1 differentiation; curcumin combined with ATRA could obviously induce CD11b expression; the cell morphology showed obvious differentiation characteristics. ATRA could promote phosphorylation of AKT in NB4 cells at short time, but not had effect on phosphorylation of AKT in NB4-R1 cells; the curcumin could enhance the phosphorylation of AKT in NB4-1R cells, the curcumin combined with ATRA could further enhance the phosphorylation of AKT. It is concluded that PI3K/AKT pathway inactivation may be one of the factors of drug resistance in APL and curcumin promotes differentiation of NB4-R1 through activating PI3K/AKT pathway.

  6. Flood Mtyths and Atra-Hasis

    Directory of Open Access Journals (Sweden)

    Fırat CANER

    2017-07-01

    Full Text Available The Flood comprises and signposts one of the most sig-nificant archetypes of human history: Divine retribution. It has been explored so far in a myriad of myths as the supernatural punishment of people. In the Flood narra-tives, people who have grown corrupted or committed an offense against gods, are destroyed by the deities. However, a few people are made to survive so that hu-mankind would find a way to breed again. The first known great Flood narrative is the myth of Atra-hasis, a biblical story. Atra-hasis is the first literary piece em-phasising the belief that the class struggle ends up al-most always in the favour and reinforcement of the up-per-class. However, the discourse generated by the Flood narratives, unlike Atra-hasis, mostly stress the centrality of an all-encompassing and self-oriented ab-solute authority. In this respect, many of the flood nar-ratives spread the idea that it is necessary to side with the gods or that which receive their power from gods, thereby legalizing the emergence of the cler-gy or continuation of its presence. However, the Flood narratives produced in the Chinese and Islamic cultures are different than those of the others: the former fore-grounds science (knowledge and truth and the latter does not produce a class-conscious discourse.

  7. Flood Mtyths and Atra-Hasis

    OpenAIRE

    Fırat CANER

    2017-01-01

    The Flood comprises and signposts one of the most sig-nificant archetypes of human history: Divine retribution. It has been explored so far in a myriad of myths as the supernatural punishment of people. In the Flood narra-tives, people who have grown corrupted or committed an offense against gods, are destroyed by the deities. However, a few people are made to survive so that hu-mankind would find a way to breed again. The first known great Flood narrative is the myth of Atra-hasis, a biblica...

  8. Bioactive compounds from Holothuria atra of Indian ocean.

    Science.gov (United States)

    Dhinakaran, Devaraj Isaac; Lipton, Aaron Premnath

    2014-01-01

    The sea cucumber (Holothuria atra) extracts have been evaluated for the presence of bioactive compounds and various biological activities. The methanol extracts showed anti proliferative activities against the Hela and MCF-7 cell lines. Similarly the inhibitory effects of Herpes simplex virus 1 and 2 cells were detected using the plaque reduction assay. The extracts of H. atra were purified using the silica gel column chromatography. The active fractions collected were observed for antimicrobial activity. The GC-MS analysis showed the availability of 59 compounds. The active bioactive compounds found in the H. atra were analyzed and their structure was identified using the (1)HNMR and (13)C NMR experiments.

  9. Cytoprotective Effects of Lysophospholipids from Sea Cucumber Holothuria atra.

    Science.gov (United States)

    Nishikawa, Yoshifumi; Furukawa, Ayumi; Shiga, Ikumi; Muroi, Yoshikage; Ishii, Toshiaki; Hongo, Yayoi; Takahashi, Shunya; Sugawara, Tatsuya; Koshino, Hiroyuki; Ohnishi, Masao

    2015-01-01

    Lysophospholipids are important signaling molecules in animals and metazoan cells. They are widely distributed among marine invertebrates, where their physiological roles are unknown. Sea cucumbers produce unique lysophospholipids. In this study, two lysophospholipids were detected in Holothuria atra for the first time, lyso-platelet activating factor and lysophosphatidylcholine, with nuclear magnetic resonance and liquid chromatography-time-of-flight mass spectrometric analyses. The lipid fraction of H. atra contained lyso-platelet activating factor and lysophosphatidylcholine, and inhibited H2O2-induced apoptosis in the macrophage cell line J774A.1. The antioxidant activity of the lysophospholipid-containing lipid fraction of H. atra was confirmed with the oxygen radical absorbance capacity method. Our results suggest that the lysophospholipids from H. atra are potential therapeutic agents for the inflammation induced by oxidative stress.

  10. Cytoprotective Effects of Lysophospholipids from Sea Cucumber Holothuria atra.

    Directory of Open Access Journals (Sweden)

    Yoshifumi Nishikawa

    Full Text Available Lysophospholipids are important signaling molecules in animals and metazoan cells. They are widely distributed among marine invertebrates, where their physiological roles are unknown. Sea cucumbers produce unique lysophospholipids. In this study, two lysophospholipids were detected in Holothuria atra for the first time, lyso-platelet activating factor and lysophosphatidylcholine, with nuclear magnetic resonance and liquid chromatography-time-of-flight mass spectrometric analyses. The lipid fraction of H. atra contained lyso-platelet activating factor and lysophosphatidylcholine, and inhibited H2O2-induced apoptosis in the macrophage cell line J774A.1. The antioxidant activity of the lysophospholipid-containing lipid fraction of H. atra was confirmed with the oxygen radical absorbance capacity method. Our results suggest that the lysophospholipids from H. atra are potential therapeutic agents for the inflammation induced by oxidative stress.

  11. The uropygial gland fat of the coot (Fulica atra)

    National Research Council Canada - National Science Library

    Jacob, J; Zeman, A

    1973-01-01

    The composition of the uropygial gland waxes of the coot, Fulica atra, was investigated by GLC/MS combination, in order to ascertain whether there are characteristic uropygial gland components which...

  12. ATRA and ATO team up against NPM1.

    Science.gov (United States)

    Grant, Steven

    2015-05-28

    In this issue of Blood, Martelli et al and El Hajj et al independently report that nucleophosmin-1 (NPM1)-mutant leukemia is particularly vulnerable to a novel strategy combining all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). The era of targeted therapy has seen some of its greatest successes in the hematologic arena (eg, breakpoint cluster region [BCR]/Abelson [ABL] kinase inhibitors in chronic myeloblastic leukemia and ATRA in acute promyelocytic leukemia [APL]). Moreover, addition of ATO, an agent that induces oxidative stress and interferes with protein translation, to ATRA sharply increases APL cell killing to the extent that cures in this disease are no longer unrealistic. A theoretical (and practical) basis for translating ATRA/ATO-based strategies to non-APL acute myelocytic leukemia (AML) is currently lacking.

  13. Antioxidant potential of all-trans retinoic acid (ATRA) and enhanced activity of liposome encapsulated ATRA against inflammation and tumor-directed angiogenesis.

    Science.gov (United States)

    Siddikuzzaman; Grace, V M Berlin

    2013-02-01

    The purpose of this study was to investigate whether all-trans retinoic acid (ATRA) has antioxidant property. The study was also focused on its inhibitory effect on the acute and chronic inflammation and tumor-associated capillary formation in terms of angiogenesis in C57BL/6 mice after incorporated in liposome composed of distearoylphosphatidylcholine (DSPC/cholesterol). ATRA possesses a number of important biologic activities including oncostatic, antioxidant and immunostimulatory actions. Our study was designed to evaluate the antioxidant activity of free ATRA by nitric oxide scavenging, superoxide radical scavenging, hydroxyl radical scavenging and lipid peroxide scavenging assays. The ATRA showed significant scavenging activities in all these antioxidant assays comparable to the standard antioxidant. We have also evaluated the activity of encapsulated ATRA against anti-inflammatory activity in C57BL/6 mice. The paw oedema inhibition was found in carrageenan model as 55.56% and 66.67% for free ATRA and encapsulated ATRA treatment respectively and for formaldehyde model it was found to be 60.87% and 69.57% respectively compared with saline treated control mice. Encapsulated ATRA inhibited the tumor-associated capillary formation in mice induced by highly metastatic B16F10 melanoma cells significantly than the free ATRA did. In this study the inhibition of tumor-directed capillary formation was found to be 56.25% and 62.50% for free ATRA and encapsulated ATRA treatment respectively. In conclusion, ATRA showed a significant antioxidant property in vitro. Free ATRA has anti-inflammatory activity as proved by us in animal model of acute and chronic inflammation and antiangiogenesis activity. Furthermore, its activity was boosted by encapsulation in liposome.

  14. PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.

    Science.gov (United States)

    Cicconi, L; Divona, M; Ciardi, C; Ottone, T; Ferrantini, A; Lavorgna, S; Alfonso, V; Paoloni, F; Piciocchi, A; Avvisati, G; Ferrara, F; Di Bona, E; Albano, F; Breccia, M; Cerqui, E; Sborgia, M; Kropp, M G; Santoro, A; Levis, A; Sica, S; Amadori, S; Voso, M T; Mandelli, F; Lo-Coco, F

    2016-10-01

    The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

  15. Anti-metastatic study of liposome-encapsulated all trans retinoic acid (ATRA) in B16F10 melanoma cells-implanted C57BL/6 mice.

    Science.gov (United States)

    Siddikuzzaman; Grace, V M Berlin

    2014-12-01

    B16F10 cells-induced C57BL/6 mice were divided into several groups and the free all trans retinoic acid (ATRA) and liposome-encapsulated ATRA were given for 21 days. The encapsulated ATRA treatment lowered the oxidative stress and lipid profile near to the normal level in the drug-treated mice. Encapsulated ATRA treatment showed substantial decrease in serum cytokines and increase in lifespan when compared with free ATRA treatment. These results imply that the liposome-encapsulated ATRA may help to achieve a higher level of ATRA in comparison with free ATRA treatment and helps to enhance anticancer drug delivery in liposome-encapsulated ATRA treatment.

  16. The effect of all-trans retinoic acid (ATRA) on the expression of ...

    African Journals Online (AJOL)

    Retinoic acid is effective in inhibiting the expression of vascular endothelial growth factor (VEGF) in some cancer. In this study, we investigated the effect of ATRA on the expression of VEGF and its receptors in LoVo cells, and its possible mechanisms. LoVo cells were treated with ATRA at different concentrations for different ...

  17. The effect of all-trans retinoic acid (ATRA) on the expression of ...

    African Journals Online (AJOL)

    Administrator

    2011-09-28

    Sep 28, 2011 ... All-trans retinoic acid (ATRA) was found to inhibit cell growth, induce differentiation and enhance apoptosis in a ... ATRA on the expression of VEGF and its receptors in LoVo cells, and its possible mechanisms. LoVo cells were ..... differentiation of myeloid cells and immune response in cancer patients.

  18. Inhibition of the all-trans Retinoic Acid (atRA) Hydroxylases CYP26A1 and CYP26B1 Results in Dynamic, Tissue-Specific Changes in Endogenous atRA Signaling.

    Science.gov (United States)

    Stevison, Faith; Hogarth, Cathryn; Tripathy, Sasmita; Kent, Travis; Isoherranen, Nina

    2017-07-01

    All-trans retinoic acid (atRA), the active metabolite of vitamin A, is a ligand for several nuclear receptors and acts as a critical regulator of many physiologic processes. The cytochrome P450 family 26 (CYP26) enzymes are responsible for atRA clearance, and are potential drug targets to increase concentrations of endogenous atRA in a tissue-specific manner. Talarozole is a potent inhibitor of CYP26A1 and CYP26B1, and has shown some success in clinical trials. However, it is not known what magnitude of change is needed in tissue atRA concentrations to promote atRA signaling changes. The aim of this study was to quantify the increase in endogenous atRA concentrations necessary to alter atRA signaling in target organs, and to establish the relationship between CYP26 inhibition and altered atRA concentrations in tissues. Following a single 2.5-mg/kg dose of talarozole to mice, atRA concentrations increased up to 5.7-, 2.7-, and 2.5-fold in serum, liver, and testis, respectively, resulting in induction of Cyp26a1 in the liver and testis and Rar β and Pgc 1β in liver. The increase in atRA concentrations was well predicted from talarozole pharmacokinetics and in vitro data of CYP26 inhibition. After multiple doses of talarozole, a significant increase in atRA concentrations was observed in serum but not in liver or testis. This lack of increase in atRA concentrations correlated with an increase in CYP26A1 expression in the liver. The increased atRA concentrations in serum without a change in liver suggest that CYP26B1 in extrahepatic sites plays a key role in regulating systemic atRA exposure. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Insuficiência renal aguda em paciente tratada com ATRA e anfotericina B: relato de caso

    Directory of Open Access Journals (Sweden)

    Gelcimar Moresco

    2011-06-01

    Full Text Available O presente relato apresenta o caso clínico de uma paciente com leucemia promie-locítica aguda tratada com ácido todo-transretinoico (ATRA, que apresentou suspeita de síndrome do ácido transreti-noico (síndrome de ATRA. Com a ocor-rência de leucopenia febril inespecífica, foram associados ao tratamento antimi-crobianos e antifúngicos. A diminuição da função renal, observada inicialmente, contribuiu para a suspeita de síndrome de ATRA, que foi agravada pelos antifúngi-cos. Assim, o uso de ATRA foi suspenso, mas somente 8 dias depois foi caracteriza-da pneumonia e descartada a hipótese de síndrome de ATRA. Nesse contexto, foi discutida a nefrotoxicidade do ATRA e a potencialização desse efeito adverso pelo uso de antifúngicos nefrotóxicos, em par-ticular da anfotericina B, assim como a im-portância do diagnóstico diferencial entre síndrome de ATRA e doença infecciosa.

  20. Transcriptional Regulation of the Daptomycin Gene Cluster in Streptomyces roseosporus by an Autoregulator, AtrA*

    Science.gov (United States)

    Mao, Xu-Ming; Luo, Shuai; Zhou, Ri-Cheng; Wang, Feng; Yu, Pin; Sun, Ning; Chen, Xiao-Xia; Tang, Yi; Li, Yong-Quan

    2015-01-01

    Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus. To reveal the transcriptional regulatory mechanism of daptomycin biosynthesis, we used the biotinylated dptE promoter (dptEp) as a probe to affinity isolate the dptEp-interactive protein AtrA, a TetR family transcriptional regulator, from the proteome of mycelia. AtrA bound directly to dptEp to positively regulate gene cluster expression and daptomycin production. Meanwhile, both ΔatrA and ΔadpA mutants showed bald phenotype and null production of daptomycin. AdpA positively regulated atrA expression by direct interaction with atrA promoter (atrAp), and removal of ArpA in S. roseosporus, a homolog of the A-factor receptor, resulted in accelerated morphological development and increased daptomycin production, suggesting that atrA was the target of AdpA to mediate the A-factor signaling pathway. Furthermore, AtrA was positively autoregulated by binding to its own promoter atrAp. Thus, for the first time at the transcriptional level, we have identified an autoregulator, AtrA, that directly mediates the A-factor signaling pathway to regulate the proper production of daptomycin. PMID:25648897

  1. [Significance of PLSCR1 in Matrine Induced Differentiation of ATRA Resistant APL Cells].

    Science.gov (United States)

    Wu, Di-jiong; Liu, Ting-ting; Zhou, Qi-hao; Sun, Jie; Shao, Ke-ding; Ye, Bao-dong; Zhou, Yu-hong

    2015-11-01

    To observe the expression of phospholipid scramblase 1 (PLSCR1) in matrine (MAT) induced differentiation of all-trans retinoic acid (ATRA) resistant acute promyelocytic leukemia (APL) cells, and to explore its correlation to cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signal pathway. NB4 (an APL cell line sensitive to ATRA) and NB4-R1 (a resistant strain of ATRA) were observed as subjects in this study. Effects of combined treatment of 0.1 mmol/L MAT and 1 [mol/L ATRA on the differentiation of two cell lines were detected using nitroblue tetrazolium (NBT) reduction test and flow cytometry (CD11b). Expressions of PML/RARot and PLSCR1 protein/gene were detected using Western blot and Real-time fluorescence quantitative PCR assay. Meanwhile, H89, PKA antagonist, was used to observe cell differentiation antigen and changes of aforesaid proteins and genes. MAT combined ATRA could significantly elevate positive rates of NBT and CD11 b in NB4-R1 cells, and significantly down-regulate the expression of PML/RARapha-fusion protein/gene (P ATRA used alone could obviously enhance the expression of PLSCRI in NB4 cells at protein and mRNA levels (P ATRA could significantly induce the differentiation of NB4-R1 cells, and inhibit the expression of PML/RARalpha fusion gene/protein, which might be associated with up-regulating PLSCR1 expression.

  2. Transcriptional regulation of the daptomycin gene cluster in Streptomyces roseosporus by an autoregulator, AtrA.

    Science.gov (United States)

    Mao, Xu-Ming; Luo, Shuai; Zhou, Ri-Cheng; Wang, Feng; Yu, Pin; Sun, Ning; Chen, Xiao-Xia; Tang, Yi; Li, Yong-Quan

    2015-03-20

    Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus. To reveal the transcriptional regulatory mechanism of daptomycin biosynthesis, we used the biotinylated dptE promoter (dptEp) as a probe to affinity isolate the dptEp-interactive protein AtrA, a TetR family transcriptional regulator, from the proteome of mycelia. AtrA bound directly to dptEp to positively regulate gene cluster expression and daptomycin production. Meanwhile, both ΔatrA and ΔadpA mutants showed bald phenotype and null production of daptomycin. AdpA positively regulated atrA expression by direct interaction with atrA promoter (atrAp), and removal of ArpA in S. roseosporus, a homolog of the A-factor receptor, resulted in accelerated morphological development and increased daptomycin production, suggesting that atrA was the target of AdpA to mediate the A-factor signaling pathway. Furthermore, AtrA was positively autoregulated by binding to its own promoter atrAp. Thus, for the first time at the transcriptional level, we have identified an autoregulator, AtrA, that directly mediates the A-factor signaling pathway to regulate the proper production of daptomycin. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Inhibition of Zymosan-Induced Inflammatory Factors Expression by ATRA Nanostructured Lipid Carriers.

    Science.gov (United States)

    Zhou, Hongyan; Zhang, Wensong; Gao, Xunyi; Zhang, Hongguang; Kong, Ning

    2016-01-01

    Purpose. The study aimed to evaluate the effect of all-trans retinoic acid-loaded nanostructured lipid carriers (ATRA-NLCs) on the zymosan-induced expression of the cytokines IL-4, IL-10, and IFN-γ and the matrix metalloproteinases/tissue inhibitor of metalloproteinases (MMPs/TIMPs) and TLR2 in rabbit corneal fibroblasts (RCFs). Methods. ATRA-NLCs were prepared by emulsification. RCFs were isolated and harvested after four to seven passages in monolayer culture. Cytokine release (IL-4, IL-10, and IFN-γ) induced by zymosan was analyzed by cytokine release assay, reverse transcription, and real-time polymerase chain reaction (RT-PCR) analysis detection. MMP-1, MMP-3, and MMP-13, TIMP-1 and TIMP-2, and TLR2 expression were analyzed by immunoblotting. Results. ATRA-NLCs were resistant to light and physically stable, and the average size of the ATRA-NLCs was 200 nm. ATRA-NLCs increased the zymosan-induced release of IL-4 and IL-10 and decreased the release of IFN-γ by RCFs. ATRA-NLCs decreased the levels of TLR2 and MMPs/TIMPs above. Conclusions. ATRA may be a potent anti-inflammatory agent for the therapy of fungal keratitis (FK).

  4. Combined Treatment of ATRA with Epigenetic Drugs Increases Aggressiveness of Glioma Xenografts.

    Science.gov (United States)

    Schmoch, Thomas; Gal, Zoltan; Mock, Andreas; Mossemann, Jan; Lahrmann, Bernd; Grabe, Niels; Schmezer, Peter; Lasitschka, Felix; Beckhove, Philipp; Unterberg, Andreas; Herold-Mende, Christel

    2016-04-01

    Recently, anti-tumourigenic effects of all-trans-retinoic-acid (ATRA) on glioblastoma stem cells were demonstrated. Therefore we investigated if these beneficial effects could be enhanced by co-medication with epigenetic drugs such as the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) or the DNA-methyltransferase inhibitor 5-aza-2'deoxycytidine (5-AZA). Glioma stem cell xenografts were treated for 42 days with ATRA plus SAHA or ATRA plus 5-AZA or the correspondent monotherapies. Tumour sizes, histological features, proliferation and apoptosis rates were assessed. Neither SAHA nor 5-AZA were able to enhance the anti-tumourigenic effect of ATRA. Instead, tumours became more aggressive. Combination of ATRA plus 5-AZA increased tumour size (pATRA plus SAHA. Combining ATRA with epigenetic drug therapies led to the unwanted opposite effect and increased aggressiveness of glioma xenografts, arguing against future clinical applications of such combinations. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  5. Sorafenib inhibition of Mcl-1 accelerates ATRA induced apoptosis in differentiation responsive AML cells

    Science.gov (United States)

    Wang, Rui; Xia, Lijuan; Gabrilove, Janice; Waxman, Samuel; Jing, Yongkui

    2015-01-01

    Purpose All trans retinoic acid (ATRA) is successful in treating acute promyelocytic leukemia (APL) by inducing terminal differentiation-mediated cell death, but it has limited activity in non-APL acute myeloid leukemia (AML). We aim to improve ATRA therapy of AML by enhancing apoptosis through repression of the anti-apoptotic proteins Bcl-2 and Mcl-1. Experimental Design APL and AML cell lines, as well as primary AML samples, were used to explore the mechanisms regulating differentiation and apoptosis during ATRA treatment. Stable transfection and gene silencing with siRNA were used to identify the key factors that inhibit apoptosis during induction of differentiation and drugs that accelerate apoptosis. Results In differentiation responsive AML cells, ATRA treatment induces long-lasting repression of Bcl-2 while first up-modulating and then reducing the Mcl-1 level. The Mcl-1 level appears to serve as a gatekeeper between differentiation and apoptosis. During differentiation induction, activation of MEK/ERK and PI3K/Akt pathways by ATRA leads to activation of p90RSK and inactivation of glycogen synthase kinase 3β (GSK3β), which increase Mcl-1 levels by increasing its translation and stability. Sorafenib blocks ATRA-induced Mcl-1 increase by reversing p90RSK activation and GSK3β inactivation, maintains the repressed Bcl-2 level, and enhances ATRA induced apoptosis in non-APL AML cell lines and in primary AML cells. Conclusion Inhibition of Mcl-1 is required for apoptosis induction in ATRA differentiation responsive AML cells. ATRA and Sorafenib can be developed as a novel drug combination therapy for AML patients because this drug combination augments apoptosis by inhibiting Bcl-2 and Mcl-1. PMID:26459180

  6. Sorafenib Inhibition of Mcl-1 Accelerates ATRA-Induced Apoptosis in Differentiation-Responsive AML Cells.

    Science.gov (United States)

    Wang, Rui; Xia, Lijuan; Gabrilove, Janice; Waxman, Samuel; Jing, Yongkui

    2016-03-01

    All trans-retinoic acid (ATRA) is successful in treating acute promyelocytic leukemia (APL) by inducing terminal differentiation-mediated cell death, but it has limited activity in non-APL acute myeloid leukemia (AML). We aim to improve ATRA therapy of AML by enhancing apoptosis through repression of the antiapoptotic proteins Bcl-2 and Mcl-1. APL and AML cell lines, as well as primary AML samples, were used to explore the mechanisms regulating differentiation and apoptosis during ATRA treatment. Stable transfection and gene silencing with siRNA were used to identify the key factors that inhibit apoptosis during induction of differentiation and drugs that accelerate apoptosis. In differentiation-responsive AML cells, ATRA treatment induces long-lasting repression of Bcl-2 while first upmodulating and then reducing the Mcl-1 level. The Mcl-1 level appears to serve as a gatekeeper between differentiation and apoptosis. During differentiation induction, activation of MEK/ERK and PI3K/Akt pathways by ATRA leads to activation of p90RSK and inactivation of glycogen synthase kinase 3β (GSK3β), which increase Mcl-1 levels by increasing its translation and stability. Sorafenib blocks ATRA-induced Mcl-1 increase by reversing p90RSK activation and GSK3β inactivation, maintains the repressed Bcl-2 level, and enhances ATRA induced apoptosis in non-APL AML cell lines and in primary AML cells. Inhibition of Mcl-1 is required for apoptosis induction in ATRA differentiation-responsive AML cells. ATRA and sorafenib can be developed as a novel drug combination therapy for AML patients because this drug combination augments apoptosis by inhibiting Bcl-2 and Mcl-1. ©2015 American Association for Cancer Research.

  7. The complete mitochondrial genome of Fulica atra (Avian, Gruiformes, Rallidae).

    Science.gov (United States)

    He, Ke; Ren, Ting; Zhu, Songhui; Zhao, Ayong

    2016-09-01

    To analyze the gene structure and the evolutionary roadmap of Fulica atra, the complete mitogenome is sequenced. It is composed of 37 genes and 1 control region, and the structure and arrangement of all genes are identical to other Rallidae. The comparative mitogenome revealed that the start codon and stop codon varied in Rallidae, and the gene lengths are different in ND2, COX1, ND3, ND5 and CYTB due to incompleteness of stop codon, frameshift mutation and various numbers of amino acids. We analyzed the correlation between phylogeny and gene characteristic in Rallidae with respect to the usage of start/stop codon and gene length, but no correlation was found. It indicates these discrepancies might happen independently. This work can afford an in-depth insight of phyletic evolution in Rallidae.

  8. [Isolation and pharmacological properties of analgesic fraction from venom of Naja Naja atra].

    Science.gov (United States)

    Liang, Ying-Xia; Han, Li-Ping; Jiang, Wei-Jian; Zhao, Shu-Jin

    2009-07-01

    To separate main analgesic fraction from venom of Guangdong Naja naja atra, to establish the basis for the using of Naja naja atra and find new analgesic fraction. Affinity chromatography and size exclusion were used to isolate the analgesic fraction from the venom of Naja naja atra, and then to determine its properties by biochemical methods, such as SDS-polyacryamide gel electrophoresis ( SDS-PAGE), HPLC and Mole-toff. HPLC showed its relative purity was 95% (HPLC)and Mw was 6741. 236 Da. We observed that peripheral administration of neurotoxin strongly reduced the mechanical allogynia and thermal hyperalgesia for 24 hours, associated with this neuropathy (L5 spinal nerve ligation). The fraction from venom of Naja naja atra has significant analgesic effect and it is worth further developing.

  9. CDDO and ATRA Instigate Differentiation of IMR32 Human Neuroblastoma Cells

    National Research Council Canada - National Science Library

    Namrata Chaudhari; Priti Talwar; Christian Lefebvre D'hellencourt; Palaniyandi Ravanan

    2017-01-01

    ...(11)-dien-28-oic acid (CDDO) on human neuroblastoma IMR32 cells. Our results demonstrate that treatment with low concentration of CDDO and particularly in combination with all trans retinoic acid (ATRA...

  10. ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation.

    Science.gov (United States)

    Clarke, Christopher J; Shamseddine, Achraf A; Jacob, Joseph J; Khalife, Gabrielle; Burns, Tara A; Hannun, Yusuf A

    2016-05-01

    Neutral sphingomyelinase-2 (nSMase2) is a key ceramide-producing enzyme in cellular stress responses. While many posttranslational regulators of nSMase2 are known, emerging evidence suggests a more protracted regulation of nSMase2 at the transcriptional level. Previously, we reported that nSMase2 is induced by all-trans retinoic acid (ATRA) in MCF7 cells and implicated nSMase2 in ATRA-induced growth arrest. Here, we further investigated how ATRA regulates nSMase2. We find that ATRA regulates nSMase2 transcriptionally through the retinoic acid receptor-α, but this is independent of previously identified transcriptional regulators of nSMase2 (Sp1, Sp3, Runx2) and is not through increased promoter activity. Epigenetically, the nSMase2 gene is not repressively methylated in MCF7 cells. However, inhibition of histone deacetylases (HDACs) with trichostatin A (TSA) induced nSMase2 comparably to ATRA; furthermore, combined ATRA and TSA treatment was not additive, suggesting ATRA regulates nSMase2 through direct modulation of histone acetylation. Confirming this, the histone acetyltransferases CREB-binding protein and p300 were required for ATRA induction of nSMase2. Finally, use of class-specific HDAC inhibitors suggested that HDAC4 and/or HDAC5 are negative regulators of nSMase2 expression. Collectively, these results identify a novel pathway of nSMase2 regulation and suggest that physiological or pharmacological modulation of histone acetylation can directly affect nSMase2 levels. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

  11. Effects of that ATRA inhibits Nrf2-ARE pathway on glial cells activation after intracerebral hemorrhage.

    Science.gov (United States)

    Yin, Xiao-Ping; Zhou, Jun; Wu, Dan; Chen, Zhi-Ying; Bao, Bing

    2015-01-01

    Previous studies indicate that the Nrf2-ARE signaling pathway plays a neruo-protective role in glia cell, however, the mechanism was also elusive. This study aims to explore the inhibitive function of all-trans-retinoic (ATRA) on Nrf2-ARE pathway in intracerebral hemorrhage (ICH), and investigate the mechanism. In this study, the femoral artery injection method was employed to establish ICH model. The model rats were randomly divided into four groups, including Sham group, ICH group, ATRA group and DMSO group. The neurological scores were evaluated for the four groups at different time points. Hematoxylin-Eosin staining was used to stain the CD11b positive glia cells. Double immunofluorescence staining method was utilized to observe the co-expression of HO-1, NF-κB, Nrf2 and TNF-α and CD11b marker in glia cells. Western blot assay was used to detect the Nrf2 protein (total and binding Nrf2), HO-1, NF-κB and TNF-α proteins in every group. The results indicated that neurologiclal scores were significantly decreased in ATRA group compared to ICH gorup (P ATRA significantly decreased co-expression of Nrf2, HO-1 and CD11b, and increased co-expression of NF-κB, TNF-α and CD11b of glia cells. ATRA significantly decreased total Nrf2 expression and increased binding Nrf2 expression in ATRA group compared to ICH group (P ATRA decreased anti-oxygen protein Nrf2 and HO-1, and increases inflammatory factors NF-κB and TNF-α. In conclusion, the application of ATRA could inhibit the neuro-protective function effectively by blocking the Nrf2-ARE pathway in glia cells.

  12. Toxicity effects of water extracts of Holothuria atra Jaeger in mice.

    Science.gov (United States)

    Hashim, Ridzwan Bin; Azizan, Nurul Alia; Zamli, Zaitunnatakin; Zulkipli, Farah Hanis; Mazlan, Nurzafirah; Althunibat, Osama Yousef

    2014-08-01

    To determine lethal median dose (LD50) and histopathological toxicity of water extract of Holothuria atra (H. atra) in mice. The behavioral changes, mortality and histopathology examination on liver were assessed in mice 14 d after the administration (i.p.) of H. atra water extract. Seven doses (10, 20, 30, 50, 100, 150 and 200 mg/kg) of H. atra were used. The control group was treated with normal saline. In the acute study in mice, the water extracts of H. atra caused dose-dependent general behavior adverse affects and mortality. The main behavioral sign of toxicity was hypoactivity, noticed immediately after administration of the extract which was more obvious at the higher doses and persisted until death. Mortality increased with increasing doses, the calculated LD50 was 41 mg/kg in mice. The liver toxicity was confirmed by histopathological examination, which indicated the presence of abnormal hepatocytes with a distorted shape and undefined cell lining as well as enlarged nuclei in low doses groups. High doses groups indicated a more prominent distortion of the polyhedral hepatocytes with undefined cell lining, massive cytoplasm, pyknotic, karyorhexis and karyolytic nuclei (necrosis of hepatocytes). Control group showed polyhedral hepatocytes with defined cell lining arranged in cords and normal round nuclei, with granular cytoplasm. Because of the relatively low LD50 value in the acute study in mice, it may be concluded that the H. atra water extract is toxic.

  13. All trans-retinoic acid (ATRA) induces re-differentiation of early transformed breast epithelial cells.

    Science.gov (United States)

    Arisi, Maria F; Starker, Rebecca A; Addya, Sankar; Huang, Yong; Fernandez, Sandra V

    2014-06-01

    Retinoids have been used as potential chemotherapeutic or chemopreventive agents because of their differentiative, anti-proliferative, pro-apoptotic and antioxidant properties. We investigated the effect of all trans-retinoic acid (ATRA) at different stages of the neoplastic transformation using an in vitro model of breast cancer progression. This model was previously developed by treating the MCF-10F human normal breast epithelial cells with high dose of estradiol and consists of four cell lines which show a progressive neoplastic transformation: MCF-10F, normal stage; trMCF, transformed MCF-10F; bsMCF, invasive stage; and caMCF, tumorigenic stage. In 3D cultures, MCF-10F cells form tubules resembling the structures in the normal mammary gland. After treatment with estradiol, these cells formed tubules and spherical masses which are indicative of transformation. Cells that only formed spherical masses in collagen were isolated (trMCF clone 11) and treated with ATRA. After treatment with 10 or 1 µM ATRA, the trMCF clone 11 cells showed tubules in collagen; 10 and 43% of the structures were tubules in cells treated with 10 and 1 µM ATRA, respectively. Gene expression studies showed that 207 genes upregulated in transformed trMCF clone 11 cells were downregulated after 1 µM ATRA treatment to levels comparable to those found in the normal breast epithelial cells MCF-10F. Furthermore, 236 genes that were downregulated in trMCF clone 11 were upregulated after 1 µM ATRA treatment to similar levels shown in normal epithelial cells. These 443 genes defined a signature of the ATRA re-programming effect. Our results showed that 1 µM ATRA was able to re-differentiate transformed cells at early stages of the neoplastic process and antagonistically regulate breast cancer associated genes. The invasive and tumorigenic cells did not show any changes in morphology after ATRA treatment. These results suggest that ATRA could be used as a chemopreventive agent to

  14. Differential Effects of Naja naja atra Venom on Immune Activity.

    Science.gov (United States)

    Kou, Jian-Qun; Han, Rong; Xu, Yin-Li; Ding, Xiao-Lan; Wang, Shu-Zhi; Chen, Cao-Xin; Ji, Hong-Zhang; Ding, Zhi-Hui; Qin, Zheng-Hong

    2014-01-01

    Previous studies reported that Naja naja atra venom (NNAV) inhibited inflammation and adjuvant arthritis. Here we investigated the role of NNAV in regulation of immune responses in mice. Oral administration of NNAV to normal mice showed significant increase in natural killer cell activity, B lymphocyte proliferation stimulated by lipopolysaccharides, and antibody production in response to sheep red blood cells. Meanwhile, NNAV markedly decreased T lymphocyte proliferation stimulated by concanavalin A, arrested the cell cycle at G0/G1 phase, and suppressed CD4 and CD8 T cell divisions. Furthermore, NNAV inhibited the dinitrofluorobenzene-induced delayed-type hypersensitivity reaction. This modulation of immune responses may be partly attributed to the selective increase in Th1 and Th2 cytokines (IFN-γ, IL-4) secretion and inhibition of Th17 cytokine (IL-17) production. In dexamethasone-induced immunosuppressed mice, NNAV restored the concentration of serum IgG and IgM, while decreasing the percentage of CD4 and CD8 T-cell subsets. These results indicate that NNAV enhances the innate and humoral immune responses while inhibiting CD4 Th17 and CD8 T cell actions, suggesting that NNAV could be a potential therapeutic agent for autoimmune diseases.

  15. Differential Effects of Naja naja atra Venom on Immune Activity

    Directory of Open Access Journals (Sweden)

    Jian-Qun Kou

    2014-01-01

    Full Text Available Previous studies reported that Naja naja atra venom (NNAV inhibited inflammation and adjuvant arthritis. Here we investigated the role of NNAV in regulation of immune responses in mice. Oral administration of NNAV to normal mice showed significant increase in natural killer cell activity, B lymphocyte proliferation stimulated by lipopolysaccharides, and antibody production in response to sheep red blood cells. Meanwhile, NNAV markedly decreased T lymphocyte proliferation stimulated by concanavalin A, arrested the cell cycle at G0/G1 phase, and suppressed CD4 and CD8 T cell divisions. Furthermore, NNAV inhibited the dinitrofluorobenzene-induced delayed-type hypersensitivity reaction. This modulation of immune responses may be partly attributed to the selective increase in Th1 and Th2 cytokines (IFN-γ, IL-4 secretion and inhibition of Th17 cytokine (IL-17 production. In dexamethasone-induced immunosuppressed mice, NNAV restored the concentration of serum IgG and IgM, while decreasing the percentage of CD4 and CD8 T-cell subsets. These results indicate that NNAV enhances the innate and humoral immune responses while inhibiting CD4 Th17 and CD8 T cell actions, suggesting that NNAV could be a potential therapeutic agent for autoimmune diseases.

  16. ATRA alters humoral responses associated with amelioration of EAMG symptoms by balancing Tfh/Tfr helper cell profiles.

    Science.gov (United States)

    Xie, Xiaoli; Mu, Lili; Yao, Xiuhua; Li, Na; Sun, Bo; Li, Ying; Zhan, Xiaoxia; Wang, Xinyue; Kang, Xiaoying; Wang, Jinghua; Liu, Yumei; Zhang, Yao; Wang, Guangyou; Wang, Dandan; Liu, Xijun; Kong, Qingfei; Li, Hulun

    2013-08-01

    All-trans retinoic acid (ATRA) is a vitamin A metabolite with diverse immunomodulatory actions used therapeutically in the treatment of some autoimmune diseases. However, the effects that ATRA may have on diminishing myasthenia gravis (MG) symptoms remain undefined. This study investigated the effect of ATRA on experimental autoimmune myasthenia gravis (EAMG) in vivo and in vitro. Data presented in this study demonstrated that intraperitoneal injection of ATRA ameliorated EAMG pathology in rats associated with reduced total anti-acetylcholine receptor (AChR) serum IgG levels. We observed that EAMG development was accompanied by an increase in follicular helper T cells (Tfh, defined as CD4(+)CXCR5(+)ICOS(high)) and a decrease of follicular regulatory T cells (Tfr, defined as CD4(+)Foxp3(+)CXCR5(+)ICOS(median)) and that the Tfh:Tfr ratio was altered following ATRA administration. In addition, ATRA treatment restored the Th1/Th2/Th17/Treg balance. In vitro, ATRA inhibited AChR-specific cell proliferation and eliciting apoptosis in these cells without affecting the cell cycle. ATRA also altered the Th distribution in animals presenting with EAMG resulting in a reduction in Th1/Th17/Tfh cells and increasing the number of Th2/Treg/Tfr cell types. These results suggested that ATRA reduced EAMG severity by regulating Th cell profiles thereby providing new insights into the development of novel MG (or related) therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death.

    Science.gov (United States)

    Altman, Jessica K; Rademaker, Alfred; Cull, Elizabeth; Weitner, Bing Bing; Ofran, Yishai; Rosenblat, Todd L; Haidau, Augustin; Park, Jae H; Ram, Sharona Lee; Orsini, James M; Sandhu, Sonia; Catchatourian, Rosalind; Trifilio, Steven M; Adel, Nelly G; Frankfurt, Olga; Stein, Eytan M; Mallios, George; Deblasio, Tony; Jurcic, Joseph G; Nimer, Stephen; Peterson, Loann C; Kwaan, Hau C; Rowe, Jacob M; Douer, Dan; Tallman, Martin S

    2013-09-01

    We hypothesized that the high early death rate (EDR) due to bleeding in acute promyelocytic leukemia (APL) is in part attributable to delays in all- trans retinoic acid (ATRA). We conducted a retrospective analysis of the timing of ATRA administration. 204 consecutive patients with newly diagnosed APL between 1992 and 2009 were identified. The EDR was 11%. 44% of early deaths occurred in the first week. Hemorrhage accounted for 61% of early deaths. ATRA was ordered the day APL was suspected in 31% of patients. Delays in ATRA administration led to increases in the percentage of early deaths from hemorrhage. Copyright © 2013 Elsevier Ltd. All rights reserved.

  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. ATRA (all-trans-retinoic acid) syndrome in acute promyelocytic leukemia: clinical and radiologic findings

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Keon Ha; Goo, Jin Mo; Im, Jung Gi; Chung, Myung Jin; Do, Kyung Hyun; Park, Seon Yang [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of); Seo, Joon Beom [Gachon Univ. Medical School, Gil Medical Center, Seoul (Korea, Republic of)

    2001-03-01

    To describe the clinical and radiologic findings of all-trans-retinoic acid (ATRA) syndrome in acute promyelocytic leukemia. Among 21 patients with acute promyelocytic leukemia who were treated with all-trans-retinoic acid between 1995 and 1998, we retrospectively evaluated the cases of four with ATRA syndrome. Two were male and two were female, and their mean age was 58 years. The clinical and radiologic findings of chest radiography (n=4) and HRCT (n=1) were analyzed. Between seven and 13 days after ATRA treatment, dry cough, dyspnea and high fever developed in all patients. The WBC count in peripheral blood was significantly higher [2.9-25.3(mean, 10.8)-fold] than before ATRA treatment, and in all patients, chest radiography revealed ill-defined consolidation and pleural effusion. Kerley's B line (n=3) and hilar enlargement (n=3) were also seen, and in one patient, HRCT demonstrated septal line thickening. Among four patients treated with prednisolone and Ara-C, three recovered and one died. In acute promyelocytic patients treated with all-trans-retinoic acid, radiologic findings of ill-de-fined consolidation, pleural effusion, hilar prominence and Kerley's B line may suggest ATRA syndrome. The early diagnosis of this will improve the patients' prognosis.

  20. ATRA and Genistein synergistically inhibit the metastatic potential of human lung adenocarcinoma cells.

    Science.gov (United States)

    Cheng, Ji; Qi, Jun; Li, Xue-Tao; Zhou, Kun; Xu, Jing-Han; Zhou, Yong; Zhang, Guo-Qiang; Xu, Jian-Ping; Zhou, Ren-Jie

    2015-01-01

    This study was to investigate the effects of all-trans retinoic acid (ATRA) in combination with Genistein on the proliferation, expression of apoptosis related proteins and adhesion molecules (MUC1 and ICAM-1) and invasiveness of A549 cells, aiming to investigate whether combined therapy of ATRA and Genistein is superior to monotherapy in suppressing metastasis of lung cancer cells. ATRA, Genistein and both were used to treat human lung adenocarcinoma cells (A549 cells). Immunohistochemistry was done for MUC1 expression, flow cytometry for ICAM-1 expression, fluorescence quantitative PCR for MUC1 expression and Western blot assay for the expressions of cell cycle related proteins (CDK4, Rb and p-ERK1/2) and apoptosis related proteins (Bax and Bcl-2). Cells were seeded into Matrigel pre-coated Transwell chambers, and the migrating cells were counted. Combined treatment with ATRA and Genistein was able to reduce the expressions of Bcl-2, MUC1 and ICAM-1 and exerted synergistic effects to inhibit the invasion of A549 cells. ATRA and Genistein may synergistically inhibit MUC1 and ICAM-1 expressions and affect the expressions of cell cycle related proteins (CDK4, Rb and p-ERK1/2) and apoptosis related proteins (Bax and Bcl-2), inhibit the metastatic potential of lung cancer A549 cells.

  1. [Expression of CSN Complex in ATRA-induced APL Cell Differentiation and Its Clinical Significance].

    Science.gov (United States)

    Liu, Shu-Yuan; Wan, La-Gen; Gao, Lin-Lin; Kong, Yun-Yuan; Li, Xin; Zhang, Zhang-Lin

    2015-10-01

    To investigate the expression of CSN complex (COP9 signal some subunits) in the patients with acute promyelocytic leukemia (APL) and its significance in the ATRA-induced APL differentiation. Using the NB4 cells as a model, morphologic observation and myeloid differentiation marker CD11b detection were used to monitor ATRA-induced APL differentiation, the expression of CSN complex in cell differentiation was detected by Western blot and reverse transcription real time fluorescent quantitative PCR (RT-qPCR) method. RT-qPCR was also used to detect the relative expression level of COP9 signalosome subunits in the APL patients and remission after treatment. ATRA could obviously enhance CD11b expression; the cell morphology showed obvious differentiation characteristics. During the differentiation, the expression of COP9 signalosome subunits was down-regulated by ATRA. Meanwhile, the CSN expression level in newly diagnosed APL patients was much higher than that in controls (non-leukemia) (P ATRA. CSN complex may have a significant effect on the pathogenesis and therapy of APL.

  2. Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Akter, Jesmin [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Takatori, Atsushi, E-mail: atakatori@chiba-cc.jp [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Islam, Md. Sazzadul [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakazawa, Atsuko [Department of Pathology, National Center for Child Health and Development, Tokyo (Japan); Ozaki, Toshinori, E-mail: tozaki@chiba-cc.jp [Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nagase, Hiroki [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakagawara, Akira [Saga Medical Centre, 840-8571 (Japan)

    2014-10-10

    Highlights: • NLRR3 is a membrane protein highly expressed in favorable neuroblastoma. • NLRR3-ICD was produced through proteolytic processing by secretases. • NLRR3-ICD was induced to be translocated into cell nucleus following ATRA exposure. • NLRR3-ICD plays a pivotal role in ATRA-mediated neuroblastoma differentiation. - Abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas.

  3. Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era.

    Science.gov (United States)

    Mantha, Simon; Goldman, Debra A; Devlin, Sean M; Lee, Ju-Whei; Zannino, Diana; Collins, Marnie; Douer, Dan; Iland, Harry J; Litzow, Mark R; Stein, Eytan M; Appelbaum, Frederick R; Larson, Richard A; Stone, Richard; Powell, Bayard L; Geyer, Susan; Laumann, Kristina; Rowe, Jacob M; Erba, Harry; Coutre, Steven; Othus, Megan; Park, Jae H; Wiernik, Peter H; Tallman, Martin S

    2017-03-30

    Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all-trans retinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were ALLG APML3 (single arm of ATRA + idarubicin ± prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA + cytarabine + daunorubicin). A total of 1009 patients were included in the original trials, of which 995 had sufficient data to be included in our multivariate analysis. In this final cohort, there were 37 HD cases during the first 30 days following induction, for an estimated cumulative incidence of 3.7% (95% confidence interval [CI], 2.6% to 5.0%). Using multivariate Cox proportional hazards regression, the hazard ratio of HD in the first 30 days was 2.17 (95% CI, 0.84-5.62) for an ECOG performance status of 3-4 vs 0-2 and 5.20 (95% CI, 2.70-10.02) for a white blood cell count of ≥20 000/μL vs <20 000/μL. In this large cohort of APL patients, high white blood cell count emerged as an independent predictor of early HD. © 2017 by The American Society of Hematology.

  4. Genetic variation in an endemic salamander, Salamandra atra, using amplified fragment length polymorphism.

    Science.gov (United States)

    Riberon, Alexandre; Miaud, Claude; Guyetant, R; Taberlet, P

    2004-06-01

    The pattern of genetic differentiation of the endemic alpine salamander, Salamandra atra, has been studied using amplified fragment length polymorphism (AFLP) from 11 populations throughout the range of the two currently recognized subspecies, atra and aurorae. Five different primer combinations produced 706 bands and were analyzed by constructing a phylogenetic tree using NJ and principal component analysis. Significant genetic variation was revealed by AFLP between and within populations but, our results show a lack of genetic structure. AFLP markers seems to be unsuitable to investigate complex and recent diversification.

  5. LG-362B targets PML-RARα and blocks ATRA resistance of acute promyelocytic leukemia.

    Science.gov (United States)

    Wang, X; Lin, Q; Lv, F; Liu, N; Xu, Y; Liu, M; Chen, Y; Yi, Z

    2016-07-01

    Acute promyelocytic leukemia (APL) is a M3 subtype of acute myeloid leukemia (AML). Promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) translocation generally occurs in APL patients and makes APL unique both for diagnosis and treatment. However, some conventional drugs like all-transretinoic acid (ATRA) and arsenic trioxide (ATO), as the preferred ones for APL therapy, induce irreversible resistance and responsible for clinical failure of complete remission. Herein, we screened a library of novel chemical compounds with structural diversity and discovered a novel synthetic small compound, named LG-362B, specifically inhibited the proliferation of APL and induced apoptosis. Notably, the differentiation arrest was also relieved by LG-362B in cultured APL cells and APL mouse models. Moreover, LG-362B overcame the ATRA resistance on cellular differentiation and transplantable APL mice. These positive effects were driven by caspases-mediated degradation of PML-RARα when treated with LG-362B, making it specific to APL and reasonable for ATRA resistance relief. We propose that LG-362B would be a potential candidate agent for the treatment of the relapsed APL with ATRA resistance in the future.

  6. Discovery of Salamandra atra aurorae (Trevisan, 1982 on the Altopiano di Vezzena, Trentino (Northeastern Italy

    Directory of Open Access Journals (Sweden)

    Wouter Beukema

    2008-05-01

    Full Text Available Aurora’s Alpine Salamander is a limited distributed subspecies endemic to the Altopiano di Asiago, Veneto. In the current paper the occurrence of Salamandra atra aurorae is described for the Altopiano di Vezzena, Trentino. The aim of this paper is to review the distribution as well as to comment on the conservational status of the subspecies in Trentino.

  7. Timing of reproduction and fledging success in the coot Fulica atra : evidence for a causal relationship

    NARCIS (Netherlands)

    Brinkhof, Martin W.G.; Cavé, Anton J.; Hage, Fred J.; Verhulst, Simon

    1993-01-01

    1. We investigated the relationship between hatching date and fledging success in the European coot (Fulica atra). 2. The production of fledglings per brood increased in the first half of the season and decreased in the second half, independent of clutch size or egg size. We tested experimentally

  8. Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation.

    Science.gov (United States)

    Akter, Jesmin; Takatori, Atsushi; Islam, Md Sazzadul; Nakazawa, Atsuko; Ozaki, Toshinori; Nagase, Hiroki; Nakagawara, Akira

    2014-10-10

    We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Niet Ptenothrix atra maar P. ciliata komt voor in Nederland (Hexapoda: Entognatha: Collembola)

    NARCIS (Netherlands)

    Berg, M.P.

    2009-01-01

    In een recent artikel werd het springstaartengenus Ptenothrix besproken, met een nieuwe soort voor de Nederlandse fauna: P. atra. Na toezending van het artikel aan de Belgische springstaartenspecialist Frans Janssens kwam er een mailtje retour met de opmerking dat op de foto’s P. ciliata te zien is

  10. Rosmarinic acid potentiates ATRA-induced macrophage differentiation in acute promyelocytic leukemia NB4 cells.

    Science.gov (United States)

    Heo, Sook-Kyoung; Noh, Eui-Kyu; Yoon, Dong-Joon; Jo, Jae-Cheol; Koh, SuJin; Baek, Jin Ho; Park, Jae-Hoo; Min, Young Joo; Kim, Hawk

    2015-01-15

    Rosmarinic acid (RA, an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid) has a number of biological activities, but little is known about anti-leukemic activities of RA combined with all-trans retinoic acid (ATRA) against acute promyelocytic leukemia (APL) cells. We examined the differentiation marker, CD11b, in bone marrow cells (BMC) of an APL patient, in NB4 cells (APL cell line), and in normal BMC and peripheral blood mononuclear cells (PBMC) of healthy subjects by flow cytometric analysis. ATRA/RA induced expression of CD11b in the BMC of the APL patient and in NB4 cells, but not in normal BMC or PBMC. Therefore, we realized that RA potentiated ATRA-induced macrophage differentiation in APL cells. Further characterization of the induced macrophages showed that they exhibited morphological changes and were able to phagocytose and generate reactive oxygen species. Th also had typical expression of C-C chemokine receptor type 1 (CCR1), CCR2, and intercellular adhesion molecule-1 (ICAM-1). Moreover, the expression of CD11b(+) and CD14(+) cells depended on ERK-NF-κB axis activation. Together, these results indicate that RA potentiates ATRA-induced macrophage differentiation in APL cells. Thus, RA may play an important role as an appurtenant differentiation agent for functional macrophage differentiation in APL. Additionally, the differentiated macrophages might have a normal life span and, they could die. These data indicate that co-treatment with RA and ATRA has potential as an anti-leukemic therapy in APL. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. All-trans retinoic acid (ATRA) prevents lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment in aged rats.

    Science.gov (United States)

    Behairi, Nassima; Belkhelfa, Mourad; Rafa, Hayet; Labsi, Moussa; Deghbar, Nahla; Bouzid, Nora; Mesbah-Amroun, Hamida; Touil-Boukoffa, Chafia

    2016-11-15

    We aimed to investigate preventive effects of All-trans retinoic acid (ATRA) on a lipopolysaccharide (LPS)-induced aged neuroinflammation model. We analyzed behavior, systemic nitric oxide (NO) production, cerebral NO synthase (NOS2) and β-amyloid (Aβ) 1-42 expression and tissue integrity in the neuroinflammation model pretreated with ATRA (150μg/ml/rat/day) for 30days. Our results showed that LPS treatment (500μg/kg/day) for 7days disturbed memory, enhanced systemic NO production, NOS2 and Aβ 1-42 cerebral expression and generated an Alzheimer's disease (AD)-like neuronal degeneration. Interestingly, ATRA pretreatment prevented the LPS-induced deleterious effects. ATRA could be a potent preventive approach in AD. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Inhibition of p38 MAPK Phosphorylation Is Critical for Bestatin to Enhance ATRA-Induced Cell Differentiation in Acute Promyelocytic Leukemia NB4 Cells.

    Science.gov (United States)

    Qian, Xijun; He, Jingsong; Zhao, Yi; Lin, Maofang

    2016-01-01

    Bestatin has been known as an immunomodulating agent in anti-leukemia treatment. The mechanism by which Bestatin enhances all-trans retinoic acid (ATRA)-induced cell differentiation of acute promyelocytic leukemia (APL) cells is generally attributed to inhibition of cell surface CD13/aminopeptidase N activity. Bestatin also exerts its biological activities besides its ability to inhibit aminopeptidase N enzymatic activity. This article provides data to support an alternative mechanism regarding an important role of inhibition of p38 mitogen-activated protein kinase (MAPK) signal pathway in Bestatin's anti-leukemia effect. Bestatin enhanced ATRA-induced differentiation and inhibited ATRA-driven phosphorylation of p38 MAPK in ATRA-sensitive APL NB4 cells. In contrast, Bestatin could not reverse the differentiation block in ATRA-resistant APL MR2 cells, in which ATRA was unable to induce phosphorylation of p38 MAPK. Moreover, CD13 ligation with anti-CD13 antibody WM-15 resulted in phosphorylation of p38 MAPK, reduced the inhibition of Bestatin on the phosphorylation of p38 MAPK, and completely abolished the enhancement of Bestatin on ATRA-inducing differentiation in NB4 cells. This study shows that inhibition of p38 MAPK phosphorylation is critical for Bestatin to enhance ATRA-induced cell differentiation in ATRA-sensitive APL NB4 cells. Results suggested that pharmacological inhibition of the p38 MAPK pathway might enhance ATRA-dependent differentiation.

  13. WNT4 acts downstream of BMP2 to mediate the regulation of ATRA signaling on RUNX1 expression: Implications for terminal differentiation of antler chondrocytes.

    Science.gov (United States)

    Zhang, Hong-Liang; Yang, Zhan-Qing; Duan, Cui-Cui; Geng, Shuang; Wang, Kai; Yu, Hai-Fan; Yue, Zhan-Peng; Guo, Bin

    2017-04-24

    Although ATRA is involved in regulating the proliferation and differentiation of chondrocytes, its underlying mechanism remains unknown. Here we showed that ATRA could stimulate the proliferation of antler chondrocytes and expression of COL X and MMP13 which were two well-known markers for hypertrophic chondrocytes. Silencing of CRABP2 prevented the induction of ATRA on chondrocyte terminal differentiation, while overexpression of CRABP2 exhibited the opposite effects. CYP26A1 and CYP26B1 weakened the sensitivity of antler chondrocytes to ATRA. Further analysis evidenced that ATRA might induce chondrocyte terminal differentiation and modulate the expression of BMP2, WNT4, and RUNX1 through RARα/RXRα. Knockdown of BMP2 enhanced the induction of ATRA on the expression of COL X and MMP13, whereas overexpression of BMP2 abrogated this effectiveness. WNT4 might mediate the effects of ATRA and BMP2 on chondrocyte terminal differentiation. Dysregulation of BMP2 impaired the regulation of ATRA on WNT4 expression. Administration of ATRA to antler chondrocytes transfected with RUNX1 siRNA failed to induce the differentiation. Conversely, rRUNX1 strengthened the stimulation of ATRA on the expression of COL X and MMP13. Simultaneously, RUNX1 was a downstream effector of BMP2 and WNT4 in chondrocyte terminal differentiation. Moreover, WNT4 might play an important role in the crosstalk between BMP2 and RUNX1. Attenuation of BMP2 or WNT4 enhanced the interaction between ATRA and RUNX1, while constitutive expression of BMP2 or WNT4 reversed the regulation of ATRA on RUNX1. Collectively, WNT4 may act downstream of BMP2 to mediate the effects of ATRA on the terminal differentiation of antler chondrocytes through targeting RUNX1. © 2017 Wiley Periodicals, Inc.

  14. Enhancement of ATRA-induced differentiation of neuroblastoma cells with LOX/COX inhibitors: an expression profiling study

    Directory of Open Access Journals (Sweden)

    Hermanova Marketa

    2010-05-01

    Full Text Available Abstract Background We performed expression profiling of two neuroblastoma cell lines, SK-N-BE(2 and SH-SY5Y, after combined treatment with all-trans retinoic acid (ATRA and inhibitors of lipoxygenases (LOX and cyclooxygenases (COX. This study is a continuation of our previous work confirming the possibility of enhancing ATRA-induced cell differentiation in these cell lines by the application of LOX/COX inhibitors and brings more detailed information concerning the mechanisms of the enhancement of ATRA-induced differentiation of neuroblastoma cells. Methods Caffeic acid, as an inhibitor of 5-lipoxygenase, and celecoxib, as an inhibitor on cyclooxygenase-2, were used in this study. Expression profiling was performed using Human Cancer Oligo GEArray membranes that cover 440 cancer-related genes. Results Cluster analyses of the changes in gene expression showed the concentration-dependent increase in genes known to be involved in the process of retinoid-induced neuronal differentiation, especially in cytoskeleton remodeling. These changes were detected in both cell lines, and they were independent of the type of specific inhibitors, suggesting a common mechanism of ATRA-induced differentiation enhancement. Furthermore, we also found overexpression of some genes in the same cell line (SK-N-BE(2 or SH-SY5Y after combined treatment with both ATRA and CA, or ATRA and CX. Finally, we also detected that gene expression was changed after treatment with the same inhibitor (CA or CX in combination with ATRA in both cell lines. Conclusions Obtained results confirmed our initial hypothesis of the common mechanism of enhancement in ATRA-induced cell differentiation via inhibition of arachidonic acid metabolic pathway.

  15. ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation[S

    Science.gov (United States)

    Clarke, Christopher J.; Shamseddine, Achraf A.; Jacob, Joseph J.; Khalife, Gabrielle; Burns, Tara A.; Hannun, Yusuf A.

    2016-01-01

    Neutral sphingomyelinase-2 (nSMase2) is a key ceramide-producing enzyme in cellular stress responses. While many posttranslational regulators of nSMase2 are known, emerging evidence suggests a more protracted regulation of nSMase2 at the transcriptional level. Previously, we reported that nSMase2 is induced by all-trans retinoic acid (ATRA) in MCF7 cells and implicated nSMase2 in ATRA-induced growth arrest. Here, we further investigated how ATRA regulates nSMase2. We find that ATRA regulates nSMase2 transcriptionally through the retinoic acid receptor-α, but this is independent of previously identified transcriptional regulators of nSMase2 (Sp1, Sp3, Runx2) and is not through increased promoter activity. Epigenetically, the nSMase2 gene is not repressively methylated in MCF7 cells. However, inhibition of histone deacetylases (HDACs) with trichostatin A (TSA) induced nSMase2 comparably to ATRA; furthermore, combined ATRA and TSA treatment was not additive, suggesting ATRA regulates nSMase2 through direct modulation of histone acetylation. Confirming this, the histone acetyltransferases CREB-binding protein and p300 were required for ATRA induction of nSMase2. Finally, use of class-specific HDAC inhibitors suggested that HDAC4 and/or HDAC5 are negative regulators of nSMase2 expression. Collectively, these results identify a novel pathway of nSMase2 regulation and suggest that physiological or pharmacological modulation of histone acetylation can directly affect nSMase2 levels. PMID:27013100

  16. Liposome encapsulated all trans retinoic acid (ATRA) has enhanced immunomodulatory and inflammation reducing activities in mice model.

    Science.gov (United States)

    Grace, V M Berlin; Siddikuzzaman; Rimashree, B

    2015-01-01

    The all trans retinoic acid (ATRA) is found to have a promising regulatory effect on immune system and inflammatory responses in experimental research. The purpose of this study was to investigate whether this therapeutic efficiency of ATRA could be enhanced by encapsulating into a liposome formulation composed of Distearoyl-L-phosphatidylcholine (DSPC) and cholesterol utilizing a well-established mice model. The humoral antibody titer (HA), delayed-type hypersensitivity (DTH), bone marrow cellularity, hematology, and levels of α- esterase-positive cells, were taken as parameters to assess the level of immunomodulation in the sheep red blood cells (SRBC) immunized and challenged BALB/c mice. The anti-inflammatory effect of encapsulated ATRA was evaluated by the size changes in the induced inflammation edema in the mice paw as well as its histopathology. The results showed a significant immunostimulatory effect for both the free and encapsulated ATRA as indicated by the increase in the levels of total leukocyte, bone marrow and α-esterase positive cells and decreased Hb level respectively. We have also observed an enhanced specific antibody hemagglutinin titre value and the DTH response developed in response to SRBC challenge in these treatments. Both the immunostimulatory as well as inflammation reducing property were significantly higher in encapsulated ATRA treated group of mice over that of in free ATRA treated group of mice. Based on these results, we conclude that the encapsulated ATRA has a higher potency over free ATRA in its immunomodulatory activity and also has a significant impact on reducing inflammation in BALB/c mice model.

  17. Evaluation of immunomodulatory and antitumor activity of all trans retinoic acid (ATRA) in solid tumor bearing mice.

    Science.gov (United States)

    Siddikuzzaman; Berlin, Grace V M

    2013-02-01

    Natural or synthetic agents can modify the immune system and, in some cases, impart a therapeutic benefit. Cancer, a disease of uncontrolled growth and spread of abnormal cells, is a major cause of death. The Vitamin A metabolite all-trans retinoic acid (ATRA) and its other active derivatives are potent modulators of cell growth and differentiation, and because it has an influence on cancer, it can be used as a chemotherapeutic and -preventive agent. To evaluate the immunomodulatory activity of ATRA, the impact of treatment on various parameters, e.g. delayed-type hypersensitivity (DTH), bone marrow cellularity, hematology, and levels of esterase-positive cells, was assessed in Balb/c mice. To evaluate antitumor effects of ATRA, tumor volume and host survival rate were monitored in B16F10 melanoma cell-injected mice. The results showed that administration of ATRA (0.60 mg/kg/dose, IP) caused a decrease in DTH (footpad thickness) in response to challenge with sheep red blood cells (SRBC) in SRBC-sensitized hosts. ATRA also caused increases in WBC counts and bone marrow cell numbers. In tumor-inoculated mice, ATRA caused tumor growth suppression and gave rise to a heightened survival rate. It was also found that ATRA had differential effects on serum levels of reduced glutathione (GSH) and nitric oxide (NO) was reduced in serum. Based on these results, we conclude that ATRA has a potent immunomodulatory potential but also could significantly impact upon solid tumor growth and prolong host survival.

  18. ATRA inhibits the proliferation of DU145 prostate cancer cells through reducing the methylation level of HOXB13 gene.

    Directory of Open Access Journals (Sweden)

    Zhiwei Liu

    Full Text Available All-trans retinoic acid (ATRA has been widely investigated for treatments of many cancers including prostate cancer. HOXB13, silenced in androgen receptor-negative (AR(- prostate cancer cells, plays a role in AR(- prostate cancer cell growth arrest. In this study we intended to elucidate the mechanisms that are involved in the proliferation inhibition of AR(- prostate cancer cells triggered by ATRA. We discovered that ATRA was able to induce the growth arrest and to increase HOXB13 expression in AR(- prostate cancer cells. Both EZH2 and DNMT3b participated in the repression of HOXB13 expression through an epigenetic mechanism involving DNA and histone methylation modifications. Specifically, EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. Moreover, ATRA could upregulate HOXB13 through decreasing EZH2 and DNMT3b expressions and reducing their interactions with the HOXB13 promoter. Concurrently, the methylation level of the HOXB13 promoter was reduced upon the treatment of ATRA. Results from this study implicated a novel effect of ATRA in inhibition of the growth of AR(- resistant human prostate cancer cells through alteration of HOXB13 expression as a result of epigenetic modifications.

  19. AtRAE1 is involved in degradation of ABA receptor RCAR1 and negatively regulates ABA signaling in Arabidopsis.

    Science.gov (United States)

    Li, Dekuan; Zhang, Liang; Li, Xiaoyi; Kong, Xiangge; Wang, Xiaoyu; Li, Ying; Liu, Zhibin; Wang, Jianmei; Li, Xufeng; Yang, Yi

    2017-10-18

    The phytohormone abscisic acid (ABA) plays an important role in regulating plant growth, development and adaption to various environmental stresses. Regulatory components of ABA receptors (RCARs, also known as PYR/PYLs) sense ABA and initiate ABA signaling through inhibiting the activities of protein phosphatase 2C (PP2C) in Arabidopsis. However, the way in which ABA receptors are regulated is not well known. A DWD protein AtRAE1 (for RNA export factor 1 in Arabidopsis), which may act as a substrate receptor of CUL4-DDB1 E3 ligase, is an interacting partner of RCAR1/PYL9. The physical interaction between RCAR1 and AtRAE1 is confirmed in vitro and in vivo. Overexpression of AtRAE1 in Arabidopsis causes reduced sensitivity of plants to ABA, while suppression of AtRAE1 causes increased sensitivity to ABA. Analysis of protein stability demonstrates that RCAR1 is ubiquitinated and degraded in plant cells and AtRAE1 regulates the degradation speed of RCAR1. Our findings indicate that AtRAE1 likely participates in ABA signaling through regulating the degradation of ABA receptor RCAR1. This article is protected by copyright. All rights reserved.

  20. Atrações e prazeres visuais em um pornô feminino

    OpenAIRE

    Mariana Baltar

    2015-01-01

    Este artigo correlaciona os conceitos de excesso e atrações como estratégicos para refletir sobre processos de engajamento e afetação no campo da pornografia que desestabilizam morais tradicionais em direção a uma política de gêneros. Nesse sentido, mobiliza-se uma lógica de excesso de atrações que estabelece um jogo ambivalente de recusa e adesão aos códigos genéricos mais básicos da pornografia. Os argumentos são empreendidos a partir da análise de Dirty Diaries, um projeto declaradamente a...

  1. Atrações e prazeres visuais em um pornô feminino

    Directory of Open Access Journals (Sweden)

    Mariana Baltar

    2015-08-01

    Full Text Available Este artigo correlaciona os conceitos de excesso e atrações como estratégicos para refletir sobre processos de engajamento e afetação no campo da pornografia que desestabilizam morais tradicionais em direção a uma política de gêneros. Nesse sentido, mobiliza-se uma lógica de excesso de atrações que estabelece um jogo ambivalente de recusa e adesão aos códigos genéricos mais básicos da pornografia. Os argumentos são empreendidos a partir da análise de Dirty Diaries, um projeto declaradamente associado ao campo da pornografia feminista empreendido com apoio do Swedish Film Institut.

  2. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

    Science.gov (United States)

    Chronopoulos, Antonios; Robinson, Benjamin; Sarper, Muge; Cortes, Ernesto; Auernheimer, Vera; Lachowski, Dariusz; Attwood, Simon; García, Rebeca; Ghassemi, Saba; Fabry, Ben; del Río Hernández, Armando

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC. PMID:27600527

  3. Neutron dosimetry and damage calculations for the ATR-A1 irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Greenwood, L.R.; Ratner, R.T. [Pacific Northwest National Lab., Richland, WA (United States)

    1998-09-01

    Neutron fluence measurements and radiation damage calculations are reported for the collaborative US/Japan ATR-A1 irradiation in the Advanced Test Reactor (ATR) at Idaho National Engineering Laboratory (INEL). The maximum total neutron fluence at midplane was 9.4 {times} 10{sup 21} n/cm{sup 2} (5.5 {times} 10{sup 21} n/cm{sup 2} above 0.1 MeV), resulting in about 4.6 dpa in vanadium.

  4. All-trans retinoic acid (ATRA) and the regulation of adhesion molecules in acute myeloid leukemia.

    Science.gov (United States)

    Di Noto, R; Lo Pardo, C; Schiavone, E M; Ferrara, F; Manzo, C; Vacca, C; Del Vecchio, L

    1996-04-01

    A review of recent information on the expression and the ATRA-driven modulation of cell surface adhesion molecules of acute myelogenous leukemia blast cells is presented. Cytofluorometric studies on fresh blast cells have demonstrated that CD11a, CD11b CD11c, CD15, CD45RO and CD54 expression is significantly lower in acute promyelocytic leukemia (APL) than is acute myeloid leukemia of other subtypes (AML). In vitro treatment with ATRA dramatically modifies the adhesion phenotype of APL blast cells, promoting a consistently striking up-regulation of CD11b, CD11c, CD15, CD65, CD54, and CD38. Which is in general, poorly demonstrable in AML. The behaviour of CD15s is variable and fully independent from CD15 and CD65 in induction experiments, suggesting a differential enzyme regulation within the selectin ligand system. ATRA is capable, in both APL and AML, of producing a switch from the high- (RA) to the low- (RO) molecular weight isoform of CD54, Moreover, treatment with this retinoid exerts a negative regulation of the membrane expression of CD49e, CD58 and CD11a in APL as well as in AML. Of particular interest is the fact that the negative effect on CD1 1a expression generates an asynchronous phenotype in APL (CD11a-, CD11b+, CD15+), undetectable on normal maturing myeloid cells. In the last part of this review the possible implications of adhesion molecule modulation in the pathogenesis of ATRA syndrome are discussed.

  5. Realgar-induced apoptosis and differentiation in all-trans retinoic acid (ATRA)-sensitive NB4 and ATRA-resistant MR2 cells.

    Science.gov (United States)

    Chen, Siyu; Fang, Yi; Ma, Liheng; Liu, Shanxi; Li, Xinmin

    2012-04-01

    Realgar has been used in Western medicine and Chinese traditional medicine since ancient times, and its promising anticancer activity has attracted much attention in recent years, especially for acute promyelocytic leukemia (APL). However, the therapeutic action of realgar treatment for APL remains to be fully elucidated. Cellular cytotoxicity, proliferation, apoptosis and differentiation were comprehensively investigated in realgar-treated cell lines derived from PML-RARα+ APL patient, including the all-trans retinoic acid (ATRA)-sensitive NB4 and ATRA-resistant MR2 cell lines. For analysis of key regulators of apoptosis and differentiation, gene expression profiles were performed in NB4 cells. Realgar was found to induce apoptosis and differentiation in both cell lines, and these effects were exerted simultaneously. Gene expression profiles indicated that genes influenced by realgar treatment were involved in the modulation of signal transduction, translation, transcription, metabolism and the immune response. Given its low toxicity, realgar is a promising alternative reagent for the therapy of APL. Our data contribute to an understanding of the underlying mechanism responsible for the therapeutic effects of realgar in the clinical treatment of APL.

  6. Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA.

    Science.gov (United States)

    Heo, Jin-Chul; Jung, Tae-Hoon; Lee, Sungjin; Kim, Hyun Young; Choi, Gildon; Jung, Myungeun; Jung, Daeyoung; Lee, Heung Kyoung; Lee, Jung-Ok; Park, Ji-Hwan; Hwang, Daehee; Seol, Ho Jun; Cho, Heeyeong

    2016-06-01

    Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM.

  7. Bacteriology of Naja atra Snakebite Wound and Its Implications for Antibiotic Therapy.

    Science.gov (United States)

    Mao, Yan-Chiao; Liu, Po-Yu; Hung, Dong-Zong; Lai, Wei-Cheng; Huang, Shih-Ting; Hung, Yao-Min; Yang, Chen-Chang

    2016-05-04

    A total of 112 cases of Naja atra envenomation were examined at two referring hospitals: Taichung Veterans General Hospital in central Taiwan and Taipei Veterans General Hospital (VGH-TP) in northern Taiwan. Overall, 77% (86/112) of cases developed clinically suspected wound infections and 54% (61/112) required surgery secondary to tissue necrosis, finger or toe gangrene, and/or necrotizing fasciitis. Morganella morganii was the most abundant gram-negative bacterial strain isolated from bite wounds, followed by Proteus spp., Aeromonas hydrophila, Pseudomonas aeruginosa, and Providencia spp. in descending order; Enterococcus spp. were the most common gram-positive bacteria and Bacteroides spp. were the only anaerobic bacteria. A few episodes of bacteremia were caused by Bacteroides and Shewanella spp. There were no significant variations in the distribution of bacterial species between these two hospitals except for a higher incidence of M. morganii, Enterococcus spp., and polymicrobial infection observed at VGH-TP, which may have been related to variations in the fecal flora of prey and oral flora of individual snakes in different geographic areas in Taiwan. According to the susceptibility test involving various pathogens, first-line drug options for the management of N. atra snakebite wound infections may include monotherapy with ureidopenicillin or combination therapy with aminopenicillin and a third-generation cephalosporin or fluoroquinolone. A prospective evaluation of empiric antibiotic therapy for the management of N. atra snakebite should be considered. © The American Society of Tropical Medicine and Hygiene.

  8. CNS relapse in a low risk acute promyelocytic leukemia patient treated with ATRA-based regimen: is there a role for prophylactic CNS therapy in acute promyelocytic leukemia?

    OpenAIRE

    Gangadharan, K. V.; Prabhu, Raghuveer; Mampilly, Neena

    2009-01-01

    Though the incidence of CNS relapse in acute promyelocytic leukemia (AML-M3 FAB classification) has increased following the advent of all-trans retinoic acid (ATRA), still CNS relapse accounts for only 2–3% of all relapses in AML-M3 trated with standard ATRA plus chemotherapy regimen. We report a case of low risk AML-M3 treated with standard therapy, developing CNS relapse while on maintenance therapy with ATRA + 6-mercaptopurine (6-MP) + methotrexate (MTX).

  9. ATRA Entrapped in DSPC Liposome Enhances Anti-metastasis Effect on Lung and Liver During B16F10 Cell Line Metastasis in C57BL6 Mice.

    Science.gov (United States)

    Reji, Reshma Mahima; Siddikuzzaman; V M, Berlin Grace

    2017-01-01

    The high mortality rate of lung cancer is highly associated with faster metastasis spread. All Trans Retinoic Acid (ATRA), being the first choice drug for leukemia therapy is now under intense study for its therapeutic efficiency in other solid cancers. This study was aimed to investigate the anti-metastasis activity of free ATRA and liposome entrapped ATRA (5:4:1) in the experimental C57BL/6 mice model developed by the injection of B16F10 cell line into the tail vein. The ATRA drug was given via i.p for 21 days. The visual lung and liver metastatic tumor nodules were noted. Various biochemical markers of cancer metastasis in the serum as well as tissues were also analyzed after sacrifice. Tumor nodules have significantly decreased in ATRA treatment groups (32.83 ± 1.83 for free ATRA, 23 ± 2.36 for DSPC Lipo-ATRA) when compared with metastasis control (63.16 ± 2.9) in the lungs. Among the treatment groups, the DSPC lipo-ATRA treated group showed a significant tumor growth inhibition (63.6%) than that of in the free ATRA treated groups (48%). Similar anti-metastatic effect was observed in liver also. Furthermore lipo-ATRA has shown a significant change in the levels of biochemical cancer markers analyzed in this study. Our results concluded that the liposome encapsulated ATRA has an enhanced anti-metastasis potency than the free ATRA during B16F10 metastatic cell line implantation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Staurosporine enhances ATRA-induced granulocytic differentiation in human leukemia U937 cells via the MEK/ERK signaling pathway.

    Science.gov (United States)

    Shi, Lei; Weng, Xiang-Qin; Sheng, Yan; Wu, Jing; Ding, Ming; Cai, Xun

    2016-11-01

    Although all-trans retinoic acid (ATRA) is regarded as a prominent example of differentiation therapy, it is not effective for the treatment of other subtypes of acute myeloid leukemia (AML) beyond acute promyelocytic leukemia (APL). Therefore, new strategies need to be explored to extend the efficacy of ATRA-based therapy to non-APL AML patients. In the present study, staurosporine, a protein kinase C (PKC) pan-inhibitor, exhibited synergism with ATRA to promote granulocytic differentiation in poorly ATRA-sensitive U937 cells but not in ATRA unresponsive K562 and Kasumi cells. Staurosporine or the combined treatment did not affect PKC activity in U937 cells. Moreover, other selective PKC inhibitors, UCN-01, Go6976 or rottlerin failed to enhance ATRA‑induced granulocytic differentiation in U937 cells. Therefore, staurosporine-enhanced ATRA-induced granulocytic differentiation in U937 cells may be independent of PKC. Staurosporine activated mitogen‑activated protein kinase kinase (MEK) and extracellular signal‑regulated kinase (ERK). Meanwhile, staurosporine also enhanced ATRA-promoted upregulation of the protein level of CCAAT/enhancer‑binding protein β (C/EBPβ) and C/EBPε in U937 cells. Furthermore, blockade of MEK activation suppressed staurosporine‑enhanced differentiation as well as the elevated protein level of C/EBPs. Taken together, we concluded that staurosporine enhanced ATRA‑induced granulocytic differentiation in U937 cells via MEK/ERK-mediated modulation of the protein level of C/EBPs.

  11. Purification and characterization of a novel antinociceptive toxin from Cobra venom (Naja naja atra).

    Science.gov (United States)

    Jiang, Wei-jian; Liang, Ying-xia; Han, Li-ping; Qiu, Peng-xin; Yuan, Jin; Zhao, Shu-jin

    2008-10-01

    Snake venoms have demonstrated antinociceptive activity, and certain isolated neurotoxins have demonstrated significant analgesia in animal models. Here we report a novel analgesic toxin which was isolated from Naja naja atra and was given the name 'najanalgesin'. The LD(50) of the crude venom and najanalgesin were 0.89mg/kg and 2.69mg/kg, respectively. We used the writhing test and hot plate test to evaluate the antinociceptive properties of the crude venom and najanalgesin after intraperitoneal (ip) administration. The analgesic mechanism of najanalgesin was also studied. The response latency time was significantly prolonged in the hot plate test after ip administration of the crude venom of Naja naja atra (0.111-0.445mg/kg) in a dose-dependent manner. Najanalgesin (1mg/kg) elicited almost the same antinociceptive effect as that of the crude venom of Naja naja atra at the dose of 0.445mg/kg and remained for 6h after intraperitoneal injection, shown by hot plate test. The percentage of increase in the latency time for the venom and the najanalgesin 3h after drug administration was 96.2% and 112%, respectively. The number of writhes decreased to almost 1/3, 1/6, and 1/12 of the NS (physiological saline) group after intraperitoneal administration of najanalgesin at 0.25, 0.5, and 1.0mg/kg, respectively. Pretreatment with atropine (1mg/kg) or naloxone (3mg/kg) blocked the antinociception of najanalgesin in the hot plate test. Based on the sequence information, najanalgesin is found to be highly homologous with the conventional CTXs (cardiotoxins). To our knowledge, no study had previously reported that a toxin which was homologous with CTXs possessed the antinociceptive activity. Thus, this is the first report that the antinociceptive effect induced by najanalgesin is mediated by cholinergic and opioidergic mechanisms.

  12. Emodin enhances ATRA-induced differentiation and induces apoptosis in acute myeloid leukemia cells.

    Science.gov (United States)

    Chen, Yingyu; Li, Jing; Hu, Jianda; Zheng, Jing; Zheng, Zhihong; Liu, Tingbo; Lin, Zhenxing; Lin, Minhui

    2014-11-01

    Emodin, an extracted natural compound from the root and rhizome of Rheum palmatum L, has been shown to have multiple biological activities including anticancer functions in previous studies. In this study, we investigated the anti-leukemic activity of emodin alone or emodin in the presence all-trans retinoic acid (ATRA) in acute myeloid leukemia (AML) cells and the potential signaling pathway involved. We demonstrated that emodin could significantly enhance the sensitivity to ATRA and present additive differentiation-inducing effects in AML cell line NB4 cells and, especially, in NB4-derived ATRA-resistant MR2 cells. Further study showed that increasing dose of emodin could effectively induce growth inhibition and apoptotic effects in both cell lines as well as in primary leukemic cells from AML patients. Moreover, the apoptotic induction in AML cells was associated with the activation of caspase cascades involving caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage. In addition, leukemic cell response to emodin stimuli in vitro was observed through the decreased expression levels of Bcl-2 and retinoic acid receptor α (RARα). Importantly, emodin was demonstrated as a new inhibitor of PI3K/Akt in AML cells, even in primary AML cells. It inhibited Akt phosphoration (p-Akt) at Ser473 as efficiently as mTOR at Ser2448. Consistently, it exerted suppression effects on the phosphoration of mTOR downstream targets, 4E-BP1 and p70S6K. Taken together, these findings indicate that emodin might be developed as a promising anti-leukemic agent to improve the patient outcome in AML.

  13. Identification of transcription factors expressed during ATRA-induced neutrophil differentiation of HL60 cells.

    Science.gov (United States)

    Mills, K I; Walsh, V; Gilkes, A F; Woodgate, L J; Brown, G; Burnett, A K

    1998-10-01

    A recent clinical therapeutic initiative has been the use of chemical agents which induce the leukaemic cells to overcome their block in differentiation. In order to understand this block the cascade of molecular events needs to be characterized. Haemopoietic differentiation is ultimately controlled at the level of gene transcription which is mediated by an array of transcription factors. Many transcription factors contain similar structural protein sequences, and we have used an RT-PCR-based approach to isolate sequences, from transcription factor gene families which share similar domains. Degenerate primers corresponding to the TFIIIA zinc-finger consensus amino acid sequences and to the POU-homeodomain and POU-specific domain were used to amplify genes on the basis that they contained similarities in structural motifs shared within these families of transcription factors. A serum-independent HL60 cell line was induced towards the neutrophil lineage by treatment with all-trans retinoic acid (ATRA) for 24 h. CD38+ cells committed towards this lineage were enriched and a population of these cells treated with dihydroxyvitamin D3 to induce neutrophil maturation. RNA extracted from uninduced, ATRA-induced CD38+ cells, and vitamin D3 treated maturing cell cultures were amplified using the degenerate primers. PCR fragments were cloned, sequenced, clustered into homologous groups, and the group sequences searched on the GenBank database. The Oct 1 transcription factor, and a very close homologue, KIAA0144, was identified using the POU family primers. The zinc-finger primers identified three zinc-finger genes. The pattern of gene expression was suggested from the number of clones in each group at neutrophil commitment and maturation. The differential expression of the genes in the zinc finger and POU families will lead to a better understanding of the cascade of gene expression which occurs following ATRA-induced differentiation.

  14. Movimentos sob atração focal em campos vetoriais planares

    OpenAIRE

    MARTINS, Tiberio Bittencourt de Oliveira

    2008-01-01

    Neste trabalho, desenvolvemos o artigo On the motion under focal attraction in a rotating medium de J. Sotomayor [9] que trata de um sistema de equações diferenciais bidimensional que modela o seguinte problema na Biologia: num recipiente raso de seção circular, com líquido, girando a uma velocidade angular ω, existem platelmintos, organismos vermiforme, eles s ao atra´ıdos por um ponto luminoso fixo perto da borda do recipiente e nadam com uma velocidade v em direçãoa este p...

  15. [Efficacy of combination of ATRA, ATO and anthracyclines induction therapy in patients with acute promyelocytic leukemia].

    Science.gov (United States)

    Ma, R J; Zhu, Z M; Yuan, X L; Jiang, L; Yang, S W; Yang, J; Guo, J M; Zhang, L; Lei, P C; Wang, Z; Zang, Y Z; Chen, Y Q; Wang, T B; Kong, D; Sun, K; Zhang, Y

    2017-06-14

    Objective: To explore the efficacies of regimens of three-drug induction therapy (ATRA+ATO+anthracyclines) versus two-drug induction therapy (ATRA+ATO) in patients with acute promyelocytic leukemia (APL). Methods: Of 184 patients diagnosed with APL from January 2009 to March 2016, 58 patients underwent three-drug induction therapy, while the rest were treated with two-drug induction therapy. Three-drug induction therapy was of ATRA (20 mg·m(-2)·d(-1), d(1-28)) + ATO (0.16 mg·kg(-1)·d(-1), d(1-28)) + Idarubicin (8 mg·m(-2)·d(-1), d(3-5)) /daunorubicin (40 mg·m(-2)·d(-1), d(3-5)) , while two-drug induction therapy ATRA+ATO with the same doses and methods as above. Of 184 cases, 69 cases accompanied with WBC counts>10×10(9)/L, 115 cases with WBC counts≤10×10(9)/L at onset. Results: ①Short-term efficacy: After one cycle induction therapy, the rates of hematologic remission, genetic remission, molecular remission and induced differentiation syndrome (DS) in three-drug regimen group were 98.3%, 87.9%, 72.4% and 0 respectively, while those in two-drug regimen group were 87.3%, 65.9%, 51.6% and 12.7% respectively. In patients with WBC >10×10(9)/L, DS rate and early mortality in three-drug regimen group were lower than in two-drug regimen group (0 vs 15.6%, 4.2% vs 15.6%, respectively). In patients with WBC≤10×10(9)/L, DS rate in three-drug regimen group was also lower than in two-drug regimen group (0 vs 12.3%) , but there were no statistical differences in terms of relapse and early mortality. ② Long-term efficacy: The relapse rate, overall survival (OS) and disease free survival (DFS) in three-drug regimen group were 0, 98.5%, 96.6% respectively, while those in two-drug regimen group were 8.6%, 86.5% and 84.1% respectively; the advantages of three-drug over two-drug regimen, especially in cases of WBC >10×10(9)/L were observed. ③ Side effects: the incidences of gastrointestinal reaction, liver dysfunction, myocardial damage and headache in three

  16. ÚLCERAS ESCROTALES SECUNDARIAS A TRATAMIENTO CON ÁCIDO TRANSRETINOICO (ATRA

    Directory of Open Access Journals (Sweden)

    Cuevas-Ruiz MV

    2011-01-01

    Full Text Available El ácido trans retinoico es el fármaco de elección en el tratamiento de la Leucemia Promielocítica Aguda. El efecto secundario más grave del fármaco es el síndrome de diferenciación, pero puede ocasionar lesiones en piel y úlceras escrotales. Presentamos el caso de un varón con leucemia promielocítica aguda que recibió ATRA y presentó úlceras escrotales

  17. Antifungal effect of Sticophus hermanii and Holothuria atra extract and its cytotoxicity on gingiva-derived mesenchymal stem cell

    Directory of Open Access Journals (Sweden)

    Kristanti Parisihni

    2013-12-01

    Full Text Available Background: Sea cucumber had been acknowledged to have some medical properties Sticophus hermanii and Holothuria atra are species of sea cucumber which has been known to have antifungal properties thus potentially explored as therapeutic agent in oral candidiasis. Purpose: The aim of this study was to examine the antifungal property Sticophus hermanii and Holothuria atra extract against Candida albicans and its cytotoxicity to human gingiva-derived mesenchymal stem cell. Methods: The study was an experimental laboratories research with post test only control group design. Methanolic extract of Sticophus hermanii and Holothuria atra in concentrations of 1%, 0.5%; 0.25%; 0.13%, 0.07%; 0.03%, 0.02% and 0.01%; were tested its cytotoxicity on gingiva-derived mesenchymal stem cell. Cell viability were measured by MTT assay. The antifungal property against Candida albicans was tested by disk diffusion method. Data were analyzed by ANOVA followed by LSD. Results: Extract of Sticophus hermanii showed no cytotoxicity in all concentrations (p>0.05, while Holothuria atra showed toxicity in the concentration of 1% and not cytotoxic in the concentrations below (p<0.05. Both sea cucumber extract could inhibit the growth Candida albicans, in vitro, proved by the clear zone around the disc in all concentrations (p<0.05. Conclusion: Stichopus hermanii and Holothuria atra extract had the antifungal effect against Candida albicans. Sea cucumber extract were not cytotoxic togingiva-derived mesenchymal stem cell in the concentration of Sticophus hermanii ≤ 1% and Holothuria atra ≤ 0.5%.Latar belakang: Teripang telah diketahui mempunyai berbagai khasiat medis. Sticophus hermanii dan Holothuria atra adalah spesies teripang yang telah diketahui mempunyai sifat anti jamur sehingga santat potensial untuk diekplorasi sebagai agen terapeutik pada infeksi di rongga mulut. Tujuan: Tujuan dari penelitian ini adalah untuk meneliti sifat anti jamur ekstrak Sticophus hermanii

  18. PRAME-induced inhibition of retinoic acid receptor signaling-mediated differentiation--a possible target for ATRA response in AML without t(15;17).

    Science.gov (United States)

    Bullinger, Lars; Schlenk, Richard F; Götz, Marlies; Botzenhardt, Ursula; Hofmann, Susanne; Russ, Annika C; Babiak, Anna; Zhang, Lu; Schneider, Vanessa; Döhner, Konstanze; Schmitt, Michael; Döhner, Hartmut; Greiner, Jochen

    2013-05-01

    In acute myeloid leukemia (AML) without retinoic acid receptor (RAR) rearrangement, the effect of all-trans-retinoic acid (ATRA) is still poorly understood despite an association of NPM1 mutation and ATRA response. Recently, preferentially expressed antigen in melanoma (PRAME) has been shown to be a dominant repressor of RAR signaling. Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA responsiveness. We profiled gene expression in diagnostic samples derived from our AML HD98B trial, in which ATRA was administered in addition to intensive chemotherapy. Our data revealed a PRAME expression-associated gene pattern to be significantly enriched for genes involved in the retinoic acid metabolic process. In leukemia cell line models, we could show that retinoic acid-regulated cell proliferation and differentiation are impacted by PRAME expression. In patients with primary AML, repressor activity of high-PRAME levels might be overcome by the addition of ATRA as indicated by better outcome in 2 independent studies (P = 0.029). PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR signaling, which might be reversed by ATRA. PRAME therefore represents a promising target for both ATRA treatment and possibly future immunotherapeutic approaches in AML. ©2013 AACR.

  19. Proteomic characterization and comparison of venoms from two elapid snakes (Bungarus multicinctus and Naja atra) from China.

    Science.gov (United States)

    Shan, Lin-Lin; Gao, Jian-Fang; Zhang, Yan-Xia; Shen, Shan-Shan; He, Ying; Wang, Jin; Ma, Xiao-Mei; Ji, Xiang

    2016-04-14

    Bungarus multicinctus (many-banded krait) and Naja atra (Chinese cobra) are widely distributed and medically important venomous snakes in China; however, their venom proteomic profiles have not been fully compared. Here, we fractionated crude venoms and analyzed them using a combination of proteomic techniques. Three-finger toxins (3-FTx) and phospholipase A2 (PLA2) were most abundant in both species, respectively accounting for 32.6% and 66.4% of total B. multicinctus venom, and 84.3% and 12.2% of total N. atra venom. Venoms from these two species contained one common protein family and six less abundant species-specific protein families. The proteomic profiles of B. multicinctus and N. atra venoms and analysis of toxicological activity in mice suggested that 3-FTx and PLA2 are the major contributors to clinical symptoms caused by envenomation. The venoms differed in enzymatic activity, likely the result of inter-specific variation in the amount of related venom components. Antivenomics assessment revealed that a small number of venom components (3-FTxs and PLA2s in B. multicinctus, and 3-FTxs in N. atra) could not be immunocaptured completely, suggesting that we should pay attention to enhancing the immune response of these components in designing commercial antivenoms for B. multicinctus and N. atra. The proteomic profiles of venoms from two medically important snake species - B. multicinctus and N. atra - have been explored. Quantitative and qualitative differences are evident in both venoms when proteomic profiles and transcriptomic results are compared; this is a reminder that combined approaches are needed to explore the precise composition of snake venom. Two protein families (3-FTx and PLA2) of high abundance in these snake venoms are major players in the biochemical and pharmacological effects of envenomation. Elucidation of the proteomic profiles of these snake venoms is helpful in understanding composition-function relationships and will facilitate the

  20. The ATRA-induced differentiation of medulloblastoma cells is enhanced with LOX/COX inhibitors: an analysis of gene expression.

    Science.gov (United States)

    Chlapek, Petr; Neradil, Jakub; Redova, Martina; Zitterbart, Karel; Sterba, Jaroslav; Veselska, Renata

    2014-01-01

    A detailed analysis of the expression of 440 cancer-related genes was performed after the combined treatment of medulloblastoma cells with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). The combinations of retinoids and celecoxib as a COX-2 inhibitor were reported to be effective in some regimens of metronomic therapy of relapsed solid tumors with poor prognosis. Our previous findings on neuroblastoma cells using expression profiling showed that LOX/COX inhibitors have the capability of enhancing the differentiating action of ATRA. Presented study focused on the continuation of our previous work to confirm the possibility of enhancing ATRA-induced cell differentiation in these cell lines via the application of LOX/COX inhibitors. This study provides more detailed information concerning the mechanisms of the enhancement of the ATRA-induced differentiation of medulloblastoma cells. The Daoy and D283 Med medulloblastoma cell lines were chosen for this study. Caffeic acid (an inhibitor of 5-LOX) and celecoxib (an inhibitor on COX-2) were used in combined treatment with ATRA. The expression profiling was performed using Human Cancer Oligo GEArray membranes, and the most promising results were verified using RT-PCR. The expression profiling of the selected cancer-related genes clearly confirmed that the differentiating effects of ATRA should be enhanced via its combined administration with caffeic acid or celecoxib. This effect was detected in both cell lines. An increased expression of the genes that encoded the proteins participating in induced differentiation and cytoskeleton remodeling was detected in both cell lines in a concentration-dependent manner. This effect was also observed for the CDKN1A gene encoding the p21 protein, which is an important regulator of the cell cycle, and for the genes encoding proteins that are associated with proteasome activity. Furthermore, our results showed that D283 Med cells are

  1. Isolation and Characterization of Microsatellite Loci in the Chinese Cobra Naja atra (Elapidae

    Directory of Open Access Journals (Sweden)

    Xiang Ji

    2011-07-01

    Full Text Available We characterize thirteen polymorphic microsatellite loci isolated from Naja atra genomic libraries, which were enriched for AC-motif microsatellites. The thirteen loci were screened on a group of 48 individuals from two populations, one in Yong’an and the other in Ganzhou. These markers revealed a relatively high degree of genetic diversity (4–12 alleles per locus and heterozygosity (Ho ranged from 0.213–0.854 and He ranged from 0.301–0.838. Tests for departure from Hardy-Weinberg equilibrium and for linkage disequilibrium were conducted for each of the two populations separately. After sequential Bonferroni correction, none of the 13 loci showed significant departures from Hardy-Weinberg equilibrium. Hierarchical analysis of molecular variance indicated that a small but significant (P < 0.001 proportion (16.0% of the total variation in the microsatellite DNA data were attributable to differences among populations, indicating geographical structuring and restricted gene flow. It could be attributable to the Wuyi mountains in the area having a sufficiently isolating effect to significantly reduce gene flow. Our microsatellite data also showed a low Nm (1.31 value in the two populations from mainland China. Thus, the Yong’an and Ganzhou populations could be treated as distinct evolutionarily significant units (ESUs. The high level of polymorphism revealed by these microsatellite markers will be useful for the study of gene flow, population structure and evolutionary history of N. atra.

  2. Isolation, identification and characterization of Morganella morganii from Naja naja atra in Beijing, China.

    Science.gov (United States)

    Wang, H-F; Du, L-Y; Luo, J; He, H-X

    2017-08-15

    Morganella morganii is an important opportunistic human pathogen and belongs to the family of Enterobacteriaceae. Although it is widely distribution, it only be considered a rare cause of human infections. We report the isolate of M. morganii from Naja naja atra following infections of heart, lung and liver. Seven strains were confirmed using 16S rDNA amplified and sequences. Antimicrobial susceptibility testing of M. morganii isolates demonstrated ubiquitous resistance to ampicillin, amoxicillin/clavulanic acid, cefazolin, cephalothin, sulfamethoxazole/trimethoprim, sulfamethoxazole et al. However, M. morganii ubiquitous susceptible to piperacillin, ampicillin/sulbactam, piperacillin/tazobactam, cefixime et al. Further investigate display gyr B and Sul2 genes presence in all M. morganii isolates. AAC(3)-II was found in E2, E3 and E6 M. morganii. gyrA and qnrB expression in M3 and M6 M. morganii. This is the first description in M. morganii carrying AAC(3)-II, gyrB, gyrA, qnrB, and Sul2 genes from Naja naja atra, which suggests the increasing risk of pathogen transmission between humans and wildlife.

  3. Isolation and characterization of microsatellite loci in the Chinese Cobra Naja atra (Elapidae).

    Science.gov (United States)

    Lin, Long-Hui; Mao, Lu-Xi; Luo, Xia; Qu, Yan-Fu; Ji, Xiang

    2011-01-01

    We characterize thirteen polymorphic microsatellite loci isolated from Naja atra genomic libraries, which were enriched for AC-motif microsatellites. The thirteen loci were screened on a group of 48 individuals from two populations, one in Yong'an and the other in Ganzhou. These markers revealed a relatively high degree of genetic diversity (4-12 alleles per locus) and heterozygosity (Ho ranged from 0.213-0.854 and He ranged from 0.301-0.838). Tests for departure from Hardy-Weinberg equilibrium and for linkage disequilibrium were conducted for each of the two populations separately. After sequential Bonferroni correction, none of the 13 loci showed significant departures from Hardy-Weinberg equilibrium. Hierarchical analysis of molecular variance indicated that a small but significant (P < 0.001) proportion (16.0%) of the total variation in the microsatellite DNA data were attributable to differences among populations, indicating geographical structuring and restricted gene flow. It could be attributable to the Wuyi mountains in the area having a sufficiently isolating effect to significantly reduce gene flow. Our microsatellite data also showed a low N(m) (1.31) value in the two populations from mainland China. Thus, the Yong'an and Ganzhou populations could be treated as distinct evolutionarily significant units (ESUs). The high level of polymorphism revealed by these microsatellite markers will be useful for the study of gene flow, population structure and evolutionary history of N. atra.

  4. Can surgical need in patients with Naja atra (Taiwan or Chinese cobra) envenomation be predicted in the emergency department?

    Science.gov (United States)

    Su, H Y; Wang, M J; Li, Y H; Tang, C N; Tsai, M J

    2016-10-01

    To investigate the clinical predictors and the aetiologies for surgery in patients with Naja atra (Taiwan or Chinese cobra) envenomation. This case series was conducted in the only tertiary care centre in eastern Taiwan. Patients who presented to the emergency department with Naja atra bite between January 2008 and September 2014 were included. Clinical information was collected and compared between surgical and non-surgical patients. A total of 28 patients with Naja atra envenomation presented to the emergency department during the study period. Of these, 60.7% (n=17) required surgery. Necrotising fasciitis (76.5%) was the main finding in surgery. Comparisons between surgical and non-surgical patients showed skin ecchymosis (odds ratio=34.36; 95% confidence interval, 2.20-536.08; P=0.012) and a high total dose of antivenin (≥6 vials; odds ratio=14.59; 95% confidence interval, 1.10-192.72; P=0.042) to be the most significant predictors of surgery. The rate of bacterial isolation from the surgical wound was 88.2%. Morganella morganii (76.5%), Enterococcus faecalis (58.8%), and Bacteroides fragilis (29.4%) were the most common pathogens involved. Bacterial susceptibility testing indicated that combined broad-spectrum antibiotics were needed to cover mixed aerobic and anaerobic bacterial infection. Patients with Naja atra envenomation who present with skin ecchymosis or the need for a high dose of antivenin may require early surgical assessment. Combined broad-spectrum antibiotics are mandatory.

  5. ATRA-Induced Cellular Differentiation and CD38 Expression Inhibits Acquisition of BCR-ABL Mutations for CML Acquired Resistance

    Science.gov (United States)

    Wu, Xiwei; Chu, Su; Wang, Jinhui; Yuan, Hongfeng; Roth, Mendel; Yuan, Yate-Ching; Bhatia, Ravi; Chen, WenYong

    2014-01-01

    Acquired resistance through genetic mutations is a major obstacle in targeted cancer therapy, but the underlying mechanisms are poorly understood. Here we studied mechanisms of acquired resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) by examining genome-wide gene expression changes in KCL-22 CML cells versus their resistant KCL-22M cells that acquire T315I BCR-ABL mutation following TKI exposure. Although T315I BCR-ABL is sufficient to confer resistance to TKIs in CML cells, surprisingly we found that multiple drug resistance pathways were activated in KCL-22M cells along with reduced expression of a set of myeloid differentiation genes. Forced myeloid differentiation by all-trans-retinoic acid (ATRA) effectively blocked acquisition of BCR-ABL mutations and resistance to the TKIs imatinib, nilotinib or dasatinib in our previously described in vitro models of acquired TKI resistance. ATRA induced robust expression of CD38, a cell surface marker and cellular NADase. High levels of CD38 reduced intracellular nicotinamide adenine dinucleotide (NAD+) levels and blocked acquired resistance by inhibiting the activity of the NAD+-dependent SIRT1 deacetylase that we have previously shown to promote resistance in CML cells by facilitating error-prone DNA damage repair. Consequently, ATRA treatment decreased DNA damage repair and suppressed acquisition of BCR-ABL mutations. This study sheds novel insight into mechanisms underlying acquired resistance in CML, and suggests potential benefit of combining ATRA with TKIs in treating CML, particularly in advanced phases. PMID:24967705

  6. Sirenophila ovis-atra a new species of maritime Teloschistaceae from the Southern Hemisphere

    DEFF Research Database (Denmark)

    Søchting, Ulrik; Søgaard, Majbrit Zeuthen; Sancho, Leopoldo G.

    2016-01-01

    A new species, Sirenophila ovis-atra is described from maritime rocks of southern Patagonia, the Falkland Islands and Macquarie Island, where it grows in the upper part of the black ‘Verrucaria-zone’, most often on members of the genus Hydropunctaria. It is so far the only known species of Sireno...

  7. Binding of a biosynthetic intermediate to AtrA modulates the production of lidamycin by Streptomyces globisporus.

    Science.gov (United States)

    Li, Xingxing; Yu, Tengfei; He, Qing; McDowall, Kenneth J; Jiang, Bingya; Jiang, Zhibo; Wu, Linzhuan; Li, Guangwei; Li, Qinglian; Wang, Songmei; Shi, Yuanyuan; Wang, Lifei; Hong, Bin

    2015-06-01

    The control of secondary production in streptomycetes involves the funneling of environmental and physiological signals to the cluster-situated (transcriptional) regulators (CSRs) of the biosynthetic genes. For some systems, the binding of biosynthetic products to the CSR has been shown to provide negative feedback. Here we show for the production of lidamycin (C-1027), a clinically relevant antitumor agent, by Streptomyces globisporus that negative feedback can extend to a point higher in the regulatory cascade. We show that the DNA-binding activity of the S. globisporus orthologue of AtrA, which was initially described as a transcriptional activator of actinorhodin biosynthesis in S. coelicolor, is inhibited by the binding of heptaene, a biosynthetic intermediate of lidamycin. Additional experiments described here show that S. globisporus AtrA binds in vivo as well as in vitro to the promoter region of the gene encoding SgcR1, one of the CSRs of lidamycin production. The feedback to the pleiotropic regulator AtrA is likely to provide a mechanism for coordinating the production of lidamycin with that of other secondary metabolites. The activity of AtrA is also regulated by actinorhodin. As AtrA is evolutionarily conserved, negative feedback of the type described here may be widespread within the streptomycetes. © 2015 John Wiley & Sons Ltd.

  8. Oroxylin A inhibits ATRA-induced IL-6 expression involved in retinoic acid syndrome by down-regulating CHOP.

    Science.gov (United States)

    Hui, Hui; Yang, Hao; Dai, Qinsheng; Wang, Qian; Yao, Jing; Zhao, Kai; Guo, Qinglong; Lu, Na

    2014-11-10

    Production of IL-6 constituted the major cause of death in the ATRA trial called retinoic acid syndrome (RAS). LAP and LIP are active and inactive isoforms of C/EBPβ, respectively. Inactive LIP dimerized with LAP to eliminate its activity. Following treatment with ATRA, CHOP expression was increased and dimerized with LIP more preferentially than LAP to rescue function of LAP. Oroxylin A has been reported to activate CHOP, a key mediator of unfolded protein response (UPR) pathway, and resulted in apoptosis. Interestingly, we found that low concentration of oroxylin A (≦ 40 μM) showed no apoptosis effect on NB4 and HL-60 cells and decreased the CHOP protein level via promoting its degradation. MG132 was utilized to conform the effect of oroxylin A on degrading CHOP. Our results showed that oroxylin A decreased the level of IL-6 secretion of NB4 cells with or without ATRA treatment while the effect was eliminated by C/EBPβ siRNA. We conclude that oroxylin A possessed abilities of inhibiting the ATRA-induced IL-6 production via modulation of LAP/LIP/CHOP in leukemia cell lines, which could providing a therapeutic strategy for RAS. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance.

    Science.gov (United States)

    Wang, Zhiqiang; Liu, Zheng; Wu, Xiwei; Chu, Su; Wang, Jinhui; Yuan, Hongfeng; Roth, Mendel; Yuan, Yate-Ching; Bhatia, Ravi; Chen, WenYong

    2014-06-01

    Acquired resistance through genetic mutations is a major obstacle in targeted cancer therapy, but the underlying mechanisms are poorly understood. Here we studied mechanisms of acquired resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) by examining genome-wide gene expression changes in KCL-22 CML cells versus their resistant KCL-22M cells that acquire T315I BCR-ABL mutation following TKI exposure. Although T315I BCR-ABL is sufficient to confer resistance to TKIs in CML cells, surprisingly we found that multiple drug resistance pathways were activated in KCL-22M cells along with reduced expression of a set of myeloid differentiation genes. Forced myeloid differentiation by all-trans-retinoic acid (ATRA) effectively blocked acquisition of BCR-ABL mutations and resistance to the TKIs imatinib, nilotinib or dasatinib in our previously described in vitro models of acquired TKI resistance. ATRA induced robust expression of CD38, a cell surface marker and cellular NADase. High levels of CD38 reduced intracellular nicotinamide adenine dinucleotide (NAD+) levels and blocked acquired resistance by inhibiting the activity of the NAD+-dependent SIRT1 deacetylase that we have previously shown to promote resistance in CML cells by facilitating error-prone DNA damage repair. Consequently, ATRA treatment decreased DNA damage repair and suppressed acquisition of BCR-ABL mutations. This study sheds novel insight into mechanisms underlying acquired resistance in CML, and suggests potential benefit of combining ATRA with TKIs in treating CML, particularly in advanced phases.

  10. ATO/ATRA/anthracycline-chemotherapy sequential consolidation achieves long-term efficacy in primary acute promyelocytic leukemia.

    Science.gov (United States)

    Long, Zi-Jie; Hu, Yuan; Li, Xu-Dong; He, Yi; Xiao, Ruo-Zhi; Fang, Zhi-Gang; Wang, Dong-Ning; Liu, Jia-Jun; Yan, Jin-Song; Huang, Ren-Wei; Lin, Dong-Jun; Liu, Quentin

    2014-01-01

    The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3, ATO) has been effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but the long-term efficacy and safety among newly diagnosed APL patients are unclear. In this retrospective study, total 45 newly diagnosed APL patients received ATRA/chemotherapy combination regimen to induce remission. Among them, 43 patients (95.6%) achieved complete remission (CR) after induction therapy, followed by ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment with a median follow-up of 55 months. In these patients, the estimated overall survival (OS) and the relapse-free survival (RFS) were 94.4% ± 3.9% and 94.6 ± 3.7%, respectively. The toxicity profile was mild and reversible. No secondary carcinoma was observed. These results demonstrated the high efficacy and minimal toxicity of ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for APL.

  11. Venom gland transcriptomes of two elapid snakes (Bungarus multicinctus and Naja atra) and evolution of toxin genes

    National Research Council Canada - National Science Library

    Jiang, Yu; Li, Yan; Lee, Wenhui; Xu, Xun; Zhang, Yue; Zhao, Ruoping; Zhang, Yun; Wang, Wen

    2011-01-01

    ...) libraries for Bungarus multicinctus and Naja atra, respectively. We sequenced about 1500 cDNA clones for each of the venom cDNA libraries and screened BAC libraries of the two snakes by blot analysis using four kinds of toxin probes; i.e...

  12. ATRA + ATO: has a new standard of care been established in low-risk acute promyelocytic leukaemia?

    Science.gov (United States)

    Breccia, Massimo; Cicconi, Laura; Lo-Coco, Francesco

    2014-03-01

    Arsenic trioxide (ATO) has been shown to be the most effective single agent in acute promyelocytic leukaemia (APL) and has been approved for the treatment of relapsed patients both in the US and Europe. The role of ATO in front-line therapy of APL is under investigation. Pilot studies using ATO with or without all-trans retinoic acid (ATRA) have been carried out in newly diagnosed APL patients with the aim to reduce the short and long-term toxic effects of chemotherapy and to improve clinical outcome. Especially in patients with non-high-risk APL, the ATRA + ATO approach allowed significant increase in event-free survival and overall survival rates compared to standard ATRA and chemotherapy. This has been demonstrated by pilot studies and, more recently, by a randomized comparative multi-centre study conducted in Italy and Germany. The ATO + ATRA strategy for APL may provide the first paradigm of acute leukaemia curability by targeted agents and without chemotherapy. However, longer follow-up of available studies and independent confirmation of the Italian-German findings are awaited to firmly establish this paradigm. Finally, extension of this approach to other patient categories such as high-risk, elderly and children will need to be explored in the near future.

  13. Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats.

    Science.gov (United States)

    Gregory, Elaine K; Webb, Antonio R; Vercammen, Janet M; Flynn, Megan E; Ameer, Guillermo A; Kibbe, Melina R

    2014-11-15

    Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POC membranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 μg of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 μmol/l) inhibited [(3)H]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POC membranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P atRA inhibited neointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit

  14. ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells.

    Science.gov (United States)

    Chee, L C Y; Hendy, J; Purton, L E; McArthur, G A

    2013-06-01

    All-trans retinoic acid (ATRA) is used successfully in the treatment of acute promyelocytic leukemia (APL). ATRA enhances hematopoietic stem cell self-renewal through retinoic acid receptor (RAR)γ activation while promoting differentiation of committed myeloid progenitors through RARα activation. Its lack of success in the treatment of non-APL acute myeloid leukemia (AML) may be related to ATRA's non-selectivity for the RARα and RARγ isotypes, and specific RARα activation may be more beneficial in promoting myeloid differentiation. To investigate this hypothesis, the effects of ATRA and the specific RARα agonist NRX195183 was assessed in AML1-ETO (AE)-expressing murine bone marrow (BM) progenitors. ATRA potentiated the in vitro clonogenicity of these cells while NRX195183 had the opposite effect. Morphological and flow cytometric analysis confirmed a predominantly immature myeloid population in the ATRA-treated AE cells while the NRX195183-treated cells demonstrated an increase in the mature myeloid population. Similarly, NRX195183 treatment promoted myeloid differentiation in an AE9a in vivo murine model. In the ATRA-treated AE cells, gene expression analyses revealed functional networks involving SERPINE1 and bone morphogenetic protein 2; AKT phosphorylation was upregulated. Collectively, these findings confirm the contrasting roles of specific RARα and RARγ activation in the clonogenicity and differentiation of AE cells with potential significant implications in the treatment of non-APL AML using a specific RARα agonist.

  15. Over-expression of Mcl-1 impairs the ability of ATRA to induce growth arrest and differentiation in acute promyelocytic leukemia cells.

    Science.gov (United States)

    Yang, Jing; Ikezoe, Takayuki; Nishioka, Chie; Yokoyama, Akihito

    2013-11-01

    Exposure of acute promyelocytic leukemia (APL) cells to all-trans retinoic acid (ATRA) increases levels of Mcl-1, however, the implication of ATRA-mediated expressions of Mcl-1 in these cells remains to be fully elucidated. This study found that exposure of NB4 and PL-21 cells to ATRA increased levels of Mcl-1 in association with phosphorylation of c-jun N-terminus kinases. Down-regulation of Mcl-1 by a small interfering (siRNA) or an inhibitor of JNK significantly potentiated the ability of ATRA to induce differentiation and apoptosis in these cells. On the other hand, the anti-leukemia effects of ATRA were blunted when Mcl-1 was forced expressed in NB4 and PL-21 cells as well as leukemia cells isolated from individuals with APL. Furthermore, down-regulation of Mcl-1 by an siRNA sensitized non-APL U937 and KG-1 leukemia cells to ATRA-mediated differentiation and apoptosis. Taken together, inhibition of Mcl-1 might be useful to potentiate the action of ATRA in APL as well as non-APL AML cells.

  16. Discovery, structural characterization and functional analysis of alpha-2-macroglobulin, a novel immune-related molecule from Holothuria atra.

    Science.gov (United States)

    Qian, Jing; Ren, Chunhua; Xia, Jianjun; Chen, Ting; Yu, Zonghe; Hu, Chaoqun

    2016-07-10

    The non-specific protease inhibitor alpha-2-macroglobulin (A2M) is a key macromolecular glycoprotein that involved in host immune defense against pathogens in vertebrates and invertebrates. However, no research regarding A2M has been developed in echinoderms to date. In this study, the full-length cDNA of A2M was cloned from the sea cucumber (Holothuria atra), which is a tropical species widely distributed along the coasts of the South China Sea and designated HaA2M. HaA2M possesses all three conserved functional domains of known A2M proteins, including the bait region domain, thioester domain and receptor-binding domain. Compared to fish and shrimp A2Ms, the histidine residue from the catalytical regions is well conserved in HaA2M. HaA2M mRNA was predominantly expressed in coelomocytes and, to a lesser extent, in the body wall, intestine and respiratory tree. A2M activity was detected in the coelomic fluids of H. atra. The mRNA expression and activity levels were investigated in the major immune tissues and coelomic fluids of H. atra after challenge with inactivated Vibrio alginolyticus or polyriboinosinic polyribocytidylic acid [Poly (I: C)]. RNA interference (RNAi)-mediated knockdown of HaA2M resulted in a significant reduction of HaA2M gene transcript level (86%). RNAi-mediated silencing of HaA2M gene significantly decreased the A2M activity (38%) and increased the number of viable bacteria (2.8-fold) in the coelomic fluids of H. atra infected by V. alginolyticus. Our study, as a whole, supplied the evidences for HaA2M as an immune-relevant molecule and it might have multiple functions in the innate immune system of H. atra. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Health Impact of Retinoic Acid (ATRA) on Ovalbumin-Sensitized F344 Rat Lung and Improvement of Tissue Pathology by Citral.

    Science.gov (United States)

    Farah, Ibrahim O; Holt-Gray, Carlene; Cameron, Joseph A; Tucci, Michelle; Cason, Zelma; Benghuzzi, Hamed

    2015-01-01

    The health impact of retinoic acid (All Trans Retinoic Acid; ATRA) in the development of lung pathology and tissue remodeling has not been well established in the literature. Equally, the role of Citral (inhibitor of retinoid function) in the improvement of lung pathology has not been ascertained in vivo. Therefore, it is hypothesized that ATRA and Ovalbumin (Egg albumin; OVA) exposure will sensitize lung tissues leading to lung tissue pathology and that citrals (C1 and C2) will reverse or ameliorate the related pathological damage to lung tissues. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=35). Animals were sensitized to OVA and then exposed to six different treatments; negative control (-ve), ATRA, Citrals (C1 and C2) and their triple combinations (OVA+ ATRA + C1, OVA+ ATRA + C2), by intra-peritoneal route. Rat weight data and blood were collected on Days 1 and 21, all animals were sacrificed on day 21, and lung tissues were processed for histopathology. Results from rat weights and blood (ANOVA and Duncan) as well as from the histopathological analysis of exposing the F344 rats to OVA in combinations with ATRA and citrals, revealed various levels of lung tissue damage that was impacted by exposure to citral. We conclude that OVA+ATRA+C1 combination treatment did improve lung pathology as compared to single individual treatments. However, the OVA+ATRA+C2 combination not only failed to improve these parameters, but even worsened the lung pathology of this model. This promising study showed variable responses on the interaction of Ovalbumin, citrals, and ATRA as related to their damage/improvement of related lung tissue pathologies.

  18. ATRA Signaling Regulates the Expression of COL9A1 through BMP2-WNT4-RUNX1 Pathway in Antler Chondrocytes.

    Science.gov (United States)

    Zhang, Hong-Liang; Guo, Bin; Yang, Zhan-Qing; Duan, Cui-Cui; Geng, Shuang; Wang, Kai; Yu, Hai-Fan; Yue, Zhan-Peng

    2017-09-01

    Although all-trans retinoic acid (ATRA) is involved in the regulation of cartilage growth and development, its regulatory mechanisms remain unknown. Here, we showed that ATRA could induce the expression of COL9A1 in antler chondrocytes. Silencing of cellular retinoic acid binding protein 2 (CRABP2) could impede the ATRA-induced upregulation of COL9A1, whereas overexpression of CRABP2 presented the opposite effect. RARα agonist Am80 induced the expression of COL9A1, whereas treatment with RARα antagonist Ro 41-5253 or RXRα small-interfering RNA (siRNA) caused an obvious blockage of ATRA on COL9A1. In antler chondrocytes, CYP26A1 and CYP26B1 weakened the sensitivity of ATRA to COL9A1. Simultaneously, Bone morphogenetic protein 2 (BMP2) and WNT4 mediated the regulation of ATRA on COL9A1 expression. Knockdown of WNT4 could abrogate the inhibitory effect of BMP2 overexpression on COL9A1. Conversely, constitutive expression of WNT4 reversed the upregulation of COL9A1 elicited by BMP2 siRNA. Together these data indicated that WNT4 might act downstream of BMP2 to mediate the effect of ATRA on COL9A1 expression. Further analysis evidenced that attenuation of runt-related transcription factor 1 (RUNX1) could prevent the stimulation of ATRA on COL9A1 expression, while exogenous rRUNX1 further enhanced this effectiveness. Moreover, RUNX1 might serve as an intermediate to mediate the regulation of BMP2 and WNT4 on COL9A1 expression. Collectively, ATRA signaling might regulate the expression of COL9A1 through BMP2-WNT4-RUNX1 pathway. © 2017 Wiley Periodicals, Inc.

  19. Status of ATR-A1 irradiation experiment on vanadium alloys and low-activation steels

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, H.; Strain, R.V.; Gomes, I.; Smith, D.L. [Argonne National Lab., IL (United States); Matsui, H. [Tohoku Univ. (Japan)

    1996-10-01

    The ATR-A1 irradiation experiment was a collaborative U.S./Japan effort to study at low temperature the effects of neutron damage on vanadium alloys. The experiment also contained a limited quantity of low-activation ferritic steel specimens from Japan as part of the collaboration agreement. The irradiation started in the Advanced Test Reactor (ATR) on November 30, 1995, and ended as planned on May 5, 1996. Total exposure was 132.9 effective full power days (EFPDs) and estimated neutron damage in the vanadium was 4.7 dpa. The vehicle has been discharged from the ATR core and is scheduled to be disassembled in the next reporting period.

  20. Hemolitic action of Naja naja atra cardiotoxin on erythrocytes from different animals

    Directory of Open Access Journals (Sweden)

    J. C. Troiano

    2006-01-01

    Full Text Available A comparative study on the sensitivity of erythrocytes from different vertebrate species (avian, mammalian and reptilian to the hemolytic action caused by cardiotoxin isolated from Naja naja atra venom was carried out. Cardiotoxin was able to induce direct hemolysis in washed erythrocytes from several animals, except for llama. The EC50 values from hemolysis of the most sensitive (cat and the most resistant (snake animal varied approximately tenfold. According to the cell behavior, it was possible to characterize four types of behavior: The first was observed in cat, horse and human cells; the second in rat, rabbit and dog erythrocytes; and the third only in llama erythrocytes, which were resistant to cardiotoxin concentrations up to 300 µg/ml. Finally, avian and reptilian erythrocytes were more resistant to cardiotoxin III-induced hemolysis than those of the mammalian species.

  1. Laboratory experiments on membrane filter sampling of airborne mycotoxins produced by Stachybotrys atra corda

    Science.gov (United States)

    Pasanen, A.-L.; Nikulin, M.; Tuomainen, M.; Berg, S.; Parikka, P.; Hintikka, E.-L.

    A membrane filter method for sampling of airborne stachybotrystoxins was studied in the laboratory. Toxigenic strains of Stachybotrys atra on wallpaper, grain, hay and straw were used as toxin sources in the experiments. Air samples were collected on cellulose nitrate and polycarbonate membrane filters at air flow rates of 10-20 ℓ min -1. After the filter sampling, the air was passed through methanol. The results showed that stachybotrystoxins (trichothecenes) were concentrated in airborne fungal propagules, and thus can be collected on filters. Polycarbonate filters with a pore size of 0.2 μm collected the highest percentage of toxic samples. The laboratory experiments indicated that polycarbonate filter sampling for the collection of airborne mycotoxins is a promising method for extension to field measurements.

  2. Novel Naja atra cardiotoxin 1 (CTX-1) derived antimicrobial peptides with broad spectrum activity.

    Science.gov (United States)

    Sala, Andrea; Cabassi, Clotilde Silvia; Santospirito, Davide; Polverini, Eugenia; Flisi, Sara; Cavirani, Sandro; Taddei, Simone

    2018-01-01

    Naja atra subsp. atra cardiotoxin 1 (CTX-1), produced by Chinese cobra snakes, belonging to Elapidae family, is included in the three-finger toxin family and exerts high cytotoxicity and antimicrobial activity too. Using as template mainly the tip and the subsequent β-strand of the first "finger" of this toxin, different sequences of 20 amino acids linear peptides have been designed in order to avoid toxic effects but to maintain or even strengthen the partial antimicrobial activity already seen for the complete toxin. As a result, the sequence NCP-0 (Naja Cardiotoxin Peptide-0) was designed as ancestor and subsequently 4 other variant sequences of NCP-0 were developed. These synthesized variant sequences have shown microbicidal activity towards a panel of reference and field strains of Gram-positive and Gram-negative bacteria. The sequence named NCP-3, and its variants NCP-3a and NCP-3b, have shown the best antimicrobial activity, together with low cytotoxicity against eukaryotic cells and low hemolytic activity. Bactericidal activity has been demonstrated by minimum bactericidal concentration (MBC) assay at values below 10 μg/ml for most of the tested bacterial strains. This potent antimicrobial activity was confirmed even for unicellular fungi Candida albicans, Candida glabrata and Malassezia pachydermatis (MBC 50-6.3 μg/ml), and against the fast-growing mycobacteria Mycobacterium smegmatis and Mycobacterium fortuitum. Moreover, NCP-3 has shown virucidal activity on Bovine Herpesvirus 1 (BoHV1) belonging to Herpesviridae family. The bactericidal activity is maintained even in a high salt concentration medium (125 and 250 mM NaCl) and phosphate buffer with 20% Mueller Hinton (MH) medium against E. coli, methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa reference strains. Considering these in vitro obtained data, the search for active sequences within proteins presenting an intrinsic microbicidal activity could provide a new way for

  3. Naja naja atra venom ameliorates pulmonary fibrosis by inhibiting inflammatory response and oxidative stress.

    Science.gov (United States)

    Cui, Kui; Kou, Jian-Qun; Gu, Jin-Hua; Han, Rong; Wang, Guanghui; Zhen, Xuechu; Qin, Zheng-Hong

    2014-12-02

    Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action. To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 μg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-β/Smad signaling pathway and oxidative stress were examined. The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1β and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-β/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model. The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

  4. Venom gland transcriptomes of two elapid snakes (Bungarus multicinctus and Naja atra) and evolution of toxin genes

    Science.gov (United States)

    2011-01-01

    Background Kraits (genus Bungarus) and cobras (genus Naja) are two representative toxic genera of elapids in the old world. Although they are closely related genera and both of their venoms are very toxic, the compositions of their venoms are very different. To unveil their detailed venoms and their evolutionary patterns, we constructed venom gland cDNA libraries and genomic bacterial artificial chromosome (BAC) libraries for Bungarus multicinctus and Naja atra, respectively. We sequenced about 1500 cDNA clones for each of the venom cDNA libraries and screened BAC libraries of the two snakes by blot analysis using four kinds of toxin probes; i.e., three-finger toxin (3FTx), phospholipase A2 (PLA2), kunitz-type protease inhibitor (Kunitz), and natriuretic peptide (NP). Results In total, 1092 valid expressed sequences tags (ESTs) for B. multicinctus and 1166 ESTs for N. atra were generated. About 70% of these ESTs can be annotated as snake toxin transcripts. 3FTx (64.5%) and β bungarotoxin (25.1%) comprise the main toxin classes in B. multicinctus, while 3FTx (95.8%) is the dominant toxin in N. atra. We also observed several less abundant venom families in B. multicinctus and N. atra, such as PLA2, C-type lectins, and Kunitz. Peculiarly a cluster of NP precursors with tandem NPs was detected in B. multicinctus. A total of 71 positive toxin BAC clones in B. multicinctus and N. atra were identified using four kinds of toxin probes (3FTx, PLA2, Kunitz, and NP), among which 39 3FTx-postive BACs were sequenced to reveal gene structures of 3FTx toxin genes. Conclusions Based on the toxin ESTs and 3FTx gene sequences, the major components of B. multicinctus venom transcriptome are neurotoxins, including long chain alpha neurotoxins (α-ntx) and the recently originated β bungarotoxin, whereas the N. atra venom transcriptome mainly contains 3FTxs with cytotoxicity and neurotoxicity (short chain α-ntx). The data also revealed that tandem duplications contributed the most to

  5. Reduced medical costs and hospital days when using oral arsenic plus ATRA as the first-line treatment of acute promyelocytic leukemia.

    Science.gov (United States)

    Jiang, Hao; Liang, Gong-Wen; Huang, Xiao-Jun; Jiang, Qian; Han, Sheng; Shi, Lu-Wen; Zhu, Hong-Hu

    2015-12-01

    We have demonstrated that oral arsenic (Realgar-Indigo naturalis formula, RIF) plus all-trans retinoic acid (ATRA) is not inferior to intravenous arsenic trioxide (ATO) plus ATRA as the first-line treatment of acute promyelocytic leukemia (APL). To compare the cost-effectiveness of oral and intravenous arsenic, we analyzed the results of 30 patients in each group involved in a randomized controlled trial at our center. The median total medical costs were $13,183.49 in the RIF group compared with $24136.98 in the ATO group (pATRA significantly reduced the medical costs and length of hospital stay during induction and remission therapy compared with ATO plus ATRA in APL patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Synthesis of (11)C-labeled retinoic acid, [(11)C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[(11)C]methylation.

    Science.gov (United States)

    Suzuki, Masaaki; Takashima-Hirano, Misato; Ishii, Hideki; Watanabe, Chika; Sumi, Kengo; Koyama, Hiroko; Doi, Hisashi

    2014-08-01

    Retinoids are a class of chemical compounds which include both natural dietary vitamin A (retinol) metabolites and active synthetic analogs. Both experimental and clinical studies have revealed that retinoids regulate a wide variety of essential biological processes. In this study, we synthesized (11)C-labeled all-trans-retinoic acid (ATRA), the most potent biologically active metabolite of retinol and used in the treatment of acute promyelocytic leukemia. The synthesis of (11)C-labeled ATRA was accomplished by a combination of rapid Pd(0)-mediated C-[(11)C]methylation of the corresponding pinacol borate precursor prepared by 8 steps and hydrolysis. [(11)C]ATRA will prove useful as a PET imaging agent, particularly for elucidating the improved therapeutic activity of ATRA (natural retinoid) for acute promyelocytic leukemia by comparing with the corresponding PET probe [(11)C]Tamibarotene (artificial retinoid). Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Biphasic pro-melanogenic and pro-apoptotic effects of all-trans-retinoic acid (ATRA) on human melanocytes: time-course study.

    Science.gov (United States)

    Baldea, Ioana; Costin, Gertrude-Emilia; Shellman, Yiqun; Kechris, Katerina; Olteanu, Elena Diana; Filip, Adriana; Cosgarea, Maria Rodica; Norris, David Albert; Birlea, Stanca Ariana

    2013-11-01

    The effects of retinoids on melanogenesis and their mechanism as depigmenting agents in topical therapy have not been fully elucidated. Conflicting data about their impact on melanogenic pathways have been reported. To investigate the effects of all-trans-retinoic acid (ATRA) on normal human melanocytes from Caucasian subjects. We assessed ATRA's cytotoxicity by measuring viability with a cell proliferation assay, and apoptotic effects using Annexin V and γ-H2AX markers. ATRA's melanogenic activity was investigated based on spectrophotometric measurement of melanin content and tyrosinase enzymatic activity. Tyrosinase expression was assessed by Western blotting. We tested the antioxidant activity of superoxide dismutase (SOD) and catalase (CAT) in melanocytes using a spectrophotometric assay. Of the concentrations tested in this 72h time-course study, the 1.0μM ATRA had a well-defined two-stage pro-melanogenic and pro-apoptotic effect on melanocytes. In the first 6h, treated cells showed significant increase (p≤0.01) of melanin content, tyrosinase, SOD, and CAT activities compared to the controls. While overall tyrosinase expression was not affected by ATRA, all other tested parameters decreased progressively beyond the short-term point of 6h. ATRA treatment of over 6h induced melanocyte apoptosis, as shown by the time-dependent decrease in cell viability, coupled with significant increase in Annexin V positive cells and nuclear accumulation of γ-H2AX foci. The results obtained using this testing platform show a biphasic ATRA action: immediate pro-melanogenic effect and longer-term exposure pro-apoptotic activity. These data qualify ATRA as a potent tool to better understand the mechanisms that regulate the pigmentary system. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  8. ATRA and As₂O₃ regulate differentiation of human hematopoietic stem cells into granulocyte progenitor via alteration of HoxB8 expression.

    Science.gov (United States)

    Liu, W-J; Jiang, N-J; Guo, Q-L; Xu, Q

    2015-01-01

    This study aimed to investigate the effect of all-trans retinoic acid (ATRA) and/or arsenic trioxide (As2O3) on homeobox B8 (HOXB8) mRNA and protein expressions during the differentiation and proliferation of hematopoietic stem cells (HSCs) to colony forming unit-granulocyte (CFU-G) in order to explore the pathogenesis of leukemia mediated by HOXB8 at mRNA and protein level. Twelve cord blood samples were collected from the fetal placenta umbilical vein and cultured in vitro. The proliferation and differentiation of cord blood HSCs into CFU-G was continuously disrupted with 10 nmol/l of ATRA and/or 10 nmol/l of As2O3. The expression of HOXB8 mRNA and protein were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western-blot, respectively. HOXB8 mRNA/protein expression was detected in control, ATRA, As2O3 and ATRA +As2O3 groups on days 3, 7, and 12 of culture. HOXB8 mRNA/protein expression was detectable on day 3, reached its highest level on day 7 and decreased on day 12. HOXB8 mRNA/protein expression in ATRA, As2O3 and ATRA+As2O3 was upregulated compared with control group (p ATRA/As2O3 up-regulate the expression of HOXB8 mRNA/protein, and treatment of leukemia with ATRA/As2O3 may regulate HOX gene expression.

  9. The Negative Impact of Combining Retinoic Acid (ATRA) and Mold Spores on F344 Rat Lung and Improvement of Tissue Pathology by Citral.

    Science.gov (United States)

    Farah, Ibrahim O; Holt-Gray, Carlene; Cameron, Joseph A; Tucci, Michelle; Cason, Zelma; Benghuzzi, Hamed

    2015-01-01

    The impact of retinoic acid (All Trans Retinoic Acid; ATRA) and Mold spores (MLD) in the development of lung pathology and in vivo tissue remodeling have not been well established in the literature. In addition, the role of citral (inhibitor of retinoid function) in the improvement of lung pathology has not been ascertained in animal studies. Therefore, it is hypothesized that ATRA and Mold (MLD) exposure will sensitize lung tissues leading to lung tissue pathology and that Citrals (C1 and C2) will reverse, ameliorate or improve the associated pathological damage to lung tissues. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=40). Animals were exposed to eight different treatments including vehicle, MLD, ATRA, Citrals (C1 and C2) and their MLD combinations (MLD+ ATRA, MLD+ C1, and MLD+ C2) by intra-peritoneal route. Rat weight and blood data were collected on Days 1 and 21, all animals were sacrificed on day 21, and lung tissues were processed for histopathology. Results from weight and blood data (ANOVA and Duncan) as well as from histopathological analyses supported the findings that exposure of F344 rats to MLD combinations with ATRA and Citrals showed various levels of lung tissue damage that were impacted by either C1 or C2. This promising study showed impressive responses on the interaction of MLD, Citrals, and ATRA as related to their impact on associated lung tissue pathologies.

  10. IMPACT OF PAIRED COMBINATIONS OF RETINOIC ACID (ATRA) AND OVALBUMIN ON F344 RAT LUNG TISSUES AND IMPROVEMENT OF RELATED PATHOLOGY BY CITRAL

    Science.gov (United States)

    Farah, Ibrahim O.; Holt-Gray, Carlene; Cameron, Joseph A.; Tucci, Michelle; Cason, Zelma; Benghuzzi, Hamed

    2014-01-01

    The impact of retinoic acid (All Trans Retinoic Acid; ATRA) in the development of lung pathology and tissue remodeling are not well established in the literature. As well, the role of citral (inhibitor of retinoid function) in the improvement of lung pathology was not ascertained under an in vivo setting. Therefore, it is hypothesized that ATRA and ovalbumin exposure will sensitize lung tissues leading to lung tissue pathology and that citrals (C1 and C2) will reverse or ameliorate the related pathological damage to lung tissues. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=40). Animals were exposed to 8 different treatments including vehicle, OVA, ATRA, citrals (C1 and C2) and their ovalbumin combinations (OVA+ ATRA, OVA+ C1, and OVA+ C2) by intra-peritoneal route. Rat weight data and blood were collected on Days 1 and 21, all animals were sacrificed on day 21 and lung tissues were processed for histopathology. Results from weights and blood (ANOVA and Duncan) as well as from the histopatholgical analysis supported the findings that exposure of F344 rats to OVA combinations with ATRA and citrals showed various levels of lung tissue damage that was improved or worsened by either C1 or C2. This promising study showed variable responses on the interaction of ovalbumin, citrals, and ATRA as related to their damage/improvement of related lung tissue pathologies. PMID:25405454

  11. The Negative Impact of Combining Retinoic Acid (ATRA) and Mold Spores on F344 Rat Lung and Improvement of Tissue Pathology by Citral

    Science.gov (United States)

    Farah, Ibrahim O.; Holt-Gray, Carlene; Cameron, Joseph A.; Tucci, Michelle; Cason, Zelma; Benghuzzi, Hamed

    2015-01-01

    The impact of retinoic acid (All Trans Retinoic Acid; ATRA) and Mold spores (MLD) in the development of lung pathology and in vivo tissue remodeling have not been well established in the literature. In addition, the role of citral (inhibitor of retinoid function) in the improvement of lung pathology has not been ascertained in animal studies. Therefore, it is hypothesized that ATRA and Mold (MLD) exposure will sensitize lung tissues leading to lung tissue pathology and that Citrals (C1 and C2) will reverse, ameliorate or improve the associated pathological damage to lung tissues. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=40). Animals were exposed to eight different treatments including vehicle, MLD, ATRA, Citrals (C1 and C2) and their MLD combinations (MLD+ ATRA, MLD+ C1, and MLD+ C2) by intra-peritoneal route. Rat weight and blood data were collected on Days 1 and 21, all animals were sacrificed on day 21, and lung tissues were processed for histopathology. Results from weight and blood data (ANOVA and Duncan) as well as from histopathological analyses supported the findings that exposure of F344 rats to MLD combinations with ATRA and Citrals showed various levels of lung tissue damage that were impacted by either C1 or C2. This promising study showed impressive responses on the interaction of MLD, Citrals, and ATRA as related to their impact on associated lung tissue pathologies PMID:25996741

  12. Impact of paired combinations of retinoic Acid (atra) and ovalbumin on f344 rat lung tissues and improvement of related pathology by citral.

    Science.gov (United States)

    Farah, Ibrahim O; Holt Gray, Charlene; Cameron, Joseph A; Tucci, Michelle A; Cason, Zelma; Benghuzzi, Hamed A

    2014-01-01

    The impact of retinoic acid (All Trans Retinoic Acid; ATRA) in the development of lung pathology and tissue remodeling are not well established in the literature. As well, the role of citral (inhibitor of retinoid function) in the improvement of lung pathology was not ascertained under an in vivo setting. Therefore, it is hypothesized that ATRA and ovalbumin exposure will sensitize lung tissues leading to lung tissue pathology and that citrals (C1 and C2) will reverse or ameliorate the related pathological damage to lung tissues. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=40). Animals were exposed to 8 different treatments including vehicle, OVA, ATRA, citrals (C1 and C2) and their ovalbumin combinations (OVA+ ATRA, OVA+ C1, and OVA+ C2) by intra-peritoneal route. Rat weight data and blood were collected on Days 1 and 21, all animals were sacrificed on day 21 and lung tissues were processed for histopathology. Results from weights and blood (ANOVA and Duncan) as well as from the histopatholgical analysis supported the findings that exposure of F344 rats to OVA combinations with ATRA and citrals showed various levels of lung tissue damage that was improved or worsened by either C1 or C2. This promising study showed variable responses on the interaction of ovalbumin, citrals, and ATRA as related to their damage/improvement of related lung tissue pathologies.

  13. Phylogeography of the Alpine salamander, Salamandra atra (Salamandridae) and the influence of the Pleistocene climatic oscillations on population divergence.

    Science.gov (United States)

    Riberon, A; Miaud, C; Grossenbacher, K; Taberlet, P

    2001-10-01

    Fifty individuals of the endemic Alpine salamander, Salamandra atra, representing 13 populations throughout the range of the two currently recognized subspecies, atra and aurorae, were examined for sequence variation in a large portion (1050 bp) of the mitochondrial cytochrome b gene. We revealed a large number of mitochondrial DNA (mtDNA) haplotypes (10). Interpopulation sequence divergence was very low, ranging from 0 to 3.1%. The relationships among haplotypes were poorly resolved. The divergence time estimate between several mtDNA haplotypes suggested a pre-Pleistocene differentiation approximately 3 million years ago. Moreover, the impact of the Pleistocene glaciations on the phylogeographical patterns appears to have been secondary, although a somewhat reduced genetic variability was found in populations living in areas that were directly affected by the glaciation.

  14. ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance.

    Directory of Open Access Journals (Sweden)

    Zhiqiang Wang

    2014-06-01

    Full Text Available Acquired resistance through genetic mutations is a major obstacle in targeted cancer therapy, but the underlying mechanisms are poorly understood. Here we studied mechanisms of acquired resistance of chronic myeloid leukemia (CML to tyrosine kinase inhibitors (TKIs by examining genome-wide gene expression changes in KCL-22 CML cells versus their resistant KCL-22M cells that acquire T315I BCR-ABL mutation following TKI exposure. Although T315I BCR-ABL is sufficient to confer resistance to TKIs in CML cells, surprisingly we found that multiple drug resistance pathways were activated in KCL-22M cells along with reduced expression of a set of myeloid differentiation genes. Forced myeloid differentiation by all-trans-retinoic acid (ATRA effectively blocked acquisition of BCR-ABL mutations and resistance to the TKIs imatinib, nilotinib or dasatinib in our previously described in vitro models of acquired TKI resistance. ATRA induced robust expression of CD38, a cell surface marker and cellular NADase. High levels of CD38 reduced intracellular nicotinamide adenine dinucleotide (NAD+ levels and blocked acquired resistance by inhibiting the activity of the NAD+-dependent SIRT1 deacetylase that we have previously shown to promote resistance in CML cells by facilitating error-prone DNA damage repair. Consequently, ATRA treatment decreased DNA damage repair and suppressed acquisition of BCR-ABL mutations. This study sheds novel insight into mechanisms underlying acquired resistance in CML, and suggests potential benefit of combining ATRA with TKIs in treating CML, particularly in advanced phases.

  15. Decitabine and SAHA-Induced Apoptosis Is Accompanied by Survivin Downregulation and Potentiated by ATRA in p53-Deficient Cells

    Directory of Open Access Journals (Sweden)

    Barbora Brodská

    2014-01-01

    Full Text Available While p53-dependent apoptosis is triggered by combination of methyltransferase inhibitor decitabine (DAC and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA in leukemic cell line CML-T1, reactive oxygen species (ROS generation as well as survivin and Bcl-2 deregulation participated in DAC + SAHA-induced apoptosis in p53-deficient HL-60 cell line. Moreover, decrease of survivin expression level is accompanied by its delocalization from centromere-related position in mitotic cells suggesting that both antiapoptotic and cell cycle regulation roles of survivin are affected by DAC + SAHA action. Addition of subtoxic concentration of all-trans-retinoic acid (ATRA increases the efficiency of DAC + SAHA combination on viability, apoptosis induction, and ROS generation in HL-60 cells but has no effect in CML-T1 cell line. Peripheral blood lymphocytes from healthy donors showed no damage induced by DAC + SAHA + ATRA combination. Therefore, combination of ATRA with DAC and SAHA represents promising tool for therapy of leukemic disease with nonfunctional p53 signalization.

  16. RIG-G inhibits the proliferation of NB4 cells and propels ATRA-induced differentiation of APL cells.

    Science.gov (United States)

    Lou, Ye-jiang; Pan, Xiao-rong; Jia, Pei-min; Jin, Jie; Tong, Jian-hua

    2016-01-01

    RIG-G (retinoic acid-induced gene G) was originally identified in ATRA (all-trans retinoic acid)-treated NB4 acute promyelocytic leukemia (APL) cells. It was induced to expression by ATRA along with the differentiation of the cells. However, little is known about its role(s). Here, we established a RIG-G stably expression transformant of NB4 cells. By using the transformant, we showed that expression of RIG-G in NB4 cells not only arrested the cells at G1/G0 transition phase and inhibited their proliferation, but also markedly drive the maturation of NB4 cells in the presence of very low concentration of ATRA (10(-9)mol/L). What's more, by detecting the expression of RIG-G in fresh primary bone marrow mononuclear cells of APL patients in different morbid states, we found high RIG-G expression level in complete remission patients, while low level in untreated or relapsed patients. These results indicated that RIG-G level was high in maturated cells and low in blast cells, and suggested that RIG-G might play a role in the differentiation of bone marrow hemocytes in vivo. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Suppression of Inflammation and Arthritis by Orally Administrated Cardiotoxin from Naja naja atra.

    Science.gov (United States)

    Chen, Cao-Xin; Chen, Jie-Yu; Kou, Jian-Qun; Xu, Yin-Li; Wang, Shu-Zhi; Zhu, Qi; Yang, Lu; Qin, Zheng-Hong

    2015-01-01

    Cardiotoxin (CTX) from Naja naja atra venom (NNAV) reportedly had analgesic effect in animal models but its role in inflammation and arthritis was unknown. In this study, we investigated the analgesic, anti-inflammatory, and antiarthritic actions of orally administered CTX-IV isolated from NNAV on rodent models of inflammation and adjuvant arthritis. CTX had significant anti-inflammatory effects in models of egg white induced nonspecific inflammation, filter paper induced rat granuloma formation, and capillary osmosis tests. CTX significantly reduced the swelling of paw induced by egg white, the inflammatory exudation, and the formation of granulomas. CTX reduced the swelling of paw, the AA clinical scores, and pathological alterations of joint. CTX significantly decreased the number of the CD4 T cells and inhibited the expression of relevant proinflammatory cytokines IL-17 and IL-6. CTX significantly inhibited the secretion of proinflammatory cytokine IL-6 and reduced the level of p-STAT3 in FLS. These results suggest that CTX inhibits inflammation and inflammatory pain and adjuvant-induced arthritis. CTX may be a novel therapeutic drug for treatment of arthritis.

  18. NMR solution structure of a Chymotrypsin inhibitor from the Taiwan cobra Naja naja atra.

    Science.gov (United States)

    Lin, Yi-Jan; Ikeya, Teppei; Güntert, Peter; Chang, Long-Sen

    2013-07-26

    The Taiwan cobra (Naja naja atra) chymotrypsin inhibitor (NACI) consists of 57 amino acids and is related to other Kunitz-type inhibitors such as bovine pancreatic trypsin inhibitor (BPTI) and Bungarus fasciatus fraction IX (BF9), another chymotrypsin inhibitor. Here we present the solution structure of NACI. We determined the NMR structure of NACI with a root-mean-square deviation of 0.37 Å for the backbone atoms and 0.73 Å for the heavy atoms on the basis of 1,075 upper distance limits derived from NOE peaks measured in its NOESY spectra. To investigate the structural characteristics of NACI, we compared the three-dimensional structure of NACI with BPTI and BF9. The structure of the NACI protein comprises one 310-helix, one α-helix and one double-stranded antiparallel β-sheet, which is comparable with the secondary structures in BPTI and BF9. The RMSD value between the mean structures is 1.09 Å between NACI and BPTI and 1.27 Å between NACI and BF9. In addition to similar secondary and tertiary structure, NACI might possess similar types of protein conformational fluctuations as reported in BPTI, such as Cys14-Cys38 disulfide bond isomerization, based on line broadening of resonances from residues which are mainly confined to a region around the Cys14-Cys38 disulfide bond.

  19. Suppression of Inflammation and Arthritis by Orally Administrated Cardiotoxin from Naja naja atra

    Directory of Open Access Journals (Sweden)

    Cao-Xin Chen

    2015-01-01

    Full Text Available Cardiotoxin (CTX from Naja naja atra venom (NNAV reportedly had analgesic effect in animal models but its role in inflammation and arthritis was unknown. In this study, we investigated the analgesic, anti-inflammatory, and antiarthritic actions of orally administered CTX-IV isolated from NNAV on rodent models of inflammation and adjuvant arthritis. CTX had significant anti-inflammatory effects in models of egg white induced nonspecific inflammation, filter paper induced rat granuloma formation, and capillary osmosis tests. CTX significantly reduced the swelling of paw induced by egg white, the inflammatory exudation, and the formation of granulomas. CTX reduced the swelling of paw, the AA clinical scores, and pathological alterations of joint. CTX significantly decreased the number of the CD4 T cells and inhibited the expression of relevant proinflammatory cytokines IL-17 and IL-6. CTX significantly inhibited the secretion of proinflammatory cytokine IL-6 and reduced the level of p-STAT3 in FLS. These results suggest that CTX inhibits inflammation and inflammatory pain and adjuvant-induced arthritis. CTX may be a novel therapeutic drug for treatment of arthritis.

  20. Naja naja atra Venom Protects against Manifestations of Systemic Lupus Erythematosus in MRL/lpr Mice

    Directory of Open Access Journals (Sweden)

    Jiali Zhu

    2014-01-01

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disease and effective therapy for this pathology is currently unavailable. We previously reported that oral administration of Naja naja atra venom (NNAV had anti-inflammatory and immune regulatory actions. We speculated that NNAV may have therapeutic effects in MRL/lpr SLE mice. Twelve-week-old MRL/lpr mice received oral administration of NNAV (20, 40, and 80 μg/kg or Tripterygium wilfordii polyglycosidium (10 mg/kg daily for 16 weeks. The effects of NNAV on SLE manifestations, including skin erythema, proteinuria, and anxiety-like behaviors, were assessed with visual inspection and Multistix 8 SG strips and open field test, respectively. The pathology of spleen and kidney was examined with H&E staining. The changes in autoimmune antibodies and cytokines were determined with ELISA kits. The results showed that NNAV protected against the manifestation of SLE, including skin erythema and proteinuria. In addition, although no apparent histological change was found in liver and heart in MRL/lpr SLE mice, NNAV reduced the levels of glutamate pyruvate transaminase and creatine kinase. Furthermore, NNAV increased serum C3 and reduced concentrations of circulating globulin, anti-dsDNA antibody, and inflammatory cytokines IL-6 and TNF-α. NNAV also reduced lymphadenopathy and renal injury. These results suggest that NNAV may have therapeutic values in the treatment of SLE by inhibiting autoimmune responses.

  1. Naja naja atra Venom Protects against Manifestations of Systemic Lupus Erythematosus in MRL/lpr Mice.

    Science.gov (United States)

    Zhu, Jiali; Cui, Kui; Kou, Jianqun; Wang, Shuzhi; Xu, Yinli; Ding, Zhihui; Han, Rong; Qin, Zhenghong

    2014-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease and effective therapy for this pathology is currently unavailable. We previously reported that oral administration of Naja naja atra venom (NNAV) had anti-inflammatory and immune regulatory actions. We speculated that NNAV may have therapeutic effects in MRL/lpr SLE mice. Twelve-week-old MRL/lpr mice received oral administration of NNAV (20, 40, and 80 μg/kg) or Tripterygium wilfordii polyglycosidium (10 mg/kg) daily for 16 weeks. The effects of NNAV on SLE manifestations, including skin erythema, proteinuria, and anxiety-like behaviors, were assessed with visual inspection and Multistix 8 SG strips and open field test, respectively. The pathology of spleen and kidney was examined with H&E staining. The changes in autoimmune antibodies and cytokines were determined with ELISA kits. The results showed that NNAV protected against the manifestation of SLE, including skin erythema and proteinuria. In addition, although no apparent histological change was found in liver and heart in MRL/lpr SLE mice, NNAV reduced the levels of glutamate pyruvate transaminase and creatine kinase. Furthermore, NNAV increased serum C3 and reduced concentrations of circulating globulin, anti-dsDNA antibody, and inflammatory cytokines IL-6 and TNF-α. NNAV also reduced lymphadenopathy and renal injury. These results suggest that NNAV may have therapeutic values in the treatment of SLE by inhibiting autoimmune responses.

  2. The Protective Effects of Cobra Venom from Naja naja atra on Acute and Chronic Nephropathy

    Directory of Open Access Journals (Sweden)

    Shu-Zhi Wang

    2013-01-01

    Full Text Available This study investigated the effects of Naja naja atra venom (NNAV on acute and chronic nephropathy in rats. Rats received 6 mg/kg adriamycin (ADR once to evoke the chronic nephropathy or 8 ml/kg 50% v/v glycerol to produce acute renal failure (ARF. The NNAV was given orally once a day starting five days prior to ADR or glycerol injection and continued to the end of experiments. The animals were placed in metabolic cages for 24 h for urine collection for urinary protein determination. The kidney function-related biochemical changes and index of oxidative stress were determined with automatic biochemistry analyzer or colorimetric enzyme assay kits. The pathomorphological changes were observed using light and transmission electron microcopies. The levels of inflammatory cytokines and NF-κB activation were determined using ELISA kits, Western blot analysis, or immunofluorescence. The results showed that NNAV relieved ADR-induced chronic nephropathy and glycerol-triggered acute renal failure syndromes including proteinuria, hypoalbuminemia, hyperlipidemia, serum electrolyte unbalance, renal oxidative stress, and pathological damages. NNAV reduced kidney levels of TNF-α and IL-1β, but it increased the levels of IκB-α and inhibited NF-κB p65 nuclear localization. These findings suggest that NNAV may be a valuable therapeutic drug for acute and chronic kidney diseases.

  3. Purification and cloning of cysteine-rich proteins from Trimeresurus jerdonii and Naja atra venoms.

    Science.gov (United States)

    Jin, Yang; Lu, Qiumin; Zhou, Xingding; Zhu, Shaowen; Li, Rui; Wang, Wanyu; Xiong, Yuliang

    2003-10-01

    Three 26 kDa proteins, named as TJ-CRVP, NA-CRVP1 and NA-CRVP2, were isolated from the venoms of Trimeresurus jerdonii and Naja atra, respectively. The N-terminal sequences of TJ-CRVP and NA-CRVPs were determined. These components were devoid of the enzymatic activities tested, such as phospholipase A(2), arginine esterase, proteolysis, L-amino acid oxidase, 5'nucleotidase, acetylcholinesterase. Furthermore, these three components did not have the following biological activities: coagulant and anticoagulant activities, lethal activity, myotoxicity, hemorrhagic activity, platelet aggregation and platelet aggregation-inhibiting activities. These proteins are named as cysteine-rich venom protein (CRVP) because their sequences showed high level of similarity with mammalian cysteine-rich secretory protein (CRISP) family. Recently, some CRISP-like proteins were also isolated from several different snake venoms, including Agkistrodon blomhoffi, Trimeresurus flavoviridis, Lanticauda semifascita and king cobra. We presumed that CRVP might be a common component in snake venoms. Of particular interest, phylogenetic analysis and sequence alignment showed that NA-CRVP1 and ophanin, both from elapid snakes, share higher similarity with CRVPs from Viperidae snakes.

  4. Effect of All-Trans Retinoic Acid (ATRA against expression of Matrix Metalloproteinase-2 (MMP-2 in model mice (Rattus norvegicus periodontitis

    Directory of Open Access Journals (Sweden)

    Ilma Soraya

    2017-08-01

    Full Text Available Introduction: Periodontitis is a condition of inflammation of the tooth supporting tissues generally caused by bacteria Phorphyromonas gingivalis (Pg. and is usually characterized by the occurrence of the alveolar bone resorption. Matrix metalloproteinase-2 (MMP-2 is an enzyme that plays an important role in inflammatory conditions. All-trans retinoic acid (ATRA is a metabolite of vitamin A which plays a role in healing the inflamed tissue and maintain the immune system. The purpose of this study was to determine the effect of ATRA on the expression of MMP-2 in mouse models Rattus norvegicus of periodontitis. Methods: Experimental laboratory by using post test only with control group design. This study used 25 male Wistar mice (Rattus norvegicus that divided into 5 groups. Group 1 (G1 is a group of healthy mice, group 2 (G2 is a group of sick mice as induced periodontitis without treatment, group 3 (G3 is a group of periodontitis mice treated with 5 mg/kg dose of ATRA, group 4 (G4 is a group of periodontitis mice treated with 10 mg/kg dose of ATRA, group 5 (G5 is a group of periodontitis mice treated with 20 mg/kg dose of ATRA. Periodontitis induction was induced by Pg. bacteria every 3 days for 28 days and followed by administration of ATRA for 7 days. Expression of MMP-2 from gingival tissues and periodontal ligament was obtained by immunohistochemical methods. Results were analyzed using the Shapiro-Wilk Test and Mann-Whitney Test. Results: The results showed there were significant differences in the positive area of MMP-2 and MMP-2 color intensity (p < 0.05 between groups. Conclusion: ATRA dose of 20 mg/kg is the most effective dose in inhibiting the expression of MMP-2 in mice models of periodontitis when compared with the dose on other groups.

  5. All-trans-retinoid acid (ATRA) may have inhibited chondrogenesis of primary hind limb bud mesenchymal cells by downregulating Pitx1 expression.

    Science.gov (United States)

    Wang, Yun-guo; Li, Xue-dong; Liu, Zhao-yong; Zhang, Tao-gen; Chen, Bin; Hou, Guo-qing; Hong, Quan; Xie, Peng; Du, Shi-xin

    2014-01-13

    Despite frequently well-established role of all-trans-retinoid acid (ATRA) in congenital limb deformities, its mechanism of action, thus far, is still ambiguous. Pitx1, which is expressed in the hindlimb bud mesenchyme, or its pathways may be etiologically responsible for the increased incidence of clubfoot. Here, we sought to investigate the mechanisms whereby Pitx1 regulated chondrogenesis of hindlimb bud mesenchymal cells in vitro. E12.5 embryonic rat hind limb bud mesenchymal cells were treated with ATRA at appropriate concentrations. Cell Counting Kit-8 (CCK-8) assay was performed to evaluate cell proliferation. Hematoxylin-safranin-O-fast-green staining assays were used to observe cartilage nodules, and Pitx1 expression was examined by immunofluorescent microscopy. Real-time quantitative PCR and immunoblotting assays were applied to determine the mRNA expressions of Pitx1, Sox9 and type II collagen (Col2al), respectively. The results showed that ATRA inhibited the proliferation of hind limb bud cells dose-dependently. ATRA also induced a dose-dependent reduction in the number of cartilage nodules and the area of cartilage nodules compared with controls. Our real-time quantitative RT-PCR assays revealed that the mRNA expression of Pitx1, Sox9 and Col2al were significantly downregulated by ATRA. Furthermore, our immunofluorescent microscopy and Western blotting assays indicated that Pitx1 was mainly expressed in the cartilage nodules and the levels of Pitx1, Sox9 and Col2al were also downregulated by ATRA dose-dependently. The results indicated that ATRA may decrease chondrogenesis of hind limb bud mesenchymal cells by inhibiting cartilage-specific molecules, such as Sox9 and Col2al, via downregulating Pitx1 expression. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. Activation of G0S2 is coordinated by recruitment of PML/RARα and C/EBPε to its promoter during ATRA-induced APL differentiation.

    Science.gov (United States)

    Zhang, Fang; Zhu, Yong Lan; Deng, Wang Long; Zhu, Jiang; Zhang, Ji

    2017-03-01

    All-trans retinoic acid (ATRA) binds the promyelocytic leukemia/retinoic acid receptor α (PML/RARα) fusion protein and is an effective oncogene-targeted therapy for acute promyelocytic leukemia (APL). However, the molecular basis of PML/RARα-mediated transcriptional control during ATRA-induced differentiation is unclear. Previous studies have shown that the PML/RARα fusion protein behaves as a type II nuclear receptor, binding to DNA regardless of ligand status. Here, we performed a series of chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) experiments, demonstrating that there is an additional mode of action of PML/RARα, wherein PML/RARα does not bind DNA in the absence of ATRA but binds DNA and activates adjacent genes in the presence of ATRA. This mode of action is similar to that of a type I nuclear receptor and is highlighted by activation of G0/G1 switch gene 2 (G0S2) during ATRA-induced neutrophil differentiation of leukemia cell lines (NB4 and PR9) and primary human APL cells. C/EBPε occupancy of the G0S2 promoter was elevated in parallel with recruitment of PML/RARα in ATRA-treated NB4, PR9, and primary APL cells. Furthermore, we verified that the p30 isoform of C/EBPε is crucial for activation of G0S2 and that PML/RARα interacts physically and cooperates functionally with C/EBPε to up-regulate G0S2 Our data not only demonstrate a new mode of action of PML/RARα but also suggest a novel model in which PML/RARα synergizes with C/EBPε to reactivate the C/EBPε target G0S2, thereby contributing to ATRA-mediated APL differentiation and potentially, clinical remission. © Society for Leukocyte Biology.

  7. ATRA-induced HL-60 myeloid leukemia cell differentiation depends on the CD38 cytosolic tail needed for membrane localization, but CD38 enzymatic activity is unnecessary.

    Science.gov (United States)

    Congleton, Johanna; Jiang, Hong; Malavasi, Fabio; Lin, Hening; Yen, Andrew

    2011-04-15

    Leukocyte antigen CD38 expression is an early marker of all-trans retinoic acid (ATRA) stimulated differentiation in the leukemic cell line HL-60. It promotes induced myeloid maturation when overexpressed, whereas knocking it down is inhibitory. It is a type II membrane protein with an extracellular C-terminal enzymatic domain with NADase/NADPase and ADPR cyclase activity and a short cytoplasmic N-terminal tail. Here we determined whether CD38 enzymatic activity or the cytoplasmic tail is required for ATRA-induced differentiation. Neither a specific CD38 ectoenzyme inhibitor nor a point mutation that cripples enzymatic activity (CD38 E226Q) diminishes ATRA-induced differentiation or G1/0 arrest. In contrast a cytosolic deletion mutation (CD38 Δ11-20) prevents membrane expression and inhibits differentiation and G1/0 arrest. These results may be consistent with disrupting the function of critical molecules necessary for membrane-expressed CD38 signal transduction. One candidate molecule is the Src family kinase Fgr, which failed to undergo ATRA-induced upregulation in CD38 Δ11-20 expressing cells. Another is Vav1, which also showed only basal expression after ATRA treatment in CD38 Δ11-20 expressing cells. Therefore, the ability of CD38 to propel ATRA-induced myeloid differentiation and G1/0 arrest is unimpaired by loss of its ectoenzyme activity. However a cytosolic tail deletion mutation disrupted membrane localization and inhibited differentiation. ATRA-induced differentiation thus does not require the CD38 ectoenzyme function, but is dependent on a membrane receptor function. Copyright © 2010. Published by Elsevier Inc.

  8. EXPERIMENTAL INDUCTION OF LUNG DAMAGE IN THE F344 RAT UPON EXPOSURE TO CITRAL, RETINOIC ACID (ATRA), OVALBUMIN AND MOLD SPORES

    Science.gov (United States)

    Holt-Gray, Carlene; Cameron, Joseph A.; Tucci, Michelle; Cason, Zelma; Benghuzzi, Hamed

    2014-01-01

    The experimental impact of retinoic acid (All Trans Retinoic Acid; ATRA), citrals, ovalbumin and mold spores in the development of lung pathology and tissue remodeling are not well established in the literature. As well, the role of these agents in lung pathology was not ascertained under an in vivo setting. Therefore, it is hypothesized that citrals, ATRA, ovalbumin and mold-spore exposure will sensitize lung tissues and will lead to the development of lung tissue pathology in these animals. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=30). Mold spores were applied to animals by intra-tracheal route whereas vehicle, ovalbumin, C1, C2 and ATRA were administered by intra-peritoneal route. Rat weight data and blood were collected on Days 1 and 21. All animals were sacrificed on day 21 and lung tissues were processed for histopathology. Evidence from weights and blood (ANOVA and Duncan) as well as histopatholgical analysis supported the findings that exposure of these animals to C1, C2, ATRA, ovalbumin and mold spores showed different levels of lung tissue damage representing environmental exposure to these agents. This promising study showed variable lung tissue responses to the administration of ATRA, ovalbumin, citrals, and mold spores in the development of various levels of lung tissue pathologies. PMID:25405452

  9. RAF-1/MEK/ERK pathway regulates ATRA-induced differentiation in acute promyelocytic leukemia cells through C/EBPβ, C/EBPε and PU.1.

    Science.gov (United States)

    Weng, Xiang-Qin; Sheng, Yan; Ge, Dong-Zheng; Wu, Jing; Shi, Lei; Cai, Xun

    2016-06-01

    MEK/ERK signal pathway was required for the differentiation of granulocytes, megakaryocytes and erythrocytes. Recently, MEK/ERK cascade was reported to be involved in all-trans retinoic acid (ATRA) induced differentiation in acute promyelocytic leukemia (APL) cells. However, the upstream and downstream molecules of MEK/ERK signal pathway in this cell model remains to be elucidated. In this work, we showed that RAF-1 was activated and the blockade of RAF-1 activation attenuated MEK/ERK activation as well as ATRA-induced differentiation. ATRA-enhanced protein levels of C/EBPβ, C/EBPε and PU.1, which were required for differentiation in APL cells, were suppressed by the specific inhibitor of MEK. However, MEK inhibition had no effect on the degradation of PML-RARα fusion protein or the restoration of PML nuclear bodies by ATRA treatment. Taken together, our study suggested that RAF-1/MEK/ERK cascade was involved in ATRA-induced differentiation in APL cells through enhancing the protein level of C/EBPβ, C/EBPε and PU.1. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Induction mortality, ATRA administration, and resource utilization in a nationally representative cohort of children with acute promyelocytic leukemia in the United States from 1999 to 2009.

    Science.gov (United States)

    Fisher, Brian T; Singh, Sonia; Huang, Yuan-Shung; Li, Yimei; Gregory, John; Walker, Dana; Seif, Alix E; Kavcic, Marko; Aplenc, Richard

    2014-01-01

    Limited data exist on induction mortality of pediatric patients with acute promyelocytic leukemia in the United States, usage of all-trans retinoic acid (ATRA) during acute promyelocytic leukemia induction, and the resources needed to deliver induction therapy. Using the Pediatric Health Information System database we established a retrospective cohort of patients treated for newly diagnosed acute promyelocytic leukemia with ATRA between January 1999 and September 2009 in 32 of 43 PHIS contributing free-standing pediatric hospitals in the United States. Standard statistical methods were used to determine in-hospital induction mortality, ATRA administration, and resource utilization during a 60-day observation period. A total of 163 children were identified who met eligibility criteria for cohort inclusion; 52% were female and 76% were white with an average age of 12.7 years. A total of 12 patients (7.4%) died, with 7 (58.3%) dying within the first 7 days of first admission. The mean time to first ATRA exposure increased with decreasing age (P = 0.0016). Resource utilization for management of retinoic acid syndrome was higher than anticipated based on prior studies and differed significantly from patients with non-M3 acute myeloid leukemia. The induction mortality for pediatric acute promyelocytic leukemia remains substantial with wide variation in ATRA administration and high rates of resource utilization. © 2013 Wiley Periodicals, Inc.

  11. Pseudotumour cerebri in acute promyelocytic leukemia on treatment with all-trans-retinoic acid (ATRA) - an experience from a tertiary care centre.

    Science.gov (United States)

    Ahmad Tali, Manzoor; Bashir, Yasir; Bhat, Shuaeb; Manzoor, Fahim; Bashir, Nusrat; Geelani, Sajad; Rasool, Javid; Waheed Mir, Abdul

    2015-08-01

    Acute promyelocytic leukemia (APML) is considered to be sensitive to all-trans-retinoic acid (ATRA) which acts as a differentiating agent. ATRA is considered to be a well-tolerated agent and is known to achieve complete remission in acute promyelocytic leukemia. However, a few cases on long term all-trans-retinoic acid (ATRA) use can develop pseudotumor cerebri. Out of 32 patients with APML who were treated in our Centre over a 4-year-period, we encountered 6 patients who developed ATRA-related pseudotumor cerebri while on maintenance treatment. The patients ranged from 12 to 40 years of age. 3 patients complained of unbearable headache, 2 of diplopia and 1 of gross reduction in visual acuity. CT scans and MRI did not reveal any intracranial lesions. Cerebrospinal fluid (CSF) examination was normal with CSF manometry revealing a high CSF pressure (average of 345mmH2O). Fundoscopy revealed papilledema in 5 patients and optic atrophy in 1 patient. The patients were successfully managed with decrease dose/discontinuation of ATRA, use of acetazolamide, corticosteroids and therapeutic CSF drainage.

  12. Experimental induction of lung damage in the f344 rat upon exposure to citral, retinoic Acid (atra), ovalbumin and mold spores.

    Science.gov (United States)

    Farah, Ibrahim O; Holt Gray, Carlene; Cameron, Joseph A; Tucci, Michelle A; Cason, Zelma; Benghuzzi, Hamed A

    2014-01-01

    The experimental impact of retinoic acid (All Trans Retinoic Acid; ATRA), citrals, ovalbumin and mold spores in the development of lung pathology and tissue remodeling are not well established in the literature. As well, the role of these agents in lung pathology was not ascertained under an in vivo setting. Therefore, it is hypothesized that citrals, ATRA, ovalbumin and mold-spore exposure will sensitize lung tissues and will lead to the development of lung tissue pathology in these animals. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=30). Mold spores were applied to animals by intra-tracheal route whereas vehicle, ovalbumin, C1, C2 and ATRA were administered by intra-peritoneal route. Rat weight data and blood were collected on Days 1 and 21. All animals were sacrificed on day 21 and lung tissues were processed for histopathology. Evidence from weights and blood (ANOVA and Duncan) as well as histopatholgical analysis supported the findings that exposure of these animals to C1, C2, ATRA, ovalbumin and mold spores showed different levels of lung tissue damage representing environmental exposure to these agents. This promising study showed variable lung tissue responses to the administration of ATRA, ovalbumin, citrals, and mold spores in the development of various levels of lung tissue pathologies.

  13. Neurotoxin from Naja naja atra venom inhibits skin allograft rejection in rats.

    Science.gov (United States)

    Xu, Yin-Li; Kou, Jian-Qun; Wang, Shu-Zhi; Chen, Cao-Xin; Qin, Zheng-Hong

    2015-09-01

    Recent studies reported that Naja naja atra venom (NNAV) regulated immune function and had a therapeutic effect on adjunctive arthritis and nephropathy. We hypothesized that NNAV and its active component, neurotoxin (NTX), might inhibit skin allograft rejection. Skin allografts were used to induce immune rejection in rats. In addition, mixed lymphocyte culture (MLC) was used to mimic immune rejection reaction in vitro. Both NNAV and NTX were orally given starting from 5days prior to skin allograft surgery. The results showed that oral administration of NNAV or NTX prolonged the survival of skin allografts and inhibited inflammatory response. The production of Th1 cytokines (IFN-γ, IL-2) was also suppressed. NTX inhibited T-cell proliferation and CD4(+) T cell division induced by skin allografts. NTX also showed immunosuppressive activity in mixed lymphocyte culture. Atropine alone inhibited Con A-induced proliferation of T cells and potentiated NTX' s inhibitory effects on T cells, while pilocarpine only slightly enhanced Con A-induced T cell proliferation and partially reversed the inhibitory effect of NTX. On the other hand, neither nicotine nor mecamylamine had an influence on NTX's inhibitory effects on Con A-induced T cell proliferation in vitro. NTX inhibited T cell proliferation by arresting the cell cycle at the G0/G1 phase. The present study revealed that NNAV and NTX suppressed skin allograft rejection by inhibiting T cell-mediated immune responses. These findings suggest both NNAV and NTX as potential immunosuppressants for preventing the immune response to skin allografts. Copyright © 2015. Published by Elsevier B.V.

  14. Transcriptional regulation of Tal2 gene by all-trans retinoic acid (atRA) in P19 cells.

    Science.gov (United States)

    Kobayashi, Takanobu; Suzuki, Masayo; Morikawa, Masayuki; Kino, Katsuhito; Tanuma, Sei-ichi; Miyazawa, Hiroshi

    2015-01-01

    TAL2 is a transcription factor required in the normal development of mouse brain. In a previous study, we demonstrated that the expression of Tal2 gene is induced by the complex of all-trans retinoic acid (atRA) and retinoic acid receptor α (RARα) in mouse embryonal carcinoma P19 cells. atRA is also known to be important in inducing P19 cells to differentiate into the neural lineage. Therefore, we believe that the function of TAL2 in neural differentiation may be clarified by utilizing P19 cells. As the atRA-RARα complex induced the expression of Tal2, we focused on the regulatory region that is involved in its transcription. The atRA-RARα complex occupies a characteristic retinoic acid response element (RARE) located in the promoter of target genes. Therefore, we searched for RARE on the mouse Tal2 and found that a RARE-like element was located in the intron. We also found that a TATA-box-like element was located in the 5'-region of Tal2. Involvement between transcriptional activity and the TATA-box-like element was confirmed in the luciferase assay, and TATA-box binding protein was bound to this element upstream of Tal2 in P19 cells. atRA signaling activated the transcription through the RARE-like element, and RARα was bound to this element on Tal2 in P19 cells. In addition, the interaction between these elements on Tal2 was shown in the chromatin immunoprecipitation assay. These results suggest that the transcription of Tal2 is coordinately mediated by two distal regulatory elements.

  15. Microstructural examination of V-(3-6%)Cr-(3-5%)Ti irradiated in the ATR-A1 experiment

    Energy Technology Data Exchange (ETDEWEB)

    Gelles, D.S. [Pacific Northwest National Lab., Richland, WA (United States)

    1998-09-01

    Microstructural examination results are reported for four heats of V-(3-6%)Cr-(3-5%)Ti irradiated in the ATR-A1 experiment to {approximately}4 dpa at {approximately}200 and 300 C to provide an understanding of the microstructural evolution that may be associated with degradation of mechanical properties. Fine precipitates were observed in high density intermixed with small defect clusters for all conditions examined following the irradiation. The irradiation-induced precipitation does not appear to be affected by preirradiation heat treatment or composition.

  16. Thwarting PTEN Expression by siRNA Augments HL-60 Cell Differentiation to Neutrophil-Like Cells by DMSO and ATRA.

    Science.gov (United States)

    Teimourian, Shahram; Moghanloo, Ehsan

    2016-10-01

    Abnormal cell differentiation, in particular suppression of terminal cell differentiation, exists in all tumors. Therapeutic interventions to restore terminal differentiation ("differentiation therapy") are a very attractive way to treat cancer, especially leukemia. A variety of chemicals stimulates differentiation of leukemic cells, such as dimethyl sulfoxide (DMSO) and all-trans retinoic acid (ATRA). Tumor suppressor genes have a vital role in the gateway to terminal cell differentiation. In this study, we inhibited PTEN tumor suppressor gene expression by siRNA to investigate the effect of potentiating cell survival and inhibiting apoptosis on HL-60 cell differentiation by DMSO and ATRA. Our results show that PTEN siRNA increases HL-60 cell differentiation in the presence of DMSO and ATRA. At the same time, the presence of siRNA hampers accumulation of apoptotic cells during incubation. Our study suggests that manipulation of PTEN could hold promise for enhancing efficacy of differentiation therapy of acute myelogenous leukemia.

  17. Enhanced expression of tumour suppressor RAR-β by DSPC nano-formulated lipo-ATRA in the lung of B16F10 cell-implanted C57BL6 mice and in A549 cells.

    Science.gov (United States)

    Berlin Grace, V M; Reji, Reshma Mahima; Sundaram, Viswanathan

    2017-09-01

    All Trans Retinoic acid (ATRA) is an efficient drug for leukemia, but is not efficient therapy for solid cancers. Hence we have used 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol lipo-ATRA to investigate its molecular therapeutic effect on lung cancer. The objective was to find whether it could enhance ATRA receptor, RAR-β expression in lung cells as it was lost in majority of cancers including lung cancer. The study was made in an experimental C57BL/6 mice model developed by tail vein injection of B16F10 cells and in A549 human lung cancer cells. The RAR-β protein expression was studied by Immunohistochemistry/Immunocytochemistry and the mRNA expression was studied by RT-PCR and qPCR methods. Both free and lipo-ATRA treatments showed an enhancement of RAR-β protein and gene expressions, indicating its induction on RAR β. However, lipo-ATRA treatment has shown significant induction when compared with free ATRA treatment. Our results implies that the DSPC lipo-ATRA treatment might have accumulated more ATRA in to the target cells which might have resulted in the induction of its receptor RAR-β expression in a hypothesis of ligand induced receptor expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Effect of ATRA on the expression of HOXA5 gene in K562 cells and its relationship with cell cycle and apoptosis.

    Science.gov (United States)

    Liu, Wen-Jun; Zhang, Teng; Guo, Qu-Lian; Liu, Chun-Yan; Bai, Yong-Qi

    2016-05-01

    Leukemia is the most common malignant disease in children with high incidence and mortality rates, and a poor treatment effect. The aim of the present study was to examine the changes in the expression of homeobox (Hox) A5 gene and its relationship with cell cycle and apoptosis through the intervention of human K562 myeloid leukemia cell line by all-trans retinoic acid (ATRA), to analyze the role of HOXA5 in the pathogenesis and development process of myeloid leukemia. The optimal concentration of ATRA to be used with K562 cells was determined using a cell counting kit‑8 (CCK‑8). After 24, 72 and 48 h following treatment of K562 cells with 10 µmol/l ATRA, cell cycle events and apoptosis were measured using flow cytometry. HOXA5 mRNA and protein expression in K562 cells was assessed by RT‑PCR and western blot analysis, and the relationship between HOXA5 expression and cell cycle and apoptosis was analyzed. The HOXA5 mRNA and protein expression levels were increased following treatment with ATRA in K562 cells. Apoptosis was increased significantly. The cell cycle was inhibited in G0/G1 phase. Cell proliferation was also inhibited. HOXA5 mRNA and protein expression rates positively correlated with cell apoptosis and the increased percentage and cell cycle of the G0/G1 phase. However, HOXA5 negatively correlated with the reduced percentage of S stage. In conclusion, the expression of HOXA5 in cells was increased following treatment with ATRA in K562 cells, in a time-dependent manner. Additionally, ATRA may inhibit the proliferation of K562 cells and promote apoptosis by upregulating the HOXA5 mRNA and protein expression.

  19. Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O 3) in acute promyelocytic leukemia.

    Science.gov (United States)

    Tomita, Akihiro; Kiyoi, Hitoshi; Naoe, Tomoki

    2013-06-01

    Since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) for the treatment of acute promyelocytic leukemia (APL), the overall survival rate has improved dramatically. However, relapse/refractory patients showing resistance to ATRA and/or As2O3 are recognized as a clinically significant problem. Genetic mutations resulting in amino acid substitution in the retinoic acid receptor alpha (RARα) ligand binding domain (LBD) and the PML-B2 domain of PML-RARα, respectively, have been reported as molecular mechanisms underlying resistance to ATRA and As2O3. In the LBD mutation, ATRA binding with LBD is generally impaired, and ligand-dependent co-repressor dissociation and degradation of PML-RARα by the proteasome pathway, leading to cell differentiation, are inhibited. The PML-B2 mutation interferes with the direct binding of As2O3 with PML-B2, and PML-RARα SUMOylation with As2O3 followed by multimerization and degradation is impaired. To overcome ATRA resistance, utilization of As2O3 provides a preferable outcome, and recently, a synthetic retinoid Am80, which has a higher binding affinity with PML-RARα than ATRA, has been tested in the clinical setting. However, no strategy attempted to date has been successful in overcoming As2O3 resistance. Detailed genomic analyses using patient samples harvested repeatedly may help in predicting the prognosis, selecting the effective targeting drugs, and designing new sophisticated strategies for the treatment of APL.

  20. Down-regulation of sphingosine kinase 2 (SphK2) increases the effects of all-trans-retinoic acid (ATRA) on colon cancer cells.

    Science.gov (United States)

    Chu, Jia-Hui; Gao, Zu-Hua; Qu, Xian-Jun

    2014-10-01

    Sphingosine kinase 2 (SphK2) is a type of sphingosine kinase, which express highly in most of cancers. SphK2 produce sphingosine-1-phosphate (S1P) and then accumulate in cancer cells. Our previous study showed that S1P antagonized the effects of all-trans-retinoic acid (ATRA) via the receptor-dependent and independent pathway. In this study, we aimed to investigate the roles of SphK2 in affecting ATRA's activity in human colon cancer cells. Cell proliferation was estimated by the clonogenic assay. The distribution of cell cycle was analyzed by flow cytometry assay. The apoptotic cells were determined by Annexin V-FITC/PI staining method. Western blotting assay was performed to analyze the levels of the proteins related to apoptosis and cell cycle. The mRNA levels of SphK2 and RARβ were evaluated by real-time PCR assay. RNA interference assay was performed to evaluate SphK2 activity. S1P antagonized the effect of ATRA on HT-29 cell proliferation, the ATRA-induced RARβ expression, the arrest of cell cycle in G1-phase, and induction of apoptosis. Down-regulation of SphK2 resulted in the reverse actions on the S1P-induced antagonistic effects on ATRA. Western blotting analysis indicated that down-regulation of SphK2 might activate apoptotic proteins, regulation of p53/p21(Waf1/Cip1) and EGFR and PI3K/AKT signaling pathways. In conclusion, down-regulation of SphK2 increased the effects of ATRA on colon cancer cells. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  1. The retinoic acid receptor-α modulators ATRA and Ro415253 reciprocally regulate human IL-5+ Th2 cell proliferation and cytokine expression.

    Science.gov (United States)

    Wansley, Daniel L; Yin, Yuzhi; Prussin, Calman

    2013-12-06

    Th2 cytokine responses are enhanced by all trans retinoic acid (ATRA), the bioavailable form of vitamin A. Retinoic acid receptor alpha (RARα) is the high affinity receptor for ATRA that mediates these pro-Th2 effects. We have previously characterized two major human Th2 subpopulations: IL-5- Th2 (IL-5-, IL-4+, IL-13+) and IL-5+ Th2 cells (IL-5+, IL-4+, IL-13+), which represent less and more highly differentiated Th2 cells, respectively. We hypothesized that the pro-Th2 effects of ATRA may differentially affect these Th2 subpopulations. Specific cytokine producing Th2 subpopulations were identified using intracellular cytokine staining. Proliferation was measured using the Cell Trace Violet proliferation tracking dye. Apoptotic cells were identified using either annexin-V or active caspase 3 staining. Th2 gene expression was measured using quantitative polymerase chain reaction. ATRA increased the output of Th2 cells from house dust mite allergen (HDM) specific short-term cell lines, and this enhancement was limited to the IL-5+ Th2 subpopulation. Conversely, the RARα antagonist Ro415253 decreased Th2 cell output from these cultures, and this effect was again limited to the IL-5+ Th2 subpopulation. ATRA and Ro415253 respectively augmented and inhibited Th2 cell proliferation, and this affect was more pronounced for the IL-5+ vs. IL-5- Th2 subpopulation. ATRA and Ro415253 respectively augmented and inhibited the expression of IL5 in a significant manner, which was not found for IL4 or IL13. We report that the reciprocal regulation of Th2 cytokine expression and proliferation by RARα modulators are largely limited to modulation of IL-5 gene expression and to proliferation of the highly differentiated IL-5+ Th2 subpopulation. These results suggest that RARα antagonism is a potential means to therapeutically target allergic inflammation. Clinicaltrials.gov identifier: NCT01212016.

  2. Hierarchical structure and mechanical properties of snake (Naja atra) and turtle (Ocadia sinensis) eggshells.

    Science.gov (United States)

    Chang, Yin; Chen, Po-Yu

    2016-02-01

    After hundreds of million years of evolution, natural armors have evolved in various organisms, and has manifested in diverse forms such as eggshells, abalone shells, alligator osteoderms, turtle shells, and fish scales. Eggshells serve as multifunctional shields for successful embryogenesis, such as protection, moisture control and thermal regulation. Unlike calcareous avian eggshells which are brittle and hard, reptilians have leathery eggshells that are tough and flexible. Reptilian eggshells can withstand collision damages when laid in holes and dropped onto each other, and reduce abrasion caused by buried sand. In this study, we investigate structure and mechanical properties of eggshells of Taiwan cobra snake (Naja atra) and Chinese striped-neck turtle (Ocadia sinensis). From Acid Fuchsin Orange G (AFOG) staining and ATR-FTIR examination, we found that both eggshells are mainly composed of keratin. The mechanical properties of demineralized snake and turtle eggshells were evaluated by tensile and fracture tests and show distinctly difference. Turtle eggshells are relatively stiff and rigid, while snake eggshells behave as elastomers, which are highly extensible and reversible. The exceptional deformability (110-230% tensile strain) and toughness of snake eggshells are contributed by the wavy and random arrangement of keratin fibers as well as collagen layers. Multi-scale toughening mechanisms of snake eggshells were observed and elucidated, including crack deflection and twisting, fibers reorientation, sliding and bridging, inter-laminar shear effect, as well as the α-β phase transition of keratin. Inspirations from the structural and mechanical designs of reptilian eggshells may lead to the synthesis of tough, extensible, lightweight composites which could be further applied in the flexible devices, packaging and bio-medical fields. Amniotic eggshells serve as multifunctional shields for successful embryogenesis. The avian eggshells have been extensively

  3. Ameliorating Adriamycin-Induced Chronic Kidney Disease in Rats by Orally Administrated Cardiotoxin from Naja naja atra Venom.

    Science.gov (United States)

    Ding, Zhi-Hui; Xu, Li-Min; Wang, Shu-Zhi; Kou, Jian-Qun; Xu, Yin-Li; Chen, Cao-Xin; Yu, Hong-Pei; Qin, Zheng-Hong; Xie, Yan

    2014-01-01

    Previous studies reported the oral administration of Naja naja atra venom (NNAV) reduced adriamycin-induced chronic kidney damage. This study investigated the effects of intragastric administrated cardiotoxin from Naja naja atra venom on chronic kidney disease in rats. Wistar rats were injected with adriamycin (ADR; 6 mg/kg body weight) via the tail vein to induce chronic kidney disease. The cardiotoxin was administrated daily by intragastric injection at doses of 45, 90, and 180  μ g/kg body weight until the end of the protocol. The rats were placed in metabolic cages for 24 hours to collect urine, for determination of proteinuria, once a week. After 6 weeks, the rats were sacrificed to determine serum profiles relevant to chronic kidney disease, including albumin, total cholesterol, phosphorus, blood urea nitrogen, and serum creatinine. Kidney histology was examined with hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining. The levels of kidney podocin were analyzed by Western blot analysis and immunofluorescence. We found that cardiotoxin reduced proteinuria and can improve biological parameters in the adriamycin-induced kidney disease model. Cardiotoxin also reduced adriamycin-induced kidney pathology, suggesting that cardiotoxin is an active component of NNAV for ameliorating adriamycin-induced kidney damage and may have a potential therapeutic value on chronic kidney disease.

  4. Correlation of proliferation, TGF-β3 promoter methylation, and Smad signaling in MEPM cells during the development of ATRA-induced cleft palate.

    Science.gov (United States)

    Liu, Xiaozhuan; Qi, Jingjiao; Tao, Yuchang; Zhang, Huanhuan; Yin, Jun; Ji, Mengmeng; Gao, Zhan; Li, Zhitao; Li, Ning; Yu, Zengli

    2016-06-01

    Mesenchymal cell proliferation is one of the processes in shelf outgrowth. Both all-trans retinoic acid (atRA) and transforming growth factor-β3 (TGF-β3) play an important role in mouse embryonic palate mesenchymal (MEPM) cell proliferation. The cellular effects of TGF-β are mediated by Smad-dependent or Smad-independent pathways. In the present study, we demonstrate that atRA promotes TGF-β3 promoter demethylation and protein expression, but can cause depression of mesenchymal cell proliferation, especially at embryonic day 14 (E14). Moreover, the inhibition of MEPM cell proliferation by atRA results in the downregulation of Smad signaling mediated by transforming growth interacting factor (TGIF). We speculate that the effects of atRA on MEPM cell proliferation may be mediated by Smad pathways, which are regulated by TGIF but are not related to TGF-β3 expression. Finally, the cellular effects of TGF-β3 on MEPM cell proliferation may be mediated by Smad-independent pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Distinct TP73-DAPK2-ATG5 pathway involvement in ATO-mediated cell death versus ATRA-mediated autophagy responses in APL.

    Science.gov (United States)

    Humbert, Magali; Federzoni, Elena A; Tschan, Mario P

    2017-10-04

    We have previously demonstrated that the death-associated protein kinase 2 (DAPK2) expression is significantly reduced in acute myeloid leukemia (AML), particularly in acute promyelocytic leukemia (APL) blast cells. In this study, we aimed at further understanding DAPK2 function and regulation during arsenic trioxide (ATO) cytotoxic or all-trans retinoic acid (ATRA) differentiation therapy in APL cells. We found that the p53 family member transactivation domain-p73 isoform (TAp73) binds to and activates the DAPK2 promoter, whereas the dominant-negative ΔNp73 isoform inhibits DAPK2 transcription. Furthermore, the knocking down of tumor protein p73 (TP73) in NB4 cells resulted in reduced DAPK2 expression associated with decreased cell death and autophagy upon ATO and ATRA treatment, respectively. Moreover, the silencing of DAPK2 revealed that DAPK2 is an important downstream effector of p73 in ATO-induced apoptosis but not autophagy responses of APL cells. In contrast, the p73-DAPK2 pathway is essential for ATRA-induced autophagy that is mediated by an interaction of DAPK2 with the key autophagy-related protein (ATG)5. Lastly, we show that DAPK2 binds and stabilizes the p73 protein; thus, we propose a novel mechanism by which ATO- or ATRA-induced therapy responses initiate a positive p73-DAPK2 feedback loop. © Society for Leukocyte Biology.

  6. All-trans retinoic acid (ATRA) enhances maintenance of primitive human hematopoietic progenitors and skews them towards myeloid differentiation in a stroma-noncontact culture system.

    Science.gov (United States)

    Leung, Anskar Y H; Verfaillie, Catherine M

    2005-04-01

    We have previously shown that hematopoietic progenitor cells (HPCs) from umbilical cord blood (UCB) can be maintained in a cytokine-supplemented stroma-noncontact (SNC) system. Here, we tested if all-trans retinoic acid (ATRA), known to improve expansion of murine hematopoietic stem cells, would enhance human HPC maintenance in a SNC culture system. CD34+CD38-Lin- cells from UCB were cultured in transwells above AFT024 in the presence of Flt-3 ligand (FLT) and thrombopoietin (TPO), with or without ATRA. Total nucleated cells (TNC), colony-forming units (CFUs), long-term culture-initiating cells (LTC-ICs), myeloid-lymphoid initiating cells (ML-ICs) and SCID repopulating cells (SRCs) were evaluated 1 to 5 weeks after culture. All-trans retinoic acid (1 mumol/L) reduced expansion of CD34+CD38-Lin- TNC and CFUs after 2 to 5 weeks of culture. However, it significantly increased LTC-IC expansion after 1 to 3 and, even more so, 5 weeks of culture. ATRA also increased recovery of more primitive ML-ICs and SRCs. Increased HPC recovery appeared dependent on the presence of stromal cells, as LTC-IC expansion was significantly reduced when ATRA was added to stroma-free cultures. All-trans retinoic acid increases expansion of early HPCs in a stromal cell-dependent fashion.

  7. Celastrol inhibits lung infiltration in differential syndrome animal models by reducing TNF-α and ICAM-1 levels while preserving differentiation in ATRA-induced acute promyelocytic leukemia cells.

    Directory of Open Access Journals (Sweden)

    Li-min Xu

    Full Text Available All-trans retinoic acid (ATRA is a revolutionary agent for acute promyelocytic leukemia (APL treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1 expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1β secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.

  8. Celastrol inhibits lung infiltration in differential syndrome animal models by reducing TNF-α and ICAM-1 levels while preserving differentiation in ATRA-induced acute promyelocytic leukemia cells.

    Science.gov (United States)

    Xu, Li-min; Zheng, Yue-juan; Wang, Ying; Yang, Yang; Cao, Fan-fan; Peng, Bin; Xu, Xiong-fei; An, Hua-zhang; Zheng, Ao-xiang; Zhang, Deng-hai; Uzan, Georges; Yu, Yi-zhi

    2014-01-01

    All-trans retinoic acid (ATRA) is a revolutionary agent for acute promyelocytic leukemia (APL) treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1) expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS) which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1β secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.

  9. Tensile and impact properties of vanadium-base alloys irradiated at low temperatures in the ATR-A1 experiment

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, H.; Nowicki, L.J.; Billone, M.C.; Chung, H.M.; Smith, D.L. [Argonne National Lab., IL (United States)

    1998-03-01

    Subsize tensile and Charpy specimens made from several V-(4-5)Cr-(4-5)Ti alloys were irradiated in the ATR-A1 experiment to study the effects of low-temperature irradiation on mechanical properties. These specimens were contained in lithium-bonded subcapsules and irradiated at temperatures between {approx}200 and 300 C. Peak neutron damage was {approx}4.7 dpa. Postirradiation testing of these specimens has begun. Preliminary results from a limited number of specimens indicate a significant loss of work-hardening capability and dynamic toughness due to the irradiation. These results are consistent with data from previous low-temperature neutron irradiation experiments on these alloys.

  10. Cobrotoxin extracted from Naja atra venom relieves arthritis symptoms through anti-inflammation and immunosuppression effects in rat arthritis model.

    Science.gov (United States)

    Zhu, Qi; Huang, Jun; Wang, Shu-Zhi; Qin, Zheng-Hong; Lin, Fang

    2016-12-24

    The Naja atra (Chinese cobra), primarily distributing in the low or medium altitude areas of southern China and Taiwan, was considered as a medicine in traditional Chinese medicine and used to treat pain, inflammation and arthritis. To study the anti-inflammatory and anti-arthritic activities of cobrotoxin (CTX), an active component of the venom from Naja atra. Adjuvant-induced arthritis (AA) rats were used as the animal model of rheumatoid arthritis. The anti-arthritic effects of CTX were evaluated through the arthritis score, paw edema and histopathology changes of joints. The anti-inflammation effects were assayed by the level of IL-6, TNF-α, IL-1β and the number of inflammatory cells in peripheral blood, as well as the proliferation of fibroblast-like synoviocytes (FLS). The immune level was valued by the proliferation of T cells and the level of CD4 and CD8. CTX alleviated the disease development of AA rats according to the ameliorating arthritis score, paw edema and histopathology character. At the meanwhile, CTX decreased the levels of IL-6, TNF-α, IL-1β and the numbers of inflammatory cells in peripheral blood. CTX also suppressed the abnormal increasing of CD4+ T cells/ CD8+ T cells ratio, and could significantly inhibit T cell proliferation. Consistent with its effects on inhibiting granuloma's formation, CTX inhibited the proliferation of the cultured FLSs. Further studies on inflammatory signaling in FLSs revealed that CTX could inhibit the NF-κB signaling pathway. CTX has beneficial effects on rheumatoid arthritis by its immune regulation effects and anti-inflammation effects. The inhibition of NF-κB pathway partly contributes to the anti-inflammatory properties of CTX. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. All trans retinoic acid (ATRA) mediated modulation of N-methyl D-aspartate receptor (NMDAR) and Kruppel like factor 11 (KLF11) expressions in the mitigation of ethanol induced alterations in the brain.

    Science.gov (United States)

    Nair, Saritha S; Prathibha, P; Syam Das, S; Kavitha, S; Indira, M

    2015-01-01

    Damaging effects that chronic ethanol exposure causes to the brain and the neurons are well documented. Ethanol and its toxic metabolites increase the oxidative stress in brain. Chronic exposure to ethanol leads to upregulation of N-methyl D-aspartate receptors (NMDAR) and also activates Kruppel like factor 11 (KLF11) mediated death cascade and thereby neurodegeneration. Ethanol depletes vitamin A stores. But supplementation of vitamin A exacerbates ethanol induced toxicity since alcohol and its metabolites are competitive inhibitors of the enzymes involved in the metabolism of vitamin A. Hence, in this study we investigated the impact of co-administration of ethanol and all trans retinoic acid (ATRA), active metabolite of vitamin A, on ethanol induced alterations to the brain. Male Sprague Dawley rats, adolescent, were grouped as follows and maintained for 90 days. I - Control, II - Ethanol (4 g/kg b.w.), III - ATRA (100 µg/kg b.w.), IV - Ethanol (4 g/kg b.w.), +ATRA (100 µg/kg b.w.). Oxidative stress and the mRNA expression of various receptors for the neurotransmitter involved in glutamergic, serotonergic and gabaergic pathways were studied in the brain homogenate. Ethanol treatment was shown to decrease brain weight and it was increased on ATRA treatment. Increase in oxidative stress due to ethanol treatment was also brought down on ATRA administration. Ethanol induced upregulation of NMDAR and KLF11 was also downregulated on ATRA supplementation. The alterations in the levels of neurotransmitters and the expression of their receptors due to ethanol treatment also were ameliorated on ATRA supplementation. Our results show that ATRA supplementation mitigates the ethanol induced alterations in the brain by reducing oxidative stress in the brain with concurrent suppression of NMDAR and KLF11 expression leading to enhanced catabolism of neurotransmitters. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Upregulation of CD54 and downregulation of HLA‑ABC contribute to the novel enhancement of the susceptibility of HL-60 cells to NK cell-mediated cytolysis induced by ATRA plus VPA.

    Science.gov (United States)

    Zou, Huijuan; Li, Lianlian; Han, Yang; Ma, Ruiping; Liao, Qiong; Tian, Jing; Zhang, Xiaoyu; Ren, Xia; Song, Guanhua; Guo, Qiang; Li, Xia; Ding, Huifang; Jiang, Guosheng

    2017-01-01

    Enhancement of the susceptibility of HL-60 cells to NK cell-mediated cytolysis induced by all-trans-retinoic acid (ATRA) plus valproate (VPA) was evaluated. In addition to the synergistic effect of ATRA plus VPA on HL-60 cells, the optimal concentration of 1 mM VPA plus 0.5 µM ATRA increased the cytotoxic sensitivity of HL-60 cells to NK cells. The expression of the activated receptors NKp30 and NKG2D on NK-92 cells was higher compared with the levels noted for the other receptors, and the expression of NKG2D ligands MICA/B on HL-60 cells was not significantly upregulated in the ATRA plus VPA goup compared with the control. Moreover, it was observed that the ligands of NKp30 on HL-60 cells presented the same variation trend. As to the co-stimulatory and adhesion molecules on NK-92 and their ligands on HL-60 cells post exposure to ATRA and VPA alone or their combination, there was no obvious change in the expression of CD112, CD48 and CD70 on the HL-60 cells. However, the expression of CD54 on HL-60 cells was significantly upregulated. In contrast, the expression of NKG2A ligands HLA-ABC on HL-60 cells was obviously downregulated. In addition, the expression of HLA-E on the HL-60 cells in the group treated with ATRA plus VPA was not significantly increased. In conclusion, the combination of VPA and ATRA not only induced the differentiation of HL-60 cells, but also induced enhancement of the sensitivity of HL-60 cells to NK cells by downregulating the expression of HLA-ABC and upregulating the expression of CD54, but not MICA/MICB. The results provide experimental and theoretical basis for the clinical combination of a low-dose of ATRA plus VPA for the treatment of leukemia.

  13. Diverse Regulation of Vitamin D Receptor Gene Expression by 1,25-Dihydroxyvitamin D and ATRA in Murine and Human Blood Cells at Early Stages of Their Differentiation.

    Science.gov (United States)

    Janik, Sylwia; Nowak, Urszula; Łaszkiewicz, Agnieszka; Satyr, Anastasiia; Majkowski, Michał; Marchwicka, Aleksandra; Śnieżewski, Łukasz; Berkowska, Klaudia; Gabryś, Marian; Cebrat, Małgorzata; Marcinkowska, Ewa

    2017-06-21

    Vitamin D receptor (VDR) is present in multiple blood cells, and the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is essential for the proper functioning of the immune system. The role of retinoic acid receptor α (RARα) in hematopoiesis is very important, as the fusion of RARα gene with PML gene initiates acute promyelocytic leukemia where differentiation of the myeloid lineage is blocked, followed by an uncontrolled proliferation of leukemic blasts. RARα takes part in regulation of VDR transcription, and unliganded RARα acts as a transcriptional repressor to VDR gene in acute myeloid leukemia (AML) cells. This is why we decided to examine the effects of the combination of 1,25D and all-trans-retinoic acid (ATRA) on VDR gene expression in normal human and murine blood cells at various steps of their development. We tested the expression of VDR and regulation of this gene in response to 1,25D or ATRA, as well as transcriptional activities of nuclear receptors VDR and RARs in human and murine blood cells. We discovered that regulation of VDR expression in humans is different from in mice. In human blood cells at early stages of their differentiation ATRA, but not 1,25D, upregulates the expression of VDR. In contrast, in murine blood cells 1,25D, but not ATRA, upregulates the expression of VDR. VDR and RAR receptors are present and transcriptionally active in blood cells of both species, especially at early steps of blood development.

  14. ATRA-induced HL-60 myeloid leukemia cell differentiation depends on the CD38 cytosolic tail needed for membrane localization, but CD38 enzymatic activity is unnecessary

    OpenAIRE

    Congleton, Johanna; Hong JIANG; Malavasi, Fabio; Lin, Hening; Yen, Andrew

    2010-01-01

    Leukocyte antigen CD38 expression is an early marker of all-trans retinoic acid (ATRA) stimulated differentiation in the leukemic cell line HL-60. It promotes induced myeloid maturation when overexpressed, whereas knocking it down is inhibitory. It is a type II membrane protein with an extracellular C-terminal enzymatic domain with NADase/NADPase and ADPR cyclase activity and a short cytoplasmic N-terminal tail. Here we determined whether CD38 enzymatic activity or the cytoplasmic tail is req...

  15. All-trans retinoic acid (ATRA) enhances maintenance of primitive human hematopoietic progenitors and skews them towards myeloid differentiation in a stroma-noncontact culture system

    OpenAIRE

    Leung, Anskar Y. H.; Verfaillie, Catherine

    2005-01-01

    OBJECTIVE: We have previously shown that hematopoietic progenitor cells (HPCs) from umbilical cord blood (UCB) can be maintained in a cytokine-supplemented stroma-noncontact (SNC) system. Here, we tested if all-trans retinoic acid (ATRA), known to improve expansion of murine hematopoietic stem cells, would enhance human HPC maintenance in a SNC culture system. METHODS: CD34+CD38-Lin- cells from UCB were cultured in transwells above AFT024 in the presence of Flt-3 ligand (FLT) and thrombopoiet...

  16. The impact of ATRA on shaping human myeloid cell responses to epithelial cell-derived stimuli and on T-lymphocyte polarization.

    Science.gov (United States)

    Chatterjee, Arunima; Gogolak, Péter; Blottière, Hervé M; Rajnavölgyi, Éva

    2015-01-01

    Vitamin A plays an essential role in the maintenance of gut homeostasis but its interplay with chemokines has not been explored so far. Using an in vitro model system we studied the effects of human colonic epithelial cells (Caco2, HT-29, and HCT116) derived inflammatory stimuli on monocyte-derived dendritic cells and macrophages. Unstimulated Caco2 and HT-29 cells secreted CCL19, CCL21, and CCL22 chemokines, which could attract dendritic cells and macrophages and induced CCR7 receptor up-regulation by retinoic-acid resulting in dendritic cell migration. The chemokines Mk, CXCL16, and CXCL7 were secreted by all the 3 cell lines tested, and upon stimulation by IL-1β or TNF-α this effect was inhibited by ATRA but had no impact on CXCL1, CXCL8, and CCL20 secretion in response to IL-1β. In the presence of ATRA the supernatants of these cells induced CD103 expression on monocyte-derived dendritic cells and when conditioned by ATRA and cocultured with CD4(+) T-lymphocytes they reduced the proportion of Th17 T-cells. However, in the macrophage-T-cell cocultures the number of these effector T-cells was increased. Thus cytokine-activated colonic epithelial cells trigger the secretion of distinct combinations of chemokines depending on the proinflammatory stimulus and are controlled by retinoic acid, which also governs dendritic cell and macrophage responses.

  17. Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir.

    Science.gov (United States)

    Hu, Chenxi; Chen, Zheng; Zhao, Wenjun; Wei, Lirong; Zheng, Yanwen; He, Chao; Zeng, Yan; Yin, Bin

    2014-02-01

    Refractoriness of acute myeloid leukemia (AML) cells to chemotherapeutics represents a major clinical barrier. Suicide gene therapy for cancer has been attractive but with limited clinical efficacy. In this study, we investigated the potential application of herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) based system to inhibit chemoresistant AML cells. We first generated Ara-C resistant K562 cells and doxorubicin-resistant THP-1 cells. We found that the HSV-TK/GCV anticancer system suppressed drug resistant leukemic cells in culture. Chemoresistant AML cell lines displayed similar sensitivity to HSV-TK/GCV. Moreover, HSV-TK/GCV killing of leukemic cells was augmented to a mild but significant extent by all-trans retinoic acid (ATRA) with concomitant upregulation of Connexin 43, a major component of gap junctions. Interestingly, HSV-TK/GCV killing was enhanced by expression of vesicular stomatitis virus G glycoprotein (VSV-G), a fusogenic membrane protein, which also increased leukemic cell fusion. Co-culture resistant cells expressing HSV-TK and cells stably transduced with VSV-G showed that expression of VSV-G could promote the bystander killing effect of HSV-TK/GCV. Furthermore, combination of HSV-TK/GCV with VSV-G plus ATRA produced more pronounced antileukemia effect. These results suggest that the HSV-TK/GCV system in combination with fusogenic membrane proteins and/or ATRA could provide a strategy to mitigate the chemoresistance of AML.

  18. Changes in Sediment Fatty Acid Composition during Passage through the Gut of Deposit Feeding Holothurians: Holothuria atra (Jaeger, 1883) and Holothuria leucospilota (Brandt, 1835).

    Science.gov (United States)

    Mfilinge, Prosper L; Tsuchiya, Makoto

    2016-01-01

    Sea cucumbers Holothuria atra and Holothuria leucospilota play an important role in the bioturbation of sediment in coral reef and rocky intertidal ecosystems. This study investigated changes in sediment fatty acid (FA) composition during gut passage in H. atra and H. leucospilota. The FA composition did not differ significantly between species. Comparison of FA composition in ambient sediment (AS), foregut (FG), midgut (MG), hindgut (HG), and faecal pellets (FPs) indicated that marked changes in FA composition occurred during passage through the gut of H. atra and H. leucospilota. Saturated fatty acids (SAFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and branched fatty acids (BrFAs) were significantly higher in FG than in AS, suggesting that both species selectively ingested nutrient rich particles. Significant reduction of SAFAs, MUFAs, PUFAs, and BrFAs occurred in MD and HD, with complete elimination of most PUFAs in FPs. A decrease in PUFAs 20:5ω3, 18:4ω3, 22:5ω3, 22:6ω3, 18:2ω6, 18:3ω3, 18:3ω6, odd-numbered BrFAs, and MUFA 18:1ω7 indicated that algal detritus and bacteria were important part of diet. These results have implications for the fate of specific dietary FAs, especially ω3 and ω6, and the contribution holothurian FPs make to the FA composition of coral reef and rocky intertidal ecosystems.

  19. Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination

    Science.gov (United States)

    Shi, Wen-Na; Cui, Shu-Xiang; Song, Zhi-Yu; Wang, Shu-Qing; Sun, Shi-Yue; Yu, Xin-Feng; Li, Ye; Zhang, Yu-Hang; Gao, Zu-Hua; Qu, Xian-Jun

    2017-01-01

    The resistance mechanisms that limit the efficacy of retinoid therapy in cancer are poorly understood. Sphingosine kinase 2 (SphK2) is a highly conserved enzyme that is mainly located in the nucleus and endoplasmic reticulum. Unlike well-studied sphingosine kinase 1 (SphK1) located in the cytosol, little has yet understood the functions of SphK2. Here we show that SphK2 overexpression contributes to the resistance of all-trans retinoic acid (ATRA) therapy in colon cancer through rapid degradation of cytoplasmic retinoid X receptor α (RXRα) by lysine 48 (K48)- and lysine 63 (K63)-based polyubiquitination. Human colonic adenocarcinoma HCT-116 cells transfected with SphK2 (HCT-116Sphk2 cells) demonstrate resistance to ATRA therapy as determined by in vitro and in vivo assays. Sphk2 overexpression increases the ATRA-induced nuclear RXRα export to cytoplasm and then rapidly degrades RXRα through the polyubiquitination pathway. We further show that Sphk2 activates the ubiquitin-proteasome system through the signal mechanisms of (1) K48-linked proteosomal degradation and (2) K63-linked ubiquitin-dependent autophagic degradation. These results provide new insights into the biological functions of Sphk2 and the molecular mechanisms that underlie the Sphk2-mediated resistance to retinoid therapy. PMID:28465486

  20. A network including PU.1, Vav1 and miR-142-3p sustains ATRA-induced differentiation of acute promyelocytic leukemia cells - a short report.

    Science.gov (United States)

    Grassilli, Silvia; Nika, Ervin; Lambertini, Elisabetta; Brugnoli, Federica; Piva, Roberta; Capitani, Silvano; Bertagnolo, Valeria

    2016-10-01

    Reduced expression of miR-142-3p has been found to be associated with the development of various subtypes of myeloid leukemia, including acute promyelocytic leukemia (APL). In APL-derived cells, miR-142-3p expression can be restored by all-trans retinoic acid (ATRA), which induces the completion of their maturation program. Here, we aimed to assess whether PU.1, essential for ATRA-induced gene transcription, regulates the expression of miR-142-3p in APL-derived cells and, based on the established cooperation between PU.1 and Vav1 in modulating gene expression, to evaluate the role of Vav1 in restoring the expression of miR-142-3p. ATRA-induced increases in PU.1 and Vav1 expression in APL-derived NB4 cells were counteracted with specific siRNAs, and the expression of miR-142-3p was measured by quantitative real-time PCR (qRT-PCR). The recruitment of PU.1 and/or Vav1 to the regulatory region of miR-142 was assessed by quantitative chromatin immunoprecipitation (Q-ChIP). Synthetic inhibitors or mimics for miR-142-3p were used to assess whether this miRNA plays a role in regulating the expression of PU.1 and/or Vav1. We found that the expression of miR-142-3p in differentiating APL-derived NB4 cells is dependent on PU.1, and that Vav1 is essential for the recruitment of this transcription factor to its cis-binding element on the miR-142 promoter. In addition, we found that in ATRA-treated NB4 cells miR-142-3p sustains agonist-induced increases in both PU.1 and Vav1. Our results suggest the existence of a Vav1/PU.1/miR-142-3p network that supports ATRA-induced differentiation in APL-derived cells. Since selective regulation of miRNAs may play a role in the future treatment of hematopoietic malignancies, our results may provide a basis for the development of new therapeutic strategies to restore the expression of miR-142-3p.

  1. Protective and Curative Effects of the Sea Cucumber Holothuria atra Extract against DMBA-Induced Hepatorenal Diseases in Rats

    Directory of Open Access Journals (Sweden)

    Ahmed I. Dakrory

    2015-01-01

    Full Text Available Oxidative stress is a common mechanism contributing to the initiation and progression of hepatic damage. Hence there is a great demand for the development of agents with potent antioxidant effect. The aim of the present study is to evaluate the efficacy of Holothuria atra extract (HaE as an antioxidant against 7,12-dimethylbenz[a]anthracene- (DMBA- induced hepatorenal dysfunction. Experimental animals were divided into two main groups: protective and curative. Each group was then divided into five subgroups pre- or posttreated either with distilled water (DMBA subgroups or with HaE (200 mg/kg body weight for seven and fourteen days. Single oral administration of DMBA (15 mg/kg body weight to Wistar rats resulted in a significant increase in the serum liver enzymes and kidney function’s parameters. DMBA increased level of liver malondialdehyde (MDA, decreased levels of reduced glutathione (GSH, glutathione-S-transferase (GST, superoxide dismutase (SOD, and catalase (CAT in the liver tissue, and induced liver histopathological alterations. Pre- or posttreatment with HaE orally for 14 days significantly reversed the hepatorenal alterations induced following DMBA administration. In conclusion, HaE exhibits good hepatoprotective, curative, and antioxidant potential against DMBA-induced hepatorenal dysfunction in rats that might be due to decreased free radical generation.

  2. The Phylogeographical Pattern and Conservation of the Chinese Cobra (Naja atra) across Its Range Based on Mitochondrial Control Region Sequences

    Science.gov (United States)

    Lin, Long-Hui; Hua, Lei; Qu, Yan-Fu; Gao, Jian-Fang; Ji, Xiang

    2014-01-01

    The vulnerable Chinese cobra (Naja atra) ranges from southeastern China south of the Yangtze River to northern Vietnam and Laos. Large mountain ranges and water bodies may influence the pattern of genetic diversity of this species. We sequenced the mitochondrial DNA control region (1029 bp) using 285 individuals collected from 23 localities across the species' range and obtained 18 sequences unique to Taiwan from GenBank for phylogenetic and population analysis. Two distinct clades were identified, one including haplotypes from the two westernmost localities (Hekou and Miyi) and the other including haplotypes from all sampling sites except Miyi. A strong population structure was found (Φst = 0.76, P<0.0001) with high haplotype diversity (h = 1.00) and low nucleotide diversity (π = 0.0049). The Luoxiao and Nanling Mountains act as historical geographical barriers limiting gene exchange. In the haplotype network there were two “star” clusters. Haplotypes from populations east of the Luoxiao Mountains were represented within one cluster and haplotypes from populations west of the mountain range within the other, with haplotypes from populations south of the Nanling Mountains in between. Lineage sorting between mainland and island populations is incomplete. It remains unknown as to how much adaptive differentiation there is between population groups or within each group. We caution against long-distance transfers within any group, especially when environmental differences are apparent. PMID:25184236

  3. Antinociceptive and Anti-Inflammatory Effects of Orally Administrated Denatured Naja Naja Atra Venom on Murine Rheumatoid Arthritis Models

    Directory of Open Access Journals (Sweden)

    Kou-Zhu Zhu

    2013-01-01

    Full Text Available To investigate the antinociceptive and anti-inflammatory activities of the denatured Naja Naja atra venom (NNAV in rheumatoid arthritis-associated models, the denatured NNAV (heat treated; 30, 90, 270 μg/kg, the native NNAV (untreated with heat; 90 μg/kg, and Tripterygium wilfordii polyglycoside (TWP, 15 mg/kg were administrated orally either prophylactically or therapeutically. We measured time of licking the affected paw in formaldehyde-induced inflammatory model, paw volume in egg-white-induced inflammation, and granuloma weight in formalin-soaked filter paper-induced granuloma. For adjuvant-induced arthritis (AIA rats, paw edema, mechanical withdrawal threshold, serum levels of TNF-α and IL-10, and histopathological changes of the affected paw were assessed. We found that the denatured NNAV (90, 270 μg/kg significantly reduced time of licking paw, paw volume, and granuloma weight in above inflammatory models and also attenuated paw edema, mechanical hyperalgesia, and histopathology changes in AIA rats. Additionally, the increase in serum TNF-α and the decrease in serum IL-10 in AIA rats were reversed by the denatured NNAV. Although the native NNAV and TWP rendered the similar pharmacological actions on the above four models with less potency than that of the denatured NNAV, these findings demonstrate that oral administration of the denatured NNAV produces antinociceptive and anti-inflammatory activities on rheumatoid arthritis.

  4. Interaction of Naja naja atra cardiotoxin 3 with H-trisaccharide modulates its hemolytic activity and membrane-damaging activity.

    Science.gov (United States)

    Kao, Pei-Hsiu; Lin, Shinne-Ren; Chang, Long-Sen

    2010-06-15

    To address whether saccharide moieties of blood groups A, B and O antigens modulate hemolytic activity of Naja naja atra cardiotoxins (CTXs), the present study was carried out. Unlike other CTX isotoxins, hemolytic activity of CTX3 toward blood group O cholesterol-depleted red blood cells (RBCs) was notably lower than that of blood groups A and B cholesterol-depleted RBCs. Conversion of blood group B RBCs into blood group O RBCs by alpha-galactosidase treatment attenuated the susceptibility for hemolytic activity of CTX3, suggesting that H-antigen affected hemolytic potency of CTX3. Pre-incubation with H-trisaccharide reduced hemolytic activity and membrane-damaging activity of CTX3. Moreover, CTX3 showed a higher binding capability with H-trisaccharide than other CTXs did. CD spectra showed that the binding with H-trisaccharide induced changes in gross conformation of CTX3. Self-quenching studies revealed that oligomerization of CTX3 was affected in the presence of H-trisaccharide. Taken together, our data suggest that the binding of CTX3 with H-antigen alters its membrane-bound mode, thus reducing its hemolytic activity toward blood group O cholesterol-depleted RBCs. 2010 Elsevier Ltd. All rights reserved.

  5. Oral bacterial flora of the Chinese cobra (Naja atra) and bamboo pit viper (Trimeresurus albolabris) in Hong Kong SAR, China.

    Science.gov (United States)

    Shek, K C; Tsui, K L; Lam, K K; Crow, P; Ng, Kenneth H L; Ades, G; Yip, K T; Grioni, Alessandro; Tan, K S; Lung, David C; Lam, Tommy S K; Fung, H T; Que, T L; Kam, C W

    2009-06-01

    To determine the oral bacterial flora associated with two common local venomous snakes in Hong Kong, namely the Chinese cobra (Naja atra) and the bamboo pit viper (Trimeresurus albolabris). Cross-sectional study. A non-government organisation and a regional hospital in Hong Kong. Thirty-two Chinese cobras and seven bamboo pit vipers. Species identification of bacteria in the oral cavity of both snakes and their antibiotic susceptibilities. The oral cavity of Chinese cobra harbour a wide range of pathogenic bacteria, including: Gram-negative bacterial species like Morganella morganii, Aeromonas hydrophila and Proteus, and Gram-positive bacteria like Enterococcus faecalis, coagulase-negative Staphylococcus as well as anaerobic species (clostridia). The oral cavity of the Chinese cobra is more likely than that of the bamboo pit viper to harbour pathogenic bacteria associated with snakebite infection (Pcobra (Pcobra bites may be beneficial, owing to the multiple pathogenic bacteria in its oral cavity and the higher risk of ensuing necrosis. The regimen of levofloxacin plus amoxicillin/clavulanate appears promising for this purpose, but further study is required to confirm its clinical utility in patients.

  6. The phylogeographical pattern and conservation of the Chinese cobra (Naja atra) across its range based on mitochondrial control region sequences.

    Science.gov (United States)

    Lin, Long-Hui; Hua, Lei; Qu, Yan-Fu; Gao, Jian-Fang; Ji, Xiang

    2014-01-01

    The vulnerable Chinese cobra (Naja atra) ranges from southeastern China south of the Yangtze River to northern Vietnam and Laos. Large mountain ranges and water bodies may influence the pattern of genetic diversity of this species. We sequenced the mitochondrial DNA control region (1029 bp) using 285 individuals collected from 23 localities across the species' range and obtained 18 sequences unique to Taiwan from GenBank for phylogenetic and population analysis. Two distinct clades were identified, one including haplotypes from the two westernmost localities (Hekou and Miyi) and the other including haplotypes from all sampling sites except Miyi. A strong population structure was found (Φst = 0.76, P<0.0001) with high haplotype diversity (h = 1.00) and low nucleotide diversity (π = 0.0049). The Luoxiao and Nanling Mountains act as historical geographical barriers limiting gene exchange. In the haplotype network there were two "star" clusters. Haplotypes from populations east of the Luoxiao Mountains were represented within one cluster and haplotypes from populations west of the mountain range within the other, with haplotypes from populations south of the Nanling Mountains in between. Lineage sorting between mainland and island populations is incomplete. It remains unknown as to how much adaptive differentiation there is between population groups or within each group. We caution against long-distance transfers within any group, especially when environmental differences are apparent.

  7. Five-year experience with Chinese cobra (Naja atra)--related injuries in two acute hospitals in Hong Kong.

    Science.gov (United States)

    Wong, O F; Lam, T S K; Fung, H T; Choy, C H

    2010-02-01

    To review the clinical features and management of patients with injuries related to the Chinese cobra (Naja atra). Retrospective study. Two acute hospitals in Hong Kong. The nature of injuries, envenoming features, complications, response to antivenom therapy, and outcome. Eighteen patients were recruited during the 5-year study period. Fifteen of them were snake-bitten, the remaining three suffered ocular injuries. Of the 15 patients with cobra bites, 14 (93%) presented with local swelling. No patient developed severe neurotoxic symptoms. Two patients had laboratory features of haemolysis. Fourteen patients received antivenom therapy and five of them subsequently underwent surgical interventions for extensive local tissue damage and necrosis. There was no fatality. Bites from Chinese cobra result in serious local complications with extensive tissue necrosis and minimal neurotoxic symptoms. There is an apparent trend of favourable outcomes following the early administration of antivenom to patients without early signs of irreversible tissue damage. Further research is needed to evaluate the effectiveness of early antivenom use in Chinese cobra bites in order to minimise extent of tissue damage.

  8. Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC).

    Science.gov (United States)

    Rajasekaran, Devaraja; Srivastava, Jyoti; Ebeid, Kareem; Gredler, Rachel; Akiel, Maaged; Jariwala, Nidhi; Robertson, Chadia L; Shen, Xue-Ning; Siddiq, Ayesha; Fisher, Paul B; Salem, Aliasger K; Sarkar, Devanand

    2015-08-19

    Hepatocellular carcinoma (HCC) is a fatal cancer with no effective therapy. Astrocyte elevated gene-1 (AEG-1) plays a pivotal role in hepatocarcinogenesis and inhibits retinoic acid-induced gene expression and cell death. The combination of a lentivirus expressing AEG-1 shRNA and all-trans retinoic acid (ATRA) profoundly and synergistically inhibited subcutaneous human HCC xenografts in nude mice. We have now developed liver-targeted nanoplexes by conjugating poly(amidoamine) (PAMAM) dendrimers with polyethylene glycol (PEG) and lactobionic acid (Gal) (PAMAM-PEG-Gal) which were complexed with AEG-1 siRNA (PAMAM-AEG-1si). The polymer conjugate was characterized by (1)H-NMR, MALDI, and mass spectrometry; and optimal nanoplex formulations were characterized for surface charge, size, and morphology. Orthotopic xenografts of human HCC cell QGY-7703 expressing luciferase (QGY-luc) were established in the livers of athymic nude mice and tumor development was monitored by bioluminescence imaging (BLI). Tumor-bearing mice were treated with PAMAM-siCon, PAMAM-siCon+ATRA, PAMAM-AEG-1si, and PAMAM-AEG-1si+ATRA. In the control group the tumor developed aggressively. ATRA showed little effect due to high AEG-1 levels in QGY-luc cells. PAMAM-AEG-1si showed significant reduction in tumor growth, and the combination of PAMAM-AEG-1si+ATRA showed profound and synergistic inhibition so that the tumors were almost undetectable by BLI. A marked decrease in AEG-1 level was observed in tumor samples treated with PAMAM-AEG-1si. The group treated with PAMAM-AEG-1si+ATRA nanoplexes showed increased necrosis, inhibition of proliferation, and increased apoptosis when compared to other groups. Liver is an ideal organ for RNAi therapy and ATRA is an approved anticancer agent. Our exciting observations suggest that the combinatorial approach might be an effective way to combat HCC.

  9. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial.

    Science.gov (United States)

    Milligan, Donald W; Wheatley, Keith; Littlewood, Timothy; Craig, Jenny I O; Burnett, Alan K

    2006-06-15

    The optimum chemotherapy schedule for reinduction of patients with high-risk acute myeloid leukemia (relapsed, resistant/refractory, or adverse genetic disease) is uncertain. The MRC AML (Medical Research Council Acute Myeloid Leukemia) Working Group designed a trial comparing fludarabine and high-dose cytosine (FLA) with standard chemotherapy comprising cytosine arabinoside, daunorubicin, and etoposide (ADE). Patients were also randomly assigned to receive filgrastim (G-CSF) from day 0 until neutrophil count was greater than 0.5 x 10(9)/L (or for a maximum of 28 days) and all-trans retinoic acid (ATRA) for 90 days. Between 1998 and 2003, 405 patients were entered: 250 were randomly assigned between FLA and ADE; 356 to G-CSF versus no G-CSF; 362 to ATRA versus no ATRA. The complete remission rate was 61% with 4-year disease-free survival of 29%. There were no significant differences in the CR rate, deaths in CR, relapse rate, or DFS between ADE and FLA, although survival at 4 years was worse with FLA (16% versus 27%, P = .05). Neither the addition of ATRA nor G-CSF demonstrated any differences in the CR rate, relapse rate, DFS, or overall survival between the groups. In conclusion these findings indicate that FLA may be inferior to standard chemotherapy in high-risk AML and that the outcome is not improved with the addition of either G-CSF or ATRA.

  10. Morphological Characteristics of the Oropharyngeal Cavity (Tongue, Palate and Laryngeal Entrance) in the Eurasian Coot (Fulica atra, Linnaeus, 1758).

    Science.gov (United States)

    Abumandour, M M A; El-Bakary, N E R

    2017-08-01

    The present study represents the first definitive anatomical description of the oropharyngeal cavity of the coot Fulica atra. For this purpose, the organs of six birds were prepared to examine grossly and by SEM and stereomicroscope. The oval lingual apex had multiple overlapping branched acicular processes on its anterior and lateral border. The lingual apex and body had multiple caudally directed filiform-like papillae. By stereomicroscopy, the lingual root had a characteristic appearance and consisted of four parts. The openings of the anterior glands were present on the dorsal lingual surface of the body, while the projected papillae with wide openings of the posterior glands were present on the dorsal surface of lingual root. There was a row of caudally directed pharyngeal papillae at the caudal border of the laryngeal mound. Grossly, the pharyngeal papillae arrangement took a W-shape, while by stereomicroscopy was observed to be heart shape. The palate was divided into two regions: a small rostral non-papillary and a large caudal papillary region, but the rostral region was characterized by the presence of three longitudinal ridges. The papillary crest had two paramedian longitudinal papillary rows, which continued caudally until the beginning of the third median row. The freely distributed papillae took a caudolateral direction, while the papillae encircling the rostral part of choanal cleft took a caudomedial direction. There was a transverse papillary row between the two parts of choanal cleft. There was a transverse papillary row between the caudal border of the infundibular cleft and oesophagus. © 2017 Blackwell Verlag GmbH.

  11. Modulated mechanism of phosphatidylserine on the catalytic activity of Naja naja atra phospholipase A2 and Notechis scutatus scutatus notexin.

    Science.gov (United States)

    Chiou, Yi-Ling; Lin, Shinne-Ren; Hu, Wan-Ping; Chang, Long-Sen

    2014-12-15

    Phosphatidylserine (PS) externalization is a hallmark for apoptotic death of cells. Previous studies showed that Naja naja atra phospholipase A2 (NnaPLA2) and Notechis scutatus scutatus notexin induced apoptosis of human cancer cells. However, NnaPLA2 and notexin did not markedly disrupt the integrity of cellular membrane as evidenced by membrane permeability of propidium iodide. These findings reflected that the ability of NnaPLA2 and notexin to hydrolyze membrane phospholipids may be affected by PS externalization. To address that question, this study investigated the membrane-interacted mode and catalytic activity of NnaPLA2 and notexin toward outer leaflet (phosphatidylcholine/sphingomyelin/cholesterol, PC/SM/Chol) and inner leaflet (phosphatidylserine/phosphatidylethanolamine/cholesterol, PS/PE/Chol) of plasma membrane-mimicking vesicles. PS incorporation promoted enzymatic activity of NnaPLA2 and notexin on PC and PC/SM vesicles, but suppressed NnaPLA2 and notexin activity on PC/SM/Chol and PE/Chol vesicles. PS incorporation increased the membrane fluidity of PC vesicles but reduced membrane fluidity of PC/SM, PC/SM/Chol and PE/Chol vesicles. PS increased the phospholipid order of all the tested vesicles. Moreover, PS incorporation did not greatly alter the binding affinity of notexin and NnaPLA2 with phospholipid vesicles. Acrylamide quenching studies and trinitrophenylation of Lys residues revealed that membrane-bound mode of notexin and NnaPLA2 varied with the targeted membrane compositions. The fine structure of catalytic site in NnaPLA2 and notexin in all the tested vesicles showed different changes. Collectively, the present data suggest that membrane-inserted PS modulates PLA2 interfacial activity via its effects on membrane structure and membrane-bound mode of NnaPLA2 and notexin, and membrane compositions determine the effect of PS on PLA2 activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Fusogenicity of Naja naja atra cardiotoxin-like basic protein on sphingomyelin vesicles containing oxidized phosphatidylcholine and cholesterol.

    Science.gov (United States)

    Kao, Pei-Hsiu; Chen, Ying-Jung; Yang, Shin-Yi; Lin, Shinne-Ren; Hu, Wan-Ping; Chang, Long-Sen

    2013-06-01

    This study investigated the effect of oxidized phosphatidylcholine (oxPC) and cholesterol (Chol) on Naja naja atra cardiotoxin-like basic protein (CLBP)-induced fusion and leakage in sphingomyelin (SM) vesicles. Compared with those on PC/SM/Chol vesicles, CLBP showed a lower activity to induce membrane permeability but a higher fusogenicity on oxPC/SM/Chol vesicles. A reduction in inner-leaflet fusion elucidated that CLBP fusogenicity was not in parallel to its membrane-leakage activity on oxPC/SM/Chol vesicles. The lipid domain formed by Chol and SM supported CLBP fusogenicity on oxPC/SM/Chol vesicles, while oxPC altered the interacted mode of CLBP with oxPC/SM/Chol vesicles as evidenced by Fourier transform infrared spectra analyses and colorimetric phospholipid/polydiacetylene membrane assay. Although CLBP showed similar binding affinity with PC/SM/Chol and oxPC/SM/Chol vesicles, the binding capability of CLBP with PC/SM/Chol and oxPC/SM/Chol vesicles was affected differently by NaCl. This emphasized that CLBP adopted different membrane interaction modes upon binding with PC/SM/Chol and oxPC/SM/Chol vesicles. CLBP induced fusion in vesicles containing oxPC bearing the aldehyde group, and aldehyde scavenger methoxyamine abrogated the CLBP ability to induce oxPC/SM/Chol fusion. Taken together, our data indicate that Chol and oxPC bearing aldehyde group alter the CLBP membrane-binding mode, leading to fusogenicity promotion while reducing the membrane-damaging activity of CLBP.

  13. Naja naja atra and Naja nigricollis cardiotoxins induce fusion of Escherichia coli and Staphylococcus aureus membrane-mimicking liposomes.

    Science.gov (United States)

    Kao, Pei-Hsiu; Lin, Shinne-Ren; Hu, Wan-Ping; Chang, Long-Sen

    2012-09-01

    Our previous studies showed that the bactericidal effect of Naja naja atra cardiotoxin 3 (CTX3) and Naja nigricollis toxin γ was associated with their membrane-damaging activity. To elucidate the mechanism responsible for CTX3- and toxin γ-induced membrane permeability, we investigated the interacted mode of CTX3 and toxin γ with model membrane of Escherichia coli (phosphatidylethanolamine (PE)/phosphatidylglycerol (PG), mol/mol, 75/25) and Staphylococcus aureus (PG/cardiolipin, mol/mol, 60/40) in this study. Membrane-damaging activity of toxin γ on PE/PG and PG/cardiolipin vesicles were similar, while CTX3-induced leakage of PG/cardiolipin vesicles was notably higher than that of PE/PG vesicles. Noticeably, fusogenic activity of CTX3 and toxin γ on the phospholipid vesicles correlated positively with their membrane-damaging activity. Unlike toxin γ, CTX3 induced increasingly leakage and fusion of phospholipid vesicles with increased cardiolipin content. Changes in membrane fluidity and lipid packing occurred with the binding of CTX3 and toxin γ with vesicles, reflecting the penetration of toxin molecules into membrane bilayers. Consistent with the finding that PE/PG and PG/cardiolipin vesicles induced differently conformational changes of CTX3 and toxin γ, CTX3 and toxin γ adopted different membrane bound-mode upon absorption onto either PE/PG or PG/cardiolipin vesicles. Taken together, our data indicate that membrane-bound mode and membrane-perturbing effect of CTX3 and toxin γ in concert with targeted membrane compositions determine their fusogenicity and membrane-damaging activity, and suggest a causal relationship between bactericidal activity and fusogenicity of CTX3 and toxin γ. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.

    Science.gov (United States)

    Watamura, Naoto; Toba, Junya; Yoshii, Aya; Nikkuni, Miyu; Ohshima, Toshio

    2016-01-01

    Alzheimer's disease (AD) is the most common type of dementia among the elderly. Neurofibrillary tangles (NFTs), a major pathological hallmark of AD, are composed of tau protein that is hyperphosphorylated by cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK3β). NFTs also contain Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) and collapsin response-mediator protein 2 (CRMP2). Although Cdk5 is known to phosphorylate tau, WAVE1, and CRMP2, the significance of this with respect to NFT formation remains to be elucidated. This study examines the involvement of phosphorylated (p-) CRMP2 and WAVE1 in p-tau aggregates using a triple-transgenic (3×Tg; APPswe/PS1M146V/tauP301L) AD mouse model. First, we verified the colocalization of p-WAVE1 and p-CRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates. To test the significance of phosphorylation of these proteins further, we administered all-trans-retinoic acid (ATRA) to the 3×Tg mice, which downregulates Cdk5 and GSK3β activity. In ATRA-treated mice, fewer and smaller tau aggregates were observed compared with non-ATRA-treated mice. These results suggest the possibility of novel therapeutic target molecules for preventing tau pathology. © 2015 Wiley Periodicals, Inc.

  15. Atração e desligamento voluntário de jovens empregados: um estudo de caso no setor jornalístico

    Directory of Open Access Journals (Sweden)

    Lucia Barbosa de Oliveira

    2014-12-01

    Full Text Available Neste estudo de caso de natureza exploratória, desenvolvido em uma grande empresa do setor jornalístico, o objetivo foi analisar fatores de atração e perda de jovens que voluntariamente optaram por deixar a organização. A fundamentação teórica para a pesquisa foi construída a partir dos seguintes pilares: aspirações de trabalho e carreira da chamada geração Y, fatores de atração e retenção e cultura organizacional, tendo em vista a identificação da necessidade de adaptação da cultura da empresa aos novos desafios estratégicos e competitivos que vem enfrentando. O levantamento de dados foi feito por meio de 17 entrevistas em profundidade com jovens da geração Y que pediram demissão após pelo menos um ano de estágio e/ou trabalho na empresa. Como principais fatores de atração, destacaram-se a imagem e a reputação do principal jornal da empresa, que muito contribui para a construção de sua marca empregadora. Por outro lado, alguns traços da cultura organizacional apresentaram contraste com aspectos valorizados pelos participantes, indicando incongruência de valores, que pode estar levando a organização a perder jovens talentos, considerados importantes ante a necessidade de renovar seu quadro funcional e sua cultura. Com relação às motivações pessoais para deixar a empresa, foram identificados três grupos de jovens – idealistas, carreiristas e imediatistas –, orientados por anseios e perspectivas profissionais distintos.

  16. All-trans-retinoid acid (ATRA) suppresses chondrogenesis of rat primary hind limb bud mesenchymal cells by downregulating p63 and cartilage-specific molecules.

    Science.gov (United States)

    Wang, Yun-Guo; Xie, Peng; Wang, Yun-Gong; Li, Xue-Dong; Zhang, Tao-Gen; Liu, Zhao-Yong; Hong, Quan; Du, Shi-Xin

    2014-09-01

    P63 null mice have no or truncated limbs and mutations in human p63 cause several skeletal syndromes that also show limb and digit abnormalities, suggesting its essential role in bone development. In the current study, we investigated the effect of ATRA on chondrogenesis using mesenchymal cells from rat hind limb bud and further examined the mRNA and protein expression of Sox9 and Col2a1 and p63 in rat hind limb bud cells. Limb buds were isolated from embryos from euthanized female rats. Growth of hind limb bud mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays. Formation of cartilage nodules was examined by Alcian blue-nuclear fast red staining. The expression of Sox9, Col2al and p63 was determined by Real-time RT-PCR and immunoblotting assays, respectively. Our MTT assays revealed that ATRA at 1 and 10μM significantly suppressed the growth of mesenchymal cells from rat hind limb bud at 24 and 48h (PATRA caused a significant dose-dependent reduction in the area of cartilage nodules (PATRA, the area of cartilage nodules from hind limb bud cells was reduced to 0.05±0.03mm from 0.15±0.01mm in controls. Real-time RT-PCR assays further indicated that 1 and 10μM ATRA markedly reduced the mRNA expression of Sox9, Col2al and p63 in hind limb bud cells (PATRA time-dependently inhibits the mRNA expression of p63, Sox9 and Col2al. Western blotting assays additionally showed that ATRA dose-dependently reduced the expression of Sox9, Col2al and p63 (PATRA suppresses chondrogenesis by modulating the expression of Sox9, Col2al and p63 in primary hind limb bud mesenchymal cells. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. AChE and EROD activities in two echinoderms, Holothuria leucospilota and Holoturia atra (Holothuroidea), in a coral reef (Reunion Island, South-western Indian Ocean).

    Science.gov (United States)

    Kolasinski, Joanna; Taddei, Dorothée; Cuet, Pascale; Frouin, Patrick

    2010-01-01

    AChE and EROD activities were investigated in two holothurian species, Holothuria leucospilota and Holoturia atra, from a tropical coral reef. These organisms were collected from 3 back-reef stations, where temperature and salinity were homogeneous. The activity levels of both AChE and EROD varied significantly between the two species, but were in the range of values determined in other echinoderm species. AChE activity levels were higher in the longitudinal muscle than in the tentacle tegument. Among the several tissues tested, the digestive tract wall exhibited higher EROD activity levels. Sex did not influence AChE and EROD activity levels in both species. Animal biomass and EROD activity levels were only correlated in the tegument tissue of H. atra, and we hypothesize a possible influence of age. EROD activity did not show intraspecific variability. A significant relationship was found between AChE activity and Cuvierian tubules time of expulsion in Holothuria leucospilota. Individuals collected at the southern site presented both lower AChE activity levels and Cuvierian tubules time of expulsion, indicating possible neural disturbance. More information on holothurians biology and physiology is needed to further assess biomarkers in these key species. This study is the first of its kind performed in the coastal waters of Reunion Island and data obtained represent reference values.

  18. Purification, partial characterization, crystallization and preliminary X-ray diffraction of a novel cardiotoxin-like basic protein from Naja naja atra (South Anhui) venom

    Energy Technology Data Exchange (ETDEWEB)

    Rong, Hui; Li, Yan; Lou, Xiao-hua; Zhang, Xio; Gao, Yong-xiang; Teng, Mai-kun, E-mail: mkteng@ustc.edu.cn; Niu, Li-wen, E-mail: mkteng@ustc.edu.cn [Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230027 (China); Key Laboratory of Structural Biology, Chinese Academy of Sciences, 96 Jinzhai Road, Hefei, Anhui 230027 (China)

    2007-02-01

    A novel cardiotoxin-like basic protein from Naja naja atra was crystallized and diffraction data were collected to 2.35 Å resolution. A novel cardiotoxin-like basic protein was isolated from the venom of the Chinese cobra (Naja naja atra) from the south of Anhui in China. The protein inhibits the expression of vascular endothelial growth factor and basic fibroblast growth factor in human lung cancer cell line H1299 and induces the haemolysis of rabbit erythrocytes under low-lecithin conditions. After a two-step chromatographic purification, the resultant 7 kDa protein was crystallized by the hanging-drop vapour-diffusion method at room temperature. A complete data set was collected to 2.35 Å resolution using an in-house X-ray diffraction system. The crystal belongs to space group P4{sub 1}2{sub 1}2, with unit-cell parameters a = b = 43.2, c = 147.9 Å. There are two molecules in the crystallographic asymmetric unit.

  19. Crystallographic observation of pH-induced conformational changes in the Amyelois transitella pheromone-binding protein AtraPBP1.

    Directory of Open Access Journals (Sweden)

    Eric di Luccio

    Full Text Available The navel orangeworm, Amyelois transitella is a major agricultural pest causing large losses in a variety of tree crops. Control of this insect pest may be achieved by interfering with olfactory pathways to block detection of female-produced sex pheromones and consequently, disrupt mating. The first component of this pathway is the pheromone-binding protein AtraPBP1, which recognizes the pheromone and presents it to the odorant receptor housed in a sensory neuron of the male antennae. Release of the ligand depends on a pH-induced conformational change associated with the acidity of the membrane surface. To characterize this conformational change and to understand how pheromones bind, we have determined the high resolution crystal structures of AtraPBP1 in complex with two main constituents of the sex pheromone, i.e., (11Z,13Z-hexadecadienal and (11Z,13Z-hexadecadienol. Comparison with the structure of the unliganded form demonstrates a large ∼90° movement of the C-terminal helix which is observed in other pheromone- or odorant-binding proteins accompanied by an unpredicted 37° displacement of the N-terminal helix. Molecular dynamic trajectories suggest that the conformational change of the α1 helix facilitates the movement of the C-terminal helix.

  20. Comparative ultrastructural investigations of the uterine epithelium in the viviparous Salamandra atra Laur. and the ovoviviparous Salamandra salamandra (l.) (amphibia, urodela).

    Science.gov (United States)

    Greven, H

    1977-07-11

    The uterine epithelium of the viviparous Salamandra atra and the ovoviviparous Salamandra salamandra was studied in non pregnant and ovulating females and in females during different stages of pregnancy. The epithelium of both species is organized in a monolayer. The epithelial cells are characterized by a moderate secretory activity, a variable amount of apical granules which include PAS-positive material and by some apical and basal exo- or endocytotic vesicles. Adjacent cells are joined by junctional complexes. The lateral surfaces form a tortuous boundary with adjoining cells which suggest that the epithelium is involved in transport. Sporadic light cells possess highly variable cytoplasmic inclusions and are not joined with neighbouring cells. Possibly they represent migratory cells. The entire epithelium, except for a small cranial portion of the uterus in S. atra, undergoes no remarkable morphological changes during the different physiological stages examined except that flattened cells seem to be more numerous in pregnant females. The results are discussed with regard to the possible supply of the developing young by the mother.

  1. In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells.

    Science.gov (United States)

    Kvestad, Hilde; Evensen, Lasse; Lorens, James B; Bruserud, Oystein; Hatfield, Kimberley J

    2014-01-01

    The combined use of the histone deacetylase inhibitor valproic acid (VPA), the retinoic acid receptor- α agonist all-trans retinoic acid (ATRA), and the deoxyribonucleic acid polymerase- α inhibitor cytarabine (Ara-C) is now considered for disease-stabilizing treatment of acute myeloid leukemia (AML). Leukemogenesis and leukemia cell chemoresistance seem to be supported by neighbouring stromal cells in the bone marrow, and we have therefore investigated the effects of these drugs on primary human endothelial cells and the osteoblastic Cal72 cell line. The results show that VPA and Ara-C have antiproliferative effects, and the antiproliferative/cytotoxic effect of Ara-C was seen at low concentrations corresponding to serum levels found during low-dose in vivo treatment. Furthermore, in functional assays of endothelial migration and tube formation VPA elicited an antiangiogenic effect, whereas ATRA elicited a proangiogenic effect. Finally, VPA and ATRA altered the endothelial cell release of angiogenic mediators; ATRA increased levels of CXCL8, PDGF-AA, and VEGF-D, while VPA decreased VEGF-D and PDGF-AA/BB levels and both drugs reduced MMP-2 levels. Several of these mediators can enhance AML cell proliferation and/or are involved in AML-induced bone marrow angiogenesis, and direct pharmacological effects on stromal cells may thus indirectly contribute to the overall antileukemic activity of this triple drug combination.

  2. Análise estratégica de Xanxerê como polo de atração comercial da região da AMA

    Directory of Open Access Journals (Sweden)

    Marcus Vinicius Machado Carneiro

    2010-08-01

    Full Text Available A relação comercial que se estabelece entre os 14 (catorze municípios da região da AMAI , considerando os aspectos demográfico, social, cultural, econômico e de distância, demonstra a relação que existe na atração de consumo para o município com a maior população da região, Xanxerê-SC. O problema que se apresenta é saber qual o raio de atratividade comercial de Xanxerê em relação aos municípios da AMAI. Para atingir os objetivos propostos, realizou-se um estudo quantitativo do perfil das populações dos municípios da região da AMAI, com dados divulgados pelo IBGE. Para calcular o raio de atratividade comercial utilizou-se a fórmula de Reilly (lei de gravitação. O resultado obtido com a equação de Reilly estabelece a relação entre as vendas perdidas pelo centro menor (cidades limítrofes em favor da localidade maior e as vendas mantidas. Observou-se que o comércio das cidades limítrofes, atraído pelo município de Xanxerê, está em função direta da densidade populacional, no sentido de que, em igualdade de condições, uma cidade com população dupla em relação à outra, atrai para si um volume de comércio duplo. Assim, o município de Xanxerê reafirma-se como um polo de atração comercial na região da AMAI, fato que pode ser utilizado pelos empresários locais como elemento para a melhora competitiva das suas atividades. Também pode ser utilizado como referência para possíveis investidores, ao analisar a viabilidade econômica, financeira e mercadológica de um novo negócio no município.

  3. IMPACT OF ATRA ON OVALBUMIN AND MOLD-SENSITIZED F344 RATS AND REVERSAL OF HEALTH-RELATED IMPLICATIONS BY CITRAL.

    Science.gov (United States)

    Farah, Ibrahim O; Holt-Gray, Carlene; Cameron, Joseph A; Tucci, Michelle; Benghuzzi, Hamed

    2017-01-01

    The role of retinoic acid (All Trans Retinoic Acid; ATRA) in the development of hypervitaminosis A pathophysiology is not well understood or established in the literature. As well, the role of Citral (inhibitor of retinoid function; a non-toxic chemical that exists in two forms (diethyl; C1 or cis-trans dimethyl; C2).) in the reversal of pathophysiological implications is also not ascertained under an in vivo setting. Therefore, it is hypothesized that ovalbumin exposure will sensitize the body to supra-physiologic levels of retinoic acid leading to a negative pathophysiological impact and that Citrals 1 and 2 will reverse or ameliorate the related damage to the body's pathophysiology. Even though ovalbumin and retinoic have been previously applied through intra-tracheal route in cancer prevention and immunological research, the objective of this study was to evaluate their interaction as a remedy for hypervitaminosis A. This IACUC approved in vivo study used Fischer 344 rats (n = 80 ;229 to 273g), which were randomly assigned to controls as well as ovalbumin and mold-sensitized treatment groups (0.80 mg/kg and 1X109 mold spores combined from 4 strains/100 μl intra-tracheal; all others were dosed by intra-peritoneal injection at days 1 and 7 with 80 mg/kg each of ATRA as well as 20 and 50 mg/kg each of Citrals 1 or 2 individually or in combination to represent all four chemicals and mold spores treatments.. Positive and negative controls for each treatment were also included in the study. Animals were housed in rat cages at the JSU Research Animal Core Facilities and were placed on a 12:12 light dark cycle. A standard rodent diet and water access were provided ad-libidum. Rat weights were recorded on day 1 and 21, all animals were sacrificed on day 21 and blood was collected and processed for hematological parameters. Results showed that even though C1 and C2 were not toxic individually, their combination at high dosing was lethal. Exposure of ovalbumin

  4. Atração e distração na publicidade externa dos candidatos à eleição em 2014

    OpenAIRE

    Trein, Sérgio

    2015-01-01

    Em 2014, em função de uma série de limitações impostas pela legislação eleitoral, a publicidade externa foi muito usada pelos candidatos. O problema é que as principais avenidas e cruzamentos das cidades foram tomadas por estes cavaletes, gerando uma enorme poluição visual. A partir desta questão é que surge o nosso problema de pesquisa: este acúmulo de quase um cavalete sobre o outro cria uma sensação de atração ou de distração em relação às propagandas políticas dos candidatos? Para isso, c...

  5. Spatio-temporal transcriptome analysis in the marine snail Tegula atra along central-northern Chile (28-31°S).

    Science.gov (United States)

    Tapia, Fabian J; Gallardo-Escárate, Cristian

    2015-10-01

    This study describes the results from transcriptomes sequenced by illumina technology from four populations in the marine snail Tegula atra along central-northern Chile (28-31°S) during summer and winter 2014. In silico differential expression of transcripts annotated to known proteins revealed several local patterns associated to the environmental thermal variability. Herein, northern populations evidenced lower number of genes highly regulated, while southern populations displayed opposite patterns. This relationship could suggest that northern snail populations are more adapted to high temperature variations, enabling specific genes (e.g. HSPs and antioxidant system) to maintain high transcriptional activity under controlled physiological conditions. This transcriptome response or "frontloading" strategy can significantly increase the speed of response to thermal stress, and also be a relevant molecular underpinning to explain the genomic diversity along the Chilean coast. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy.

    Science.gov (United States)

    Abla, Oussama; Ribeiro, Raul C; Testi, Anna Maria; Montesinos, Pau; Creutzig, Ursula; Sung, Lillian; Di Giuseppe, Giancarlo; Stephens, Derek; Feusner, James H; Powell, Bayard L; Hasle, Henrik; Kaspers, Gertjan J L; Dalla-Pozza, Luciano; Lassaletta, Alvaro; Tallman, Martin S; Locatelli, Franco; Reinhardt, Dirk; Lo-Coco, Francesco; Hitzler, Johann; Sanz, Miguel A

    2017-09-01

    Clinical trials on childhood acute promyelocytic leukemia (APL) report early death (ED) rates of 3-8%, but predictors of thrombohemorrhagic (TH)-ED are not well understood. In a retrospective study, we aimed to determine the incidence and predictors of TH-ED in childhood APL. Data were analyzed from children and adolescents with t(15;17)-positive APL (n = 683) who started treatment with all-trans retinoic acid (ATRA) and chemotherapy in different international studies. Demographic data; initial white blood cell (WBC), peripheral blood (PB) blast, and platelet counts; hemoglobin value; coagulation parameters; morphologic variant (M3 or M3v); and induction details were analyzed. Early death was defined as death occurring within 30 days of presentation. The incidence of ED was 4.7% (32 of 683 patients). Predictors of TH-ED were identified by univariable and multivariable Cox proportional hazard regression analyses (n = 25). In univariable analysis, high WBC (>10 × 10(9)/L) (P 30 × 10(9)/L) (P < 0.001), M3v (P < 0.01), and black ethnicity (P < 0.001) were independent predictors of TH-ED. In multivariable analysis, high WBC count (P < 0.01) and obesity (i.e., body mass index ≥95th percentile for age) (P = 0.03) were predictors of TH-ED. Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL. The efficacy of novel drugs for APL-associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates in childhood APL remains to be established.

  7. Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8.

    Science.gov (United States)

    Adhikary, Santanu; Sanyal, Sulagna; Basu, Moitri; Sengupta, Isha; Sen, Sabyasachi; Srivastava, Dushyant Kumar; Roy, Siddhartha; Das, Chandrima

    2016-02-05

    ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), a newly identified component of the transcriptional coregulator network, was found to interact with the Nucleosome Remodeling and Deacetylase (NuRD) complex. Previous reports have shown that ZMYND8 is instrumental in recruiting the NuRD complex to damaged chromatin for repressing transcription and promoting double strand break repair by homologous recombination. However, the mode of transcription regulation by ZMYND8 has remained elusive. Here, we report that through its specific key residues present in its conserved chromatin-binding modules, ZMYND8 interacts with the selective epigenetic marks H3.1K36Me2/H4K16Ac. Furthermore, ZMYND8 shows a clear preference for canonical histone H3.1 over variant H3.3. Interestingly, ZMYND8 was found to be recruited to several developmental genes, including the all-trans-retinoic acid (ATRA)-responsive ones, through its modified histone-binding ability. Being itself inducible by ATRA, this zinc finger transcription factor is involved in modulating other ATRA-inducible genes. We found that ZMYND8 interacts with transcription initiation-competent RNA polymerase II phosphorylated at Ser-5 in a DNA template-dependent manner and can alter the global gene transcription. Overall, our study identifies that ZMYND8 has CHD4-independent functions in regulating gene expression through its modified histone-binding ability. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Effect of all-trans retinoic acids (ATRA) on the expression of α-smooth muscle actin (α-SMA) in the lung tissues of rats with pulmonary arterial hypertension (PAH).

    Science.gov (United States)

    Xin, Y; Lv, J-Q; Wang, Y-Z; Zhang, J; Zhang, X

    2015-11-13

    The effect of all-trans retinoic acid (ATRA) on the expression of α-smooth muscle actin (α-SMA) in rats with pulmonary arterial hypertension (PAH) was studied, and the mechanism of the effect of ATRA on PAH was proposed. Thirty male SD rats were randomly divided into normal control, monocrotaline (MCT) model, and ATRA [30 mg/(kg.day)]intervention groups (N = 10 each). The mean pulmonary arterial pressure was recorded. Right ventricular hypertrophy index (RVHI) was calculated (weight of right ventricle: total weight of left ventricle and interventricular septum). The percentages of wall thickness of pulmonary arteriole (WT) to external diameter of artery (WT%) and vascular wall area (WA) to total vascular area (WA%) were determined. Real-time fluorescence-based quantitative PCR and western blot analyses were employed to detect the α-SMA mRNA and protein expressions. The mean pulmonary arterial pressure, RVHI, WT%, and WA% were all obviously higher in the model group than in the control and intervention groups. The values of these indicators in the intervention group were also higher than those in the control group (P rats than those in the control and intervention groups. However, the intervention group showed no statistically significant differences in α-SMA mRNA and protein expression levels compared to the control (P rats with MCT-induced PAH, and could be used to treat PAH.

  9. Lyn, a tyrosine kinase closely linked to the differentiation status of primary acute myeloid leukemia blasts, associates with negative regulation of all-trans retinoic acid (ATRA) and dihydroxyvitamin D3 (VD3)-induced HL-60 cells differentiation.

    Science.gov (United States)

    Iriyama, Noriyoshi; Yuan, Bo; Hatta, Yoshihiro; Takagi, Norio; Takei, Masami

    2016-01-01

    Lyn, an import member of Src family kinases (SFKs), is supposed to be implicated in acute myeloid leukemia (AML) pathogenesis and development by participation in AML differentiation, yet the details still remain incompletely understood. The expression status of Lyn and its correlation with multiple clinical parameters including cell differentiation degree, different cytogenetic risk classification, and the activity of myeloperoxidase (MPO) were thus investigated. To address the mechanisms underlying the involvement of Lyn in differentiation induction, the effects of dasatinib, an inhibitor for SFKs including Lyn, on the alterations of all-trans retinoic acid (ATRA)- or dihydroxyvitamin D3 (VD3)-induced differentiation, and c-Myc protein expression were investigated. Primary AML blasts were obtained from 31 newly diagnosed AML patients with different French-American-British (FAB) subtypes. The expression of phosphorylated and total Lyn, c-Myc, and CD11b, CD11c and CD15 was analyzed by flow cytometry. The activation of Akt and Erk known to be involved in the regulation of c-Myc expression was investigated using western blotting. Significant higher expression levels of total Lyn were observed in AML patients with favorable cytogenetics, higher MPO activity and FAB M2 subtype. A clear positive correlation between the expression levels of Lyn and differentiation status of primary AML blasts was observed. Dasatinib inhibited the expression of phosphorylated Lyn, and further enhanced the differentiation-inducing activity of ATRA and VD3 in HL-60 cells. Augmented downregulation of c-Myc protein expression was observed in the combination treatment with ATRA, VD3 and dasatinib compared to treatment with each reagent alone in HL-60 cells. The suppression of the activation of Akt and Erk was also observed concomitantly. The expression level of total Lyn is closely linked to the differentiation status of AML blasts. The enhancement of differentiation-inducing activity of ATRA

  10. Blocking effect and crystal structure of natrin toxin, a cysteine-rich secretory protein from Naja atra venom that targets the BKCa channel.

    Science.gov (United States)

    Wang, Jing; Shen, Bing; Guo, Min; Lou, Xiaohua; Duan, Yuanyuan; Cheng, Xin Ping; Teng, Maikun; Niu, Liwen; Liu, Qun; Huang, Qingqiu; Hao, Quan

    2005-08-02

    Cysteine-rich secretory proteins (CRISPs) are widespread in snake venoms. Some members of these CRISPs recently have been found to block L-type Ca(2+) channels or cyclic nucleotide-gated ion (CNG) channels. Here, natrin purified from Naja atra venom, a member of the CRISP family, can induce a further contractile response in the endothelium-denuded thoracic aorta of mouse which has been contracted by a high-K(+) solution. Further experiments show it can block the high-conductance calcium-activated potassium (BK(Ca)) channel in a concentration-dependent manner with an IC(50) of 34.4 nM and a Hill coefficient of 1.02, which suggests that only a single natrin molecule is required to bind an ion channel to block BK(Ca) current. The crystal structure of natrin displaying two domains in tandem shows its cysteine-rich domain (CRD) has relatively independent flexibility, especially for the C-terminal long loop (loop I) of CRD to participate in the interface of two domains. On the basis of previous studies of CNG channel and L-Ca(2+) channel blockers, and the sequence and structural comparison of natrin and stecrisp, the deviation of the vital loop I of CRD is suggested to contribute to different effects of some CRISPs in protein-protein interaction.

  11. Identification of Immunoreactive Peptides of Toxins to Simultaneously Assess the Neutralization Potency of Antivenoms against Neurotoxicity and Cytotoxicity of Naja atra Venom.

    Science.gov (United States)

    Liu, Bin-Sin; Wu, Wen-Guey; Lin, Min-Han; Li, Chi-Han; Jiang, Bo-Rong; Wu, Suh-Chin; Leng, Chih-Hsiang; Sung, Wang-Chou

    2017-12-25

    Assessing the neutralization capability of nonlethal but medically relevant toxins in venom has been a challenging task. Nowadays, neutralization efficacy is evaluated based simply on the survival rates of animals injected with antivenom together with a predefined dose of venom, which can determine potency against neurotoxicity but not validate the capability to neutralize cytotoxin-induced complications. In this study, a high correlation with in-vivo and in-vitro neutralization assays was established using the immunoreactive peptides identified from short-chain neurotoxin and cytotoxin A3. These peptides contain conserved residues associated with toxin activities and a competition assay indicated that these peptides could specifically block the antibody binding to toxin and affect the neutralization potency of antivenom. Moreover, the titers of peptide-specific antibody in antivenoms or mouse antisera were determined by enzyme-linked immunosorbent assay (ELISA) simultaneously, and the results indicated that Taiwanese bivalent antivenom (BAV) and Vietnamese snake antivenom-Naja (SAV-Naja) exhibited superior neutralization potency against the lethal effect of short-chain neurotoxin (sNTX) and cytotoxicity of cardiotoxin/cytotoxin (CTX), respectively. Thus, the reported peptide ELISA shows not only its potential for antivenom prequalification use, but also its capability of justifying the cross-neutralization potency of antivenoms against Naja atra venom toxicity.

  12. Identification of Immunoreactive Peptides of Toxins to Simultaneously Assess the Neutralization Potency of Antivenoms against Neurotoxicity and Cytotoxicity of Naja atra Venom

    Directory of Open Access Journals (Sweden)

    Bing-Sin Liu

    2017-12-01

    Full Text Available Assessing the neutralization capability of nonlethal but medically relevant toxins in venom has been a challenging task. Nowadays, neutralization efficacy is evaluated based simply on the survival rates of animals injected with antivenom together with a predefined dose of venom, which can determine potency against neurotoxicity but not validate the capability to neutralize cytotoxin-induced complications. In this study, a high correlation with in-vivo and in-vitro neutralization assays was established using the immunoreactive peptides identified from short-chain neurotoxin and cytotoxin A3. These peptides contain conserved residues associated with toxin activities and a competition assay indicated that these peptides could specifically block the antibody binding to toxin and affect the neutralization potency of antivenom. Moreover, the titers of peptide-specific antibody in antivenoms or mouse antisera were determined by enzyme-linked immunosorbent assay (ELISA simultaneously, and the results indicated that Taiwanese bivalent antivenom (BAV and Vietnamese snake antivenom-Naja (SAV-Naja exhibited superior neutralization potency against the lethal effect of short-chain neurotoxin (sNTX and cytotoxicity of cardiotoxin/cytotoxin (CTX, respectively. Thus, the reported peptide ELISA shows not only its potential for antivenom prequalification use, but also its capability of justifying the cross-neutralization potency of antivenoms against Naja atra venom toxicity.

  13. Antinociceptive Effect of Najanalgesin from Naja Naja Atra in a Neuropathic Pain Model via Inhibition of c-Jun NH2-terminal Kinase.

    Science.gov (United States)

    Liang, Ying-Xia; Zhang, Zhi-Yu; Zhang, Rui

    2015-09-05

    Najanalgesin, a toxin isolated from the venom of Naja naja atra, has been shown to exert significant analgesic effects in a neuropathic pain model in rats. However, the molecular mechanism underlying this protective effect of najanalgesin is poorly understood. The present study sought to evaluate the intracellular signaling pathways that are involved in the antinociceptive effect of najanalgesin on neuropathic pain. The antinociceptive properties of najanalgesin were tested in hind paw withdrawal thresholds in response to mechanical stimulation. We analyzed the participation of the mitogen-activated protein kinase p38, extracellular-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) by western blot analysis. This inhibition of JNK was confirmed by immunohistochemistry. The phosphorylation levels of JNK (as well as its downstream molecule c-Jun), p38, and ERK were significantly increased after injury. Najanalgesin only inhibited JNK and c-Jun phosphorylation but had no effect on either ERK or p38. This inhibition of JNK was confirmed by immunohistochemistry, which suggested that the antinociceptive effect of najanalgesin on spinal nerve ligation-induced neuropathic pain in rats is associated with JNK activation in the spinal cord. The antinociceptive effect of najanalgesin functions by inhibiting the JNK in a neuropathic pain model.

  14. Improved method for the isolation, characterization and examination of neuromuscular and toxic properties of selected polypeptide fractions from the crude venom of the Taiwan cobra Naja naja atra.

    Science.gov (United States)

    Ständker, L; Harvey, A L; Fürst, S; Mathes, I; Forssmann, W G; Escalona de Motta, G; Béress, L

    2012-09-15

    An improved chromatographic method was developed to isolate and purify polypeptides and proteins from the crude venom of the Taiwan cobra Naja naja atra. The procedure devised is simple, easy to reproduce, and enables large scale isolation of almost all polypeptides and proteins in this cobra venom. Six pure polypeptide fractions of the venom were isolated and characterized using gel filtration on Sephadex G50 (medium), ion exchange chromatography on SP-Sephadex C25, desalting on Sephadex G25 (fine) and preparative HPLC on a RPC 18 column. The neuromuscular activity of these fractions was tested on the chick biventer cervicis nerve-muscle preparation and their toxicity (LD(50)) was determined after i.v. administration in mice. Their antinociceptive activity was tested in the mouse abdominal test by i.v. application. Two of these polypeptide samples had major physiological effects: one acted as a cardiotoxin causing reversible myocardial contractures with no effect on muscle twitches elicited by nerve stimulation (NS); another was a neurotoxin that blocked muscle contractions in response to NS and exogenously added acetylcholine. The cardiotoxic fraction was identified as CTX I, a well-known cardiotoxin present in this venom, and the neurotoxin was identified as neurotoxin-α with an LD50 in mice of 0.075 mg/kg. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Sex-specific estimates of dispersal show female philopatry and male dispersal in a promiscuous amphibian, the alpine salamander (Salamandra atra).

    Science.gov (United States)

    Helfer, V; Broquet, T; Fumagalli, L

    2012-10-01

    Amphibians display wide variations in life-history traits and life cycles that should prove useful to explore the evolution of sex-biased dispersal, but quantitative data on sex-specific dispersal patterns are scarce. Here, we focused on Salamandra atra, an endemic alpine species showing peculiar life-history traits. Strictly terrestrial and viviparous, the species has a promiscuous mating system, and females reproduce only every 3 to 4 years. In the present study, we provide quantitative estimates of asymmetries in male vs. female dispersal using both field-based (mark-recapture) and genetic approaches (detection of sex-biased dispersal and estimates of migration rates based on the contrast in genetic structure across sexes and age classes). Our results revealed a high level of gene flow among populations, which stems exclusively from male dispersal. We hypothesize that philopatric females benefit from being familiar with their natal area for the acquisition and defence of an appropriate shelter, while male dispersal has been secondarily favoured by inbreeding avoidance. Together with other studies on amphibians, our results indicate that a species' mating system alone is a poor predictor of sex-linked differences in dispersal, in particular for promiscuous species. Further studies should focus more directly on the proximate forces that favour or limit dispersal to refine our understanding of the evolution of sex-biased dispersal in animals. © 2012 Blackwell Publishing Ltd.

  16. Cobra venom proteome and glycome determined from individual snakes of Naja atra reveal medically important dynamic range and systematic geographic variation.

    Science.gov (United States)

    Huang, Hsuan-Wei; Liu, Bing-Sin; Chien, Kun-Yi; Chiang, Liao-Chun; Huang, Sheng-Yu; Sung, Wang-Chou; Wu, Wen-Guey

    2015-10-14

    Recent progress in snake venomics has shed much light on the intra-species variation among the toxins from different geographical regions and has provided important information for better snakebite management. Most previous reports on snake venomics were based on venoms pooled from different snakes. In this study, we present the proteomic and glycomic profiles of venoms from individual Naja atra snakes. The results reveal wide dynamic range of three-finger toxins. Systematic classification based on cardiotoxin (CTX-) profiles of A2/A4 and A6, respectively, allowed the identification of two putative subspecies of Taiwan cobra from the eastern and western regions. We also identified four major N-glycan moieties on cobra snake venom metalloproteinase on the bi-antennary glycan core. ELISA showed that these glycoproteins (cobra venom toxins such as small molecular weight CTXs (~60%). By removing these high-molecular weight glycoproteins from the immunogen, we demonstrated better protection than that achieved with conventional crude venom immunization in mice challenged by crude venom. We conclude that both intra-species and inter-individual variations of proteomic and glycomic profiles of snake venomics should be considered to provide better antivenomic approach for snakebite management. Based on the proteomic and glycomic profiles of venoms obtained from individual snakes, we demonstrated a surprisingly wide dynamic range and geographical variation of three-finger toxins in cobra venomics. This provides a reasonable explanation for the variable neutralization effects of antivenom treatment on victims suffering from cobra snakebite and suggests a simple and economic method to produce potent antivenom with better efficacy. Since two major venomic profiles with distinct dynamic ranges were observed for Taiwan cobra venoms isolated from the eastern and western regions, the current venomic profile should be used as a quality control for future production of antivenom in

  17. Effect of ATRA and ATO on the expression of tissue factor in NB4 acute promyelocytic leukemia cells and regulatory function of the inflammatory cytokines TNF and IL-1β.

    Science.gov (United States)

    Dunoyer-Geindre, Sylvie; Rivier-Cordey, Anne-Sophie; Tsopra, Olga; Lecompte, Thomas; Kruithof, Egbert K O

    2017-06-01

    The characteristic hemorrhages of acute promyelocytic leukemia (APL) are caused in part by the high expression of tissue factor (TF) on leukemic cells, which also produce TNF and IL-1β, proinflammatory cytokines known to increase TF in various cell types. Exposure of NB4 cells, an APL cell line, to all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) rapidly and strongly reduced TF mRNA. Both drugs also reduced TNF mRNA, but later, and moreover increased IL-1β mRNA. The effect on procoagulant activity of cells and microparticles, as measured with calibrated automated thrombography, was delayed and only partial at 24 h. TNF and IL-1β inhibition reduced TF mRNA and activity only partially. Inhibition of the inflammatory signaling intermediate p38 reduced TF mRNA by one third but increased TNF and IL-1β mRNA. NF-κB inhibition reduced, within 1 h, TF and TNF mRNA but did not change IL-1β mRNA, and rapidly and markedly reduced cell survival, with procoagulant properties still being present. In conclusion, although we provide evidence that TNF, IL-1β, and their signaling intermediates have a regulatory function on TF expression by NB4 APL cells, the effect of ATRA and ATO on TF can only partially be accounted for by their impact on these cytokines.

  18. Migração e pendularidade : as consequências de atração da população para o município de Toritama

    OpenAIRE

    VASCONCELOS, Valtemira Mendes

    2012-01-01

    Este trabalho faz uma análise sobre as intensas migrações e fluxos pendulares para o município de Toritama decorrentes da atratividade da indústria de confecções. O foco, por sua vez, foi procurar identificar, descrever e analisar os movimentos migratórios para a região do pólo de Toritama de forma quantitativa e qualitativa, observando as consequências dessa atração de população para o município, no que diz respeito à infraestrutura física e social da região. Para tanto, foram utilizados ...

  19. Atração e penetração de Meloidogyne javanica e Heterodera glycines em raízes excisadas de soja Attraction and penetration of Meloidogyne javanica and Heterodera glycines in excised soybean roots

    Directory of Open Access Journals (Sweden)

    Hercules Diniz Campos

    2011-09-01

    Full Text Available Com vista ao estudo de atração e penetração de Meloidogyne javanica (Treub Chitwood e Heterodera glycines (Ichinoe em soja (Glycine max L., desenvolveu-se uma técnica empregando-se segmento de raiz com 2cm de comprimento. Nos segmentos de raiz de soja infectados, observou-se que a penetração de juvenis de segundo estádio (J2 de M. javanica ocorre pela coifa seguida de migração entre os feixes vasculares do cilindro central. Juvenis de H. glycines penetraram, aproximadamente, 15mm da coifa. A região seccionada da raiz de soja atraiu três vezes mais J2 de M. javanica do que a região da coifa, mas esta não foi tão atrativa para J2 de H. glycines. A obstrução conjunta da coifa e do local seccionado reduziu (83% a penetração de J2, tanto de M. javanica quanto de H. glycines. Quando apenas um desses locais foi obstruído, a outra extremidade livre compensou o processo atrativo. Portanto, as substâncias atrativas são liberadas por essas extremidades. A penetração de J2 de M. javanica foi maior no segmento de raiz quando comparada com a plântula intacta de soja. Entretanto, os J2 de H. glycines penetraram menos em segmentos de raiz e em plântulas sem folhas, quando comparados com plântulas intactas e com as seccionadas no colo. Portanto, na cultivar de soja "Embrapa 20", a atração e os locais de penetração de J2 de H. glycines e M. javanica são diferenciados. Esta técnica poderá ser útil nos estudos de atração e penetração de outros nematoides endoparasitas.To study the attraction and penetration of Meloidogyne javanica (Treub Chitwood and Heterodera glycines (Ichinoe in soybean (Glycine max L., a technique using 2-cm long root segments was developed. In infected soybean root segments penetration of second stage juveniles (J2 of M. javanica occured through the root cap following migration between the vascular bundles of the central cylinder. Juveniles of H. glycines penetrated about 15mm from the root cap. The cut

  20. Atração de miracídios de Schistosoma mansoni por hospedeiros invertebrados: comportamento de miracídios frente a girinos de Hyla fuscovaria Miracidia attraction to invertebrate hosts: miracidia behavior in the presence of Hyla fuscovaria girina

    Directory of Open Access Journals (Sweden)

    Beatriz de C. Brasio

    1985-02-01

    Full Text Available Analisou-se a atração de miracídios de Schistosoma mansoni das linhagens BH e SJ frente a seus vetores simpátricos e alopátricos tendo-se em consideração a possibilidade da presença de substâncias quimiotáxicas emanadas dos moluscos. Estudou-se também o comportamento desses miracídios frente a girinos de Hyla fuscovaria. Foi verificado que houve atração dos miracídios pelos moluscos vetores e que essa atração foi mais evidente quando a larva era colocada frente ao seu hospedeiro simpátrico.As observações realizadas no decorrer da experiência demonstraram a presença de substâncias miraxonais emanadas pelos moluscos.Miracidia tropism to suitable hosts is a subject of much controversy. In this work, we try to determine the possible specificity of Schistosoma mansoni miracidia attraction and also the degree of this specificity. To this end an experiment was carried out to determine the probability of attraction in a given experimental set up, to H. fuscovaria girina or to one of two susceptible snail species. Two strains of S. mansoni were employed and also the corresponding snail species. A specially designed apparatus consisting of two circular glass chambers joined by an open channel was used. One of the girina or a snail was placed in one of the chambers (randomly chosen. In the channel a known number of miracidia were deposited and the count of miracidia in each of the three compartments (the two chambers and the channel was recorded. The experiment was carried out under strong or subdued lighting. Statistical and ad-hoc exploratory data analysis have shown that: a the miracidia, when exposed to only one species of snail, show more attraction to the sympatric snail host; bone strain of miraciadia showed more attraction under strong lighting; the other strain behaved the opposite way, with stronger attraction under weak liht; c the girina did not attract the miracidia; this seems to imply that sone chemiotropism is present

  1. Luz e galinhas como fatores de atração de Nyssomyia whitmani em ambiente rural, Paraná, Brasil Light and hens as attraction factors of Nyssomyia whitmani in a rural area, Southern Brazil

    Directory of Open Access Journals (Sweden)

    Ueslei Teodoro

    2007-06-01

    Full Text Available OBJETIVO: Verificar a influência de armadilhas com luz elétrica e galinhas como fatores de atração de flebotomíneos e comparar os resultados entre métodos de captura. MÉTODOS: O estudo foi realizado na Fazenda Palmital, município de Terra Boa, Paraná, Brasil. As coletas de flebotomíneos foram feitas com armadilhas de Falcão e aspirador elétrico, quinzenalmente, das 20 às 23 horas, na presença ou na ausência de luz e de galinhas, no ambiente peridomiciliar, de setembro de 1998 a junho de 1999. RESULTADOS: Coletaram-se 43.767 exemplares de oito espécies de flebotomíneos; Nyssomyia whitmani, N. neivai e Migonemyia migonei representando 99,9% do total coletado, com predomínio de N. whitmani. O número de exemplares coletados na presença (21.045 foi maior do que na ausência de galinhas (10.434. Na presença de galinhas, indiferentemente das intensidades de luz, coletou-se maior número de exemplares de N. whitmani com luz de 3W. Na presença de galinhas e luz (3W o número de N. whitmani coletado com aspirador elétrico (5.141 foi superior ao coletado com armadilha de Falcão (1.675. Na ausência de luz não houve diferença entre o número de N. whitmani coletado com o aspirador elétrico e na armadilha de Falcão, na presença ou na ausência de galinhas. CONCLUSÕES: As galinhas e a luz elétrica juntas atraem mais N. whitmani para o ambiente peridomiciliar. O número de N. whitmani coletado com o aspirador elétrico na presença de galinhas e luz no galinheiro foi maior do que o coletado na armadilha de Falcão, na mesma condição.OBJECTIVE: To verify the influence of traps with electric light and hens as factors that attract sandflies and compare results between capture methods. METHODS: The study was conducted in the Palmital Farm, Southern Brazil. Sandfly collections were conducted with Falcão traps and an electric aspirator, fortnightly, between 8 p.m. and 11 p.m. in the presence or absence of light and hens in

  2. A história da ciência na formação do professor de física: subsídios para um curso sobre o tema atração gravitacional visando às mudanças de postura na ação docente History of Science in teaching education: suggestions for a course plan on gravitational attraction aiming to change teachers' attitudes

    Directory of Open Access Journals (Sweden)

    Sandra Regina Teodoro Gatti

    2004-12-01

    Full Text Available O objetivo desta pesquisa foi estudar como a evolução histórica dos modelos de atração entre corpos, tendo como pano de fundo a evolução dos modelos de mundo, pode auxiliar na formação inicial do docente de Física. Para tanto, sugerimos um planejamento de curso sobre o tema atração gravitacional, destinado principalmente a docentes de Física que atuam no ensino médio. O planejamento do curso foi baseado: em dados sobre a evolução dos modelos de mundo, buscando evidenciar como o conceito de atração gravitacional desenvolveu-se historicamente; nas concepções alternativas mais comuns encontradas na literatura, incluindo um breve esboço de noções diagnosticadas em uma amostra de docentes de Física de ensino médio; e em sugestões de leituras de resultados de pesquisas recentes sobre os processos de ensino e aprendizagem de ciências. Pretende-se fornecer aos docentes elementos de reflexão que lhes proporcionem mudanças de postura, através do questionamento da visão de ciência enquanto processo de construção e sobre sua própria prática de ensino. Partindo de resultados recentes da pesquisa em Ensino de Ciências, a metodologia sugerida privilegia o trabalho coletivo, com a realização de debates e sínteses. As atividades mencionadas são acompanhadas de justificativas sobre a escolha do tema e objetivos.The main purpose of this research was to study how the attraction among bodies, having as background the evolution of models of the world, can help prospective teachers' education. To reach this goal, we suggest a course plan on gravitational attraction, addressed mainly to High School Physics teachers. This course was based: on data about world models' evolution, searching to make clear how the concept of gravitational attraction was historically developed; on the most common alternative conceptions found in the literature, including a brief outline of notions found among in-service High School Physics teachers

  3. Between-season attraction of cotton boll weevil, Anthonomus grandis Boh. (Coleoptera: Curculionidae adults by its aggregation pheromone Atração de adultos do bicudo do algodoeiro, Anthonomus grandis Boh. (Coleoptera: Curculionidae por seu feromônio de agregação na entressafra

    Directory of Open Access Journals (Sweden)

    Wedson Desidério Fernandes

    2001-06-01

    Full Text Available The present study was undertaken to investigate the attractiveness of boll weevil adults by its aggregation pheromone under winter field conditions. Two experimental fields were utilized at "Casa Branca", SP, Brazil. For each one, three areas were established near the refuge vegetation, sparated 500 m from each other. Each area was divided in three sub-areas or blocks of 100 m² to receive pheromone applications (2.5 g per block. In addition to the pre-application counting, five additional evaluations were carried out after the pheromone applicaton. Ten randomized sampling points per block were considered in each evaluation process. A. grandis adults responded immediately to the pheromone applications, and were captured for 14 days . The highest level of attractiveness was observed 24 hours after application. The application of the boll weevil aggregation pheromone during winter could increase the predation by natural enemies, due to the increase of prey availability. Chemical control can be recommended 24 hours after pheromone applications in small plots as a between-season strategy for the suppression of boll weevil adults.O presente estudo teve como objetivo investigar a atratividade do bicudo do algodoeiro ao seu feromônio de agregação em período de inverno. Foram utilizados dois campos experimentais no município de Casa Branca, SP. Em cada um destes, foram estabelecidas três áreas separadas de aproximadamente 500 metros, sempre próximas à vegetação de refúgio. Cada área foi dividida em três sub-áreas ou blocos de 100 m² para receber a aplicação do feromônio (2,5 g por bloco. Foi realizada uma contagem de bicudos adultos no solo antes, e mais cinco após a aplicação de feromônio. Em cada bloco, foram observadas dez parcelas aleatórias, para a avaliação dos bicudos. Os adultos de A. grandis foram atraídos imediatamente após a aplicação do feromônio, sendo capturados por mais de 14 dias após. O índice mais

  4. Biomonitoring Climate Change and Pollution in Marine Ecosystems: A Review on Aulacomya ater

    Directory of Open Access Journals (Sweden)

    France Caza

    2016-01-01

    Full Text Available The sedentarism and wide global distribution of the blue mussel Mytilus edulis have made it a useful bioindicator to assess changes in the health status of the marine ecosystem in response to pollution and other environmental stresses. Effective biomonitoring of an ecosystem requires, however, that multiple biomarkers be used to obtain an accurate measure of the cumulative effects of different sources of environmental stress. Here, we provide a first integrated review of the biological, economical, and geographical characteristics of another species of mussels, the ribbed mussel Aulacomya ater. We discuss the use of Aulacomya ater as a complementary biomonitor to the blue mussel to assess the impact of pollutants and climate change. Recent findings have indeed shown that Mytilus edulis and Aulacomya ater have distinctive anatomy and physiology and respond differently to environmental stress. Monitoring of mixed beds containing blue and ribbed mussels may thus represent a unique opportunity to study the effect of environmental stress on the biodiversity of marine ecosystems, most notably in the Southern hemisphere, which is particularly sensitive to climate change and where both species often cohabitate in the same intertidal zones.

  5. Calliphorid fly (Diptera, Calliphoridae attraction to different colored traps in the Tingua Biological Reserve, Rio de Janeiro, Brazil Atração de califorídeos (Diptera, Calliphoridae por diferentes cores de armadilhas na Reserva Biológica do Tinguá, Rio de Janeiro, Brasil

    Directory of Open Access Journals (Sweden)

    Renata S Mello

    2009-12-01

    Full Text Available The present study intended to analyze calliphorid attraction to traps painted in a variety of colors and the calliphorid constancy index in the Tingua Biological Reserve, Rio de Janeiro state, Brazil. The Diptera were collected monthly in the Reserve, between 2002 and 2005, totaling 24 samplings. Four traps containing sardines as bait were painted olive green, blood red, black, or white and exposed for 48 h at four equidistant points, 50 m from each other. To determine the calliphorid species constancy, the Bodenheirmer constancy index was used throughout the study. To analyze differences in the total abundance between species and in their color selection, an ANCOVA test with a significance level of 5 % and a Tukey post-test were used, considering the categories species and color as cofactors and climatic variables as co-variables (temperature, relative humidity and precipitation, since the samples were collected over two years. 10,444 insects were captured. Of these, 56 % belonged to the Calliphoridae family, totaling 13 species, with the most frequent species being Laneela nigripes (28.5 %, Hemilucilia semidiaphana (17 %, and Mesembrinella sp. (16.4 %. The other species had frequencies lower than 12 %. Nine species were considered constant, two accessories, and two accidental. The data indicated that the most frequent species presented significant differences between themselves concerning abundance over the captured months, however, the Tukey post-test indicated differences only between a few of them. The black trap presented the higher relative calliphorid frequency (27.34 %, followed by green (25 %, red (24.0 %, and white (23.7 %, although the species abundance in the different colored traps did not differ significantly among themselves. Therefore, there was no Calliphorid flies preference for any of the tested colors.O presente estudo teve como objetivo analisar a atração de califorídeos por armadilhas pintadas com diferentes cores de

  6. Orchid bee baits attracting bees of the genus Megalopta (Hymenoptera, Halictidae in Bauru region, São Paulo, Brazil: abundance, seasonality, and the importance of odors for dim-light bees Abelhas do gênero Megalopta (Hymenoptera, Halictidae atraídas por iscas químicas usadas para euglossíneos na região de Bauru, SP: abundância, sazonalidade e importância de odores para abelhas crepusculares

    Directory of Open Access Journals (Sweden)

    Fátima R. N. Knoll

    2012-12-01

    Full Text Available Nocturnal bees in the genus Megalopta Smith, 1853 are generally collected using artificial light sources. However, between 1993 and 2000, a total of 946 females (no males were captured were captured using aromatic baits commonly used for orchid bees (Euglossini in five localities in Bauru region, São Paulo, Brazil. Aromatic compounds used in bait traps were: benzyl acetate, eucalyptol, eugenol, skatole, methyl salicylate, and vanillin. The Megalopta species collected were: M. guimaraesi (71.2% of total number of specimens, M. amoena (28.1%, and M. aegis (0.6%. Using the data from these traps, we showed that there was a positive and significant correlation between the abundance of individuals and meteorological factors, rainfall and temperature. Bees were more commonly collected in the spring (September to December and summer (December to March than in the autumn and winter, the latter characterized for being a drier and colder period. Variations in the abundance were also detected among localities and years. The most attractive compounds were eugenol (54%, methyl salicylate (22%, and eucalyptol (16%. The ability to detect smells may have an important role in searching for flowers during dim-light conditions. We suggest the use of aromatic compounds in future studies on the biology of Megalopta in the Neotropical region.Abelhas noturnas do gênero Megalopta (Smith, 1853 são geralmente coletadas usando fontes artificiais de luz. Porém entre os anos de 1993 e 2000, um total de 946 fêmeas de Megalopta foram capturadas (machos não foram capturados usando iscas aromáticas frequentemente usadas para atração de machos de Euglossini, em cinco localidades na região de Bauru, São Paulo, Brasil. Os compostos aromáticos utilizados foram: acetato de benzila, eucaliptol, eugenol, escatol, salicilato de metila e vanilina. As espécies encontradas foram M. guimaraesi (71.2% do total de indivíduos, M. amoena (28.1% and M. aegis (0.6%. De modo geral

  7. Realgar-induced apoptosis and differentiation in all-trans retinoic acid (ATRA)-sensitive NB4 and ATRA-resistant MR2 cells

    OpenAIRE

    CHEN, SIYU; FANG, YI; MA, LIHENG; LIU, SHANXI; LI, XINMIN

    2011-01-01

    Realgar has been used in Western medicine and Chinese traditional medicine since ancient times, and its promising anticancer activity has attracted much attention in recent years, especially for acute promyelocytic leukemia (APL). However, the therapeutic action of realgar treatment for APL remains to be fully elucidated. Cellular cytotoxicity, proliferation, apoptosis and differentiation were comprehensively investigated in realgar-treated cell lines derived from PML-RAR?+ APL patient, inclu...

  8. Sügis 2012. Haridusteadus seab atra vaole / Virve Liivanõmm

    Index Scriptorium Estoniae

    Liivanõmm, Virve

    2012-01-01

    Tartu ülikoolis saavad alates 2018. a. lektoritena tööd ainult doktoritöö kaitsnud. Lektorite praegusest haridusseisust TLÜ kasvatusteaduste instituudis ja psühholoogiaprofessor Mati Heidmetsa visioon lektorite kvalifikatsiooninõuetest. TLÜ kasvatusteaduste instituudi algõpetuse osakonna juhataja, didaktika aluste ja matemaatikadidaktika lektor on oma instituudi värskeim doktor

  9. A new approach for surveying the Alpine Salamander (Salamandra atra in Austria

    Directory of Open Access Journals (Sweden)

    Ursula Reinthaler-Lottermoser

    2010-12-01

    Full Text Available The Alpine Salamander is a small pitch black amphibian which is endemic to the European Alps and the Dinarides. It is strictly protected according to the European FFH guidelines. Despite its central role in the alpine ecosystem our actual published record in Austria is small. In order to resolve this shortcoming our project explores its distribution in Austria. It uses a participatory and community based approach to gather data. Everybody can enter and look at Alpine Salamander observations on our website www.alpensalamander.eu. This approach also allows us to establish an “oral history” of Salamander observations in the past 50 years by conducting interviews in the local community. Since July 2009 the website and salamander report database are online. From the actual data (more than 5600 records we already obtained an overview about the present distribution and data quality. The data are an excellent basis for detailed scientific studies on these remarkable amphibians. With this new and highly interactive approach science and education are combined to initiate protection measures with the public.

  10. Evaluation of cloned cells, animal model, and ATRA sensitivity of human testicular yolk sac tumor

    Directory of Open Access Journals (Sweden)

    Zhao Junfeng

    2012-03-01

    Full Text Available Abstract The testicular yolk sac tumor (TYST is the most common neoplasm originated from germ cells differentiated abnormally, a major part of pediatric malignant testicular tumors. The present study aimed at developing and validating the in vitro and vivo models of TYST and evaluating the sensitivity of TYST to treatments, by cloning human TYST cells and investigating the histology, ultra-structure, growth kinetics and expression of specific proteins of cloned cells. We found biological characteristics of cloned TYST cells were similar to the yolk sac tumor and differentiated from the columnar to glandular-like or goblet cells-like cells. Chromosomes for tumor identification in each passage met nature of the primary tumor. TYST cells were more sensitive to all-trans-retinoic acid which had significantly inhibitory effects on cell proliferation. Cisplatin induced apoptosis of TYST cells through the activation of p53 expression and down-regulation of Bcl- expression. Thus, we believe that cloned TYST cells and the animal model developed here are useful to understand the molecular mechanism of TYST cells and develop potential therapies for human TYST.

  11. Arsenic Trioxide and Tretinoin (AsO/ATRA) for Acute Promyelocytic Leukemia (APL)

    Science.gov (United States)

    Damery, Erin; Solimando, Dominic A.; Waddell, J. Aubrey

    2016-01-01

    The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr., President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110–545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. PMID:27698500

  12. Seasonal variation in food supply and breeding success in European Coots Fulica atra

    NARCIS (Netherlands)

    Brinkhof, M.W.G.

    1997-01-01

    Chick survival in the European Coot typically shows a convex seasonal pattern. Previous experiments revealed that this pattern is directly linked to hatching date and that food supply within the first ten days after hatching is a causal factor in this relationship. However, the precise mechanism

  13. Cobrotoxin from Naja naja atra Venom Ameliorates Adriamycin Nephropathy in Rats

    Directory of Open Access Journals (Sweden)

    Shu-Zhi Wang

    2015-01-01

    Full Text Available Chronic kidney disease (CKD becomes a global health problem with high morbidity and mortality. Adriamycin- (ADR- induced rodent chronic nephropathy is a classic experimental model of human minimal lesion nephrotic syndrome. The present study investigated the effect of cobrotoxin (CTX on ADR-induced nephropathy. Rats were given 6 mg/kg ADR once through the tail vein to replicate ADR nephropathy model. CTX was administered to rats daily by placing a fast dissolving CTX membrane strip under the tongue starting from 5 days prior to ADR administration until the end of experiment. The results showed that CTX ameliorated the symptoms of ADR nephropathy syndrome with reduced body weight loss, proteinuria, hypoalbuminemia, dyslipidemia, serum electrolyte imbalance, oxidative stress, renal function abnormities, and kidney pathological lesions. Anti-inflammatory cytokine IL-10 expression was elevated after CTX administration in ADR nephropathy model. CTX inhibited the phosphorylation of IκB-α and NF-κB p65 nuclear translocation. Meanwhile, CTX upregulated the protein level of podocyte-specific nephrin and downregulated the level of fibrosis-related TGF-β. These findings suggest that CTX may be a potential drug for chronic kidney diseases.

  14. Integrated Use of Biomarkers (O : N Ratio and Acetylcholinesterase Inhibition) on Aulacomya ater (Molina, 1782) (Bivalvia: Mytilidae) as a Criteria for Effects of Organophosphate Pesticide Exposition

    Science.gov (United States)

    Führer, Eduardo; Rudolph, Anny; Espinoza, Claudio; Díaz, Rodrigo; Gajardo, Marisol; Camaño, Nuria

    2012-01-01

    The effect of residual concentrations of organophosphate pesticide chlorpyrifos (Lorsban 4E) on the activity of the acetylcholinesterase enzyme and oxygen : nitrogen ratio in the mussel Aulacomya ater was analyzed. Toxicity tests show a sensitivity to the pesticide in the bivalve estimated at 16 μg L−1 (LC50−96 hours). Concentrations between 0.2 and 1.61 μg L−1 were able to inhibit significantly the AChE activity, and concentrations between 0.8 and 1.61 μg L−1 stimulate ammonia excretion and decrease oxygen : ammonia-N (O : N) ratio, with respect to the control group. A. ater proved to be a species sensitive to pesticide exposure and easy to handle in lab conditions. Thus, it is recommended as a bioindicator for use in programs of environmental alertness in the Eastern South Pacific coastal zone. PMID:22619673

  15. Integrated Use of Biomarkers (O : N Ratio and Acetylcholinesterase Inhibition on Aulacomya ater (Molina, 1782 (Bivalvia: Mytilidae as a Criteria for Effects of Organophosphate Pesticide Exposition

    Directory of Open Access Journals (Sweden)

    Eduardo Führer

    2012-01-01

    Full Text Available The effect of residual concentrations of organophosphate pesticide chlorpyrifos (Lorsban 4E on the activity of the acetylcholinesterase enzyme and oxygen : nitrogen ratio in the mussel Aulacomya ater was analyzed. Toxicity tests show a sensitivity to the pesticide in the bivalve estimated at 16 μg L-1 (LC50-96 hours. Concentrations between 0.2 and 1.61 μg L-1 were able to inhibit significantly the AChE activity, and concentrations between 0.8 and 1.61 μg L-1 stimulate ammonia excretion and decrease oxygen : ammonia-N (O : N ratio, with respect to the control group. A. ater proved to be a species sensitive to pesticide exposure and easy to handle in lab conditions. Thus, it is recommended as a bioindicator for use in programs of environmental alertness in the Eastern South Pacific coastal zone.

  16. Isomerization of all-(E)-Retinoic Acid Mediated by Carbodiimide Activation - Synthesis of ATRA Ether Lipid Conjugates

    DEFF Research Database (Denmark)

    Christensen, Mikkel Stochkendahl; Pedersen, Palle Jacob; Andresen, Thomas Lars

    2010-01-01

    Treatment of the lysolipid 1-O-hexadecyl-sn-phosphatidylcholine with all-(E)-retinoic acid, DCC and DMAP resulted in poor acylation and caused (Z)/(E) isomerization of the alpha-beta double bond. In the presence of a proton source, the carbodiimide-activated all-(E)-retinoic acid undergoes fast...... to phosphatidylcholine and phosphatidylglycerol etherlipids....

  17. Spectroscopic investigations on the binding of persimmon tannin to phospholipase A 2 from Chinese cobra ( Naja naja atra)

    Science.gov (United States)

    Yang, Jie; Zhong, Li; Zou, Bo; Tian, Yan; Xu, Shu-fen; Yao, Ping; Li, Chun-mei

    2012-01-01

    To understand the anti-venom mechanism of persimmon tannin, the interaction between persimmon tannin (PT) and phospholipase A 2 (PLA 2) under physiological conditions was investigated by fluorescence quenching technique in combination with Fourier transform infrared (FT-IR) and circular dichroism (CD) spectra techniques. The results revealed that gradual fluorescence quenching was observed by titration of PLA 2 (2.0 μM) with increasing concentrations of PT (from 0 to 2.025 μM), and the type of quenching was found to be a static quenching process. Stern-Volmer plots were not linear but had an intersection at CPT ≈ 1.0 μM, indicating that PT binded to more than one class of sites on PLA 2. The binding sites calculated on basis of Scatchard plots were about 2, supporting this result. The enthalpy change (Δ H) and entropy change (Δ S) of the binding sites were -17.44 kJ/mol and 59.90 kJ/mol·, separately, suggesting that hydrophobic interaction played a main role in the binding. In addition, synchronous fluorescence, FT-IR and CD spectra showed that dramatic conformational changes in PLA 2 were induced by its interaction with PT.

  18. ¿Estan los paises europeos dando pasos atras? El caso de España y las politicas neoinjustas

    Directory of Open Access Journals (Sweden)

    Fernando Garcia Quero

    2014-01-01

    Full Text Available Este artículo aborda la crisis económica actual desde la óptica de sus consecuencias sobre la pérdida de derechos humanos en las sociedades supuestamente más desarrolladas del mundo. Situándose en el caso concreto de España, el objetivo principal del trabajo es mostrar y analizar el enorme retroceso que como resultado de la implantación paulatina de unas políticas neoinjustas, se está produciendo en los derechos humanos de segunda generación. Para ello se diferencian dos periodos históricos con implicaciones muy distintas para los derechos de la ciudadanía: el de consolidación de los Estados de Bienestar europeos (1945-1975; y el que abarca de mediados de los años 70 hasta la actualidad. Mediante un análisis documental y bibliográfico, el principal hallazgo al que se llega en este trabajo es la existencia de una relación bidireccional de retroalimentación entre un Estado de Bienestar fuerte y el cumplimiento de los derechos humanos, siendo imposible, como manifiesta la coyuntura actual española, un Estado cada vez más débil y una mejora en los derechos humanos. Se concluye que la dinámica seguida durante las últimas décadas está llevando a España a un escenario muy precario, que solo puede ser revertido a través de una ciudadanía activa que recupere su poder en las decisiones estatales.

  19. ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance.

    OpenAIRE

    Zhiqiang Wang; Zheng Liu; Xiwei Wu; Su Chu; Jinhui Wang; Hongfeng Yuan; Mendel Roth; Yate-Ching Yuan; Ravi Bhatia; WenYong Chen

    2014-01-01

    Acquired resistance through genetic mutations is a major obstacle in targeted cancer therapy, but the underlying mechanisms are poorly understood. Here we studied mechanisms of acquired resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) by examining genome-wide gene expression changes in KCL-22 CML cells versus their resistant KCL-22M cells that acquire T315I BCR-ABL mutation following TKI exposure. Although T315I BCR-ABL is sufficient to confer resistance to TK...

  20. Fouling community dominated by Metridium senile (Cnidaria: Anthozoa: Actiniaria in Bahía San Julián (southern Patagonia, Argentina

    Directory of Open Access Journals (Sweden)

    Juan Pablo Martin

    2015-06-01

    Full Text Available The objective of this study is to provide information about a harbour-fouling community dominated by Metridium senile in southern Patagonia. Several steel tubes from the wharf of Puerto San Julián were extracted to perform repair tasks, allowing the attached benthic community to be studied. Sampling was conducted at three levels: lower intertidal, 3-4 m depth and 6-7 m depth. In the lower intertidal, M. senile had a relative abundance of 43%, the most abundant accompanying species being Perumytilus purpuratus, Mytilus edulis platensis and Aulacomya atra atra. At subtidal level, the anemone showed relative abundances of 64% and 65%, and was accompanied by Monocorophium insidiosum at 3-4 m depth and by polychaetes of families Sabellidae and Syllidae at 6-7 m at depth. In the lower intertidal, epibiosis was more frequent on P. purpuratus, A. atra atra and M. edulis platensis, while in the subtidal, the richness of substrate-organisms increased significantly and the anemone was fixed to A. atra atra, M. edulis platensis, Paramolgula gregaria, Crepipatella dilatata, Austromegabalanus psittacus, Hiatella arctica, Polyzoa opuntia, Pyura sp. and Sabellidae tubes. The ability of M. senile to settle on many different organisms, along with other strategies, makes it a colonizer able to displace other species that could compete with it for substratum. Given the cosmopolitan nature of M. senile, the fact that this species has not been previously reported in the coastal zone of the region, and the results of our study, we discuss the possibility that this sea anemone is an invasive alien species in southern Patagonia, or at least a cryptogenic species.

  1. Marketing Digital e Turismo: Uso de Websites para Atração de Turistas nos Municípios do Rio Grande Do Sul/ Brasil

    Directory of Open Access Journals (Sweden)

    Dalva Maria Righi Dotto

    2015-12-01

    Full Text Available Com a utilização cada vez mais frequente da internet na busca de informações para a escolha dentre as opções de turismo disponíveis, a otimização dos websites turísticos por parte dos municípios pode ser uma ferramenta importante para o desenvolvimento do turismo. Informações  claras sobre os atrativos turísticos facilitam aos turistas escolher o destino, assim como informações sobre a disponibilidade de hotéis e, também, a gastronomia que o local oferece. Com o objetivo de analisar qualitativamente os websites de municípios do Rio Grande do Sul, este estudo, através de uma pesquisa exploratória, pretende disponibilizar aos gestores um diagnóstico comparativo, no intuito de auxiliar na visibilidade do atrativo turístico e sensibilização dos turistas potenciais, para incremento do setor e da economia local.

  2. Representação social de sujeitos alcoolistas acerca da atração e da dependência do uso de álcool

    Directory of Open Access Journals (Sweden)

    Silvio Eder Dias da Silva

    2015-06-01

    Full Text Available Introdução: O consumo de álcool está relacionado a vários fatores sendo considerados fatores de risco, sem restrição de classe, idade ou sexo. A família, o meio de interação social e as propagandas são três de vários fatores que podem influenciar o consumo de bebidas alcoólicas. O risco familiar e grupo de envolvimentos são considerados importantes critérios de vulnerabilidade ao alcoolismo. Este estudo objetivou conhecer a representação social do alcoolista sobre a de sua dependência química e analisar as implicações dessa representação social para o cuidado de si. Metodologia: É um estudo é do tipo descritivo e exploratório, com base na Teoria das Representações Sociais, realizado em um Centro de Atenção Psicossocial - Álcool e Drogas, em Belém-PA, com 31 sujeitos que estavam em tratamento por dependência química. Resultados: Com a análise dos dados obtivemos resultados de duas unidades temáticas: A influência parental no interesse pelo alcoolismo que mostra o meio familiar como importante influenciador para que o sujeito inicie a beber e Fatores que influenciaram o alcoolismo na adolescência em que se mostram as características da adolescência como influenciador da experimentação do álcool. Conclusão: Durante as entrevistas, pôde-se entender que, desde o início de suas vidas, os sujeitos que se tornaram alcoólatras estiveram expostos a um meio social com integrantes alcoolista, que gerou entusiasmo para uma vida cotidiana voltada para o uso do álcool; os depoimentos expressam que a família e o período da adolescência configuraram importantes fatores para sua realidade atual.

  3. Turismo e Idosos: o patrimônio imaterial como fator de atração para o turismo cultural no espaço rural

    Directory of Open Access Journals (Sweden)

    Lívia Morais Garcia Lima

    2011-01-01

    Full Text Available A pesquisa tem por objetivo investigar e analisar as formas pelas quais propriedades rurais históricas paulistas se preocupam em proporcionar atividades voltadas para idosos, trabalhando o turismo cultural com uma preocupação voltada à educação patrimonial não-formal e sob um enfoque qualitativo. O método biográfico ou da História Oral é utilizado tanto para a coleta de informações sobre o patrimônio imaterial, como para levantar as demandas do público idoso. Ela é sempre acompanhada da realização de um diário de campo em associação com registros fotográficos das atividades educacionais e turísticas observadas em duas fazendas selecionadas. Para melhor avaliar programas para o público idoso é necessário uma efetiva conexão entre os elementos encontrados em cada fazenda participante, visando à articulação de ações efetivas para o turismo cultural no espaço rural e às diretrizes da Gerontologia.

  4. Atração e distração na publicidade externa dos candidatos à eleição em 2014

    Directory of Open Access Journals (Sweden)

    Sérgio Trein

    2015-12-01

    CÉSAR, Newton. Direção de arte em propaganda. São Paulo: Futura, 2004. COLLARO, Antonio Celso. Projeto Gráfico Teoria e Prática da Diagramação. São Paulo: Summus Editorial, 1987.  DONDIS, Donis A.. Sintaxe da linguagem visual. 2. ed. São Paulo: Martins Fontes, 2003.  HILLMAN, James. Cidade & alma. São Paulo: Studio Nobel, 1993. HURLBURT, Allen. Layout o design da página impressa. São Paulo: Nobel, 2002. MOLES, Abraham Antoine. O cartaz. São Paulo: Perspectiva, 1974. MÜLLER, Josef Brockmann. History of visual communication. Teufen: Nigli, 1971. PÈNINOU, Georges. Semiótica de la publicidad. Barcelona: Gustavo Gili, 1976.   Site consultado: Outdoor.com. Acessado em: 26 de março de 2015.   Disponível em:  Url: http://opendepot.org/2703/   Abrir em (para melhor visualização em dispositivos móveis - Formato Flipbooks: Issuu / Calameo

  5. Atração e desenvolvimento de Leptoglossus gonagra (Fabr. (Hemiptera: Coreidae em cultivares de abóbora e moranga

    Directory of Open Access Journals (Sweden)

    Baldin Edson Luiz Lopes

    2002-01-01

    Full Text Available As plantas da família Cucurbitaceae são seriamente prejudicadas pelo ataque de insetos, sendo que os danos ocorrem desde a germinação até a colheita e podem ser observados em todas as partes da planta. Dentre os insetos sugadores que atacam a abóbora (Cucurbita moschata e a moranga (C. maxima, as formas jovens e adultas do percevejo Leptoglossus gonagra (Fabr. (Hemiptera: Coreidae merecem destaque por sugarem a seiva das folhas, ramos e frutos novos, nos quais causam necroses, reduzindo a produção. Visando comparar a atratividade de plântulas de cultivares de abóbora e moranga a adultos deste percevejo e os efeitos desses materiais sobre a biologia de ninfas dessa espécie, realizaram-se ensaios sob condições de laboratório. Em teste de atratividade, o cultivar de abóbora BRA015113 destacou-se como o menos atrativo em relação ao cultivar de moranga Exposição, enquanto que o cultivar de abóbora BRA003531 foi o mais atrativo. Todos os cultivares provocaram 100% de mortalidade das ninfas, indicando a presença de componentes antibióticos, adversos ao desenvolvimento de L. gonagra.

  6. Histopathology of liver and kidneys of wild living Mallards Anas platyrhynchos and Coots Fulica atra with considerable concentrations of lead and cadmium

    Energy Technology Data Exchange (ETDEWEB)

    Binkowski, Łukasz J., E-mail: ljbinkowski@gmail.com [Institute of Biology, Pedagogical University of Cracow, Podbrzezie 3, 31-054 Cracow (Poland); Sawicka-Kapusta, Katarzyna, E-mail: katarzyna.sawicka-kapusta@uj.edu.pl [Institute of Environmental Sciences, Jagiellonian University, Gronostajowa 7, 30-387 Cracow (Poland); Szarek, Józef, E-mail: szarek@uwm.edu.pl [Department of Pathophysiology, Forensic Veterinary Medicine and Administration, University of Warmia and Mazury, Oczapowskiego 13, 10-719 Olsztyn (Poland); Strzyżewska, Emilia, E-mail: emijel@wp.pl [Department of Pathophysiology, Forensic Veterinary Medicine and Administration, University of Warmia and Mazury, Oczapowskiego 13, 10-719 Olsztyn (Poland); Felsmann, Mariusz, E-mail: felsmann.mariusz@wp.pl [Department of Pathophysiology, Forensic Veterinary Medicine and Administration, University of Warmia and Mazury, Oczapowskiego 13, 10-719 Olsztyn (Poland)

    2013-04-15

    Concentrations of cadmium and lead were measured in liver and kidneys of Mallard (n = 60) and Coot (n = 50). Free living birds were collected by hunters in years 2006–2008 in the area of fishponds near Zator in southern Poland. Age group was determined according to the appearance of the plumage (Mallards) and iris color (Coot). Concentrations of metals were measured with ET-AA spectrometer. Among all birds specimens with negligible (n = 5) and high concentrations (Mallards n = 18 and Coots n = 17) of cadmium and lead were chosen for further analysis. Histopathological alterations were observed, ranging from circulatory disturbances, retrogressive changes, inflammations to leukocytic infiltration in liver and kidney. They dominated among birds with the highest concentrations of metals. The control group of birds was characterized by a very small number of mentioned lesions. Probably the higher cadmium and lead concentrations in tissues are co-factors in the development of lesions. - Highlights: ► High levels of Cd and Pb were found in liver and kidneys of Mallard and Coot. ► Lower concentrations were found in young birds. ► Amount of metals exceeded the safety threshold established for edible poultry. ► Histopathological alterations were found in studied tissues. ► Lesions in birds with the highest concentrations of metals were numerous.

  7. Arsenic Trioxide (ATO) cooperates with All Trans Retinoic Acid (ATRA) to enhance MAPK activation and differentiation in Human Myeloblastic Leukemia (HL-60) cells

    Science.gov (United States)

    Nayak, Satyaprakash; Shen, Miaoqing; Varner, Jeffrey D.; Yen, Andrew

    2016-01-01

    Arsenic trioxide (ATO) synergistically promotes retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells, a PML-RARα negative cell line. In PML-RARα positive myeloid leukemia cells, ATO is known to cause degradation of PML-RARα with subsequent induced myeloid differentiation. We find now that ATO by itself does not cause differentiation of the PML-RARα negative HL-60 cells, but enhances RA’s capability to cause differentiation. RA-induced differentiation of HL-60 cells is known to be propelled by an induced hyperactive/persistent MAPK signal. ATO augmented RA induced RAF/MEK/ERK axis signaling and expression of CD11b, an integrin receptor that is a myeloid differentiation marker. p47PHOX, a component of the respiratory burst machinery and inducible oxidative metabolism, functional differentiation marker were also enhanced. However, ATO did not enhance RA-induced CD38 expression, an early cell surface differentiation marker. ATO enhanced RA-induced population growth retardation without evidence of apoptosis or an enhanced G1/0 growth arrest. But compared to RA, ATO plus RA showed reduced pAKT, suggesting that an overall biosynthetic/metabolic retardation was seminal to the apparent enhanced growth retardation due to ATO. In sum, our results indicate that ATO can augment action of RA in causing differentiation of myeloid leukemia cells through promoting MAPK signaling and independent of PML-RARα. PMID:20615082

  8. Educando a Estudiantes con Diversidades Linguisticas y Culturales (Educating Linguistically and Culturally Diverse Students). Que Ningun Nino se Quede Atras (No Child Left Behind).

    Science.gov (United States)

    Office of English Language Acquisition, Language Enhancement, and Academic Achievement for Limited English Proficient Students (ED), Washington, DC.

    The brochure, written in Spanish, briefly outlines the U.S. Department of Education's most recent policy on educating students with diverse linguistic and cultural backgrounds. It states the Department's mission, describes today's student population, and outlines the role of the Office of English Language Acquisition, Language Enhancement and…

  9. Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy

    NARCIS (Netherlands)

    Martinez-Cuadron, D.; Montesinos, P.; Vellenga, E.; Bernal, T.; Salamero, O.; Holowiecka, A.; Brunet, S.; Gil, C.; Benavente, C.; Ribera, J. M.; Perez-Encinas, M.; De la Serna, J.; Esteve, J.; Rubio, V.; Gonzalez-Campos, J.; Escoda, L.; Amutio, M. E.; Arnan, M.; Arias, J.; Negri, S.; Lowenberg, B.; Sanz, M. A.

    Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk-and age-adapted protocol (Programa Espanol de

  10. Normalizing microbiota-induced retinoic acid deficiency stimulates protective CD8+ T-cell-mediated immunity in colorectal cancer

    OpenAIRE

    Bhattacharya, Nupur; Yuan, Robert; Prestwood, Tyler R.; Penny, Hweixian Leong; DiMaio, Michael A.; Reticker-Flynn, Nathan E.; Krois, Charles R.; Kenkel, Justin A.; Pham, Tho D.; Carmi, Yaron; Tolentino, Lorna; Choi, Okmi; Hulett, Reyna; Wang, Jinshan; Winer, Daniel

    2016-01-01

    Although all-trans retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA...

  11. Role of CX3CL1 in the chemotactic migration of all-trans retinoic acid-treated acute promyelocytic leukemic cells toward apoptotic cells

    Directory of Open Access Journals (Sweden)

    Wen-Hui Tsai

    2014-07-01

    Conclusion: CX3CL1, in either the free or MP form, is released rapidly by apoptotic ATRA-NB4 cells after induction of apoptosis to mediate the chemoattraction of living ATRA-NB4 cells toward apoptotic cells.

  12. 78 FR 45213 - Medicaid Program; State Allotments for Payment of Medicare Part B Premiums for Qualifying...

    Science.gov (United States)

    2013-07-26

    ..., enacted on January 2, 2013) (ATRA), extended the authority for the QI program for all of FY 2013 and... ($280 million plus $485 million). Finally, section 621 of ATRA further extended the authority and...

  13. 78 FR 22560 - OMB Final Sequestration Report to the President and Congress for Fiscal Year 2013

    Science.gov (United States)

    2013-04-16

    ... further revised by P.L. 112-240, the American Taxpayer Relief Act of 2012 (ATRA). Section 254 of BBEDCA... required based on OMB scoring of enacted appropriations legislation against those limits. ATRA, however...

  14. The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia

    DEFF Research Database (Denmark)

    Arteaga, Maria Francisca; Mikesch, Jan-Henrik; Qiu, Jihui

    2013-01-01

    While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We...... identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RARα fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity...... depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance....

  15. Bayesian network meta-analysis comparing five contemporary treatment strategies for newly diagnosed acute promyelocytic leukaemia

    OpenAIRE

    Wu, Fenfang; Wu, Di; Ren, Yong; Duan, Chongyang; Chen, Shangwu; Xu, Anlong

    2016-01-01

    Acute promyelocytic leukemia (APL) is a curable subtype of acute myeloid leukemia. The optimum regimen for newly diagnosed APL remains inconclusive. In this Bayesian network meta-analysis, we compared the effectiveness of five regimens-arsenic trioxide (ATO) + all-trans retinoic acid (ATRA), realgar-indigo naturalis formula (RIF) which contains arsenic tetrasulfide + ATRA, ATRA + anthracycline-based chemotherapy (CT), ATO alone and ATRA alone, based on fourteen randomized controlled trials (R...

  16. 78 FR 7387 - Continuation of 2008 Farm Bill-Dairy Forward Pricing Program

    Science.gov (United States)

    2013-02-01

    ...: Agricultural Marketing Service, USDA. ACTION: Notice. SUMMARY: The American Taxpayer Relief Act of 2012 (ATRA... September 30, 2015. However, passage of the ATRA that was signed into law on January 2, 2013, revised the... American Taxpayer Relief Act of 2012 (ATRA), (H.R. 8, Pub. L. 112-240), extended the authorization of the...

  17. 78 FR 35288 - Discretionary Grant Program

    Science.gov (United States)

    2013-06-12

    ... section 624 of the American Taxpayer Relief Act of 2012 (Pub. L. 112-240) (ATRA) with the least disruption... closeout of the program. Section 624 of the ATRA extended the F2F HICs through FY 2013. Under typical... direction of the F2F HIC program's extension, enacted in the ATRA. This will provide sufficient fiscal...

  18. A diversidade como elemento de desenvolvimento/atração nas políticas locais urbanas: contrastes e semelhanças nos eventos de celebração intercultural

    OpenAIRE

    Oliveira, Nuno; Padilla, Beatriz

    2012-01-01

    Em contextos de super-diversidade próprios das cidades globalizadas, resulta importante reflectir sobre vários aspetos associados às políticas culturais, relacionadas, direta ou indiretamente, com as migrações internacionais. Partindo de uma aplicação sociológica da metodologia das etnografias multi-situadas, comparamos dois eventos interculturais em dois territórios da Área Metropolitana de Lisboa, procurando identificar diferenças e semelhanças nas políticas de produção da in...

  19. Ten Facts Every Parent Should Know about the No Child Left Behind Act = Diez datos que cada padre debe saber sobre La Ley. Que Ningun Nino Se Quede Atras.

    Science.gov (United States)

    Department of Education, Washington, DC.

    The No Child Left Behind Act (NCLB) is President George W. Bush's education reform law passed by Republicans and Democrats in Congress. This flier, in both English and Spanish, details 10 facts concerning NCLB to inform parents as to the goals of the Act and how they will affect their child's school. The flier highlights how the Act: (1) gives…

  20. El regreso a la escuela, Sigamos adelante: Lo que significa para las familias americanas "No dejar atras a ningun nino" (Back to School, Moving Forward: What "No Child Left Behind" Means for America's Families).

    Science.gov (United States)

    Department of Education, Washington, DC. Office of the Secretary.

    This pamphlet for parents Spanish presents the components of the "No Child Left Behind" policy of the George W. Bush administration. Prefaced with remarks by President Bush and Secretary of Education Rod Paige, the pamphlet discusses the importance of high academic standards and provides guidance for parents in interpreting test scores.…

  1. Chmp 1A is a mediator of the anti-proliferative effects of All-trans Retinoic Acid in human pancreatic cancer cells

    Directory of Open Access Journals (Sweden)

    Nguyen Hanh

    2009-02-01

    Full Text Available Abstract Background We recently have shown that Charged multivesicular protein/Chromatin modifying protein1A (Chmp1A functions as a tumor suppressor in human pancreatic tumor cells. Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Preclinical studies using ATRA for treating human pancreatic cancer suggest this compound might be useful for treatment of pancreatic cancer patients. However, the molecular mechanism by which ATRA inhibits growth of pancreatic cancer cells is not clear. The objective of our study was to investigate whether Chmp1A is involved in ATRA-mediated growth inhibition of human pancreatic tumor cells. Results We performed microarray studies using HEK 293T cells and discovered that Chmp1A positively regulated Cellular retinol-binding protein 1 (CRBP-1. CRBP-1 is a key regulator of All-trans retinoic acid (ATRA through ATRA metabolism and nuclear localization. Since our microarray data indicates a potential involvement of Chmp1A in ATRA signaling, we tested this hypothesis by treating pancreatic tumor cells with ATRA in vitro. In the ATRA-responsive cell lines, ATRA significantly increased the protein expression of Chmp1A, CRBP-1, P53 and phospho-P53 at serine 15 and 37 position. We found that knockdown of Chmp1A via shRNA abolished the ATRA-mediated growth inhibition of PanC-1 cells. Also, Chmp1A silencing diminished the increase of Chmp1A, P53 and phospho-P53 protein expression induced by ATRA. In the ATRA non-responsive cells, ATRA did not have any effect on the protein level of Chmp1A and P53. Chmp1A over-expression, however, induced growth inhibition of ATRA non-responsive cells, which was accompanied by an increase of Chmp1A, P53 and phospho-P53. Interestingly, in ATRA responsive cells Chmp1A is localized to the nucleus, which became robust upon ATRA treatment. In the ATRA-non-responsive cells, Chmp1A was mainly translocated to the plasma membrane upon ATRA treatment. Conclusion

  2. All-trans retinoic acid influences viability, migration and adhesion of U251 glioblastoma cells

    Directory of Open Access Journals (Sweden)

    Marjanović-Vićentić Jelena

    2017-01-01

    Full Text Available Glioblastoma (GBM is one of the most aggressive and deadly forms of cancer. Literature data reveals that all-trans retinoic acid (ATRA has anticancer effects on different types of tumor cells. However, data about the effects of ATRA on glioblastoma cells are contradictory. In this study, we examined whether ATRA treatment affects features of human glioblastoma U251 cells. To that end, the cells were treated with different concentrations of ATRA. Results obtained by MTT and the crystal violet assays imply that ATRA affected the viability of U251 glioblastoma cells in a dose- and time-dependent manner. Fluorescence staining of microtubule cytoskeleton protein α-tubulin revealed that ATRA induced changes in cell morphology. Using semi-quantitative RT-PCR we found that the expression of SOX3 and GFAP genes, as markers of neural differentiation, was not changed upon ATRA treatment. Thus, the observed changes in cell morphology after ATRA treatment are not associated with neural differentiation of U251 glioblastoma cells. The scratch-wound healing assay revealed that ATRA changed the mode of U251 cell migration from collective to single cell motility. The cell-matrix adhesion assay demonstrated that the pharmacologically relevant concentration of ATRA lowered the cell-matrix adhesion capability of U251 cells. In conclusion, our results imply that further studies are needed before ATRA could be considered for the treatment of glioblastoma. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173051

  3. Characteristics and outcome of patients with therapy-related acute promyelocytic leukemia front-line treated with or without arsenic trioxide.

    Science.gov (United States)

    Kayser, S; Krzykalla, J; Elliott, M A; Norsworthy, K; Gonzales, P; Hills, R K; Baer, M R; Ráčil, Z; Mayer, J; Novak, J; Žák, P; Szotkowski, T; Grimwade, D; Russell, N H; Walter, R B; Estey, E H; Westermann, J; Görner, M; Benner, A; Krämer, A; Smith, B D; Burnett, A K; Thiede, C; Röllig, C; Ho, A D; Ehninger, G; Schlenk, R F; Tallman, M S; Levis, M J; Platzbecker, U

    2017-11-01

    Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.

  4. All-trans-retinoic Acid Increases SLC26A3 DRA (Down-regulated in Adenoma) Expression in Intestinal Epithelial Cells via HNF-1β*

    Science.gov (United States)

    Priyamvada, Shubha; Anbazhagan, Arivarasu N.; Gujral, Tarunmeet; Borthakur, Alip; Saksena, Seema; Gill, Ravinder K.; Alrefai, Waddah A.; Dudeja, Pradeep K.

    2015-01-01

    All-trans-retinoic acid (ATRA) is an active vitamin A derivative known to modulate a number of physiological processes, including growth and development, differentiation, and gene transcription. The protective effect of ATRA in gut inflammation and diarrheal diseases has been documented. In this regard, down-regulated in adenoma (DRA, a key luminal membrane Cl− transporter involved in NaCl absorption) has been shown to be suppressed in intestinal inflammation. This suppression of DRA is associated with diarrheal phenotype. Therefore, current studies were undertaken to examine the effects of ATRA on DRA expression. DRA mRNA levels were significantly elevated (∼4-fold) in response to ATRA with induction starting as early as 8 h of incubation. Similarly, ATRA increased DRA protein expression by ∼50%. Furthermore, DRA promoter activity was significantly increased in response to ATRA indicating transcriptional activation. ATRA effects on DRA expression appeared to be mediated via the RAR-β receptor subtype, as ATRA remarkably induced RAR-β mRNA levels, whereas RAR-β knockdown substantially attenuated the ability of ATRA to increase DRA expression. Results obtained from agonist (CH-55) and antagonist (LE-135) studies further confirmed that ATRA exerts its effects through RAR-β. Furthermore, ATRA treatment resulted in a significant increase in HNF-1β mRNA levels. The ability of ATRA to induce DRA expression was inhibited in the presence of HNF-1β siRNA indicative of its involvement in ATRA-induced effects on DRA expression. In conclusion, ATRA may act as an antidiarrheal agent by increasing DRA expression via the RAR-β/HNF-1β-dependent pathway. PMID:25887398

  5. Nanostructured lipid carriers loaded with tributyrin as an alternative to improve anticancer activity of all-trans retinoic acid

    Science.gov (United States)

    Silva, Elton Luiz; Carneiro, Guilherme; Caetano, Priscila Albuquerque; Costa, Daniel Ferreira; de Souza-Fagundes, Elaine Maria; Gomes, Dawidson Assis; Ferreira, Lucas Antônio Miranda

    2015-01-01

    Objectives All-trans retinoic acid (ATRA) is one of the most successful examples of differentiation agents and histone deacetylase inhibitors, such as tributyrin (TB), are known for their antitumor activity and potentiating action of drugs such as ATRA. Nanostructured lipid carriers (NLC) represent a promising alternative to the encapsulation of lipophilic drugs such as ATRA. This study aimed to develop, characterize, and evaluate the cytotoxicity of ATRA-TB-loaded nanostructured lipid carriers (NLC) for cancer treatment. Methods The influence of in situ formation of an ion pairing between ATRA and a lipophilic amine (benethamine; BNT) on the characteristics of NLC (size, zeta potential, encapsulation efficiency) was evaluated. Tributyrin (TB), a butyric acid donor, was used as a component of the lipid matrix. In vitro activity on cell viability and distribution of cell cycle phases were evaluated for MCF-7, MDA-MB-231, HL-60, and Jurkat cell lines. Results The presence of the amine significantly increased the encapsulation efficiency of ATRA in NLC. Inhibition of cell viability by TB-ATRA-loaded NLC was more pronounced than the free drug. Analysis of the distribution of cell cycle phases also showed increased activity for TB-ATRA-loaded NLC, with the clear effect of cell cycle arrest in G0/G1 phase transition. The presence of TB played an important role in the activity of the formulation. Conclusion Taken together, these findings suggest that TB-ATRA-loaded NLC represent a promising alternative to intravenous administration of ATRA in cancer treatment. PMID:25611812

  6. Growth increments of the recent brachiopod Magellania venosa mechanically marked in Paso Comau and Comau Fjord, Chile, 2011/2012, supplement to: Baumgarten, Sebastian; Laudien, Jürgen; Jantzen, Carin; Häussermann, Verena; Försterra, Günter (2013): Population structure, growth and production of a recent brachiopod from the Chilean fjord region. Marine Ecology, 35(4), 401-413

    KAUST Repository

    Baumgarten, Sebastian

    2015-01-01

    Magellania venosa, the largest recent brachiopod, occurs in clusters and banks in population densities of up to 416 ind/m**2 in Comau Fjord, Northern Chilean fjord region. Below 15 m, it co-occurs with the mytilid Aulacomya atra and it dominates the benthic community below 20 m. To determine the question of why M. venosa is a successful competitor, the in situ growth rate of the brachiopod was studied and its overall growth performance compared with that of other brachiopods and mussels. The growth in length was measured between February 2011 and March 2012 after mechanical tagging and calcein staining. Settlement and juvenile growth were determined from recruitment tiles installed in 2009 and from subsequent photocensus. Growth of M. venosa is best described by the general von Bertalanffy growth function, with a maximum shell length (Linf) of 71.53 mm and a Brody growth constant (K) of 0.336/year. The overall growth performance (OGP index = 5.1) is the highest recorded for a rynchonelliform brachiopod and in the range of that for Mytilus chilensis (4.8-5.27), but lower than that of A. atra (5.74). The maximal individual production (PInd) is 0.29 g AFDM/ind/year at 42 mm shell length and annual production ranges from 1.28 to 89.25 g AFDM/year/m**2 (1-57% of that of A. atra in the respective fjords). The high shell growth rate of M. venosa, together with its high overall growth performance may explain the locally high population density of this brachiopod in Comau Fjord. However, the production per biomass of the population (P/B-ratio) is low (0.535) and M. venosa may play only a minor role in the food chain. Settling dynamics indicates that M. venosa is a pioneer species with low juvenile mortality. The coexistence of the brachiopod and bivalve suggests that brachiopod survival is affected by neither the presence of potential brachiopod predators nor that of space competitors (i.e. mytilids).

  7. Population structure, growth and production of a recent brachiopod from the Chilean fjord region

    KAUST Repository

    Baumgarten, Sebastian

    2013-12-04

    Magellania venosa, the largest recent brachiopod, occurs in clusters and banks in population densities of up to 416 ind m-2 in Comau Fjord, Northern Chilean fjord region. Below 15 m, it co-occurs with the mytilid Aulacomya atra and it dominates the benthic community below 20 m. To determine the question of why M. venosa is a successful competitor, the in situ growth rate of the brachiopod was studied and its overall growth performance compared with that of other brachiopods and mussels. The growth in length was measured between February 2011 and March 2012 after mechanical tagging and calcein staining. Settlement and juvenile growth were determined from recruitment tiles installed in 2009 and from subsequent photocensus. Growth of M. venosa is best described by the general von Bertalanffy growth function, with a maximum shell length (L∞) of 71.53 mm and a Brody growth constant (K) of 0.336 year-1. The overall growth performance (OGP index = 5.1) is the highest recorded for a rynchonelliform brachiopod and in the range of that for Mytilus chilensis (4.8-5.27), but lower than that of A. atra (5.74). The maximal individual production (PInd) is 0.29 g AFDM ind-1 year-1 at 42 mm shell length and annual production ranges from 1.28 to 89.25 g AFDM year-1 m-2 (1-57% of that of A. atra in the respective fjords). The high shell growth rate of M. venosa, together with its high overall growth performance may explain the locally high population density of this brachiopod in Comau Fjord. However, the production per biomass of the population (P/B--ratio) is low (0.535) and M. venosa may play only a minor role in the food chain. Settling dynamics indicates that M. venosa is a pioneer species with low juvenile mortality. The coexistence of the brachiopod and bivalve suggests that brachiopod survival is affected by neither the presence of potential brachiopod predators nor that of space competitors (i.e. mytilids).

  8. Histone Acetyltransferase p300/CREB-binding Protein-associated Factor (PCAF) Is Required for All-trans-retinoic Acid-induced Granulocytic Differentiation in Leukemia Cells.

    Science.gov (United States)

    Sunami, Yoshitaka; Araki, Marito; Kan, Shin; Ito, Akihiro; Hironaka, Yumi; Imai, Misa; Morishita, Soji; Ohsaka, Akimichi; Komatsu, Norio

    2017-02-17

    Differentiation therapy with all-trans-retinoic acid (ATRA) improves the treatment outcome of acute promyelocytic leukemia (APL); however, the molecular mechanism by which ATRA induces granulocytic differentiation remains unclear. We previously reported that the inhibition of the NAD-dependent histone deacetylase (HDAC) SIRT2 induces granulocytic differentiation in leukemia cells, suggesting the involvement of protein acetylation in ATRA-induced leukemia cell differentiation. Herein, we show that p300/CREB-binding protein-associated factor (PCAF), a histone acetyltransferase (HAT), is a prerequisite for ATRA-induced granulocytic differentiation in leukemia cells. We found that PCAF expression was markedly increased in leukemia cell lines (NB4 and HL-60) and primary APL cells during ATRA-induced granulocytic differentiation. Consistent with these results, the expression of PCAF was markedly up-regulated in the bone marrow cells of APL patients who received ATRA-containing chemotherapy. The knockdown of PCAF inhibited ATRA-induced granulocytic differentiation in leukemia cell lines and primary APL cells. Conversely, the overexpression of PCAF induced the expression of the granulocytic differentiation marker CD11b at the mRNA level. Acetylome analysis identified the acetylated proteins after ATRA treatment, and we found that histone H3, a known PCAF acetylation substrate, was preferentially acetylated by the ATRA treatment. Furthermore, we have demonstrated that PCAF is required for the acetylation of histone H3 on the promoter of ATRA target genes, such as CCL2 and FGR, and for the expression of these genes in ATRA-treated leukemia cells. These results strongly support our hypothesis that PCAF is induced and activated by ATRA, and the subsequent acetylation of PCAF substrates promotes granulocytic differentiation in leukemia cells. Targeting PCAF and its downstream acetylation targets could serve as a novel therapeutic strategy to overcome all subtypes of AML.

  9. 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

  10. All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

    Science.gov (United States)

    Tripathy, Sasmita; Chapman, John D; Han, Chang Y; Hogarth, Cathryn A; Arnold, Samuel L.M.; Onken, Jennifer; Kent, Travis; Goodlett, David R

    2016-01-01

    All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. The liver is the main storage organ of vitamin A, but activation of the retinoic acid receptors (RARs) in mouse liver and in human liver cell lines has also been shown. Although atRA treatment improves mitochondrial function in skeletal muscle in rodents, its role in modulating mitochondrial function in the liver is controversial, and little data are available regarding the human liver. The aim of this study was to determine whether atRA regulates hepatic mitochondrial activity. atRA treatment increased the mRNA and protein expression of multiple components of mitochondrial β-oxidation, tricarboxylic acid (TCA) cycle, and respiratory chain. Additionally, atRA increased mitochondrial biogenesis in human hepatocytes and in HepG2 cells with and without lipid loading based on peroxisome proliferator activated receptor gamma coactivator 1α and 1β and nuclear respiratory factor 1 mRNA and mitochondrial DNA quantification. atRA also increased β-oxidation and ATP production in HepG2 cells and in human hepatocytes. Knockdown studies of RARα, RARβ, and PPARδ revealed that the enhancement of mitochondrial biogenesis and β-oxidation by atRA requires peroxisome proliferator activated receptor delta. In vivo in mice, atRA treatment increased mitochondrial biogenesis markers after an overnight fast. Inhibition of atRA metabolism by talarozole, a cytochrome P450 (CYP) 26 specific inhibitor, increased the effects of atRA on mitochondrial biogenesis markers in HepG2 cells and in vivo in mice. These studies show that atRA regulates mitochondrial function and lipid metabolism and that increasing atRA concentrations in human liver via CYP26 inhibition may increase mitochondrial biogenesis and fatty acid β-oxidation and provide therapeutic benefit in diseases associated with mitochondrial dysfunction. PMID:26921399

  11. Role of retinoic acid metabolizing cytochrome P450s, CYP26, in inflammation and cancer

    Science.gov (United States)

    Stevison, Faith; Jing, Jing; Tripathy, Sasmita; Isoherranen, Nina

    2016-01-01

    Vitamin A (retinol) and its active metabolite, all-trans-retinoic acid (atRA), play critical roles in regulating the differentiation, growth and migration of immune cells. Similarly, as critical signaling molecules in the regulation of the cell cycle, retinoids are important in cancers. Concentrations of atRA are tightly regulated in tissues, predominantly by the availability of retinol, synthesis of atRA by ALDH1A enzymes and metabolism and clearance of atRA by CYP26 enzymes. The ALDH1A and CYP26 enzymes are expressed in several cell types in the immune system and in cancer cells. In the immune system the ALDH1A and CYP26 enzymes appear to modulate RA concentrations. Consequently, alterations in the activity of ALDH1A and CYP26 enzymes are expected to change disease outcomes in inflammation. There is increasing evidence from various disease models of intestinal and skin inflammation that treatment with atRA has a positive effect on disease markers. However, whether aberrant atRA concentrations or atRA synthesis and metabolism play a role in inflammatory disease development and progression is not well understood. In cancers, especially in acute promyelocytic leukemia and neuroblastoma, increasing intracellular concentrations of atRA appears to provide clinical benefit. Inhibition of the CYP26 enzymes to increase atRA concentrations and combat therapy resistance has been pursued as a drug target in these cancers. This chapter covers the current knowledge of how atRA and retinol regulate the immune system and inflammation, how retinol and atRA metabolism is altered in inflammation and cancer and what roles atRA metabolizing enzymes have in immune responses and cancers. PMID:26233912

  12. All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells: possible involvement of protein kinase C-delta.

    Science.gov (United States)

    Uruno, Akira; Noguchi, Naoya; Matsuda, Ken; Nata, Koji; Yoshikawa, Takeo; Chikamatsu, Youichiro; Kagechika, Hiroyuki; Harigae, Hideo; Ito, Sadayoshi; Okamoto, Hiroshi; Sugawara, Akira

    2011-08-01

    ATRA and a synthetic RAR agonist tamibarotene (Am80) induce granulocytic differentiation of human acute leukemia HL-60 cells and have been used in antineoplastic therapy. ATRA induces CD38 antigen during HL-60 cell differentiation, which interacts with CD31 antigen on the vascular EC surface and may induce disadvantages in the therapy. We here examined the mechanisms of the ATRA-mediated CD38 induction and compared the difference between ATRA- and tamibarotene-mediated induction. Tamibarotene-induced HL-60 cell adhesion to ECs was 38% lower than ATRA, and NB4 cell adhesion to ECs by tamibarotene was equivalent to ATRA, which induced CD38 gene transcription biphasically in HL-60 cells, the early-phase induction via DR-RARE containing intron 1, and the delayed-phase induction via RARE lacking the 5'-flanking region. In contrast to ATRA, tamibarotene induced only the early-phase induction, resulting in its lower CD38 induction than ATRA. A PKCδ inhibitor, rottlerin, and siRNA-mediated PKCδ knockdown suppressed the ATRA-induced CD38 promoter activity of the 5'-flanking region, whereas a RAR antagonist, LE540, or RAR knockdown did not affect it. Cycloheximide and rottlerin suppressed the delayed-phase induction of CD38 expression by ATRA but did not affect the early-phase induction. Moreover, ATRA, but not tamibarotene, induced PKCδ expression without affecting its mRNA stability. The diminished effect of tamibarotene on CD38-mediated HL-60 cell adhesion to ECs compared with ATRA is likely a result of the lack of its delayed-phase induction of CD38 expression, which may be advantageous in antineoplastic therapy.

  13. Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer.

    Science.gov (United States)

    Bhattacharya, Nupur; Yuan, Robert; Prestwood, Tyler R; Penny, Hweixian Leong; DiMaio, Michael A; Reticker-Flynn, Nathan E; Krois, Charles R; Kenkel, Justin A; Pham, Tho D; Carmi, Yaron; Tolentino, Lorna; Choi, Okmi; Hulett, Reyna; Wang, Jinshan; Winer, Daniel A; Napoli, Joseph L; Engleman, Edgar G

    2016-09-20

    Although all-trans-retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA signaling promoted tumorigenesis, whereas atRA supplementation reduced tumor burden. The benefit of atRA treatment was mediated by cytotoxic CD8(+) T cells, which were activated due to MHCI upregulation on tumor cells. Consistent with these findings, increased colonic expression of the atRA-catabolizing enzyme, CYP26A1, correlated with reduced frequencies of tumoral cytotoxic CD8(+) T cells and with worse disease prognosis in human CRC. These results reveal a mechanism by which microbiota drive colon carcinogenesis and highlight atRA metabolism as a therapeutic target for CRC. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Knockdown of SALL4 Protein Enhances All-trans Retinoic Acid-induced Cellular Differentiation in Acute Myeloid Leukemia Cells*

    Science.gov (United States)

    Liu, Li; Liu, Liang; Leung, Lai-Han; Cooney, Austin J.; Chen, Changyi; Rosengart, Todd K.; Ma, Yupo; Yang, Jianchang

    2015-01-01

    All-trans retinoic acid (ATRA) is a differentiation agent that revolutionized the treatment of acute promyelocytic leukemia. However, it has not been useful for other types of acute myeloid leukemia (AML). Here we explored the effect of SALL4, a stem cell factor, on ATRA-induced AML differentiation in both ATRA-sensitive and ATRA-resistant AML cells. Aberrant SALL4 expression has been found in nearly all human AML cases, whereas, in normal bone marrow and peripheral blood cells, its expression is only restricted to hematopoietic stem/progenitor cells. We reason that, in AMLs, SALL4 activation may prevent cell differentiation and/or protect self-renewal that is seen in normal hematopoietic stem/progenitor cells. Indeed, our studies show that ATRA-mediated myeloid differentiation can be largely blocked by exogenous expression of SALL4, whereas ATRA plus SALL4 knockdown causes significantly increased AML differentiation and cell death. Mechanistic studies indicate that SALL4 directly associates with retinoic acid receptor α and modulates ATRA target gene expression. SALL4 is shown to recruit lysine-specific histone demethylase 1 (LSD1) to target genes and alter the histone methylation status. Furthermore, coinhibition of LSD1 and SALL4 plus ATRA treatment exhibited the strongest anti-AML effect. These findings suggest that SALL4 plays an unfavorable role in ATRA-based regimes, highlighting an important aspect of leukemia therapy. PMID:25737450

  15. Role of retinoic acid metabolizing cytochrome P450s, CYP26, in inflammation and cancer

    OpenAIRE

    Stevison, Faith; Jing, Jing; Tripathy, Sasmita; Isoherranen, Nina

    2015-01-01

    Vitamin A (retinol) and its active metabolite, all-trans-retinoic acid (atRA), play critical roles in regulating the differentiation, growth and migration of immune cells. Similarly, as critical signaling molecules in the regulation of the cell cycle, retinoids are important in cancers. Concentrations of atRA are tightly regulated in tissues, predominantly by the availability of retinol, synthesis of atRA by ALDH1A enzymes and metabolism and clearance of atRA by CYP26 enzymes. The ALDH1A and ...

  16. Pharmacological inhibition of ALDH1A in mice decreases all-trans retinoic acid concentrations in a tissue specific manner

    OpenAIRE

    Arnold, Samuel L. M.; Kent, Travis; Hogarth, Cathryn A.; Griswold, Michael D.; Amory, John K.; Isoherranen, Nina

    2015-01-01

    all-trans retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Specifically the concentrations of atRA are spatiotemporally controlled in target tissues such as the liver and the testes. While the enzymes of the aldehyde dehydrogenase 1A family (ALDH1A) are believed to control the synthesis of atRA, a direct relationship between altered ALDH1A activity and tissue atRA concentrations has never been shown. To test whether inhibition of ALDH1A enzymes dec...

  17. All-trans retinoic acid modulates ORMDL3 expression via transcriptional regulation.

    Directory of Open Access Journals (Sweden)

    Li-Li Zhuang

    Full Text Available All-trans retinoic acid (ATRA is an active metabolite of Vitamin A, it shows protective effects on asthma, including maintains airway epithelial integrity, inhibits asthma effector cells differentiation, modulates immune response, et al. However, the promoting effect of ATRA on Th2 response has restricted the clinical application of ATRA in asthma treatment. ORMDL3 is a candidate gene of childhood onset asthma, and high-transcript of ORMDL3 is associated with the development of asthma. Here we show that ATRA increases ORMDL3 production in vitro via inducing PKA-dependent CREB phosphorylation which in turn binds to the CRE element in promoter region of ORMDL3 and initiates ORMDL3 transcription. This finding is in consistent with the previous reports that ATRA could regulate target genes without the presence of retinoic acid response element (RARE in promoter region but through other signals such as PKA/CREB. Nevertheless, in the present study, the traditional signal pathway of ATRA, retinoic acid receptor (RAR signal transduction pathway, indirectly modulated ORMDL3 expression. RAR-α agonist (Am-80 increased ORMDL3 production even though there was no RARE in ORMDL3 promoter, introns or 3'-downstream region. Besides, the signal of RAR might differ from that of ATRA since Am-80 failed to induce CREB activation. In conclusion, our data indicate that ATRA facilitates ORMDL3 production probable through PKA/CREB, and this may be a starting point for more detailed mechanism researches on ATRA and asthma.

  18. The Effects of Quercetin and Retinoic acid on Skeletal System of Rat Embryos in Prenatal Period

    Directory of Open Access Journals (Sweden)

    Nahid Gohari-Behbahani

    2014-12-01

    Full Text Available Background: Prenatal rat embryo exposure to retinoid induces some malformations in various organs, the most active and teratogenic metablolite is all-trans-retinoic acid (atRA. The teratogenic effects of some drugs can be prevented by the application of antioxidant drugs and stimulation of the maternal immune system. Also, quercetin, a naturally occurring flavonoid has excellent antioxidant properties. Therefore, in this study, the prophylactic effect of quercetin on teratogenic effects of atRA was evaluated. Materials and Methods: In this experimental study, 40 pregnant rats were divided into 7 groups. Control group received normal saline and test groups received dimethylsulfoxide (DMSO, quercetin (75 mg/kg, quercetin (200 mg/kg, atRA (25 mg/kg, atRA (25 mg/kg plus quercetin (75 mg/kg and atRA (25 mg/kg plus quercetin (200 mg/kg, intraperitoneally at 8-10th days of gestation. Fetuses were collected at 20th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Results: Cleft palate, exencephaly and spina bifida incidence were 30.76%, 61.53% and 30.76% range in group which received only atRA. Cleft palate, exencephaly and spina bifida incidence were 11.11%, 16.66% and 5.55% in group which received atRA plus quercetin (75 mg/kg. However, cleft palate, exencephaly and spina bifida incidence were 10.52%, 10.52% and 0% in group which received atRA plus quercetin (200 mg/kg. The means of weight and length of fetuses from rat that received atRA plus quercetin (75 mg/kg were significantly greater than those received only atRA. Conclusion: It is concluded that quercetin decreased teratogenicity induced by atRA, but this subject needs more detailed evaluation.

  19. All‐trans retinoic acid protects against doxorubicin‐induced cardiotoxicity by activating the ERK2 signalling pathway

    Science.gov (United States)

    Yang, Liang; Luo, Cheng; Chen, Cong; Wang, Xun; Shi, Wen

    2016-01-01

    Background and Purpose Doxorubicin is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. All‐trans retinoic acid (ATRA) plays an important role in many cardiac biological processes, but its protective effects on doxorubicin‐induced cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and the underlying mechanisms. Experimental Approaches Cellular viability assays, Western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA's effects on doxorubicin cardiotoxicity. Key Results ATRA significantly inhibited doxorubicin‐induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species generation and restored expression levels of mRNA and proteins in the phase II detoxifying enzyme system: nuclear factor‐E2‐related factor 2, manganese superoxide dismutase, haem oxygenase‐1, and mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers and mitochondrial respiration capacity, biogenesis and dynamics). Both a ERK1/2 inhibitor (U0126) and ERK2 siRNA, but not ERK1 siRNA, abolished the protective effect of ATRA against doxorubicin‐induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells. Conclusions and Implications ATRA protected cardiomyocytes against doxorubicin‐induced toxicity, by activating the ERK2 pathway, without compromising its anticancer efficacy. Therefore, ATRA is a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity. PMID:26507774

  20. All-trans retinoic acid suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and metastasis in esophageal squamous cell carcinoma

    Science.gov (United States)

    Li, Na; Lu, Yanjuan; Li, Daoming; Zheng, Xiangyu; Lian, Jingyao; Li, Shanshan; Cui, Huijuan; Zhang, Linda; Sang, Luqian; Wang, Ying; Yu, Jane J.; Lu, Taiying

    2017-01-01

    Esophageal squamous cell carcinoma (ESCC) is the second common cancer in Henan province and is well-known for aggressiveness and dismal prognosis. Adjuvant therapies, chemotherapy, radiotherapy and endoscopic treatment have not improved survival rates in patients with late stage esophageal carcinoma. All-trans retinoic acid (ATRA) is the active ingredient of Vitamin A and affects a wide spectrum of biological processes including development, growth, neural function, immune function, reproduction, and vision. It is one of the most potent therapeutic agents used for treating cancers, especially lung adenocarcinomas. ATRA inhibits metastatic potential and angiogenesis in several tumor models. We investigated the effects of ATRA on the expression of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2) and receptor Tie-2 in EC1 cells in vitro. We also assessed the growth and migration of EC1 cells in vitro. ATRA treatment caused 29.5% and 40.3% reduction of the growth of EC1 cells after 24 hours and 48 hours, relative to the control. ATRA plus fluorouracil treatment reduced the viability more strongly than either drug alone, indicating an additive effect. Moreover, ATRA decreased EC1 migration by 87%. Furthermore, ATRA treatment led to a marked decrease of the transcript levels of Ang-1, Ang-2, Tie-2, VEGF, and VEGF receptors, as assessed by real-time RT-PCR. Importantly, the protein levels of Ang-1, Ang-2 and Tie-2 were reduced by ATRA treatment. In vivo, we found ATRA treatment suppressed the tumor growth and improved the cachexia of mice. Importantly, ATRA treatment decreased the expression of CD31, Ang-1, Ang-2 and Tie-2 in subcutaneous tumors of EC1 cells. Collectively, our findings demonstrate that ATRA exhibits a dose- and temporal-dependent effect on the metastatic behavior, suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and the progression of xenograft tumors of EC1 cells. PMID:28369068

  1. New strategies in acute promyelocytic leukemia: moving to an entirely oral, chemotherapy-free upfront management approach.

    Science.gov (United States)

    Zeidan, Amer M; Gore, Steven D

    2014-10-01

    Incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into the management paradigms of acute promyelocytic leukemia (APL) has markedly improved outcomes. Significant progress occurred in understanding the molecular pathogenesis of APL. ATO, in contrast with ATRA, is capable of eradicating the APL-initiating cells and can result in cure. Preclinical and clinical data confirmed the synergy of ATO and ATRA, and the ATRA-ATO combination was proved noninferior to a standard ATRA-chemotherapy regimen in patients with non-high-risk APL. Oral formulations of arsenic exhibited excellent activity in advanced clinical testing and their combinations with ATRA offer an opportunity for a completely oral, chemotherapy-free regimen for curing APL. Nonetheless, significant challenges remain. Reducing early death due to bleeding complications is an important area of unmet need. Data suggest that delays in initiation of ATRA upon suspecting APL continue to occur in the community and contribute to early mortality. Questions remain about the optimal place and schedule of arsenic in the therapeutic sequence and the role of the oral formulations. Refining the role of minimal residual disease in directing treatment decisions is important. Development of novel targeted agents to treat relapsed disease requires deeper understanding of the secondary resistance mechanisms to ATRA and ATO. ©2014 American Association for Cancer Research.

  2. Paradoxical reproduction and body size in the rock lizard, Agama ...

    African Journals Online (AJOL)

    1993-07-05

    Jul 5, 1993 ... The rock lizard Agama atra atra from Namaqualand differs in both body size and reproduction from other populations of this ... one other species with continuous reproduction and two others with tropical affinities in the same general area, suggests that the ..... Marshall's Physiology of Reproduction. (Ed.) E.

  3. The Threat of Litigation Has a Chilling Effect.

    Science.gov (United States)

    Rist, Marilee C.

    1990-01-01

    According to the American Tort Reform Association's (ATRA) survey of secondary school principals, concern about liability was cited for cutting back or terminating many activities. ATRA recommends some major legislative change including reform of the doctrine of joint and several liability, and placing limits on noneconomic and punitive damage…

  4. Experiment list: SRX014769 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available on=Bone Marrow|Tissue Diagnosis=Leukemia 5011382,90.4,4.9,177 GSM468199: RXR ChIP-seq NB4 24hoursATRA JM20 s...ource_name=NB4 cells || agent=24 hours ATRA || antibody=RXR http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/

  5. Experiment list: SRX014776 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available SRX014776 hg19 TFs and others PML Blood MR4 NA 13771907,83.8,24.4,2932 GSM468206: PML ChIP-seq MR4 24hours...ATRA JM27 source_name=MR4 cells || agent=24 hours ATRA || antibody=PML http://dbarchi

  6. Experiment list: SRX014761 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available e of Extraction=Bone Marrow|Tissue Diagnosis=Leukemia 9112104,89.5,8.1,4981 GSM468191: RNApolII ChIP-seq NB4 48hours...ATRA JM12 source_name=NB4 cells || agent=48 hours ATRA || antibody=RNAPII http://dbarchive.bioscienc

  7. Experiment list: SRX014767 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available raction=Bone Marrow|Tissue Diagnosis=Leukemia 28609298,95.5,15.2,84254 GSM468197: DNAme MeCap-seq NB4 48hours...ATRA JM18 source_name=NB4 cells || agent=48 hours ATRA || antibody=MethylCap GST MBD http://dbarchive.biosc

  8. Experiment list: SRX014768 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available n=Bone Marrow|Tissue Diagnosis=Leukemia 7567340,73.2,12.1,375 GSM468198: PML ChIP-seq NB4 24hoursATRA JM19 s...ource_name=NB4 cells || agent=24 hours ATRA || antibody=PML http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/

  9. Experiment list: SRX014770 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available on=Bone Marrow|Tissue Diagnosis=Leukemia 14403159,71.1,32.3,217 GSM468200: RAR ChIPseq NB4 24hoursATRA JM21 ...source_name=NB4 cells || agent=24 hours ATRA || antibody=RAR http://dbarchive.biosciencedbc.jp/kyushu-u/hg19

  10. Experiment list: SRX014758 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Bone Marrow|Tissue Diagnosis=Leukemia 15859913,93.5,4.4,416 GSM468188: H3K27me3 ChIP-seq NB4 24hoursATRA, JM...9a and JM9b source_name=NB4 cells || agent=24 hours ATRA || antibody=H3K27me3 http://dbarchive.biosciencedbc

  11. In Vitro and in Vivo Studies on the Antitumor Efficacy of All-Trans ...

    African Journals Online (AJOL)

    All-trans retinoic acid (atRA) potently induces differentiation and apoptosis in pancreatic cancer. However, the clinical use of retinoids is limited by retinoid ... In vivo, nude mice with AsPc-1 xenografts were treated with atRA, verapamil, and troleandomycin alone or in combination. Co-administration of inhibitors of MDR and ...

  12. Paradoxical reproduction and body size in the rock lizard, Agama ...

    African Journals Online (AJOL)

    1993-07-05

    Jul 5, 1993 ... The rock lizard Agama atra atra from Namaqualand differs in both body size and reproduction from other populations of this species occurring elsewhere in southern Africa. Both sexes from Namaqualand are significantly larger than their counterparts in the south-western Cape. While reproduction in this ...

  13. The Achilles tendon resting angle as an indirect measure of Achilles tendon length following rupture, repair, and rehabilitation

    Directory of Open Access Journals (Sweden)

    Michael R. Carmont

    2015-04-01

    Conclusion: The ATRA increases following injury, is reduced by surgery, and then increases again during initial rehabilitation. The angle also correlates with patient-reported symptoms early in the rehabilitation phase and with heel-rise height after 1 year. The ATRA might be considered a simple and effective means to evaluate Achilles tendon function 1 year after the rupture.

  14. All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia : a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies

    NARCIS (Netherlands)

    Sanz, Miguel A.; Montesinos, Pau; Kim, Haesook T.; Ruiz-Argueelles, Guillermo J.; Undurraga, Maria S.; Uriarte, Maria R.; Martinez, Lem; Jacomo, Rafael H.; Gutierrez-Aguirre, Homero; Melo, Raul A. M.; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Fagundes, Evandro M.; Vellenga, Edo; Holowiecka, Alexandra; Gonzalez-Huerta, Ana J.; Fernandez, Pascual; De la Serna, Javier; Brunet, Salut; De Lisa, Elena; Gonzalez-Campos, Jose; Ribera, Jose M.; Krsnik, Isabel; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C.; Lo-Coco, Francesco; Lowenberg, Bob; Rego, Eduardo M.

    Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly

  15. Experiment list: SRX014765 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ROGENITOR CELLS) in the bone marrow and other sites. 9180677,92.2,5.7,109 GSM468195: H3K27me3 ChIP-seq APL164 48hours...ATRA JM16 source_name=APL cells _pz164 || agent=48 hours ATRA || antibod

  16. Mechanisms of all-trans retinoic acid-induced differentiation of acute ...

    Indian Academy of Sciences (India)

    Analysing gene expression profiles in APL cells before and after ATRA treatment represents a useful approach to identify genes whose functions are involved in this new cancer treatment. A chronologically well coordinated modulation of ATRA-regulated genes has thus been revealed which seems to constitute a balanced ...

  17. All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment

    Science.gov (United States)

    Su, Meng; Alonso, Salvador; Jones, Jace W.; Yu, Jianshi; Kane, Maureen A.; Jones, Richard J.; Ghiaur, Gabriel

    2015-01-01

    Differentiation therapy with all-trans retinoic acid (atRA) has markedly improved outcome in acute promyelocytic leukemia (APL) but has had little clinical impact in other AML sub-types. Cell intrinsic mechanisms of resistance have been previously reported, yet the majority of AML blasts are sensitive to atRA in vitro. Even in APL, single agent atRA induces remission without cure. The microenvironment expression of cytochrome P450 (CYP)26, a retinoid-metabolizing enzyme was shown to determine normal hematopoietic stem cell fate. Accordingly, we hypothesized that the bone marrow (BM) microenvironment is responsible for difference between in vitro sensitivity and in vivo resistance of AML to atRA-induced differentiation. We observed that the pro-differentiation effects of atRA on APL and non-APL AML cells as well as on leukemia stem cells from clinical specimens were blocked by BM stroma. In addition, BM stroma produced a precipitous drop in atRA levels. Inhibition of CYP26 rescued atRA levels and AML cell sensitivity in the presence of stroma. Our data suggest that stromal CYP26 activity creates retinoid low sanctuaries in the BM that protect AML cells from systemic atRA therapy. Inhibition of CYP26 provides new opportunities to expand the clinical activity of atRA in both APL and non-APL AML. PMID:26047326

  18. ID1 and ID2 are retinoic acid responsive genes and induce a G0/G1 accumulation in acute promyelocytic leukemia cells.

    NARCIS (Netherlands)

    Nigten, J.; Ridder, M.C. de; Erpelinck-Verschueren, C.A.; Nikoloski, G.; Reijden, B.A. van der; Wageningen, S. van; Hennik, P.B. van; Witte, T.J.M. de; Lowenberg, B.; Jansen, J.H.

    2005-01-01

    Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA), which results in the expression of genes that induce the terminal granulocytic differentiation of the leukemic blasts. Here we report the identification of two ATRA responsive genes in APL

  19. Effect of all-trans-retinoic acid on the development of chronic hypoxia-induced pulmonary hypertension.

    Science.gov (United States)

    Zhang, Erquan; Jiang, Baohua; Yokochi, Ayumu; Maruyama, Junko; Mitani, Yoshihide; Ma, Ning; Maruyama, Kazuo

    2010-08-01

    An earlier study showed that all-trans-retinoic acid (ATRA) prevents the development of monocrotalin-induced pulmonary hypertension (PH). The purpose of the present study was to determine the effect of ATRA on another model of chronic hypoxia-induced PH. Male Sprague-Dawley rats were given 30 mg/kg ATRA or vehicle only by gavage once daily for 14 days during hypobaric hypoxic exposure. Chronic hypoxic exposure induced PH, right ventricular hypertrophy (RVH), and hypertensive pulmonary vascular changes. Quantitative morphometry of the pulmonary arteries showed that ATRA treatment significantly reduced the percentage of muscularized arteries in peripheral pulmonary arteries only with an external diameter between 15 and 50 microm. ATRA treatment also significantly reduced the medial wall thickness in small muscular arteries only with an external diameter between 50 and 100 microm. Unfortunately, these reductions did not accompany the lowering of pulmonary artery pressure nor decrease in RVH. Chronic hypoxia-induced PH rats with ATRA had a loss in body weight. Chronic hypoxia increased the expression of endothelial nitric oxide synthase in the lung on western blotting and immunohistochemistry, in which ATRA treatment had no effect. The administration of ATRA might not have a therapeutic role in preventing the development of chronic hypoxia-induced PH, because of body weight loss and the subtle preventable effects of vascular changes.

  20. All-trans retinoic acid restores gap junctional intercellular communication between oral cancer cells with upregulation of Cx32 and Cx43 expressions in vitro.

    Science.gov (United States)

    Wang, Juan; Dai, Yaohui; Huang, Yulei; Chen, Xiaohua; Wang, Hong; Hong, Yun; Xia, Juan; Cheng, Bin

    2013-07-01

    All-trans retinoic acid (ATRA) has been demonstrated to inhibit tumor growth by restoration of gap junctional intercellular communication (GJIC) via upregulation of connexin (Cx) expression in some solid tumors. However, the relationship between ATRA and GJIC remains unclear in oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the effect of ATRA on the GJIC function of OSCC. We measured the effects of ATRA on the viability and cell cycle distribution of SCC9 and Tca8113 OSCC cells. The GJIC function was observed using the scrape-loading dye transfer technique, and the mRNA and protein levels of Cx32 and Cx43 were detected by qRT-PCR, Western blot, and immunofluorescence assays. ATRA inhibited the growth of OSCC cells in a dose- and time-dependent manner (P <0.05) and caused cell cycle arrest. ATRA-treated cells showed a 2.69-fold and 2.06-fold enhancement of GJIC in SCC9 and Tca8113 cells, respectively (P <0.05). Moreover, ATRA induced upregulation of Cx32 and Cx43 at both the mRNA and protein levels in OSCC cells. Our results indicated that restoration of GJIC via enhanced Cx32 and Cx43 expression might serve as a novel mechanism for the anti-tumor effect of ATRA in OSCC.

  1. Acute effects of all-trans-retinoic acid in ischemic injury

    Science.gov (United States)

    All-trans-retinoic acid (ATRA) is a vitamin A derivative that is important in neuronal patterning, survival, and neurite outgrowth. We investigated the relatively acute effects of ATRA (100 nM and 1 µM) on cell swelling in ischemic injury and on key features hypothesized to contribute to cell swelli...

  2. In vitro induction and differentiation of umbilical cord mesenchymal stem cells into neuron-like cells by all-trans retinoic acid

    Directory of Open Access Journals (Sweden)

    Wei Jin

    2015-04-01

    Full Text Available AIM: To determine the optimal concentration for inducing the differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs into neuron-like cells, although it is understood that all-trans retinoic acid (ATRA regulates cell proliferation in the nervous system by modulating the balance between mitosis and apoptosis. METHODS: The abilities of ATRA to promote apoptosis as well as neural differentiation were assessed in cultured hUC-MSCs by morphological observation, MTT assay, annexin V-FITC/PI flow cytometry and immunocytochemistry. RESULTS: The data showed that low concentrations of ATRA (0.5 µmol, 0.25 µmol had no effect on the number of cells. However, treatment with 1.0 µmol or 2.0 µmol ATRA induced a 24.16% and 52.67% reduction in cell number, respectively, compared with vehicle-treated cultures. Further, 4.0 µmol ATRA had a potent effect on cell number, with almost no adherent cells recovered after 24h. We further showed that 0.5 µmol ATRA caused these cells to express characteristic markers of neuronal progenitor cells. CONCLUSION: Taken together, we conclude that ATRA has a dose-dependent influence on the neural differentiation and apoptosis of hUC-MSCs. These findings have implications on the use of ATRA-differentiated hUC-MSCs for the study of neural degeneration diseases.

  3. All-trans retinoic acid enhances bystander effect of suicide gene therapy in the treatment of breast cancer.

    Science.gov (United States)

    Kong, Heng; Liu, Xia; Yang, Liucheng; Qi, Ke; Zhang, Haoyun; Zhang, Jingwen; Huang, Zonghai; Wang, Hongxian

    2016-03-01

    All-trans retinoic acid (ATRA) has been shown to enhance the expression of connexin 43 (Cx43) and the bystander effect (BSE) in suicide gene therapy. These in turn improve effects of suicide gene therapies for several tumor types. However, whether ATRA can improve BSE remains unclear in suicide gene therapy for breast cancer. In the present study, MCF-7, human breast cancer cells were treated with ATRA in combination with a VEGFP-TK/CD gene suicide system developed by our group. We found that this combination enhances the efficiency of cell killing and apoptosis of breast cancer by strengthening the BSE in vitro. ATRA also promotes gap junction intercellular communication (GJIC) in MCF-7 cells by upregulation of the connexin 43 mRNA and protein in MCF-7 cells. These results indicate that enhancement of GJIC by ATRA in suicide gene system might serve as an attractive and cost-effective strategy of therapy for breast cancer cells.

  4. Acute Coronary Syndrome Manifesting as an Adverse Effect of All-trans-Retinoic Acid in Acute Promyelocytic Leukemia: A Case Report with Review of the Literature and a Spotlight on Management

    Directory of Open Access Journals (Sweden)

    K. Govind Babu

    2016-01-01

    Full Text Available Background. Acute promyelocytic leukemia is characterized by t(15;17. This leads to the formation of PML/RARα which blocks the differentiation of blasts at the stage of promyelocytes. This is reversed by all-trans-retinoic acid (ATRA, a vitamin A derivative. Acute myocardial ischemia is a rare side effect of ATRA. Case Report. We report a case of acute coronary syndrome manifesting as an adverse effect of ATRA in a lady with APL who had no other risk factors for cardiovascular disease. Conclusions. We emphasize the need for high index of suspicion for the diagnosis of this entity. In the light of this case, the rare instances of ATRA associated acute myocardial ischemia recorded in the literature and the options available for treatment of acute promyelocytic leukemia sans ATRA have been reviewed.

  5. Eosinophils from Murine Lamina Propria Induce Differentiation of Naïve T Cells into Regulatory T Cells via TGF-β1 and Retinoic Acid.

    Directory of Open Access Journals (Sweden)

    Hong-Hu Chen

    Full Text Available Treg cells play a crucial role in immune tolerance, but mechanisms that induce Treg cells are poorly understood. We here have described eosinophils in lamina propria (LP that displayed high aldehyde dehydrogenase (ALDH activity, a rate-limiting step during all-trans retinoic acid (ATRA synthesis, and expressed TGF-β1 mRNA and high levels of ATRA. Co-incubation assay confirmed that LP eosinophils induced the differentiation of naïve T cells into Treg cells. Differentiation promoted by LP eosinophils were inhibited by blocked either TGF-β1 or ATRA. Peripheral blood (PB eosinophils did not produce ATRA and could not induce Treg differentiation. These data identifies LP eosinophils as effective inducers of Treg cell differentiation through a mechanism dependent on TGF-β1 and ATRA.

  6. Direct protein-protein interactions and substrate channelling between cellular retinoic acid binding proteins and CYP26B1

    Science.gov (United States)

    Nelson, Cara H; Peng, Chi-Chi; Lutz, Justin D.; Yeung, Catherine K.; Zelter, Alex; Isoherranen, Nina

    2016-01-01

    Cellular retinoic acid binding proteins (CRABPs) bind all-trans-retinoic acid (atRA) tightly. This study aimed to determine whether atRA is channeled directly to cytochrome P450 (CYP) CYP26B1 by CRABPs, and whether CRABPs interact directly with CYP26B1. atRA bound to CRABPs (holo-CRABP) was efficiently metabolized by CYP26B1. Isotope dilution experiments showed that delivery of atRA to CYP26B1 in solution was similar with or without CRABP. Holo-CRABPs had higher affinity for CYP26B1 than free atRA, but both apo-CRABPs inhibited the formation of 4-OH-RA by CYP26B1. Similar protein-protein interactions between soluble binding proteins and CYPs may be important for other lipophilic CYP substrates. PMID:27416800

  7. Molecular mechanism of inhibitory effects of C-phycocyanin combined with all-trans-retinoic acid on the growth of HeLa cells in vitro.

    Science.gov (United States)

    Yang, Fan; Li, Bing; Chu, Xian-Ming; Lv, Cong-Yi; Xu, Ying-Jie; Yang, Peng

    2014-06-01

    We studied the effects of all-trans-retinoic acid (ATRA), C-phycocyanin (C-PC), or ATRA+C-PC on the growth of cervical cells (HeLa cells), cell cycle distribution, and apoptosis. The anticancer mechanism of the drug combination was revealed. MTT assay was adopted to determine the effects of C-PC and ATRA on the growth of HeLa cells. The expression quantities of cyclin-dependent kinase (CDK) 4, cyclin D1, Bcl-2, caspase-3, and CD59 were determined by in situ hybridization, immunofluorescence, immunohistochemistry staining, Western blot, and RT-PCR. TUNEL assay was adopted to determine the cellular apoptosis levels. Both C-PC and ATRA could inhibit the growth of HeLa cells, and the combination of ATRA+C-PC functioned cooperatively to induce apoptosis in HeLa cells. The dosage of ATRA was reduced when it cooperated with C-PC to reduce the toxicity. ATRA treated with C-PC could induce more cell cycle arrests than the single drug used by decrease in cyclin D1 and CDK4 expression. The combination of the two drugs could upregulate caspase-3 and downregulate the Bcl-2 gene and induce cell apoptosis. Moreover, the combination therapy has an important immunological significance in decreased expression of the CD59 protein. Singly, C-PC or ATRA could inhibit the growth of HeLa cells, and the effects of treatment were further enhanced in the combination group. In combination with C-PC, the dosage of ATRA was effectively reduced. The C-PC + ATRA combination might take effect by inhibiting the progress of the cell cycle, inducing cell apoptosis and promoting complement-mediated cytolysis.

  8. All-Trans Retinoic Acid plus Arsenic Trioxide versus All-Trans Retinoic Acid plus Chemotherapy for Newly Diagnosed Acute Promyelocytic Leukemia: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Yafang Ma

    Full Text Available Recently, the all-trans retinoic acid (ATRA plus arsenic trioxide (ATO protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL, but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL.We systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity.Overall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22-0.67, p = 0.009, overall survival (HR = 0.44, 95% CI: 0.24-0.82, p = 0.009, complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01-1.10; p = 0.03. There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22-1.05; p = 0.07.Thus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients.

  9. Pós-graduação na educação física brasileira: a atração (fatal para a biodinâmica Graduate studies in Brazilian physical education: the (fatal attraction to biodynamics

    Directory of Open Access Journals (Sweden)

    Edison de Jesus Manoel

    2011-08-01

    Full Text Available O objetivo do trabalho foi caracterizar academicamente a educação física no Brasil. Primeiro, fez-se um paralelo entre os eventos desse processo ocorridos nos Estados Unidos e no Brasil. A seguir, os programas de pós-graduação brasileiros foram analisados do ponto de vista de suas áreas de concentração e de sua vinculação com o corpo docente, as linhas e os projetos de pesquisa. Educação física é o termo predominante na denominação da maioria dos programas brasileiros, diferentemente dos Estados Unidos, onde se privilegia cinesiologia. A análise das áreas de concentração dos programas de pós-graduação permitiu-nos identificar três subáreas: biodinâmica, sociocultural e pedagógica. A biodinâmica sobressai-se pela dimensão do corpo docente e pela quantidade de linhas e projetos de pesquisa, sempre mais numerosos em comparação com as subáreas sociocultural e pedagógica. Tal hegemonia expressa a valorização atribuída às pesquisas orientadas pelas ciências naturais em detrimento daquelas fundamentadas pelas ciências humanas e sociais, além da dificuldade em problematizar a intervenção, particularmente no âmbito da escola. Esse quadro guarda semelhança com a realidade norte-americana, haja vista que acadêmicos norte-americanos das subáreas sociocultural e pedagógica apontam os obstáculos para compatibilizar suas concepções teóricas e metodológicas com os modos hegemônicos de pensamento, investigação e ação no campo da cinesiologia. Tanto os acontecimentos nos Estados Unidos quanto a caracterização acadêmica predominante nos programas de pós-graduação no Brasil indicam a forte presença da biodinâmica em prejuízo da educação física, no que ela compreende e agrega, sobretudo, como prática social e pedagógica de longa data.The present work aimed at the academic characterization of physical education in Brazil. First, a parallel was made between the history of academic characterization of physical education in North America and in Brazil. Next, the analysis of the areas comprehended by graduate study programs was carried out in the field around Brazil. A survey was done considering the field of concentration and its interface and links with the size of faculty, with research lines and with research projects. Physical education is the most preferred term to name the majority of the Brazilian graduate programs in contrast with the United States where Kinesiology is preferred. The analysis of the field of concentration yields three main subfields: biodynamics, sociocultural and pedagogical. Biodynamics takes precedence as one considers the size of the faculty and the number of research lines and projects always greater than the same variables in comparison with sociocultural and pedagogical subfields. This hegemony reflects a trend in which natural sciences-oriented research is privileged over human and social sciences-oriented research and difficulty in valuing the intervention, especially in schooling. This portrait resembles what happens in the US as some North American scholars from the sociocultural and pedagogical subfields have also identified difficulties in making their theoretical and methodological conceptions compatible with the hegemonic modes of thinking and investigation in kinesiology.

  10. Effect of differents baits as attractant for blowflies (diptera at Valonguinho, Universidade Federal Fluminense, Niterói, RJ, Brazil Efeito de diferentes iscas na atração de califorídeos (diptera no campus do Valonguinho, Universidade Federal Fluminense, Niterói, RJ, Brasil

    Directory of Open Access Journals (Sweden)

    José M. D'almeida

    2007-12-01

    Full Text Available It was carried out a survey of blowflies in a área of the Campus (Valonguinho of the Universidade Federal Fluminense, Niterói, Rio de Janeiro. The collections were performed with traps, using baits of fish (sardine, bovine liver, shrimps and banana. Were collected 6015 flies, Chrysomya megacephala and Lucilia eximia were the most frequent (50.55% and 21.52%, respectively. The flies were more abundant in February and March and the most attractive bait was fish (38.32%.Foi realizado um estudo sobre califorideos no Campus do Valonguinho, Universidade Federal Fluminense. A pesquisa foi efetuada de dezembro de 2003 a novembro de 2004, com coletas feitas com armadilhas utilizando iscas à base de peixe (sardinha, fígado bovino, camarão e banana. Foram coletados 6015 califorideos, Chrysomya megacephala e Lucilia eximia foram as mais freqüentes (50,55% e 21, 52%, respectivamente. A isca mais atrativa foi peixe (38,32% com picos populacionais em fevereiro e março.

  11. Impact of Triple Combinations of Retinoic Acid, Mold Spores and Citral on the F344 Rat Lung Tissue Pathology.

    Science.gov (United States)

    Farah, Ibrahim O; Holt-Gray, Carlene; Cameron, Joseph A; Tucci, Michelle; Cason, Zelma; Benghuzzi, Hamed

    2016-04-01

    The impact of retinoic acid (All Trans Retinoic Acid; ATRA) and Mold spores (MLD) in the development of lung pathology and in vivo tissue remodeling have not been well established in the literature. In addition, the role of citral (inhibitor of retinoid function) in the improvement of lung pathology has not been ascertained in animal studies. Therefore, it is hypothesized that ATRA and Mold (MLD) exposure will sensitize lung tissues leading to lung tissue pathology and that Citrals (C1 and C2) will reverse, ameliorate or improve the associated pathological damage to lung tissues. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=40). Animals were exposed to seven different treatments including untreated control, MLD, ATRA, Citrals (C1 and C2) and their MLD combinations (MLD+ ATRA+ C1, and MLD+ ATRA+ C2) by intra-peritoneal route. Rat weight and blood data were collected on Days 1 and 21, all animals were sacrificed on day 21, and lung tissues were processed for histopathology. Results from weight and blood data (ANOVA and Duncan) as well as from histopathological analyses supported the findings that exposure of F344 rats to MLD combinations with ATRA and Citrals showed various levels of lung tissue damage that were impacted by either C1 or C2 exposure. This promising study showed impressive responses on the interaction of MLD, Citrals, and ATRA as related to their impact on associated lung tissue pathologies.

  12. Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells.

    Directory of Open Access Journals (Sweden)

    Tatiana N Golovina

    Full Text Available Natural T regulatory cells (Tregs are challenging to expand ex vivo, and this has severely hindered in vivo evaluation of their therapeutic potential. All trans retinoic acid (ATRA plays an important role in mediating immune homeostasis in vivo, and we investigated whether ATRA could be used to promote the ex vivo expansion of Tregs purified from adult human peripheral blood. We found that ATRA helped maintain FOXP3 expression during the expansion process, but this effect was transient and serum-dependent. Furthermore, natural Tregs treated with rapamycin, but not with ATRA, suppressed cytokine production in co-cultured effector T cells. This suppressive activity correlated with the ability of expanded Tregs to induce FOXP3 expression in non-Treg cell populations. Examination of CD45RA+ and CD45RA- Treg subsets revealed that ATRA failed to maintain suppressive activity in either population, but interestingly, Tregs expanded in the presence of both rapamycin and ATRA displayed more suppressive activity and had a more favorable epigenetic status of the FOXP3 gene than Tregs expanded in the presence of rapamycin only. We conclude that while the use of ATRA as a single agent to expand Tregs for human therapy is not warranted, its use in combination with rapamycin may have benefit.

  13. All-Trans Retinoic Acid-Induced Pseudotumor Cerebri during Induction Therapy for Acute Promyelocytic Leukemia: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Dylan Holmes

    2012-01-01

    Full Text Available All-trans retinoic acid (ATRA, a derivative of vitamin A, is an essential component in the treatment of acute promyelocytic leukemia (APL. Though considered to be a relatively safe drug, use of ATRA can lead to several side effects such as retinoic acid syndrome and pseudotumor cerebri (PC. PC is a rare disorder characterized by neurologic and ocular signs and symptoms of increased intracranial pressure, but with normal cerebrospinal fluid composition and normal brain imaging. Most of the previous studies suggest that PC, as a complication of ATRA therapy, occurs predominantly in the pediatric age group. Herein, we report a rare case of ATRA-induced PC in a 38-year-old woman undergoing induction treatment for APL. Symptoms improved with discontinuation of ATRA and treatment with acetazolamide. Concomitant administration of medications such as triazole antifungals which influence the cytochrome P-450 system can exacerbate this potential complication of ATRA. In this paper, we also review the current literature, provide a descriptive analysis of clinical features, and discuss the principles of management of ATRA-induced PC.

  14. Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor.

    Directory of Open Access Journals (Sweden)

    Aurore Gely-Pernot

    2015-10-01

    Full Text Available All-trans retinoic acid (ATRA is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG or all ATRA receptors (RARA, RARB and RARG. We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells.

  15. Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Li Xiang-Xin

    2014-01-01

    Full Text Available Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA, Realgar-Indigo naturalis formula (RIF and chemotherapy (CT were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL. Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen, while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX plus 6-mercaptopurine (6-MP alternately (ATRA/CTlow regimen. The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity.

  16. Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

    Science.gov (United States)

    Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

    2014-01-01

    Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity. PMID:24963332

  17. The oncogene EVI1 enhances transcriptional and biological responses of human myeloid cells to all-trans retinoic acid

    Science.gov (United States)

    Steinmetz, Birgit; Hackl, Hubert; Slabáková, Eva; Schwarzinger, Ilse; Smějová, Monika; Spittler, Andreas; Arbesu, Itziar; Shehata, Medhat; Souček, Karel; Wieser, Rotraud

    2014-01-01

    The product of the ecotropic virus integration site 1 (EVI1) gene, whose overexpression is associated with a poor prognosis in myeloid leukemias and some epithelial tumors, regulates gene transcription both through direct DNA binding and through modulation of the activity of other sequence specific transcription factors. Previous results from our laboratory have shown that EVI1 influenced transcription regulation in response to the myeloid differentiation inducing agent, all-trans retinoic acid (ATRA), in a dual manner: it enhanced ATRA induced transcription of the RARβ gene, but repressed the ATRA induction of the EVI1 gene itself. In the present study, we asked whether EVI1 would modulate the ATRA regulation of a larger number of genes, as well as biological responses to this agent, in human myeloid cells. U937 and HL-60 cells ectopically expressing EVI1 through retroviral transduction were subjected to microarray based gene expression analysis, and to assays measuring cellular proliferation, differentiation, and apoptosis. These experiments showed that EVI1 modulated the ATRA response of several dozens of genes, and in fact reinforced it in the vast majority of cases. A particularly strong synergy between EVI1 and ATRA was observed for GDF15, which codes for a member of the TGF-β superfamily of cytokines. In line with the gene expression results, EVI1 enhanced cell cycle arrest, differentiation, and apoptosis in response to ATRA, and knockdown of GDF15 counteracted some of these effects. The potential clinical implications of these findings are discussed. PMID:25486480

  18. All-Trans Retinoic Acid Improves the Effects of Bone Marrow-Derived Mesenchymal Stem Cells on the Treatment of Ankylosing Spondylitis: An In Vitro Study

    Directory of Open Access Journals (Sweden)

    Deng Li

    2015-01-01

    Full Text Available Previous studies have demonstrated the immunosuppressive effects of both all-trans retinoic acid (ATRA and mesenchymal stem cells (MSCs. The present study aimed to assess the immunoregulatory effects of ATRA on MSCs in the treatment of ankylosing spondylitis (AS. Bone marrow-derived MSCs from healthy donors were pretreated with ATRA and cocultured with CD3/28-activated peripheral blood mononuclear cells (PBMCs derived from AS patients. Frequencies of Th17 and regulatory T (Treg cells were analyzed using flow cytometry. The secretion and the mRNA level of key cytokines were measured with cytometric bead array and quantitative real-time PCR, respectively. ATRA pretreatment increased interleukin-6 (IL-6 secretion of MSCs. Th17 and Treg subset populations were increased and reduced by ATRA-pretreated MSCs, respectively. ATRA-pretreated MSCs significantly decreased not only the vital pathogenic cytokine in AS, tumor necrosis factor-α (TNF-α, but also AS-boosting factors interleukin-17 (IL-17A and interferon-γ (IFN-γ. These results indicated that IL-6 may be a potential protective factor in AS and highlighted the promising role of ATRA in improving the efficacy of MSC-based treatment of AS.

  19. Arsenic trioxide and all-trans-retinoic acid selectively exert synergistic cytotoxicity against FLT3-ITD AML cells via co-inhibition of FLT3 signaling pathways.

    Science.gov (United States)

    Wang, Li-Na; Tang, Yan-Lai; Zhang, Yin-Chuan; Zhang, Zu-Han; Liu, Xiao-Jian; Ke, Zhi-Yong; Li, Yu; Tan, Hui-Zhen; Huang, Li-Bin; Luo, Xue-Qun

    2017-10-01

    FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors have in vitro but limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML. Here, we demonstrate that an ATO/ATRA combination selectively exerts synergistic cytotoxicity against FLT3-ITD AML cell lines (MV4;11/MOLM-13). The signaling pathways affected by ATO/ATRA include FLT3/STAT5/MYC, FLT3/STAT5/E2F1, FLT3/ERK/ATF5 and FLT3/AKT/ATF5.ATF5 may function as an oncogene in FLT3-ITD AML. Our findings provide experimental evidence that supports further exploration of ATO/ATRA in FLT3-ITD AML in vivo and warrants a clinical evaluation of regimens comprising an ATO/ATRA combination.

  20. All-trans retinoic acid inhibits KIT activity and induces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein

    Directory of Open Access Journals (Sweden)

    Taguchi Takahiro

    2010-12-01

    Full Text Available Abstract Background Imatinib, a selective tyrosine kinase inhibitor, has been used as a standard first-line therapy for irresectable and metastasized gastrointestinal stromal tumor (GIST patients. Unfortunately, most patients responding to imatinib will eventually exhibit imatinib-resistance, the cause of which is not fully understood. The serious clinical problem of imatinib-resistance demands alternative therapeutic strategy. This study was conducted to investigate the effect of all-trans retinoic acid (ATRA on GIST cell lines. Methods Cell proliferation was determined by trypan blue dye exclusion test. Western blot analysis was performed to test the expression of activated KIT, its downstream proteins, and apoptosis associated proteins. The cytotoxic interactions of imatinib with ATRA were evaluated using the isobologram of Steel and Peckham. Results and conclusion In this work, for the first time we have demonstrated that ATRA affected on cell proliferation of GIST-T1 and GIST-882 cell line through inhibition of cell growth in a dose dependent manner and induced apoptosis. High dose of ATRA induced morphologic change in GIST-T1 cells, rounded-up cells, and activated the caspase-3 protein. In further examination, we found that the ATRA-induced apoptosis in GIST-T1 cells was accompanied by the down-regulated expression of survivin and up-regulated expression of Bax protein. Moreover, ATRA suppressed the activity of KIT protein in GIST-T1 cells and its downstream signal, AKT activity, but not MAPK activity. We also have demonstrated that combination of ATRA with imatinib showed additive effect by isobologram, suggesting that the combination of ATRA and imatinib may be a novel potential therapeutic option for GIST treatment. Furthermore, the scracht assay result suggested that ATRA was a potential reagent to prevent the invasion or metastasis of GIST cells.

  1. Nicotinamide attenuates aquaporin 3 overexpression induced by retinoic acid through inhibition of EGFR/ERK in cultured human skin keratinocytes.

    Science.gov (United States)

    Song, Xiuzu; Xu, Aie; Pan, Wei; Wallin, Brittany; Kivlin, Rebecca; Lu, Shan; Cao, Cong; Bi, Zhigang; Wan, Yinsheng

    2008-08-01

    The most common adverse effects that are related to all-trans retinoic acid (atRA) treatment are irritation and dryness of the skin. atRA therapy is reported to impair barrier function as achieved by trans-epidermal water loss (TEWL). Treatment with nicotinamide prior to initiation of atRA therapy provides additional barrier protection and thus reduces susceptibility of retinoic acid. Our previous studies showed that atRA upregulates aquaporin 3 (AQP3) in cultured human skin keratinocytes and fibroblasts. Others have demonstrated that in atopic dermatitis, overexpression of AQP3 is linked to elevated TEWL and that nicotinamide treatment reduces skin TEWL. In this study, we observed that while atRA upregulates AQP3 expression in cultured human skin keratinocytes (HaCaT cells), nicotinamide attenuates the effect of atRA in a concentration-dependent manner. atRA treatment induces EGFR and ERK activation. PD153035, an EGFR inhibitor, and U0126, an ERK inhibitor, inhibit atRA-induced upregulation of AQP3. Nicotinamide also inhibits atRA-induced activation of EGFR/ERK signal transduction and decreases water permeability by downregulating AQP3 expression. Collectively, our results indicate that the effect of atRA on AQP3 expression is at least partly mediated by EGFR/ERK signaling in cultured human skin keratinocytes. Nicotinamide attenuates atRA-induced AQP3 expression through inhibition of EGFR/ERK signal transduction and eventually decreases water permeability and water loss. Our study provides insights into the molecular mechanism through which nicotinamide reverses the side effects of dryness in human skin after treatment with atRA.

  2. All-trans retinoic acid-triggered antimicrobial activity against Mycobacterium tuberculosis is dependent on NPC2.

    Science.gov (United States)

    Wheelwright, Matthew; Kim, Elliot W; Inkeles, Megan S; De Leon, Avelino; Pellegrini, Matteo; Krutzik, Stephan R; Liu, Philip T

    2014-03-01

    A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the mechanism is unclear. In this study, we demonstrate that vitamin A-triggered antimicrobial activity against M. tuberculosis requires expression of NPC2. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D3), the biologically active forms of vitamin A and vitamin D, respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Stimulation of primary human monocytes with ATRA did not result in expression of the antimicrobial peptide cathelicidin, which is required for 1,25D3 antimicrobial activity. In contrast, ATRA triggered a reduction in the total cellular cholesterol concentration, whereas 1,25D3 did not. Blocking ATRA-induced cellular cholesterol reduction inhibits antimicrobial activity as well. Bioinformatic analysis of ATRA- and 1,25D3-induced gene profiles suggests that NPC2 is a key gene in ATRA-induced cholesterol regulation. Knockdown experiments demonstrate that ATRA-mediated decrease in total cellular cholesterol content and increase in lysosomal acidification are both dependent upon expression of NPC2. Expression of NPC2 was lower in caseous tuberculosis granulomas and M. tuberculosis-infected monocytes compared with normal lung and uninfected cells, respectively. Loss of NPC2 expression ablated ATRA-induced antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated antimicrobial mechanism against M. tuberculosis requires NPC2-dependent expression and function, indicating a key role for cellular cholesterol regulation in the innate immune response.

  3. Study of the synergistic effects of all-transretinoic acid and C-phycocyanin on the growth and apoptosis of A549 cells.

    Science.gov (United States)

    Li, Bing; Gao, Mei-Hua; Lv, Cong-Yi; Yang, Peng; Yin, Qi-Feng

    2016-03-01

    In the present study, we investigated the effects of the combination of all-transretinoic acid (ATRA) and natural nontoxic C-phycocyanin (C-PC) on the growth of A549 lung cancer cells in vitro and in vivo. Furthermore, the anticancer mechanism of the drug combination was revealed. Results showed both C-PC and ATRA could inhibit the growth of A549 cells in vivo. The combination of ATRA+C-PC could yield a higher inhibition rate. C-PC exerted a major effect on the proliferation of human embryo lung cells, but ATRA at a high concentration exerted an inhibitory effect. In addition, ATRA+C-PC could decrease the CDK4 mRNA level, but upregulated caspase-3 protein expression and induced cell apoptosis. A mouse model with tumor was constructed by a subcutaneous injection to the left axilla of nu nude (NU/NU) mice. Compared with the control group, the tumor weight was decreased in the single-drug treatment group and was the lowest in the combination group. C-PC+ATRA could upregulate tumor necrosis factor levels and downregulate Bcl-2 expression and the cyclin D1 gene in the tumor. C-PC could promote T cells' activities and spleen weight, but a single use of ATRA exerted an opposite effect. The dosage of ATRA could be reduced when combined with C-PC to reduce the toxic side-effects. In summary, the antitumor effects of the C-PC+ATRA combination were more significant than a single drug in vivo and in vitro.

  4. The synergistic antitumor effects of all-trans retinoic acid and C-phycocyanin on the lung cancer A549 cells in vitro and in vivo.

    Science.gov (United States)

    Li, Bing; Gao, Mei-Hua; Chu, Xian-Ming; Teng, Lei; Lv, Cong-Yi; Yang, Peng; Yin, Qi-Feng

    2015-02-15

    The anticancer effects and mechanism of all-trans retinoic acid (ATRA), C-phycocyanin (C-PC) or ATRA+C-PC on the growth of A549 cells were studied in in vitro and in vivo experiments. The effects of C-PC and ATRA on the growth of A549 cells were determined. The expression of CDK-4 and caspase-3, and the cellular apoptosis levels were detected. The tumor model was established by subcutaneous injection of A549 cells to the left axilla of the NU/NU mice. The weights of tumor and the spleen were tested. The viabilities of T-cells and spleen cells, TNF levels, the expression of Bcl-2 protein and Cyclin D1 gene were examined. Results showed both C-PC and ATRA could inhibit the growth of tumor cells in vivo and in vitro. ATRA+C-PC cooperatively showed a higher antitumor activity. The dosage of ATRA was reduced when it was administered with C-PC together, and the toxicity was reduced as well. ATRA+C-PC could decrease CDK-4 but increase caspase-3 protein expression level and induce cell apoptosis. ATRA alone could lower the activities of T lymphocytes and spleen weights, but the combination with C-PC could effectively promote viability of T cells and spleen. C-PC+ATRA could up-regulate TNF, and down-regulate Bcl-2 and Cyclin D1 gene. The combination might inhibit tumor growth by inhibiting the progress of cell cycle, inducing cell apoptosis and enhancing the body immunity. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Differential enhancement of leukaemia cell differentiation without elevation of intracellular calcium by plant-derived sesquiterpene lactone compounds

    Science.gov (United States)

    Kim, S H; Danilenko, M; Kim, T S

    2008-01-01

    Background and purpose: All-trans retinoic acid (ATRA) induces complete remission in a majority of acute promyelocytic leukaemia patients, but resistance of leukaemic cells to ATRA and its toxicity, such as hypercalcaemia, lead to a limitation of treatment. Therefore, combination therapies with differentiation-enhancing agents at non-toxic concentrations of ATRA may overcome its side effects. Here, we investigated the effect of plant-derived sesquiterpene lactone compounds and their underlying mechanisms in ATRA-induced differentiation of human leukaemia HL-60 cells. Experimental approach: HL-60 cells were treated with four sesquiterpene lactones (helenalin, costunolide, parthenolide and sclareolide) and cell differentiation was determined by NBT reduction, Giemsa and cytofluorometric analyses. Signalling pathways were assessed by western blotting, gel-shift assay and kinase activity determinations and intracellular calcium levels were determined using a calcium-specific fluorescent probe. Key results: Helenalin, costunolide and parthenolide, but not sclareolide, increased ATRA-induced HL-60 cell differentiation into a granulocytic lineage. Signalling kinases PKC and ERK were involved in the ATRA-induced differentiation enhanced by all of the effective sesquiterpene lactones, but JNK and PI3-K were involved in the ATRA-induced differentiation enhanced by costunolide and parthenolide. Enhancement of cell differentiation closely correlated with inhibition of NF-κB DNA-binding activity by all three effective compounds. Importantly, enhancement of differentiation induced by 50 nM ATRA by the sesquiterpene lactones was not accompanied by elevation of basal intracellular calcium concentrations. Conclusions and implications: These results indicate that plant-derived sesquiterpene lactones may enhance ATRA-mediated cell differentiation through distinct pathways. PMID:18724384

  6. Induction of Chemoresistance by All-Trans Retinoic Acid via a Noncanonical Signaling in Multiple Myeloma Cells

    Science.gov (United States)

    Jiang, Kesheng; Huang, Qiaoli; Chen, Yicheng; Qian, Feng

    2014-01-01

    Despite the successful application of all-trans retinoic acid (ATRA) in multiple myeloma treatment, ATRA-induced chemoresistance in the myeloma patients is very common in clinic. In this study, we evaluated the effect of ATRA on the expression of apurinic endonuclease/redox factor-1 (Ape/Ref-1) in the U266 and RPMI-8226 myeloma cells to explore the chemoresistance mechanism involved. ATRA treatment induced upregulation of Ape/Ref-1 via a noncanonical signaling pathway, leading to enhanced pro-survival activity counteracting melphalan (an alkylating agent). ATRA rapidly activated p38-MSK (mitogen- and stress activated protein kinase) cascade to phosphorylate cAMP response element-binding protein (CREB). Phosphorylated CREB was recruited to the Ape/Ref-1 promoter to evoke the gene expression. The stimulation of ATRA on Ape/Ref-1 expression was attenuated by either p38-MSK inhibitors or overexpression of dominant-negative MSK1 mutants. Moreover, ATRA-mediated Ape/Ref-1 upregulation was correlated with histone modification and activation of CBP/p300, an important cofactors for CREB transcriptional activity. C646, a competitive CBP/p300 inhibitor, abolished the upregulation of Ape/Ref-1 induced by ATRA. Intriguingly, CBP rather than p300 played a dominant role in the expression of Ape/Ref-1. Hence, our study suggests the existence of a noncanonical mechanism involving p38-MSK-CREB cascade and CBP induction to mediate ATRA-induced Ape/Ref-1 expression and acquired chemoresistance in myeloma cells. PMID:24416428

  7. Retinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha.

    Science.gov (United States)

    Drach, J; McQueen, T; Engel, H; Andreeff, M; Robertson, K A; Collins, S J; Malavasi, F; Mehta, K

    1994-04-01

    CD38 is a leukocyte differentiation antigen that has been thought to be a phenotypic marker of different subpopulations of T- and B-lymphocytes. In myeloid cells, CD38 is expressed during early stages of differentiation. Virtually no information is available on regulation and functions of CD38. Recently we reported that all-trans-retinoic acid (ATRA) is a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells. Here we report that ATRA-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid-alpha receptor (RAR alpha). ATRA failed to induce CD38 expression in a mutant subclone of the HL-60 myeloid leukemia cell line (designated HL-60R) that is relatively resistant to ATRA-induced granulocytic differentiation. Retroviral vector-mediated transduction of RA receptor (RAR alpha) into this HL-60R subclone completely restored the sensitivity of these cells to ATRA in terms of their ability to express CD38. In contrast, CD38 expression was not inducible by ATRA in HL-60R cells, transfected with a functional RAR beta, RAR gamma, or RXR alpha receptor. Induction of CD38 in acute promyelocytic and acute myeloblastic leukemia cells was independent of ATRA-induced cytodifferentiation. Following culture with ATRA, increased CD38 protein levels were also observed in normal CD34+ bone marrow cells, but not on normal circulating granulocytes. From these results, we conclude that CD38 is ATRA inducible in myeloid leukemia cells and normal CD34+ bone marrow cells. This effect is independent of differentiation and is mediated by RAR alpha in HL-60 cells, suggesting a similar role for RAR alpha in CD38 expression in other hematopoietic cells.

  8. High pseudotumor cerebri incidence in tretinoin and arsenic treated acute promyelocytic leukemia and the role of topiramate after acetazolamide failure

    Directory of Open Access Journals (Sweden)

    Morgan B. Smith

    2014-01-01

    Full Text Available Dual differentiation therapy with arsenic trioxide and tretinoin (all-trans-retinoic acid; ATRA for the management of low and intermediate risk acute promyelocytic leukemia has recently been recommended by the National Comprehensive Cancer Network. Some less common toxicities of the combination may have yet to be fully realized. Of ten patients we have treated thus far, five (50% have developed pseudotumor cerebri. In one patient, temporary discontinuation of ATRA and initiation of acetazolamide controlled symptoms. In four patients, topiramate was substituted for acetazolamide to relieve symptoms and allow ATRA dose re-escalation. We conclude that providers should monitor for pseudotumor cerebri and consider topiramate if acetazolamide fails.

  9. Reversible Symptomatic Myocarditis Induced by All-Trans Retinoic Acid Administration during Induction Treatment of Acute Promyelocytic Leukemia: Rare Cardiac Manifestation as a Retinoic Acid Syndrome.

    Science.gov (United States)

    Choi, Seonghoon; Kim, Hyeong-Su; Jung, Chang-Soo; Jung, Seong-Woong; Lee, Yun-Ja; Rheu, Jin-Kyeong; Jo, Jung-Rae; Lee, Nam-Ho

    2011-06-01

    Treatment by All-trans retinoic acid (ATRA) followed by anthracycline-AraC chemotherapy has improved the outcome of acute promyelocytic leukemia. ATRA is usually well tolerated, but a few major side effects can be observed. Retinoic acid syndrome (RAS) often occurs during the induction chemotherapy of acute promyelocytic leukemia. A pericardial effusion is a common cardiac manifestation but myocarditis has been rarely documented. Here we reports a very rare case of fully recovered myocarditis as a result of RAS related to ATRA administration during induction treatment of acute promyelocytic leukemia which documented by echocardiographic evidence.

  10. Synergistic effect of all-trans-retinoic acid and arsenic trioxide on growth inhibition and apoptosis in human hepatoma, breast cancer, and lung cancer cells in vitro.

    Science.gov (United States)

    Lin, Le-Min; Li, Bao-Xin; Xiao, Jian-Bing; Lin, Dan-Hua; Yang, Bao-Feng

    2005-09-28

    To investigate the effect of all-trans-retinoic acid (ATRA) on arsenic trioxide (As(2)O(3))-induced apoptosis of human hepatoma, breast cancer, and lung cancer cells in an attempt to find a better combination therapy for solid tumors. Human hepatoma cell lines HepG2, Hep3B, human breast cancer cell line MCF-7, and human lung adenocarcinoma cell line AGZY-83-a were treated with As(2)O(3) together with ATRA. Cell survival fraction was determined by MTT assay, cell viability and apoptosis were measured by annexin V-fluorescein isothiocyanate (FITC) and PI staining, and intracellular glutathione (GSH) and glutathione-S-transferase (GST) activities were determined using commercial kits. Cytotoxicity of ATRA was low. ATRA (0.1, 1, and 10 micromol/L) could synergistically potentiate As(2)O(3) to exert a dose-dependent inhibition of growth and to induce apoptosis in each of the cell lines. HepG2 and Hep3B with low intracellular GSH or GST activities were remarkably sensitive to As(2)O(3) or As(2)O(3)+ATRA, while AGZY-83-a with higher GSH or GST activities was less sensitive to As(2)O(3) or As(2)O(3)+ATRA. Treatment with 2 micromol/L As(2)O(3) for 72 h significantly decreased intracellular GSH and GST levels in each of the cell lines, and 1 micromol/L ATRA alone reduced minimal intracellular GSH and GST levels. ATRA potentiated the effect of As(2)O(3) on intracellular GSH levels, but intracellular GST levels were not significantly affected by the combination of As(2)O(3) and ATRA for 72 h as compared to As(2)O(3) alone. ATRA can strongly potentiate As(2)O(3)-induced growth-inhibition and apoptosis in each of the cell lines, and two drugs can produce a significant synergic effect. The sensitivity to As(2)O(3) or As(2)O(3)+ATRA is inversely proportional to intracellular GSH or GST levels in each of the cell lines. The GSH redox system may be the possible mechanism by which ATRA synergistically potentiates As(2)O(3) to exert a dose-dependent inhibition of growth and to induce

  11. Development and characterization of novel and selective inhibitors of cytochrome P450 CYP26A1, the human liver retinoic acid hydroxylase

    OpenAIRE

    Diaz, Philippe; Huang, Weize; Keyari, Charles M.; Buttrick, Brian; Price, Lauren; Guilloteau, Nicolas; Tripathy, Sasmita; Sperandio, Vanessa G.; Fronczek, Frank R.; Astruc-Diaz, Fanny; Isoherranen, Nina

    2016-01-01

    Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors towards CYP26A1 and CYP26B1 is unknown, and no selective CYP26A1 or CYP26B1 inhibitors have been developed. Here the synthesis and potent inhibitory activity of the first CYP26A1 selective inhibitors is reported...

  12. Phosphorylation of c-Cbl and p85 PI3K Driven by All-trans Retinoic Acid and CD38 Depends on Lyn Kinase Activity

    OpenAIRE

    Congleton, Johanna; Shen, Miaoqing; Macdonald, Robert; Malavasi, Fabio; Yen, Andrew

    2014-01-01

    The leukocyte antigen CD38 is expressed after all-trans retinoic acid (ATRA) treatment in HL-60 myelogenous leukemia cells and promotes induced myeloid differentiation when overexpressed. We found that Vav1 and SLP-76 associate with CD38 in two cell lines, and that these proteins complex with Lyn, a Src family kinase (SFK) upregulated by ATRA. SFK inhibitors PP2 and dasatinib, which enhance ATRA-induced differentiation, were used to evaluate the involvement of Lyn kinase activity in CD38-driv...

  13. 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.

  14. The Importance of Landscape Structure for the Long-Term Conservation of Species

    DEFF Research Database (Denmark)

    Nabe-Nielsen, Jacob; Sibly, Richard M; Forchhammer, Mads C.

    population recovery was affected by landscape structure for four species in an agricultural landscape: skylark (Alauda arvensis), vole (Microtus agrestis), a ground beetle (Bembidion lampros) and a linyphiid spider (Erigone atra). We characterized population persistence based on equilibrium population sizes...

  15. Genital Ulcer Development in Patients with Acute Promyelocytic Leukaemia Treated with All-Trans Retinoic Acid: A Case Series

    Directory of Open Access Journals (Sweden)

    Mohammed Al Huneini

    2013-05-01

    Full Text Available We report here four cases of genital ulcers that developed after the administration of all-trans retinoic acid (ATRA for the treatment of acute promyelocytic leukemia (APL. Between October 2007 and March 2010, three males and one female (age range 19-35 years were identified to have genital ulcers after being prescribed all-trans retinoic acid (ATRA as a part of chemotherapy for APL. This is the first series of cases describing genital ulcers, as a unique and rare complication of ATRA used for treatment of APL in these patients, with no other cause identified. Following temporary cessation of ATRA for a few days in these three cases, improvement of the ulcers was noted.

  16. Modern Approaches to Treating Acute Promyelocytic Leukemia

    National Research Council Canada - National Science Library

    Miguel A. Sanz; Francesco Lo-Coco

    2011-01-01

    The advent of all-trans-retinoic acid (ATRA) and its combination with anthracycline-containing chemotherapy have contributed in the past 2 decades to optimize the antileukemic efficacy in acute promyelocytic leukemia (APL...

  17. Plaat

    Index Scriptorium Estoniae

    2008-01-01

    Laseringi kauplustes müügilolevatest heliplaatidest: Bizarre "Cafe De Flor", Hocico "Memorias Atras", Portishead "Third", Alanis Morissette "Flavors Of Entanglement", Radiohead "The Best Of", Kelder "Vikerkaar ja latimeeria"

  18. Aqueous dispersions of silver nanoparticles in polyelectrolyte ...

    Indian Academy of Sciences (India)

    cilomyces varioti, Penicillium glaucum, Penicillium cyclopium, Stachybotris atra, Trichoderma viride,. Scopulariopsis brevicaulis and, for both Gram pos- itive and negative bacteria: Staphiloccocus aureus,. Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species (spp), and Acine- tobacter ...

  19. Genetic structure and demographic history should inform conservation: Chinese cobras currently treated as homogenous show population divergence

    National Research Council Canada - National Science Library

    Lin, Long-Hui; Qu, Yan-Fu; Li, Hong; Zhou, Kai-Ya; Ji, Xiang

    2012-01-01

    .... The vulnerable Chinese cobra (Naja atra) has a distribution from the mouth of the Yangtze River down to northern Vietnam and Laos, within which several large mountain ranges and water bodies may influence population structure...

  20. Incidence of secondary neoplasms in patients with acute promyelocytic leukemia treated with all-trans retinoic acid plus chemotherapy or with all-trans retinoic acid plus arsenic trioxide.

    Science.gov (United States)

    Eghtedar, Alireza; Rodriguez, Ildefonso; Kantarjian, Hagop; O'Brien, Susan; Daver, Naval; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Kadia, Tapan; Pierce, Sherry; Cortes, Jorge; Ravandi, Farhad

    2015-05-01

    The incidence and pattern of secondary neoplasms in patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA)-containing regimens is not well described. We compared 160 patients with APL treated with ATRA plus idarubicin (n = 54) or ATRA plus arsenic trioxide (ATO) (n = 106) for the incidence of secondary cancers per unit time of follow-up. Median follow-up times for the two cohorts were 136 and 29 months, respectively. Nine patients developed secondary cancers in the chemotherapy group. These included two breast cancers, three myelodysplastic syndromes/acute myeloid leukemia, one vulvar cancer, one prostate cancer, one colon cancer and one soft tissue sarcoma. A melanoma and one pancreatic cancer developed in the ATO group. We conclude that treatment of patients with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p = 0.29) adjusted for unit time of exposure.

  1. Responsabilidad social empresarial: teorias, indices, estandares y certificaciones

    National Research Council Canada - National Science Library

    Duque Orozco, Yenni V; Cardona Acevedo, Marleny; Rendon Acevedo, Jaime A

    2013-01-01

    La responsabilidad social empresarial (RSE) mas que una moda en la gestion y los informes empresariales, se constituye en un ejercicio clave en la evolucion de las empresas que data de un siglo atras...

  2. Exogenous PML/RARα Fusion Gene Responds to All-trans Retinoic Acid Results in Differentiation of the Human B Cell Line.

    Science.gov (United States)

    Sumimoto, Y; Maeda, Y; Naiki, Y; Sono, H; Miyatake, J; Sakaguchi, M; Matsuda, M; Kanamaru, A

    2001-01-01

    The interaction of an exogenous PML/RARα fusion gene, associated with acute promyelocytic leukemia, with all-trans retinoic acid (ATRA) was examined in B-lymphoid cell lines. RPMI8866 cells were transfected with PML/RARα cDNA in the expression vector pGD and two stable transformants (RPMI8866Y-4 and RPMI8866Y-17) were established by selection with G418. ATRA inhibited the growth of those stable transformants, as assessed by [(3)H]-thymidine incorporation, but had no effect on the growth of control cells stably transformed with neomycin resistant gene alone. ATRA also increased expression of CD38 and immunoglobulin production in RPMI8866Y-4 cells but not in control cells. When these results are taken together, it can be observed that the exogenous PML/RARα fusion gene responds to ATRA, which results in cell differentiation of the human B cell line.

  3. Comparising the Succinylcholine onset effect with Atracurium - Alfentanyl in patient underwent rapid sequence Induction

    Directory of Open Access Journals (Sweden)

    hasan Teimouri

    2005-12-01

    Conclusion: According to results, use of Atra + Alfen method can replace the standard method (succinylcholine for contraindicated condition. Mild vocal cord movement and mild bucking in the Atracurium + Alfentanyl can be control by that a increase in Atracurium dose.

  4. Reversible effect of all-trans-retinoic acid on AML12 hepatocyte proliferation and cell cycle progression

    Science.gov (United States)

    The role of all-trans-retinoic acid (atRA) in the regulation of cellular proliferation and differentiation is well documented. Numerous studies have established the cancer preventive propertiesofatRAwhichfunctionstoregulate levels ofcellcycleproteinsessentialfortheGliS transition...

  5. All-trans-retinoic acid inhibits chondrogenesis of rat embryo hindlimb bud mesenchymal cells by downregulating p53 expression

    Science.gov (United States)

    ZHANG, TAO-GEN; LI, XUE-DONG; YU, GUO-YONG; XIE, PENG; WANG, YUN-GUO; LIU, ZHAO-YONG; HONG, QUAN; LIU, DE-ZHONG; DU, SHI-XIN

    2015-01-01

    Despite the well-established role of all-trans-retinoic acid (ATRA) in congenital clubfoot (CCF)-like deformities in in vivo models, the essential cellular and molecular targets and the signaling mechanisms for ATRA-induced CCF-like deformities remain to be elucidated. Recent studies have demonstrated that p53 and p21, expressed in the hindlimb bud mesenchyme, regulate cellular proliferation and differentiation, contributing to a significant proportion of embryonic CCF-like abnormalities. The objective of the present study was to investigate the mechanisms for ATRA-induced CCF, by assessing ATRA-regulated chondrogenesis in rat embryo hindlimb bud mesenchymal cells (rEHBMCs) in vitro. The experimental study was based on varying concentrations of ATRA exposure on embryonic day 12.5 rEHBMCs in vitro. The present study demonstrated that ATRA inhibited the proliferation of cells by stimulating apoptotic cell death of rEHBMCs. It was also observed that ATRA induced a dose-dependent reduction of cartilage nodules compared with the control group. Reverse transcription-polymerase chain reaction and western blotting assays revealed that the mRNA and protein expression of cartilage-specific molecules, including aggrecan, Sox9 and collagen, type II, α 1 (Col2a1), were downregulated by ATRA in a dose-dependent manner; the mRNA levels of p53 and p21 were dose-dependently upregulated from 16 to 20 h of incubation with ATRA, but dose-dependently downregulated from 24 to 48 h. Of note, p53 and p21 were regulated at the translational level in parallel with the transcription with rEHBMCs treated with ATRA. Furthermore, the immunofluorescent microscopy assays indicated that proteins of p53 and p21 were predominantly expressed in the cartilage nodules. The present study demonstrated that ATRA decreases the chondrogenesis of rEHBMCs by inhibiting cartilage-specific molecules, including aggrecan, Sox9 and Col2al, via regulating the expression of p53 and p21. PMID:25738595

  6. Phosphorylation of c-Cbl and p85 PI3K Driven by All-trans Retinoic Acid and CD38 Depends on Lyn Kinase Activity

    Science.gov (United States)

    Congleton, Johanna; Shen, Miaoqing; MacDonald, Robert; Malavasi, Fabio; Yen, Andrew

    2014-01-01

    The leukocyte antigen CD38 is expressed after all-trans retinoic acid (ATRA) treatment in HL-60 myelogenous leukemia cells and promotes induced myeloid differentiation when overexpressed. We found that Vav1 and SLP-76 associate with CD38 in two cell lines, and that these proteins complex with Lyn, a Src family kinase (SFK) upregulated by ATRA. SFK inhibitors PP2 and dasatinib, which enhance ATRA-induced differentiation, were used to evaluate the involvement of Lyn kinase activity in CD38-driven signaling. Cells treated with ATRA for 48 hours followed by one hour of PP2 incubation show SFK/Lyn kinase inhibition. We observed that Lyn inhibition blocked c-Cbl and p85/p55 PI3K phosphorylation driven by the anti-CD38 agonistic mAb IB4 in ATRA-treated HL-60 cells and untreated CD38+ transfectants. In contrast, cells cultured for 48 hours following concurrent ATRA and PP2 treatment did not show Lyn inhibition, suggesting ATRA regulates the effects on Lyn. 48 hours of co-treatment preserved CD38-stimulated c-Cbl and p85/p55 PI3K phosphorylation indicating Lyn kinase activity is necessary for these events. In contrast another SFK inhibitor (dasatinib) which blocks Lyn activity with ATRA co-treatment prevented ATRA-induced c-Cbl phosphorylation and crippled p85 PI3K phosphorylation, indicating Lyn kinase activity is important for ATRA-propelled events potentially regulated by CD38. We found that loss of Lyn activity coincided with a decrease in Vav1/Lyn/CD38 and SLP-76/Lyn/CD38 interaction, suggesting these molecules form a complex that regulates CD38 signaling. Lyn inhibition also reduced Lyn and CD38 binding to p85 PI3K, indicating CD38 facilitates a complex responsible for PI3K phosphorylation. Therefore, Lyn kinase activity is important for CD38-associated signaling that may drive ATRA-induced differentiation. PMID:24686085

  7. All-trans retinoic acid induces different immunophenotypic changes on human HL60 and NB4 myeloid leukaemias.

    Science.gov (United States)

    Barber, Nicole; Belov, Larissa; Christopherson, Richard I

    2008-02-01

    All-trans retinoic acid (ATRA) is used to treat patients with acute promyelocytic leukaemia (APL), inducing APL cells to differentiate into abnormal neutrophils. To investigate the possible relationship between the chromosome translocation t(15;17) found in APL and ATRA treatment, the human myeloid leukaemia cell lines HL60 and NB4, that are PML-RARalpha negative and positive, respectively, were treated with ATRA and immunophenotyped using a CD antibody microarray. For HL60 cells, ATRA induced major increases in descending order of CD38, CD11b, CD45RO, CD11c, CD54 and CD36 with repression of CD117 and CD44. For NB4 cells, ATRA induced major increases in descending order of CD11c, CD54, CD11a, CD11b, CD53, CD65, CD138, CD66c and T-cell receptor alpha/beta (TCRalpha/beta), with repression of CD38 and CD9. The induction of a number of these CD antigens is consistent with the known differentiation of these leukaemias to abnormal neutrophils. Approximately half of the antigens up-regulated by ATRA on NB4 cells were adhesion molecules, including CD11a, CD11b, CD11c, CD54, CD66c and CD138, consistent with the increased adhesiveness of leukaemia cells observed for APL patients treated with ATRA. On HL60 cells, ATRA induced expression of CD38, CD43 and CD45RO and repressed CD117, while the converse was true on NB4 cells that contain chimeric PML-RARalpha. For NB4 cells, ATRA induced some remarkable increases in CD antigens not seen for HL60: CD14 (16.6-fold), CD32 (27.8), CD53 (20.5), CD65 (139), CD66c (79.7), CD126 (15.1), and CD138 (57.6). The expression of these antigens may be regulated by PML-RARalpha in the presence of ATRA. Such CD antigens could be targets for synergistic treatment of APL with therapeutic antibodies following ATRA treatment.

  8. Phosphorylation of c-Cbl and p85 PI3K driven by all-trans retinoic acid and CD38 depends on Lyn kinase activity.

    Science.gov (United States)

    Congleton, Johanna; Shen, Miaoqing; MacDonald, Robert; Malavasi, Fabio; Yen, Andrew

    2014-07-01

    The leukocyte antigen CD38 is expressed after all-trans retinoic acid (ATRA) treatment in HL-60 myelogenous leukemia cells and promotes induced myeloid differentiation when overexpressed. We found that Vav1 and SLP-76 associate with CD38 in two cell lines, and that these proteins complex with Lyn, a Src family kinase (SFK) upregulated by ATRA. SFK inhibitors PP2 and dasatinib, which enhance ATRA-induced differentiation, were used to evaluate the involvement of Lyn kinase activity in CD38-driven signaling. Cells treated with ATRA for 48h followed by one hour of PP2 incubation show SFK/Lyn kinase inhibition. We observed that Lyn inhibition blocked c-Cbl and p85/p55 PI3K phosphorylation driven by the anti-CD38 agonistic mAb IB4 in ATRA-treated HL-60 cells and untreated CD38+ transfectants. In contrast, cells cultured for 48h following concurrent ATRA and PP2 treatment did not show Lyn inhibition, suggesting ATRA regulates the effects on Lyn. 48h of co-treatment preserved CD38-stimulated c-Cbl and p85/p55 PI3K phosphorylation indicating Lyn kinase activity is necessary for these events. In contrast another SFK inhibitor (dasatinib) which blocks Lyn activity with ATRA co-treatment prevented ATRA-induced c-Cbl phosphorylation and crippled p85 PI3K phosphorylation, indicating Lyn kinase activity is important for ATRA-propelled events potentially regulated by CD38. We found that loss of Lyn activity coincided with a decrease in Vav1/Lyn/CD38 and SLP-76/Lyn/CD38 interaction, suggesting these molecules form a complex that regulates CD38 signaling. Lyn inhibition also reduced Lyn and CD38 binding to p85 PI3K, indicating CD38 facilitates a complex responsible for PI3K phosphorylation. Therefore, Lyn kinase activity is important for CD38-associated signaling that may drive ATRA-induced differentiation. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Experiment list: SRX014757 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available =Bone Marrow|Tissue Diagnosis=Leukemia 15425671,93.9,7.3,33917 GSM468187: H3K9K14ac ChIP-seq NB4 24hoursATRA..., JM8a and JM8b source_name=NB4 cells || agent=24 hours ATRA || antibody=H3K9K14ac http://dbarchive.bioscien

  10. Predictive factors of all-trans-retinoic acid related complications during induction therapy for acute promyelocytic leukemia.

    OpenAIRE

    Jeddi, Ramzi; Kacem, Karima; Ben Neji, Hend; Mnif, Samia; Gouider, Emna; Aissaoui, Lamia; Ben Amor, Ramzi; Ben Lakhal, Raihane; Ben Abid, Hela; Belhadjali, Zaher; Meddeb, Balkis

    2008-01-01

    BACKGROUND: The combination of all-trans-retinoic acid (ATRA) and chemotherapy has made acute promyelocytic leukemia (APL) a highly curable leukemia. However, several complications are reported with this treatment the most serious and life threatening being Retinoic Acid Syndrome (RAS). We aimed at identifying factors that could predict complications caused by ATRA during induction treatment of APL. PATIENTS: Forty-two patients with confirmed APL (by t(15;17) and/or PML/RARA) treated at our i...

  11. The Role of Tumor Metastases Suppressor Gene, Drg-1, in Breast Cancer

    Science.gov (United States)

    2009-03-01

    regulates NM23 in hepatocarcinoma cells. Increased adhesion to ECM in vitro Inhibits the growth of xenograft tumors and gastric cancer cell metastasis to...expression of NM23 was also shown to be up-regulated by ATRA in human hepatocarcinoma cell line and gastric cancer cell lines [226,227]. Liu et al...invasion of human hepatocarcinoma cell line [226]. Furthermore, Wu et al. examined the effect of ATRA treatment in xenografted nude mice and found that

  12. Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yadong; Dong, Shiyi; Wang, Weicai; Wang, Jianning [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Wang, Miao [Department of Oral and Maxillofacial Surgery, Kiang Wu Hospital, Macao (China); Chen, Mu [Department of Stomatology, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen (China); Hou, Jinsong [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Huang, Hongzhang, E-mail: drhuang52@163.com [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China)

    2016-08-26

    Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation. Next, we investigated the mechanisms underlying atRA, Notch1 and MEE degradation in palate organ culture. Our results revealed that down-regulation of Notch1 partially rescued the inhibition of atRA-induced palate fusion. Molecular analysis indicated that atRA increased the expression of Notch1 and Rbpj and decreased the expression of P21. In addition, depletion of Notch1 expression decreased the expression of Rbpj and increased the expression of P21. Moreover, inhibition of Rbpj expression partially reversed atRA-induced MEE persistence and increased P21 expression. These findings demonstrate that atRA inhibits MEE degradation, which in turn induces a cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway. - Highlights: • atRA exposure on E12.0 induced MEE persistence and cleft palate. • Notch1 was up-regulated in MEE cells in the atRA-treated embryos. • atRA inhibits MEE degradation, which in turn induces cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway.

  13. Novel lineage- and stage-selective effects of retinoic acid on mouse granulopoiesis: Blockade by dexamethasone or inducible NO synthase inactivation.

    Science.gov (United States)

    Xavier-Elsas, Pedro; Vieira, Bruno Marques; Masid-de-Brito, Daniela; Santos, Juliana; Barradas, Monica Gomes; de Luca, Bianca; Gaspar-Elsas, Maria Ignez

    2017-04-01

    Despite the close relationship of eosinophils and neutrophils, these granulocyte lineages respond to distinct cytokines and play unique roles in immune responses. They nevertheless respond to shared physiological/pharmacological regulators, including glucocorticoids and retinoids, and to ubiquitous mediators, including NO. Others showed that, in humans, all-trans retinoic acid (ATRA) suppresses eosinophil differentiation, but promotes neutrophil differentiation. Mechanisms of dual co-regulation of physiological granulopoiesis were here examined in murine bone-marrow, a model system suitable for exploration of immunopharmacological mechanisms, given the availability of experimental resources, including mutant/knockout mouse strains. We examined the effects of ATRA on mouse eosinophil and neutrophil production, using wild-type (BALB/c, C57BL/6) and mutant (iNOS-, CD95L-, or CD95-KO) bone-marrow cultures, further assessing the modification of ATRA activity by dexamethasone and iNOS blockade. ATRA (10(-6)-10(-8)M) significantly decreased eosinophil production relative to IL-5 controls. This effect was iNOS-independent, but CD95L- and caspase-dependent, and prevented by dexamethasone (10(-7)M in vitro; 1-20mg·kg(-1) in vivo). In myeloid colony formation assays, ATRA markedly suppressed GM-CSF-responsive progenitors, through an iNOS-dependent, CD95-independent, dexamethasone-sensitive mechanism. By contrast, ATRA potently enhanced GM-CSF-dependent neutropoiesis in liquid culture from BALB/c or C57BL/6 bone-marrow. This novel stimulatory effect was resistant to dexamethasone and abolished in iNOS-KO bone-marrow. ATRA injections also induced lineage- and stage-selective effects on granulopoiesis in vivo. ATRA therefore co-regulates eosinophil and neutrophil production in murine bone-marrow through multiple lineage- and stage-selective mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. All-Trans Retinoic Acid Ameliorates Myocardial Ischemia/Reperfusion Injury by Reducing Cardiomyocyte Apoptosis

    Science.gov (United States)

    Zhao, Xiaoran; Yang, Ke; Lu, Lin; Zhang, Fengru; Shen, Weifeng; Zhang, Ruiyan

    2015-01-01

    Myocardial ischemia/reperfusion (I/R) injury interferes with the restoration of blood flow to ischemic myocardium. Oxidative stress-elicited apoptosis has been reported to contribute to I/R injury. All-trans retinoic acid (ATRA) has anti-apoptotic activity as previously reported. Here, we investigated the effects and the mechanism of action of ATRA on myocardial I/R injury both in vivo and in vitro. In vivo, ATRA reduced the size of the infarcted area (17.81±1.05% vs. 24.41±1.03%, PATRA on myocardial I/R injury was related to its anti-apoptotic effects. The anti-apoptotic effects of ATRA were associated with partial inhibition of reactive oxygen species (ROS) production and significantly less phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, JNK, and ERK. Western blot analysis also revealed that ATRA pre-treatment increased a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) expression (0.65 ± 0.20 vs. 0.41±0.02 in vivo) and reduced the level of receptor for advanced glycation end-products (RAGE) (0.38 ± 0.17 vs. 0.52 ± 0.11 in vivo). Concomitantly, the protective role of ATRA on I/R injury was not observed in RAGE-KO mice. The current results indicated that ATRA could prevent myocardial injury and reduced cardiomyocyte apoptosis after I/R effectively. One possible mechanism underlying these effects is that ATRA could increase ADAM10 expression and thus cleave RAGE, which is the main receptor up-stream of MAPKs in myocardial I/R injury, resulting in the down-regulation of MAPK signaling and protective role on myocardial I/R injury. PMID:26186635

  15. Stress-induced NF-κB activation differentiates promyelocytic leukemia cells to macrophages in response to all-trans-retinoic acid.

    Science.gov (United States)

    Imran, Muhammad; Park, Joon Seong; Lim, In Kyoung

    2015-03-01

    All-trans-retinoic acid (ATRA) has been known as a choice of treatment for inducing differentiation of promyelocytic leukemia cells to granulocytes. NF-κB plays a crucial role in inflammation and immunity and its activation is an important event for macrophage differentiation both in vivo and in vitro. We report here that NF-κB activation is critical for determining ATRA-induced lineage specific differentiation of myeloid leukemia cells. Our data revealed that ATRA treatment to HL-60 cells enhanced IκBα degradation and NF-κB nuclear translocation and the activated NF-κB potentiated the ability of ATRA for differentiation and switched differentiation to macrophages instead of granulocytes. Serum withdrawal and LPS treatment dampened IκBα expression via MAPK activation and reactive oxygen species generation leading to NF-κB nuclear translocation and ATRA treatment further corroborated these effects in myeloid leukemia cells. Activated NF-κB enhanced the degree of ATRA-induced differentiation of HL-60 cells to macrophages, rather than granulocytes, as assessed by morphologic examination and expressions of differentiation markers such as CD11b, CD38, CD68, MMP9 and Btg2. Employing LLnL or dominant negative IκBα attenuated NF-κB associated enhanced cell maturation and differentiation switch thus suggesting NF-κB as one of the factors that determines ATRA induced lineage specificity of myeloid leukemia cells. Furthermore, MAPK activation was observed to be central both for the differentiation of promyelocytic cells to macrophages or granulocytes regulating NF-κB or C/EBPα expressions, respectively; however, MAPK-mediated signals are modulated under various conditions affecting lineage specificity. In summary, our present data demonstrate that activation of NF-κB directly affects differentiation program of promyelocytes to macrophages, rather than granulocyte, in response to ATRA treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. All-trans-retinoic acid up-regulates CD38 but not c-Kit antigens on human marrow CD34+ cells without recruitment into cell cycle.

    Science.gov (United States)

    Herault, O; Domenech, J; Degenne, M; Bremond, J L; Sensebe, L; Bernard, M C; Binet, C; Colombat, P

    1998-11-01

    Retinoids, especially all-trans-retinoic acid (ATRA), are well known for their differentiating activity on HL-60 cells. Moreover ATRA induces CD38 antigen overexpression on these cells. In this study we examined the effects of ATRA on purified normal CD34+ cells from adult human marrows incubated with ATRA (1 microM) or stem cell factor (SCF) after 7 d liquid cultures in serum-deprived medium. Before and after the incubation, CD34+ cells were studied by flow cytometry to evaluate the cell-surface expression of CD38 and c-Kit antigens and the cycle status of these cells using high-resolution analysis (DNA content v Ki-67 antigen expression) to clarify the functional meaning of antigenic variations. When compared with control cultures, ATRA-treated cells displayed changes in their immunophenotypic profile. Particularly relevant was the up-regulation of CD38 antigen with a mean (+/-SEM) fold increase of 21 +/- 0.1 (P=0.028) for geometric mean fluorescence intensity (GMFI), without modulation of c-Kit expression. SCF only down-regulated expression of c-Kit with a fold decrease of 4.6 +/- 0.9 for GMFI (P=0.043). Unlike SCF, ATRA did not induce CD34+ cells to entry into cell cycle despite increased levels of surface CD38 antigen. Moreover morphological and functional assays did not argue for an ATRA-induced maturation process. Contrary to steady-state cells, CD34+ cells treated with pharmacological doses of ATRA alone displayed CD38 over-expression without change in c-Kit levels and cycle status, suggesting an absence of maturation pressure.

  17. Effects of cytarabine on activation of human T cells - cytarabine has concentration-dependent effects that are modulated both by valproic acid and all-trans retinoic acid

    OpenAIRE

    Ersvær, Elisabeth; Brenner, Annette; Vetås, Kristin; Reikvam, Håkon; Bruserud, Øystein

    2015-01-01

    Background Cytarabine is used in the treatment of acute myeloid leukemia (AML). Low-dose cytarabine can be combined with valproic acid and all-trans retinoic acid (ATRA) as AML-stabilizing treatment. We have investigated the possible risk of immunotoxicity by this combination. We examined the effects of cytarabine combined with valproic acid and ATRA on in vitro activated human T cells, and we tested cytarabine at concentrations reached during in vivo treatment with high doses, conventional d...

  18. All-Trans-Retinoic Acid Improves Cholestasis in α-Naphthylisothiocyanate–Treated Rats and Mdr2−/− Mice

    Science.gov (United States)

    Mennone, Albert; Soroka, Carol J.

    2014-01-01

    Chronic cholestasis results in liver injury and eventually liver failure. Although ursodeoxycholic acid (UDCA) showed limited benefits in primary biliary cirrhosis, there is an urgent need to develop alternative therapy for chronic cholestatic disorders. Previous studies from our laboratory demonstrated that all-trans-retinoic acid (atRA) is a potent suppressor of CYP7A1, the rate-limiting enzyme in bile acid synthesis. atRA also repressed the expression of tumor growth factor-β and collagen 1A1 in activated primary human stellate cells and LX2 cells. When administered together with UDCA to bile duct–ligated rats, this combined therapy significantly reduced the bile acid pool size and improved liver conditions. To further examine whether atRA alone or in combination with UDCA has greater beneficial effects than UDCA treatment alone, we assessed this treatment in two additional chronic cholestatic rodent models: α-naphthylisothiocyanate (ANIT)–treated rats and the Mdr2−/− (Abcb4−/−) knockout mouse. atRA alone significantly reduced bile duct proliferation, inflammation, and hydroxyproline levels in ANIT-treated rats, whereas the combination of atRA and UDCA significantly reduced plasma bile salt level compared with UDCA treatment. atRA alone or in combination with UDCA significantly reduced plasma levels of alkaline phosphatase and bile salts in 12-week-old Mdr2−/− mice. Reduced bile duct proliferation and inflammation were also observed in the livers of these mice. Together, atRA alone or in combination with UDCA significantly reduced the severity of liver injury in these two animal models, further supporting the combination treatment of atRA and UDCA as a potential new therapy for patients with chronic cholestatic liver disease who have not responded fully to UDCA. PMID:24492652

  19. All-trans retinoic acid upregulates the expression of ciliary neurotrophic factor in retinal pigment epithelial cells.

    Science.gov (United States)

    Zhou, Wen-Di; Wang, Lu-Lu; Zhou, Lan-Bo; Bin, Wei; Bao, Tian-Ping; Zhang, Yi; Shu, Jin; Yang, Wei-Xia; Hui, Liang-Liang; Jin, Rui; Zhuang, Li-Li; Zhou, Guo-Ping

    2017-06-01

    Retinopathy of prematurity, a leading cause of visual impairment in low birth-weight infants, remains a crucial therapeutic challenge. Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor that promotes rod and cone photoreceptor survival and cone outer segment regeneration in the degenerating retina. Ciliary neurotrophic factor expression is regulated by many factors such as all-trans retinoic acid (ATRA). In this study, we found that ATRA increased CNTF expression in mouse retinal pigment epithelial (RPE) cells in a dose- and time-dependent manner, and PKA signaling pathway is necessary for ATRA-induced CNTF upregulation. Furthermore, we showed that ATRA promoted CNTF expression through CREB binding to its promoter region. In addition, CNTF levels were decreased in serum of retinopathy of prematurity children and in retinal tissue of oxygen-induced retinopathy mice. In mouse RPE cells cultured with high oxygen, CNTF expression and secretion were decreased, but could be recovered after treatment with ATRA. In conclusion, our data suggest that ATRA administration upregulates CNTF expression in RPE cells. Copyright © 2017 John Wiley & Sons, Ltd.

  20. Temperature-controlled continuous production of all-trans retinoic acid-loaded solid lipid nanoparticles using static mixers

    Science.gov (United States)

    Shao, Wenyao; Yan, Mengwen; Chen, Tingting; Chen, Yuqing; Xiao, Zongyuan

    2017-04-01

    This work aims to develop a temperature-controlled continuous solvent emulsification-diffusion process to synthesize all-trans retinoic acid (ATRA)-loaded solid lipid nanoparticles (SLNs) using static mixers. ATRA-loaded SLNs of around 200 nm were obtained when the flow rates of the organic and aqueous phases were 50 ml min-1 and 500 ml min-1, respectively. It was found that the lipid concentration played a dominant role in the size of the obtained SLNs, and higher drug concentration resulted in relatively low entrapment efficiency. The encapsulation of ATRA in the SLNs was effective in improving its stability according to the photo-degradation test. The in vitro release of SLN was slow without an initial burst. This study demonstrates that the solvent emulsification-diffusion technique with static mixing is an effective method of producing SLNs, and could easily be scaled up for industrial applications. Highlights Higher lipid concentration leads to larger SLNs. SLN transformation occurs due to Ostwald ripening. The ATRA-loaded SLNs around 200 nm were successfully produced with static mixers. ATRA-loaded SLNs show better stability towards sunlight. ATRA in SLNs exhibited a relatively slow release rate without a significant initial burst.

  1. New Strategies in Acute Promyelocytic Leukemia: Moving to an Entirely Oral, Chemotherapy-Free Upfront Management Approach

    Science.gov (United States)

    Zeidan, Amer M.; Gore, Steven D.

    2016-01-01

    Incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into the management paradigms of acute promyelocytic leukemia (APL) has markedly improved outcomes. Significant progress occurred in understanding the molecular pathogenesis of APL. ATO, in contrast with ATRA, is capable of eradicating the APL-initiating cells and can result in cure. Preclinical and clinical data confirmed the synergy of ATO and ATRA, and the ATRA–ATO combination was proved noninferior to a standard ATRA–chemotherapy regimen in patients with non–high-risk APL. Oral formulations of arsenic exhibited excellent activity in advanced clinical testing and their combinations with ATRA offer an opportunity for a completely oral, chemotherapy-free regimen for curing APL. Nonetheless, significant challenges remain. Reducing early death due to bleeding complications is an important area of unmet need. Data suggest that delays in initiation of ATRA upon suspecting APL continue to occur in the community and contribute to early mortality. Questions remain about the optimal place and schedule of arsenic in the therapeutic sequence and the role of the oral formulations. Refining the role of minimal residual disease in directing treatment decisions is important. Development of novel targeted agents to treat relapsed disease requires deeper understanding of the secondary resistance mechanisms to ATRA and ATO. PMID:25274377

  2. [Adams-Stokes attack due to complete atrioventricular block in a patient with acute promyelocytic leukemia during remission induction therapy using all-trans retinoic acid].

    Science.gov (United States)

    Yamauchi, Takahiro; Arai, Hajime; Taga, Masahiro; Amaya, Naoki; Lee, Jong-Dae; Ueda, Takanori

    2005-03-01

    We describe a case of Adams-Stokes syncope due to complete atrioventricular block which occurred in a leukemic patient receiving all-trans retinoic acid (ATRA). Remission induction therapy was performed for a 46-year-old Japanese man with acute promyelocytic leukemia using ATRA (45 mg/m2), enocitabine (170 mg/m2, 5 days), and mitoxantrone (4 mg/m2, 3 days). On the 25th day of chemotherapy, syncope suddenly occurred. Electrocardiography revealed a complete atrioventricular block, and a temporary pacemaker was inserted on the following day. The block was persistent and the cardiac rhythm was dependent on the pacemaker. ATRA was discontinued on the 29th day because the arrhythmia was believed to be an adverse reaction to the ATRA regimen. The normal sinus rhythm was restored 15 days thereafter, and the patient eventually reached remission. He subsequently received 4 courses of consolidation therapy without any cardiovascular complications. Although ATRA sometimes induces arrhythmias, to the best of our knowledge this is the first report in the literature of such a critical ATRA-related arrhythmia.

  3. The HER2 inhibitor TAK165 Sensitizes Human Acute Myeloid Leukemia Cells to Retinoic Acid-Induced Myeloid Differentiation by activating MEK/ERK mediated RARα/STAT1 axis

    Science.gov (United States)

    Shao, Xuejing; Liu, Yujia; Li, Yangling; Xian, Miao; Zhou, Qian; Yang, Bo; Ying, Meidan; He, Qiaojun

    2016-01-01

    The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply this therapy to other types of acute myeloid leukemia (AML). However, AML, with the exception of APL, fails to respond to differentiation therapy. Therefore, research strategies to further sensitize cells to retinoids and to extend the range of AMLs that respond to retinoids beyond APLs are urgently needed. In this study, we showed that TAK165, a HER2 inhibitor, exhibited a strong synergy with ATRA to promote AML cell differentiation. We observed that TAK165 sensitized the AML cells to ATRA-induced cell growth inhibition, G0/G1 phase arrest, CD11b expression, mature morphologic changes, NBT reduction and myeloid regulator expression. Unexpectedly, HER2 pathway might not be essential for TAK165-enhanced differentiation when combined with ATRA, while the enhanced differentiation was dependent on the activation of the RARα/STAT1 axis. Furthermore, the MEK/ERK cascade regulated the activation of STAT1. Taken together, our study is the first to evaluate the synergy of TAK165 and ATRA in AML cell differentiation and to assess new opportunities for the combination of TAK165 and ATRA as a promising approach for future differentiation therapy. PMID:27074819

  4. Retinoic acid receptor antagonist inhibits CD38 antigen expression on human hematopoietic cells in vitro.

    Science.gov (United States)

    Prus, Eugenia; Chandraratna, Roshantha A S; Fibach, Eitan

    2004-05-01

    The CD34+ CD38- subset of human hematopoietic stem cells are crucial for long-term ex-vivo expansion; conditions that decreased this specific sub-population reduced the self-renewal capacity and shortened the duration of the proliferative phase of the culture. Retinoids, such as all-trans retinoic acid (ATRA), have been shown to induce CD38 expression. ATRA present in serum may be responsible for the high CD38 of cells grown in serum-containing medium. In the present study we analyzed the effects of AGN 194310, a retinoic acid receptor pan-antagonist, on CD38 expression of human hematopoietic cells. Normal cells (cord blood derived CD34+ cells) and abnormal cells (myeloid leukemic lines) were studied when grown in either serum-containing or serum-free media. The results showed that both serum and ATRA enhanced differentiation and, thereby, reduced the proportion of CD34+ CD38- cells and total CD34+ cell expansion. AGN reversed these effects of serum and ATRA: it delayed differentiation and increased CD34+ CD38- cells. These results suggest that physiological ATRA levels in serum may prevent efficient cell expansion. AGN, by neutralizing ATRA, improves cell expansion in serum-containing cultures, thus making AGN a useful agent for ex vivo expansion of stem cells and other specific sub-populations for research and clinical use.

  5. All-trans-Retinoic Acid Ameliorated High Fat Diet-Induced Atherosclerosis in Rabbits by Inhibiting Platelet Activation and Inflammation

    Directory of Open Access Journals (Sweden)

    Birong Zhou

    2012-01-01

    Full Text Available Background. All-trans-retinoic acid (atRA is effective for many proliferative diseases. We investigated the protective effects of atRA against atherosclerosis. Methods. Rabbits were randomly allocated to receive basal diet or an HFD for 4 weeks. HFD group then received rosuvastatin (3 mg/day, atRA (5 mg/kg/day, or the same volume of vehicle, respectively, for next 8 weeks. Results. HFD group showed increases in plasma lipids and aortic plaque formation. P-selectin expression and fibrinogen binding on platelets or deposition on the intima of the aorta also increased significantly as did the levels of TNF-α, IL-6, and fibrinogen in plasma. After 8 weeks of treatment with atRA, there was a significant decrease in plasma lipids and improvement in aortic lesions. AtRA also inhibited the expression of P-selectin and fibrinogen binding on platelets and deposition on the intima of the aorta. Conclusion. AtRA can ameliorate HFD-induced AS in rabbits by inhibiting platelet activation and inflammation.

  6. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes.

    Science.gov (United States)

    Arts, Rob J W; Blok, Bastiaan A; van Crevel, Reinout; Joosten, Leo A B; Aaby, Peter; Benn, Christine Stabell; Netea, Mihai G

    2015-07-01

    Epidemiologic studies suggest that VAS has long-lasting immunomodulatory effects. We hypothesized that ATRA inhibits inflammatory cytokines in a model of trained immunity in monocytes by inducing epigenetic reprogramming through histone modifications. We used an previously described in vitro model of trained immunity, in which adherent monocytes of healthy volunteers were incubated for 24 h with BCG in the presence or absence of ATRA. After washing the cells, they were incubated for an additional 6 d in culture medium and restimulated with microbial ligands, and cytokine production was assessed. ATRA inhibited cytokine responses upon restimulation of monocytes, and this effect was exerted through increased expression of SUV39H2, a histone methyltransferase that induces the inhibitory mark H3K9me3. H3K9me3 at promoter sites of several cytokines was up-regulated by ATRA, and inhibition of SUV39H2 restored cytokine production. In addition to H3K9me3, the stimulatory histone mark H3K4me3 was down-regulated by ATRA at several promoter locations of cytokine genes. Therefore, we can conclude that ATRA inhibits cytokine production in models of direct stimulation or BCG-induced trained immunity and that these effects are mediated by histone modifications. © Society for Leukocyte Biology.

  7. Differential Effects of Retinoids and Inhibitors of ERK and p38 Signaling on Adipogenic and Myogenic Differentiation of P19 Stem Cells

    Science.gov (United States)

    Bouchard, Frédéric

    2013-01-01

    All-trans-retinoic acid (atRA) is an essential signaling molecule in embryonic development. It regulates cell differentiation by activating nuclear retinoic acid receptors (RAR) and retinoid-X receptors (RXR), which both control gene expression. In addition, atRA could act in the cytoplasm by modulating the activity of mitogen-activated protein kinases (MAPK) ERK and p38, which also have a role in cell differentiation. AtRA can induce the differentiation of P19 embryonic carcinoma stem cells into adipocytes, cardiomyocytes, and skeletal muscle cells, concurrently, in the same culture. We postulated that combinations of atRA, atRA analogs exhibiting selectivity for RAR or RXR, and inhibitors of ERK and p38 signaling (ERKi and p38i) could be used to favor one mesodermal fate over the others in the P19 model. In a first series of experiments, we replaced atRA by an agonist of RXR (LG100268) or RAR (TTNPB) to preferentially stimulate one group of receptors over the other. LG100268 was as adipogenic and myogenic as atRA, whereas TTNPB strongly induced adipogenesis, but not myogenesis. ERKi enhanced the myogenic action of atRA, and p38i increased both adipogenesis and myogenesis. In a second series of experiments, we combined atRA with an RAR or RXR antagonist (RARatg or RXRatg) to preferentially deactivate each receptor group in turn. The combinations atRA+RXRatg and atRA+RARatg, including or not ERKi, had similar mesodermal actions as atRA. In contrast, there was no myogenesis with atRA+RXRatg+p38i treatment, and there were no myogenesis and no adipogenesis with the atRA+RARatg+p38i combination. Overall, the results indicate that p38 has a role in mesodermal differentiation that depends on the retinoid context. Indeed, p38 in conjunction with RXR is important in myogenesis, and p38 and RAR in adipogenesis. Under the conditions tested, it was possible to stimulate adipogenesis with a block on myogenesis, whereas increased myogenesis was accompanied by adipogenesis. PMID

  8. A PU.1 suppressive target gene, metallothionein 1G, inhibits retinoic acid-induced NB4 cell differentiation.

    Directory of Open Access Journals (Sweden)

    Naomi Hirako

    Full Text Available We recently revealed that myeloid master regulator SPI1/PU.1 directly represses metallothionein (MT 1G through its epigenetic activity of PU.1, but the functions of MT1G in myeloid differentiation remain unknown. To clarify this, we established MT1G-overexpressing acute promyelocytic leukemia NB4 (NB4MTOE cells, and investigated whether MT1G functionally contributes to all-trans retinoic acid (ATRA-induced NB4 cell differentiation. Real-time PCR analyses demonstrated that the inductions of CD11b and CD11c and reductions in myeloperoxidase and c-myc by ATRA were significantly attenuated in NB4MTOE cells. Morphological examination revealed that the percentages of differentiated cells induced by ATRA were reduced in NB4MTOE cells. Since G1 arrest is a hallmark of ATRA-induced NB4 cell differentiation, we observed a decrease in G1 accumulation, as well as decreases in p21WAF1/CIP1 and cyclin D1 inductions, by ATRA in NB4MTOE cells. Nitroblue tetrazolium (NBT reduction assays revealed that the proportions of NBT-positive cells were decreased in NB4MTOE cells in the presence of ATRA. Microarray analyses showed that the changes in expression of several myeloid differentiation-related genes (GATA2, azurocidin 1, pyrroline-5-carboxylate reductase 1, matrix metallopeptidase -8, S100 calcium-binding protein A12, neutrophil cytosolic factor 2 and oncostatin M induced by ATRA were disturbed in NB4MTOE cells. Collectively, overexpression of MT1G inhibits the proper differentiation of myeloid cells.

  9. Epigenetic priming of AML blasts for all-trans retinoic acid-induced differentiation by the HDAC class-I selective inhibitor entinostat.

    Directory of Open Access Journals (Sweden)

    Nadja Blagitko-Dorfs

    Full Text Available All-trans retinoic acid (ATRA has only limited single agent activity in AML without the PML-RARα fusion (non-M3 AML. In search of a sensitizing strategy to overcome this relative ATRA resistance, we investigated the potency of the HDAC class-I selective inhibitor entinostat in AML cell lines Kasumi-1 and HL-60 and primary AML blasts. Entinostat alone induced robust differentiation of both cell lines, which was enhanced by the combination with ATRA. This "priming" effect on ATRA-induced differentiation was at least equivalent to that achieved with the DNA hypomethylating agent decitabine, and could overall be recapitulated in primary AML blasts treated ex vivo. Moreover, entinostat treatment established the activating chromatin marks acH3, acH3K9, acH4 and H3K4me3 at the promoter of the RARβ2 gene, an essential mediator of retinoic acid (RA signaling in different solid tumor models. Similarly, RARβ2 promoter hypermethylation (which in primary blasts from 90 AML/MDS patients was surprisingly infrequent could be partially reversed by decitabine in the two cell lines. Re-induction of the epigenetically silenced RARβ2 gene was achieved only when entinostat or decitabine were given prior to ATRA treatment. Thus in this model, reactivation of RARβ2 was not necessarily required for the differentiation effect, and pharmacological RARβ2 promoter demethylation may be a bystander phenomenon rather than an essential prerequisite for the cellular effects of decitabine when combined with ATRA. In conclusion, as a "priming" agent for non-M3 AML blasts to the differentiation-inducing effects of ATRA, entinostat is at least as active as decitabine, and both act in part independently from RARβ2. Further investigation of this treatment combination in non-M3 AML patients is therefore warranted, independently of RARβ2 gene silencing by DNA methylation.

  10. Fungistatic activity of all-trans retinoic acid against Aspergillus fumigatus and Candida albicans

    Directory of Open Access Journals (Sweden)

    Campione E

    2016-04-01

    Full Text Available Elena Campione,1 Roberta Gaziano,2 Daniele Marino,2 Augusto Orlandi3 1Department of Dermatology, 2Department of Microbiology, 3Department of Anatomic Pathology, University of Rome Tor Vergata, Rome, Italy Purpose: Fungal infections are a major complication in hematologic and neoplastic patients causing severe morbidity and mortality. Aspergillus fumigatus and Candida albicans are among the most invasive opportunistic pathogens in immunocompromised patients, and classic antifungal drugs are frequently unsuccessful in these patients. Recent reports hypothesize that the antifungal efficacy of all-trans retinoic acid (ATRA is mainly related to its strong capacity to stimulate monocyte-mediated immunity, but no consideration was given to its potential direct fungistatic activity. Moreover, ATRA offers the opportunity for systemic therapy. Methods and results: We investigated the efficacy of ATRA at different concentrations for its antifungal activity against opportunistic A. fumigatus and C. albicans obtained from clinical samples according to standard protocols. A fungistatic activity of ATRA on A. fumigatus and C. albicans at 0.5–1 mM concentration was documented up to 7 days. Conclusion: This is the first evidence of a direct and strong fungistatic activity of ATRA against A. fumigatus and C. albicans. The potential adjuvant therapeutic application of ATRA might be useful in the treatment and/or prevention of systemic mycoses in immunocompromised patients. The discovery of a direct fungistatic activity, in association with its reported immunomodulatory properties, makes ATRA an excellent candidate for new combined antifungal strategies for systemic mycoses in immunocompromised and cancer patients. Keywords: all-trans retinoic acid, fungistatic activity, fungal infections

  11. The effect of 1, 25(OH)2 D3 (calcitriol) alone and in combination with all-trans retinoic acid on ROR-γt, IL-17, TGF-β, and FOXP3 gene expression in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Parastouei, Karim; Mirshafiey, Abbas; Eshraghian, Mohammad Reza; Shiri-Shahsavar, Mohammad Reza; Solaymani-Mohammadi, Farid; Chahardoli, Reza; Alvandi, Ehsan; Saboor-Yaraghi, Ali Akbar

    2016-12-20

    It has been shown that calcitriol and all-trans retinoic acid (ATRA) have modulatory effects on the immune system. The present study investigates the synergistic effects of combination treatment of calcitriol and ATRA in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The mice were allocated to four preventive groups, each consisting of eight animals, ATRA (250 μg/mouse), calcitriol (100 ng/mouse), combination of ATRA and calcitriol (125  μg/mouse and 50 ng/mouse) and vehicle groups. EAE was induced by MOG35-55 peptide in female C57BL/6 mice. Treatments were initiated at day 1 before immunization and continued every other day throughout the study until the day 21 post-immunization. Splenocytes were isolated from EAE-induced mice and the expression of retinoic acid receptor-related orphan receptor gamma t (ROR-γt), Interleukin-17 (IL-17), transforming growth factor beta (TGF-β), and forkhead box P3 (FOXP3) genes was measured using real-time polymerase chain reaction. The expression of FOXP3 and TGF-β genes in the splenocytes of combination-treated and calcitriol alone-treated mice was significantly increased compared to vehicle group (P ROR-γt and IL-17 genes in the splenocytes of ATRA, calcitriol and combination- treated mice was significantly reduced compared to those of vehicle- treated mice (P ROR-γt was significantly (P < 0.05) lower in the combination group than in the mice treated by ATRA or calcitriol alone. This study demonstrated that treatment with combination of calcitriol and ATRA can be considered as a new strategy for MS prevention and treatment.

  12. All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling.

    Science.gov (United States)

    Leem, Ah Young; Shin, Mi Hwa; Douglas, Ivor S; Song, Joo Han; Chung, Kyung Soo; Kim, Eun Young; Jung, Ji Ye; Kang, Young Ae; Chang, Joon; Kim, Young Sam; Park, Moo Suk

    2017-09-23

    The role of all-trans retinoic acid (ATRA) in pulmonary fibrosis is relatively unknown, although this metabolite modulates cell differentiation, proliferation, and development. We aimed to evaluate the role of ATRA in bleomycin-induced pulmonary fibrosis, and whether the mechanism involves EphA2-EphrinA1 and PI3K-Akt signaling. We evaluated three groups of mice: a control group (intraperitoneal DMSO injection 3 times weekly after PBS instillation), bleomycin group (intraperitoneal DMSO injection 3 times weekly after bleomycin instillation), and bleomycin + ATRA group (intraperitoneal ATRA injection 3 times weekly after bleomycin instillation). The cell counts and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology, Ashcroft score, hydroxyproline assay, expression of several signal pathway proteins including EphA2-EphrinA1, and PI3K-Akt, and cytokine levels were compared among the groups. We found that bleomycin significantly increased the protein concentration in the BALF, Ashcroft score in lung tissue, and hydroxyproline contents in lung lysates. Furthermore, bleomycin upregulated EphA2, EphrinA1, PI3K 110γ, Akt, IL-6 and TNF-α. However, administration of ATRA attenuated the upregulation of EphA2-EphrinA1 and PI3K-Akt after bleomycin instillation, and decreased pulmonary fibrosis. In addition, ATRA suppressed IL-6 and TNF-α production induced by bleomycin-induced injury. Collectively, these data suggest that ATRA attenuates bleomycin-induced pulmonary fibrosis by regulating EphA2-EphrinA1 and PI3K-Akt signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. 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

  14. Combination chemotherapy of doxorubicin, all-trans retinoic acid and low molecular weight heparin based on self-assembled multi-functional polymeric nanoparticles

    Science.gov (United States)

    Zhang, Ting; Xiong, Hui; Zohra Dahmani, Fatima; Sun, Li; Li, Yuanke; Yao, Li; Zhou, Jianping; Yao, Jing

    2015-04-01

    Based on the complementary effects of doxorubicin (DOX), all-trans retinoic acid (ATRA) and low molecular weight heparin (LMWH), the combination therapy of DOX, ATRA and LMWH was expected to exert the enhanced anti-tumor effects and reduce the side effects. In this study, amphiphilic LMWH-ATRA conjugate was synthesized for encapsulating the DOX. In this way, DOX, ATRA and LMWH were assembled into a single nano-system by both chemical and physical modes to obtain a novel anti-tumor targeting drug delivery system that can realize the simultaneous delivery of multiple drugs with different properties to the tumor. LMWH-ATRA nanoparticles exhibited good loading capacities for DOX with excellent physico-chemical properties, good biocompatibility, and good differentiation-inducing activity and antiangiogenic activity. The drug-loading capacity was up to 18.7% with an entrapment efficiency of 78.8%. It was also found that DOX-loaded LMWH-ATRA nanoparticles (DHR nanoparticles) could be efficiently taken up by tumor cells via endocytic pathway, and mainly distributed in cytoplasm at first, then transferred into cell nucleus. Cell viability assays suggested that DHR nanoparticles maintained the cytotoxicity effect of DOX on MCF-7 cells. Moreover, the in vivo imaging analysis indicated that DiR-loaded LMWH-ATRA nanoparticles could target the tumor more effectively as compared to free DiR. Furthermore, DHR nanoparticles possessed much higher anticancer activity and reduced side effects compared to free drugs solution. These results suggested that DHR nanoparticles could be considered as a promising targeted delivery system for combination cancer chemotherapy with lower adverse effects.

  15. Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is associated with the level of H3K4me2 in the RARα promoter region

    Science.gov (United States)

    Sakamoto, K; Imamura, T; Yano, M; Yoshida, H; Fujiki, A; Hirashima, Y; Hosoi, H

    2014-01-01

    All-trans retinoic acid (ATRA) is well established as differentiation therapy for acute promyelocytic leukemia (APL) in which the PML–RARα (promyelocytic leukemia-retinoic acid receptor α) fusion protein causes blockade of the retinoic acid (RA) pathway; however, in types of acute myeloid leukemia (AML) other than APL, the mechanism of RA pathway inactivation is not fully understood. This study revealed the potential mechanism of high ATRA sensitivity of mixed-lineage leukemia (MLL)-AF9-positive AML compared with MLL-AF4/5q31-positive AML. Treatment with ATRA induced significant myeloid differentiation accompanied by upregulation of RARα, C/EBPα, C/EBPɛ and PU.1 in MLL-AF9-positive but not in MLL-AF4/5q31-positive cells. Combining ATRA with cytarabine had a synergistic antileukemic effect in MLL-AF9-positive cells in vitro. The level of dimethyl histone H3 lysine 4 (H3K4me2) in the RARα gene-promoter region, PU.1 upstream regulatory region (URE) and RUNX1+24/+25 intronic enhancer was higher in MLL-AF9-positive cells than in MLL-AF4-positive cells, and inhibiting lysine-specific demethylase 1, which acts as a histone demethylase inhibitor, reactivated ATRA sensitivity in MLL-AF4-positive cells. These findings suggest that the level of H3K4me2 in the RARα gene-promoter region, PU.1 URE and RUNX1 intronic enhancer is determined by the MLL-fusion partner. Our findings provide insight into the mechanisms of ATRA sensitivity in AML and novel treatment strategies for ATRA-resistant AML. PMID:24769646

  16. HA117 endows HL60 cells with a stem-like signature by inhibiting the degradation of DNMT1 via its ability to down-regulate expression of the GGL domain of RGS6.

    Directory of Open Access Journals (Sweden)

    Shuangshuang Li

    Full Text Available All-trans retinoic acid (ATRA induces complete remission in almost all patients with acute promyelocytic leukemia (APL via its ability to induce the in vivo differentiation of APL blasts. However, prolonged ATRA treatment can result in drug resistance. In previous studies, we generated a multi-drug-resistant HL60/ATRA cell line and found it to contain a new drug resistance-related gene segment, HA117. In this study, we demonstrate that ATRA induces multi-drug-resistant subpopulations of HL60 cells with a putative stem-like signature by up-regulating the expression of the new gene segment HA117. Western blot analysis and quantitative real-time PCR demonstrated that HA117 causes alternative splicing of regulator of G-protein signaling 6 (RGS6 and down-regulation of the expression of the GGL domain of RGS6, which plays an important role in DNA methyltransferase 1 (DNMT1 degradation. Moreover, DNMT1 expression was increased in multi-drug resistance HL60/ATRA cells. Knockdown of HA117 restored expression of the GGL domain and blocked DNMT1 expression. Moreover, resistant cells displayed a putative stem-like signature with increased expression of cancer steam cell markers CD133 and CD123. The stem cell marker, Nanog, was significantly up-regulated. In conclusion, our study shows that HA117 potentially promotes the stem-like signature of the HL60/ATRA cell line by inhibiting by the ubiquitination and degradation of DNMT1 and by down-regulating the expression of the GGL domain of RGS6. These results throw light on the cellular events associated with the ATRA-induced multi-drug resistance phenotype in acute leukemia.

  17. Identification and characterization of an antennae-specific aldehyde oxidase from the navel orangeworm.

    Directory of Open Access Journals (Sweden)

    Young-Moo Choo

    Full Text Available Antennae-specific odorant-degrading enzymes (ODEs are postulated to inactivate odorant molecules after they convey their signal. Different classes of insect ODEs are specific to esters, alcohols, and aldehydes--the major functional groups of female-produced, hydrophobic sex pheromones from moth species. Esterases that rapidly inactive acetate and other esters have been well-studied, but less is known about aldehyde oxidases (AOXs. Here we report cloning of an aldehyde oxidase, AtraAOX2, from the antennae of the navel orangeworm (NOW, Amyelois transitella, and the first activity characterization of a recombinant insect AOX. AtraAOX2 gene spans 3,813 bp and encodes a protein with 1,270 amino acid residues. AtraAOX2 cDNA was expressed in baculovirus-infected insect Sf21 cells as a ≈280 kDa homodimer with 140 kDa subunits. Recombinant AtraAOX2 degraded Z11Z13-16Ald and plant volatile aldehydes as substrates. However, as expected for aldehyde oxidases, recombinant AtraAOX2 did not show specificity for Z11Z13-16Ald, the main constituent of the sex pheromone, but showed high activity for plant volatile aldehydes. Our data suggest AtraAOX2 might be involved in degradation of a diversity of aldehydes including sex pheromones, plant-derived semiochemicals, and chemical cues for oviposition sites. Additionally, AtraAOX2 could protect the insect's olfactory system from xenobiotics, including pesticides that might reach the sensillar lymph surrounding the olfactory receptor neurons.

  18. Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cheong, Su-Jin; Jang, DooRye; Jeong, Hwan-Jeong; Lim, Seok Tae; Sohn, Myung-Hee [Department of Nuclear Medicine, Cyclotron Research Center, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756 (Korea, Republic of); Katzenellenbogen, John A., E-mail: jkatzene@illinois.ed [Department of Chemistry, University of Illinois, Urbana, IL 61801 (United States); Kim, Dong Wook, E-mail: kimdw@chonbuk.ac.k [Department of Nuclear Medicine, Cyclotron Research Center, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756 (Korea, Republic of)

    2011-02-15

    Purpose: The sodium iodide symporter (NIS) mediates active iodide uptake in lactating breast tissue, and when its levels are enhanced by all-trans retinoic acid (atRA), NIS has been proposed as a target for the imaging and radiotherapy of breast cancer. Importantly, the estrogen receptor {alpha} (ER{alpha}) is an important regulator of atRA induced NIS gene expression in breast cancer cells. In this study, we investigated the effect of an ER agonist (17{beta}-estradiol, E{sub 2}) or antagonist [trans-hydroxytamoxifen (TOT) or raloxifene (RAL)] treatment on the regulation of NIS gene expression and iodide uptake in an ER{alpha}-positive breast cancer (MCF-7) model. Methods: NIS functional activity was measured in vitro by {sup 125}I uptake assay after incubation with E{sub 2} (from 10{sup -15} to 10{sup -5} M), TOT (from 5x10{sup -8} to 5x10{sup -6} M), or RAL (from 5x10{sup -8} to 5x10{sup -6} M) in the presence or absence of atRA (10{sup -7} M). Under the same conditions, NIS mRNA expression was examined by reverse transcriptase polymerase chain reaction. Athymic mice with MCF-7 xenograft tumors were treated with atRA alone or atRA together with E{sub 2} to evaluate the change of {sup 125}I uptake in tumor tissues in vivo. Results: In the iodide uptake study in cells, E{sub 2}, TOT, or RAL treatment alone did not stimulate {sup 125}I uptake. However, when iodide uptake was stimulated by atRA, cotreatment with E{sub 2}, TOT or RAL decreased {sup 125}I uptake in a concentration-dependent manner. The hormone effects on NIS mRNA expression levels in MCF-7 cells were similar. The results of the in vivo biodistribution study showed that {sup 125}I uptake was reduced 50% in tumor tissues of mice treated with atRA/E{sub 2} as compared to tumors treated only with atRA. Conclusion: Our results suggest that combination treatment of atRA and ER ligands could limit the functional activity of the NIS gene induced by atRA, thereby compromising its use as a target for diagnosis

  19. Acute Promyelocytic Leukemia (APL): Comparison Between Children and Adults

    Science.gov (United States)

    Testi, Anna Maria; D’Angiò, Mariella; Locatelli, Franco; Pession, Andrea; Lo Coco, Francesco

    2014-01-01

    The outcome of adults and children with Acute Promyelocytic Leukemia (APL) has dramatically changed since the introduction of all trans retinoic acid (ATRA) therapy. Based on the results of several multicenter trials, the current recommendations for the treatment of patients with APL include ATRA and anthracycline-based chemotherapy for the remission induction and consolidation, and ATRA combined with low-dose chemotherapy for maintenance. This has improved the prognosis of APL by increasing the complete remission (CR) rate, actually > 90%, decreasing the induction deaths and by reducing the relapse rate, leading to cure rates nowadays exceeding 80% considering both adults and children.1–9 More recently the combination of ATRA and arsenic trioxide (ATO) as induction and consolidation therapy has been shown to be at least not inferior and possibly superior to ATRA plus chemotherapy in adult patients with APL conventionally defined as non-high risk (Sanz score).10 Childhood APL has customarily been treated on adult protocols. Data from several trials have shown that the overall outcome in pediatric APL appears similar to that reported for the adult population; however, some clinical and therapeutic aspects differ in the two cohorts which require some important considerations and treatment adjustments. PMID:24804005

  20. All-trans retinoic acid induces chromatin remodeling at the promoter of the mouse liver, bone, and kidney alkaline phosphatase gene in C3H10T 1/2 cells.

    Science.gov (United States)

    Wan, Yang; Yang, Songhai; Sun, Fenyong; Wang, Jiayi; Chen, Qiongyu; Hong, An

    2012-08-01

    The alkaline phosphatase (ALP) gene is an important marker of osteoblast differentiation and bone formation. Although the molecular mechanisms of increased ALP expression in response to all-trans retinoic acid (ATRA) have been reported, the role of ATRA in chromatin structure changes remains unknown. Our results show that the expression of mouse liver, bone, and kidney ALP (mL/B/K-ALP) induced by ATRA in C3H10T 1/2 cells was related to the retinoic acid nuclear receptors, RARα and RARβ, which are not involved in the MAPK pathway. DNase I hypersensitivity analysis revealed an inducible hypersensitive site in the mL/B/K-ALP promoter at ~520 bp upstream of the transcription start site. Chromatin immunoprecipitation experiments showed a cascade of transcription cofactor recruitment events during ATRA-induced upregulation of mL/B/K-ALP. Together, our results provide a link between ATRA-induced mL/B/K-ALP gene transcription and chromatin remodeling.

  1. Terpene composited lipid nanoparticles for enhanced dermal delivery of all-trans-retinoic acids.

    Science.gov (United States)

    Charoenputtakun, Ponwanit; Pamornpathomkul, Boonnada; Opanasopit, Praneet; Rojanarata, Theerasak; Ngawhirunpat, Tanasait

    2014-01-01

    In the present study, terpene composited lipid nanoparticles and lipid nanoparticles were developed and evaluated for dermal delivery of all-trans-retinoic acids (ATRA). Terpene composited lipid nanoparticles and lipid nanoparticles were investigated for size, size distribution, zeta potential, entrapment efficiency, photostability, and cytotoxicity. In vitro skin permeation of ATRA lipid formulations were also evaluated. To explore the ability of lipid nanocarriers to target the skin, the distribution of rhodamine B base in the skin was investigated using confocal laser scanning microscopy (CLSM). The results indicated that the physicochemical characteristics of terpene composited lipid nanoparticles influenced skin permeability. All lipid nanocarriers significantly protected ATRA from photodegradation and were non-toxic to normal human foreskin fibroblast cells in vitro. Solid lipid nanoparticles containing 10% limonene (10% L-SLN) had the highest ATRA skin permeability. Terpene composited SLN and nanostructured lipid carriers (NLC) showed higher epidermal permeation of rhodamine B across the skin based on CLSM image analysis. Our study suggests that terpene composited SLN and NLC can be potentially used as dermal drug delivery carriers for ATRA.

  2. 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.

  3. Vitamin A increases nerve growth factor and retinoic acid receptor beta and improves diabetic neuropathy in rats.

    Science.gov (United States)

    Hernández-Pedro, Norma; Granados-Soto, Vinicio; Ordoñez, Graciela; Pineda, Benjamin; Rangel-López, Edgar; Salazar-Ramiro, Aleli; Arrieta, Oscar; Sotelo, Julio

    2014-09-01

    All-trans retinoic acid (ATRA) promotes the endogenous expression of both nerve growth factor (NGF) and retinoic acid receptor beta (RAR-β). We have previously shown that the administration of ATRA partly reverts the damage induced by diabetic neuropathy (DN). In this investigation, we evaluated the effects of vitamin A, a commercial, inexpensive compound of retinoic acid, on the therapy of DN. A total of 70 rats were randomized into 4 groups. Group A was the control, and groups B, C, and D received a total dose of 60 mg/kg streptozotocin intraperitoneally. When signs of DN developed, groups C and D were treated either with vitamin A (20,000 IU) or with ATRA 25 mg/kg for 60 days. Plasma glucose, contents of NGF, thermal and nociceptive tests, and RAR-β expression were evaluated. All diabetic rats developed neuropathy. The treatment with vitamin A and ATRA reverted similarly the sensorial disturbances, which was associated with increased contents of NGF and RAR-β expression. Our results indicate that the administration of vitamin A has the same therapeutic effect as ATRA on peripheral neuropathy and suggest its potential therapeutic use in patients with diabetes. Copyright © 2014 Mosby, Inc. All rights reserved.

  4. Retinoic acid induces HL-60 cell differentiation via the upregulation of miR-663

    Directory of Open Access Journals (Sweden)

    Zhuan Zhou

    2011-04-01

    Full Text Available Abstract Background Differentiation of the acute myeloid leukemia (AML cell line HL-60 can be induced by all trans-retinoic acid (ATRA; however, the mechanism regulating this process has not been fully characterized. Methods Using bioinformatics and in vitro experiments, we identified the microRNA gene expression profile of HL-60 cells during ATRA induced granulocytic differentiation. Results Six microRNAs were upregulated by ATRA treatment, miR-663, miR-494, miR-145, miR-22, miR-363* and miR-223; and three microRNAs were downregulated, miR-10a, miR-181 and miR-612. Additionally, miR-663 expression was regulated by ATRA. We used a lentivirus (LV backbone incorporating the spleen focus forming virus (SFFV-F promoter to drive miR-663 expression, as the CMV (Cytomegalovirus promoter is ineffective in some lymphocyte cells. Transfection of LV-miR-663 induced significant HL-60 cell differentiation in vitro. Conclusions Our results show miR-663 may play an important role in ATRA induced HL-60 cell differentiation. Lentivirus delivery of miR-663 could potentially be used directly as an anticancer treatment in hematological malignancies

  5. All-trans retinoic acid enhances cytotoxic effect of T cells with an anti-CD38 chimeric antigen receptor in acute myeloid leukemia.

    Science.gov (United States)

    Yoshida, Tetsumi; Mihara, Keichiro; Takei, Yoshifumi; Yanagihara, Kazuyoshi; Kubo, Takanori; Bhattacharyya, Joyeeta; Imai, Chihaya; Mino, Tatsuji; Takihara, Yoshihiro; Ichinohe, Tatsuo

    2016-12-01

    We reported that T cells with anti-CD38-chimeric antigen receptors (CAR) eliminated B-cell lymphoma cells expressing CD38. To employ anti-CD38-CAR against acute myeloid leukemia (AML) blasts not expressing CD38, it is necessary to induce or increase the intensity of CD38 expression. A lactate dehydrogenase (LDH)-releasing assay and flow cytometry showed that anti-CD38-CAR T cells were cytotoxic against AML lines (THP-1 and CMK) expressing high CD38 levels (>99%), in time- and number of effector-dependent manners. In other AML lines (KG1, U937 and HL60) partially expressing CD38, CD38(+) AML cells were killed by CD38-specific T cells, but CD38(-) AML cells remained survived. Intriguingly, 10 nM all-trans retinoic acid (ATRA) augmented CD38 expression in KG1, U937 and HL60 cells and primary leukemic cells from AML patients. Moreover, the withdrawal of ATRA from the medium decreased CD38 expression in AML cells. Killing effects of anti-CD38-CAR T cells against AML lines and AML cells were limited without ATRA, whereas CD38-specific T cells enhanced cytotoxicity on AML cells by ATRA in association with enhanced CD38 expression. These results indicate that anti-CD38-CAR T cells eliminate AML cells through CD38 expression induced by ATRA.

  6. Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity

    Directory of Open Access Journals (Sweden)

    Paulo Czarnewski

    2017-01-01

    Full Text Available Vitamin A (VA is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. In particular, VA metabolite all-trans retinoic acid (atRA has been shown to be crucial in inducing gut tropism in lymphocytes and modulating T helper differentiation. In addition to the widely recognized role in adaptive immunity, increasing evidence identifies atRA as an important modulator of innate immune cells, such as tolerogenic dendritic cells (DCs and innate lymphoid cells (ILCs. Here, we focus on the role of retinoic acid in differentiation, trafficking and the functions of innate immune cells in health and inflammation associated disorders. Lastly, we discuss the potential involvement of atRA during the plausible crosstalk between DCs and ILCs.

  7. 2-(2-Methylfuran-3-carboxamido)-3-phenylpropanoic acid, a potential CYP26A1 inhibitor to enhance all-trans retinoic acid-induced leukemia cell differentiation based on virtual screening and biological evaluation.

    Science.gov (United States)

    Li, Fengrong; Zhao, Dongmei; Ren, Jinhong; Hao, Feiyue; Liu, Guyue; Jin, Shengfei; Jing, Yongkui; Cheng, Maosheng

    2013-06-01

    To develop new CYP26A1 inhibitors, a three-cycle virtual screening was carried out based on the constructed homology model of human CYP26A1 using Dock, Fred, Gold and AutoDock. Twenty-two compounds exhibited high scores and reasonable binding modes in molecular docking were purchased from Specs Company. Eighteen compounds were tested their abilities to enhance ATRA-induced differentiation in human acute promyelocytic leukemia NB4 cells. Eight of them enhanced the ability of ATRA to induce differentiation at concentrations of 0.5 and 1 μM. Among these compounds, 2-(2-methylfuran-3-carboxamido)-3-phenylpropanoic acid (S8) is of most effective in blocking ATRA breaking down in NB4 cells based on the LC-MS/MS assay. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. A Complicated Case of Acute Promyelocytic Leukemia in the Second Trimester of Pregnancy Successfully Treated with All-trans-Retinoic Acid

    Directory of Open Access Journals (Sweden)

    Kanika Agarwal

    2015-01-01

    Full Text Available A 40-year-old female at 26-week gestation was diagnosed with acute promyelocytic leukemia (APL after an abnormal prenatal lab workup showed pancytopenia. She was treated with all-trans-retinoic acid (ATRA, idarubicin, and dexamethasone. After day one of treatment, she developed differentiation syndrome, which was treated with dexamethasone. At 30-week gestation, she had preterm premature rupture of membranes and delivered by cesarean section because of the fetus’ breech presentation. Despite ATRA’s potential for teratogenicity, a viable infant was born without apparent anomalies. Postpartum, she underwent consolidation treatment with ATRA and arsenic trioxide (ATO. The patient continued ATRA therapy after delivery and is currently in remission.

  9. Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity.

    Science.gov (United States)

    Czarnewski, Paulo; Das, Srustidhar; Parigi, Sara M; Villablanca, Eduardo J

    2017-01-13

    Vitamin A (VA) is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. In particular, VA metabolite all-trans retinoic acid (atRA) has been shown to be crucial in inducing gut tropism in lymphocytes and modulating T helper differentiation. In addition to the widely recognized role in adaptive immunity, increasing evidence identifies atRA as an important modulator of innate immune cells, such as tolerogenic dendritic cells (DCs) and innate lymphoid cells (ILCs). Here, we focus on the role of retinoic acid in differentiation, trafficking and the functions of innate immune cells in health and inflammation associated disorders. Lastly, we discuss the potential involvement of atRA during the plausible crosstalk between DCs and ILCs.

  10. Potential role of nuclear receptor ligand all-trans retinoic acids in the treatment of fungal keratitis

    Directory of Open Access Journals (Sweden)

    Hong-Yan Zhou

    2015-08-01

    Full Text Available Fungal keratitis (FK is a worldwide visual impairment disease. This infectious fungus initiates the primary innate immune response and, later the adaptive immune response. The inflammatory process is related to a variety of immune cells, including macrophages, helper T cells, neutrophils, dendritic cells, and Treg cells, and is associated with proinflammatory, chemotactic and regulatory cytokines. All-trans retinoic acids (ATRA have diverse immunomodulatory actions in a number of inflammatory and autoimmune conditions. These retinoids regulate the transcriptional levels of target genes through the activation of nuclear receptors. Retinoic acid receptor α (RAR α, retinoic acid receptor γ (RAR γ, and retinoid X receptor α (RXR α are expressed in the cornea and immune cells. This paper summarizes new findings regarding ATRA in immune and inflammatory diseases and analyzes the perspective application of ATRA in FK.

  11. Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis.

    Directory of Open Access Journals (Sweden)

    Lizhi Wu

    Full Text Available UAB30 is an RXR selective agonist that has been shown to have potential cancer chemopreventive properties. Due to high efficacy and low toxicity, it is currently being evaluated in human Phase I clinical trials by the National Cancer Institute. While UAB30 shows promise as a low toxicity chemopreventive drug, the mechanism of its action is not well understood. In this study, we investigated the effects of UAB30 on gene expression in human organotypic skin raft cultures and mouse epidermis. The results of this study indicate that treatment with UAB30 results in upregulation of genes responsible for the uptake and metabolism of all-trans-retinol to all-trans-retinoic acid (ATRA, the natural agonist of RAR nuclear receptors. Consistent with the increased expression of these genes, the steady-state levels of ATRA are elevated in human skin rafts. In ultraviolet B (UVB irradiated mouse skin, the expression of ATRA target genes is found to be reduced. A reduced expression of ATRA sensitive genes is also observed in epidermis of mouse models of UVB-induced squamous cell carcinoma and basal cell carcinomas. However, treatment of mouse skin with UAB30 prior to UVB irradiation prevents the UVB-induced decrease in expression of some of the ATRA-responsive genes. Considering its positive effects on ATRA signaling in the epidermis and its low toxicity, UAB30 could be used as a chemoprophylactic agent in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations.

  12. Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study.

    Science.gov (United States)

    Assis, David N; Abdelghany, Osama; Cai, Shi-Ying; Gossard, Andrea A; Eaton, John E; Keach, Jill C; Deng, Yanhong; Setchell, Kenneth D R; Ciarleglio, Maria; Lindor, Keith D; Boyer, James L

    2017-02-01

    To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

  13. Retinoic Acid Improves Morphology of Cultured Peritoneal Mesothelial Cells from Patients Undergoing Dialysis

    Science.gov (United States)

    Retana, Carmen; Sanchez, Elsa I.; Gonzalez, Sirenia; Perez-Lopez, Alejandro; Cruz, Armando; Lagunas-Munoz, Jesus; Alfaro-Cruz, Carmen; Vital-Flores, Socorro; Reyes, José L.

    2013-01-01

    Patients undergoing continuous ambulatory peritoneal dialysis are classified according to their peritoneal permeability as low transporter (low solute permeability) or High transporter (high solute permeability). Factors that determine the differences in permeability between them have not been fully disclosed. We investigated morphological features of cultured human peritoneal mesothelial cells from low or high transporter patients and its response to All trans retinoic Acid (ATRA, vitamin A active metabolite), as compared to non-uremic human peritoneal mesothelial cells. Control cells were isolated from human omentum. High or low transporter cells were obtained from dialysis effluents. Cells were cultured in media containing ATRA (0, 50, 100 or 200 nM). We studied length and distribution of microvilli and cilia (scanning electron microscopy), epithelial (cytokeratin, claudin-1, ZO-1 and occludin) and mesenchymal (vimentin and α-smooth muscle actin) transition markers by immunofluorescence and Western blot, and transforming growth factor β1 expression by Western blot. Low and high transporter exhibited hypertrophic cells, reduction in claudin-1, occludin and ZO-1 expression, cytokeratin and vimentin disorganization and positive α-smooth muscle actin label. Vimentin, α-smooth muscle actin and transforming growth factor- β1 were overexpressed in low transporter. Ciliated cells were diminished in low and high transporters. Microvilli number and length were severely reduced in high transporter. ATRA reduced hypertrophic cells number in low transporter. It also improved cytokeratin and vimentin organization, decreased vimentin and α-smooth muscle actin expression, and increased claudin 1, occludin and ZO-1 expression, in low and high transporter. In low transporter, ATRA reduced transforming growth factor-β1 expression. ATRA augmented percentage of ciliated cells in low and high transporter. It also augmented cilia length in high transporter. Alterations in

  14. [Beneficial effects of retinoic acid on in vitro invasiveness of human thyroid carcinoma cell lines].

    Science.gov (United States)

    Lan, Ling; Cui, Dai; Luo, Yong; Shi, Bing-yin; Deng, Li-li; Zhang, Guo-ying; Deng, Wei; Wang, Hong

    2010-09-14

    To investigate the anti metastatic potential of retinoic acid as an important determinant of metastatic behavior in thyroid carcinoma and understand the role of invasion associated proteins. Differentiated thyroid carcinoma cell lines FTC-133 and XTC.UC1, anaplastic thyroid cancer cell lines C643 and HTH74 were studied. All cell lines were cultured with all-trans-RA (ATRA) or solvent ethanol. The in vitro invasion and adhesion potency were studied by transwell experiment and short-term adhesion assay. The functions of invasion associated proteins, urokinase type plasminogen activator (uPA), uPA receptor (uPAR), MMP2 and E-cadherin were investigated by semi-quantitative RT-PCR and Western blot. In vitro invasion assay revealed that ATRA treatment could reduce the invasive potency in all the thyroid cancer cell lines. On Day 5 of ATRA treatment, the numbers of cells that migrated through extracellular matrix were as follows, in contrast to control group, FTC-133: 91±9 vs 118±10, C643: 92±17 vs 164±21, HTH74: 87±18 vs 169±15, and XTC.UC1: 95±23 vs 136±15, respectively (all PXTC.UC1. RT-PCR and Western blot both revealed diminished expression of uPAR in all four carcinoma cell lines. In C643 and HTH74 cell lines, the expression of uPA was reduced and the expression of E-Cadherin was increased; whereas the MMP2 expression was not significantly down-regulated in ATRA treated group. In ATRA treated FTC-133 and XTC.UC1 cell lines, MMP2 expression was decreased, but no significant changes in uPA and E-Cadherin expression were observed. The present study demonstrates the influence of ATRA on two important determinants of metastatic behavior ("de adhesion" and proteolysis) in thyroid carcinoma cell lines.

  15. Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells

    Directory of Open Access Journals (Sweden)

    Niu Chao

    2010-08-01

    Full Text Available Abstract Objective To investigate the effect of all-trans retinoic acid(ATRA on the proliferation and differentiation of brain tumor stem cells(BTSCs in vitro. Methods Limiting dilution and clonogenic assay were used to isolate and screen BTSCs from the fresh specimen of human brain glioblastoma. The obtained BTSCs, which were cultured in serum-free medium, were classified into four groups in accordance with the composition of the different treatments. The proliferation of the BTSCs was evaluated by MTT assay. The BTSCs were induced to differentiate in serum-containing medium, and classified into the ATRA group and control group. On the 10th day of induction, the expressions of CD133 and glial fibrillary acidic protein (GFAP in the differentiated BTSCs were detected by immunofluorescence. The differentiated BTSCs were cultured in serum-free medium, the percentage and the time required for formation of brain tumor spheres (BTS were observed. Results BTSCs obtained by limiting dilution were all identified as CD133-positive by immunofluorescence. In serum-free medium, the proliferation of BTSCs in the ATRA group was observed significantly faster than that in the control group, but slower than that in the growth factor group and ATRA/growth factor group, and the size of the BTS in the ATRA group was smaller than that in the latter two groups(P P P P Conclusion ATRA can promote the proliferation and induce the differentiation of BTSCs, but the differentiation is incomplete, terminal differentiation cannot be achieved and BTSs can be formed again.

  16. All-Trans Retinoic Acid-Induced Craniofacial Malformation Model: A Prenatal and Postnatal Morphological Analysis.

    Science.gov (United States)

    Wang, Weicai; Jian, Yutao; Cai, Bin; Wang, Miao; Chen, Mu; Huang, Hongzhang

    2017-07-01

    To characterize the prenatal and postnatal craniofacial bone development in mouse model of all-trans retinoic acid (ATRA) exposure at different ages by a quantitative and morphological analysis of skull morphology. Pregnant mice were exposed to ATRA at embryonic day 10 (E10) and 13 (E13) by oral gavage. Skulls of mice embryos at E19.5 and adult mice at postnatal day 35 (P35) were collected for high-resolution microcomputed tomography (microCT) imaging scanning and section HE staining. Reconstruction and measurement of mouse skulls were performed for prenatal and postnatal analysis of the control and ATRA-exposed mice. Craniofacial malformations in mouse models caused by ATRA exposure were age dependent. ATRA exposure at E10 induced cleft palate in 81.8% of the fetuses, whereas the palatine bone of E13-exposed mice was intact. Inhibitions of maxilla and mandible development with craniofacial asymmetry induced were observed at E19.5 and P35. Compared with control and E13-exposed mice, the palatine bones of E10-exposed mice were not elevated and were smaller in dimension. Some E10-exposed mice exhibited other craniofacial abnormalities, including premature fusion of mandibular symphysis with a missing mandibular incisor and a smaller mandible. Severe deviated snouts and amorphous craniofacial suture were detected in E13-exposed mice at P35. These morphological variations in E10- and E13-exposed mice suggested that ATRA was teratogenic in craniofacial bone development in mice and the effect was age dependent.

  17. Spatial and temporal characteristics of rainfall across Ganjiang River Basin in China

    Science.gov (United States)

    Xiao, Yang; Zhang, Xiang; Wan, Hui; Wang, Yeqiao; Liu, Cheng; Xia, Jun

    2016-04-01

    The hydrological variations of Ganjiang River Basin have significant influence on the ecological environment of Poyang Lake, which is one of the largest freshwater lake and wetland in the world. This study analyzed the spatial and temporal characteristics of rainfall across Ganjiang River Basin. The analyses include annual total rainfall amount (ATRA), annual total rainy day (ATRD) and annual mean daily rainfall intensity (AMDRI). To detect changes in the hydrological trends, data from 19 rainfall stations from 1953 to 2013 were used in the analyses. First, quality control and homogeneity detection was carried out to examine the annual rainfall series. Second, the spatial correlation analysis was used to identify the spatial relationship among the measurements from different stations. Finally, the statistics of coefficient of variation (CV) and average were used to analyze the interannual variation trend. The modified Mann-Kendall (MMK) trend test method was used to detect the temporal characteristics of rainfall. The results include: (1) Some outliers were detected and corrected. (2) The correlation of ATRA and ATRD series of all the stations had lower spatial variability while the AMDRI series of all the stations had higher spatial variability. On the other hand, the ATRA, ATRD and AMDRI series of single stations show similar spatial variability and the influencing radius of the rainfall events was less than 50 km. (3) the rainfall at the northern and southern parts of the basin had smaller CV. Further, by applying the MMK test method to the ATRA, ATRD, and AMDRI series, the ATRA series has an increasing trend which is opposite to that of the ATRD series. The increasing trend in the ATRA series also led to the increasing trend in the AMDRI series. These stations are mainly in central and northern parts of the basin which are more likely to experience droughts and floods. Thus, for the central and northern parts of the basin, they should receive particular

  18. All-trans-retinoic Acid Reduces BACE1 Expression under Inflammatory Conditions via Modulation of Nuclear Factor κB (NFκB) Signaling*

    Science.gov (United States)

    Wang, Ruishan; Chen, Shaoya; Liu, Yingchun; Diao, Shiyong; Xue, Yueqiang; You, Xiaoqing; Park, Edwards A.; Liao, Francesca-Fang

    2015-01-01

    Insulin resistance and neuroinflammation have emerged as two likely key contributors in the pathogenesis of Alzheimer disease (AD), especially in those sporadic AD cases compromised by diabetes or cardiovascular disease. Amyloid-β (Aβ) deposition and its associated inflammatory response are hallmarks in sporadic AD brains. Elevated expression and activity of β-secretase 1 (BACE1), the rate-limiting enzyme responsible for the β-cleavage of amyloid precursor proteins to Aβ peptides, are also observed in sporadic AD brains. Previous studies have suggested that there is therapeutic potential for retinoic acid in treating neurodegeneration based on decreased Aβ. Here we discovered that BACE1 expression is elevated in the brains of both Tg2576 transgenic mice and mice on high fat diets. These conditions are associated with a neuroinflammatory response. We found that administration of all-trans-retinoic acid (atRA) down-regulated the expression of BACE1 in the brains of Tg2576 mice and in mice fed a high fat diet. Moreover, in LPS-treated mice and cultured neurons, BACE1 expression was repressed by the addition of atRA, correlating with the anti-inflammatory efficacy of atRA. Mutations of the NFκB binding site in BACE1 promoter abolished the suppressive effect of atRA. Furthermore, atRA disrupted LPS-induced nuclear translocation of NFκB and its binding to BACE1 promoter as well as promoting the recruitment of the corepressor NCoR. Our findings indicate that atRA represses BACE1 gene expression under inflammatory conditions via the modulation of NFκB signaling. PMID:26240147

  19. All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo

    Science.gov (United States)

    Ma, Hayley S.; Greenblatt, Sarah M.; Shirley, Courtney M.; Duffield, Amy S.; Bruner, J. Kyle; Li, Li; Nguyen, Bao; Jung, Eric; Aplan, Peter D.; Ghiaur, Gabriel; Jones, Richard J.

    2016-01-01

    FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poor prognosis, and ineffective targeting of the leukemic stem cell (LSC) population remains one of several obstacles in treating this disease. All-trans retinoic acid (ATRA) has been used in several clinical trials for the treatment of nonpromyelocytic AML with limited clinical activity observed. FLT3 tyrosine kinase inhibitors (TKIs) used as monotherapy also achieve limited clinical responses and are thus far unable to affect cure rates in AML patients. We explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD)+ LSCs. Our studies reveal highly synergistic drug activity, preferentially inducing apoptosis in FLT3/ITD+ cell lines and patient samples. Colony-forming unit assays further demonstrate decreased clonogenicity of FLT3/ITD+ cells upon treatment with ATRA and TKI. Most importantly, the drug combination depletes FLT3/ITD+ LSCs in a genetic mouse model of AML, and prolongs survival of leukemic mice. Furthermore, engraftment of primary FLT3/ITD+ patient samples is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellular differentiation occurring in vivo. Mechanistically, we provide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein Bcl6, limiting the drug’s apoptotic effect. However, cotreatment with ATRA reduces Bcl6 expression to baseline levels through suppression of interleukin-6 receptor signaling. These studies provide evidence of the potential of this drug combination to eliminate FLT3/ITD+ LSCs and reduce the rate of relapse in AML patients with FLT3 mutations. PMID:27103744

  20. All-Trans Retinoic Acid Induces TGF-β2 in Intestinal Epithelial Cells via RhoA- and p38α MAPK-Mediated Activation of the Transcription Factor ATF2

    Science.gov (United States)

    Namachivayam, Kopperuncholan; MohanKumar, Krishnan; Arbach, Dima; Jagadeeswaran, Ramasamy; Jain, Sunil K.; Natarajan, Viswanathan; Mehta, Dolly; Jankov, Robert P.; Maheshwari, Akhil

    2015-01-01

    Objective We have shown previously that preterm infants are at risk of necrotizing enterocolitis (NEC), an inflammatory bowel necrosis typically seen in infants born prior to 32 weeks’ gestation, because of the developmental deficiency of transforming growth factor (TGF)-β2 in the intestine. The present study was designed to investigate all-trans retinoic acid (atRA) as an inducer of TGF-β2 in intestinal epithelial cells (IECs) and to elucidate the involved signaling mechanisms. Methods AtRA effects on intestinal epithelium were investigated using IEC6 cells. TGF-β2 expression was measured using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and Western blots. Signaling pathways were investigated using Western blots, transiently-transfected/transduced cells, kinase arrays, chromatin immunoprecipitation, and selective small molecule inhibitors. Results AtRA-treatment of IEC6 cells selectively increased TGF-β2 mRNA and protein expression in a time- and dose-dependent fashion, and increased the activity of the TGF-β2 promoter. AtRA effects were mediated via RhoA GTPase, Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1), p38α MAPK, and activating transcription factor (ATF)-2. AtRA increased phospho-ATF2 binding to the TGF-β2 promoter and increased histone H2B acetylation in the TGF-β2 nucleosome, which is typically associated with transcriptional activation. Conclusions AtRA induces TGF-β2 expression in IECs via RhoA- and p38α MAPK-mediated activation of the transcription factor ATF2. Further studies are needed to investigate the role of atRA as a protective/therapeutic agent in gut mucosal inflammation. PMID:26225425

  1. C/EBPalpha inactivation in FAK-overexpressed HL-60 cells impairs cell differentiation.

    Science.gov (United States)

    Hashimoto, Ken-ichiro; Sonoda, Yoshiko; Yamakado, Masakazu; Funakoshi-Tago, Megumi; Yoshida, Naomi; Rokudai, Akiko; Aizu-Yokota, Eriko; Kasahara, Tadashi

    2006-07-01

    We previously demonstrated that focal adhesion kinase (FAK)-overexpressed (HL-60/FAK) cells have marked resistance against various apoptotic stimuli such as oxidative stress, ionizing radiation and TNF-receptor-induced ligand (TRAIL) compared with vector-transfected (HL-60/Vect) cells. Here, we show that HL-60/FAK cells are highly resistant to all-trans retinoic acid (ATRA)-induced differentiation, whereas original HL-60 or HL-60/Vect cells are sensitive. Treatment with ATRA at 1 muM for 5 days markedly inhibited the proliferation and increased the expression of differentiation markers (CD38, CD11b) in HL-60/Vect cells, but showed no such effect in HL-60/FAK cells. Electrophoretic mobility shift assay (EMSA) using an oligonucleotide for the c/EBP consensus binding sequence showed that c/EBPalpha was activated in ATRA-treated HL-60/Vect cells but not in HL-60/FAK cells, indicating that c/EBPalpha activation by ATRA was impaired in HL-60/FAK cells. In addition, the association of retinoblastoma protein (pRb) and c/EBPalpha after treatment with ATRA was seen in HL-60/Vect cells but not in HL-60/FAK cells. Further, hyperphosphorylation of pRb was observed in HL-60/FAK cells. Finally, the introduction of FAK siRNA into HL-60/FAK cells resulted in the recovery of sensitivity to ATRA-induced differentiation, confirming that the inhibition of HL-60/FAK differentiation resulted from both the induction of pRb hyperphosphorylation and the inhibition of association of pRb and c/EBPalpha.

  2. Phenotypic, morphologic changes and Ig secretion induced on B-NHL cells in vitro by interferon alpha and all-trans-retinoic acid: possible progression toward a more differentiated state.

    Science.gov (United States)

    Bonnefoix, T; Sotto, M F; Gressin, R; Martin, I; Garban, F; Leroux, D; Renversez, J C; Sotto, J J

    1998-08-01

    Twenty-five B-cell-nonHodgkin's lymphomas (B-NHL): 6 lymphocytic, 2 centrocytic, 13 follicular, centrocytic/centroblastic, 2 lymphoplasmocytoid and 2 centroblastic were tested for their ability to acquire features of mature plasma cells under the effect of interferon alpha (final concentration, 600 UI/ml), all-trans-retinoic-acid (ATRA) (final concentration, 10(-6) mol/l) and the association of both. B-NHL cells were negatively purified (>99%) by an immunomagnetic method, cultured for 7 d with or without interferon and ATRA, then stained with anti-CD19, CD20, surface Ig, DR, CD38 and with anti-CD138 (syndecan-1) antibody-recognizing plasma cells. Ig production was estimated in culture supernatants by an ELISA method and changes in cell morphology were investigated on May-Grunwald-Giemsa-stained cytospin preparations. In all cases interferon and ATRA, alone or in association, were able to induce changes in the immunophenotypic profile, associated or not with morphologic changes and induction of Ig secretion. All changes were greatly variable from one to the other B-NHL sample and no relationship could be found between a particular pattern of change and the histological subtype. Interferon alpha was more potent than ATRA in inducing changes. In favour of a differentiation process, we observed a concomitant decrease of DR expression and increase of CD38 expression in 8 cases with interferon alpha, and in 4 cases with ATRA. Although interferon- or ATRA-treated cells did not display cytologic, functional features and changes of the immunophenotypic profile fully compatible with those of terminally differentiated cells, these results suggest a possible transition toward more differentiated elements, especially with interferon alpha.

  3. 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.

  4. Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis.

    Science.gov (United States)

    Wu, Lizhi; Chaudhary, Sandeep C; Atigadda, Venkatram R; Belyaeva, Olga V; Harville, Steven R; Elmets, Craig A; Muccio, Donald D; Athar, Mohammad; Kedishvili, Natalia Y

    2016-01-01

    UAB30 is an RXR selective agonist that has been shown to have potential cancer chemopreventive properties. Due to high efficacy and low toxicity, it is currently being evaluated in human Phase I clinical trials by the National Cancer Institute. While UAB30 shows promise as a low toxicity chemopreventive drug, the mechanism of its action is not well understood. In this study, we investigated the effects of UAB30 on gene expression in human organotypic skin raft cultures and mouse epidermis. The results of this study indicate that treatment with UAB30 results in upregulation of genes responsible for the uptake and metabolism of all-trans-retinol to all-trans-retinoic acid (ATRA), the natural agonist of RAR nuclear receptors. Consistent with the increased expression of these genes, the steady-state levels of ATRA are elevated in human skin rafts. In ultraviolet B (UVB) irradiated mouse skin, the expression of ATRA target genes is found to be reduced. A reduced expression of ATRA sensitive genes is also observed in epidermis of mouse models of UVB-induced squamous cell carcinoma and basal cell carcinomas. However, treatment of mouse skin with UAB30 prior to UVB irradiation prevents the UVB-induced decrease in expression of some of the ATRA-responsive genes. Considering its positive effects on ATRA signaling in the epidermis and its low toxicity, UAB30 could be used as a chemoprophylactic agent in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations.

  5. The Expression of Bone Morphogenetic Protein 2 and Matrix Metalloproteinase 2 through Retinoic Acid Receptor Beta Induced by All-Trans Retinoic Acid in Cultured ARPE-19 Cells.

    Directory of Open Access Journals (Sweden)

    Zhenya Gao

    Full Text Available All-trans retinoic acid (ATRA plays an important role in ocular development. Previous studies found that retinoic acid could influence the metabolism of scleral remodeling by promoting retinal pigment epithelium (RPE cells to secrete secondary signaling factors. The purpose of this study was to investigate whether retinoic acid affected secretion of bone morphogenetic protein 2 (BMP-2 and matrix metalloproteinase 2 (MMP-2 and to explore the signaling pathway of retinoic acid in cultured acute retinal pigment epithelial 19 (ARPE-19 cells.The effects of ATRA (concentrations from 10-9 to 10-5 mol/l on the expression of retinoic acid receptors (RARs in ARPE-19 cells were examined at the mRNA and protein levels using reverse transcription-polymerase chain reaction (RT-PCR and western blot assay, respectively. The effects of treating ARPE-19 cells with ATRA concentrations ranging from 10-9 to 10-5 mol/l for 24 h and 48 h or with 10-6mol/l ATRA at different times ranging from 6h to 72h were assessed using real-time quantitative PCR (qPCR and enzyme-linked immunosorbent assay (ELISA. The contribution of RARβ-induced activation of ARPE-19 cells was confirmed using LE135, an antagonist of RARβ.RARβ mRNA levels significantly increased in the ARPE-19 cells treated with ATRA for 24h and 48h. These increases in RARβ mRNA levels were dose dependent (at concentrations of 10-9 to 10-5 mol/l with a maximum effect observed at 10-6 mol/l. There were no significant changes in the mRNA levels of RARα and RARγ. Western blot assay revealed that RARβ protein levels were increased significantly in a time-dependent manner in ARPE-19 cells treated with 10-6 mol/l ATRA from 12 h to 72 h, with a marked increase observed at 24 h and 48 h. The upregulation of RARβ and the ATRA-induced secretion in ARPE-19 cells could be inhibited by the RARβ antagonist LE135.ATRA induced upregulation of RARβ in ARPE-19 cells and stimulated these cells to secrete BMP-2 and MMP-2.

  6. 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

  7. 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

  8. All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

    OpenAIRE

    Tripathy, Sasmita; Chapman, John D.; Han, Chang Y; Hogarth, Cathryn A.; Arnold, Samuel L. M.; Onken, Jennifer; Kent, Travis; Goodlett, David R.; Isoherranen, Nina

    2016-01-01

    All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. The liver is the main storage organ of vitamin A, but activation of the retinoic acid receptors (RARs) in mouse liver and in human liver cell lines has also been shown. Although atRA treatment improves mitochondrial function in skeletal muscle in rodents, its role in modulating mitochondrial function in the liver is controversial, and little data are available regarding the human liver. The aim of this study was to determin...

  9. All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus.

    Directory of Open Access Journals (Sweden)

    Ling Lu

    Full Text Available BACKGROUND: It has been documented all-trans retinoic acid (atRA promotes the development of TGF-β-induced CD4(+Foxp3(+ regulatory T cells (iTreg that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs. METHODOLOGY/PRINCIPAL FINDINGS: Addition of atRA to naïve CD4(+CD25(- cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3(+ iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4(+ cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4(+ cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4(+ cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4(+ cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered. CONCLUSIONS/SIGNIFICANCE: We have identified the cellular and molecular mechanism(s by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.

  10. The Retinoic Acid Receptor-α mediates human T-cell activation and Th2 cytokine and chemokine production

    OpenAIRE

    Key Michael; Pyle Robert; Collins Gary; Dawson Harry D; Taub Dennis D

    2008-01-01

    Abstract Background We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-γ and TNF-α expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-α (RAR-α)-sel...

  11. Molecular targeting of retinoic acid metabolism in neuroblastoma: the role of the CYP26 inhibitor R116010 in vitro and in vivo

    OpenAIRE

    Armstrong, J. L.; Taylor, G A; Thomas, H.D.; Boddy, A V; Redfern, C P F; Veal, G J

    2007-01-01

    Isomerisation to all-trans-retinoic acid (ATRA) is widely accepted as the key mechanism underlying the favourable clinical properties of 13-cis-retinoic acid (13cisRA). As intracellular metabolism of ATRA by CYP26 may result in clinical resistance to 13cisRA, an increase in efficacy may be achieved through modulation of this metabolic pathway. We have evaluated the effect of the CYP26 inhibitor R116010 on retinoid metabolism in neuroblastoma cell lines and a xenograft model. In neuroblastoma ...

  12. Functional Outcomes of Achilles Tendon Minimally Invasive Repair Using 4- and 6-Strand Nonabsorbable Suture: A Cohort Comparison Study

    Science.gov (United States)

    Carmont, Michael R.; Zellers, Jennifer A.; Brorsson, Annelie; Olsson, Nicklas; Nilsson-Helander, Katarina; Karlsson, Jon; Silbernagel, Karin Grävare

    2017-01-01

    Background: The aim of management of Achilles tendon rupture is to reduce tendon lengthening and maximize function while reducing the rerupture rate and minimizing other complications. Purpose: To determine changes in Achilles tendon resting angle (ATRA), heel-rise height, patient-reported outcomes, return to play, and occurrence of complications after minimally invasive repair of Achilles tendon ruptures using nonabsorbable sutures. Study Design: Cohort study; Level of evidence, 3. Methods: Between March 2013 and August 2015, a total of 70 patients (58 males, 12 females) with a mean age of 42 ± 8 years were included and evaluated at 6 weeks and 3, 6, 9, and 12 months after repair of an Achilles tendon rupture. Surgical repair was performed using either 4-strand or 6-strand nonabsorbable sutures. After surgery, patients were mobilized, fully weightbearing using a functional brace. Early active movement was permitted starting at 2 weeks. Results: There were no significant differences in the ATRA, Achilles Tendon Total Rupture Score (ATRS), and Heel-Rise Height Index (HRHI) between the 4- and 6-strand repairs. The mean (SD) relative ATRA was –13.1° (6.6°) (dorsiflexion) following injury; this was reduced to 7.6° (4.8°) (plantar flexion) directly after surgery. During initial rehabilitation at 6 weeks, the relative ATRA was 0.6° (7.4°) (neutral) and –7.0° (5.3°) (dorsiflexion) at 3 months, after which ATRA improved significantly with time to 12 months (P = .005). At 12 months, the median ATRS was 93 (range, 35-100), and the mean (SD) HRHI and Heel-Rise Repetition Index were 81% (0.22%) and 82.9% (0.17%), respectively. The relative ATRA at 3 and 12 months correlated with HRHI (r = 0.617, P Achilles tendon repair. The use of a nonabsorbable suture during minimally invasive repair when used together with accelerated rehabilitation did not prevent the development of an increased relative ATRA. The ATRA at 3 months after surgery correlated with heel

  13. Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells

    DEFF Research Database (Denmark)

    Noack, Katrin; Mahendrarajah, Nisintha; Hennig, Dorle

    2017-01-01

    the fraction of cells in the G1 phase, together with an accumulation of the cyclin-dependent kinase inhibitor p21 and a reduced expression of thymidylate synthase (TdS). In contrast, the ATRA-dependent activation of the transcription factors STAT1, NF-κB, and C/EBP hardly influences the responses of APL cells...

  14. 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.

  15. Non-coding RNAs change their expression profile after Retinoid induced differentiation of the promyelocytic cell line NB4

    Directory of Open Access Journals (Sweden)

    Caporaso Maria G

    2010-01-01

    Full Text Available Abstract Background The importance of non-coding RNAs (ncRNAs as fine regulators of eukaryotic gene expression has emerged by several studies focusing on microRNAs (miRNAs. miRNAs represent a newly discovered family of non coding-RNAs. They are thought to be crucial players of human hematopoiesis and related tumorigenesis and to represent a potential tool to detect the early stages of cancer. More recently, the expression regulation of numerous long ncRNAs has been linked to cell growth, differentiation and cancer although the molecular mechanism of their function is still unknown. NB4 cells are promyelocytic cells that can be induced to differentiation upon retinoic acid (ATRA treatment and represent a feasible model to study changes of non coding RNAs expression between cancer cells and their terminally differentiated counterpart. Findings we screened, by microarray analysis, the expression of 243 miRNAs and 492 human genes transcribing for putative long ncRNAs different from miRNAs in NB4 cells before and after ATRA induced differentiation. Our data show that 8 miRNAs, and 58 long ncRNAs were deregulated by ATRA induced NB4 differentiation. Conclusion our data suggest that ATRA-induced differentiation lead to deregulation of a large number of the ncRNAs that can play regulatory roles in both tumorigenesis and differentiation.

  16. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes

    DEFF Research Database (Denmark)

    Arts, Rob J W; Blok, Bastiaan A; van Crevel, Reinout

    2015-01-01

    Epidemiologic studies suggest that VAS has long-lasting immunomodulatory effects. We hypothesized that ATRA inhibits inflammatory cytokines in a model of trained immunity in monocytes by inducing epigenetic reprogramming through histone modifications. We used an previously described in vitro mode...

  17. AcEST: BP912704 [AcEST

    Lifescience Database Archive (English)

    Full Text Available Q7ZZN8|CRVP2_NAJAT Natrin-2 OS=Naja atra PE=1 SV=1 32 1.9 sp|P0C314|CLPP_ORYSJ ATP-dependent Clp protease pr...Sbjct: 94 RSRRPCACCCPASWPSTPCPRAPRRSPSTPAPSESLPGPGARSLPPSLPPRV 145 >sp|Q7ZZN8|CRVP2_NAJAT Natrin-2 OS=Naja a

  18. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy : long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

    NARCIS (Netherlands)

    Sanz, Miguel A.; Montesinos, Pau; Vellenga, Edo; Rayon, Consuelo; de la Serna, Javier; Parody, Ricardo; Bergua, Juan M.; Leon, Angel; Negri, Silvia; Gonzalez, Marcos; Rivas, Concha; Esteve, Jordi; Milone, Gustavo; Gonzalez, Jose D.; Amutio, Elena; Brunet, Salut; Garcia-Larana, J.; Colomer, Dolors; Calasanz, Maria J.; Chillon, Carmen; Barragan, Eva; Bolufer, Pascual; Lowenberg, Bob

    2008-01-01

    A previous report of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leukemia

  19. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: Long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

    NARCIS (Netherlands)

    M.A. Sanz (Miguel Angel); P. Montesinos (Pau); E. Vellenga (Edo); C. Rayón (Consuelo); J. de Serna (Javier); R. Parody (Ricardo); J.M. Bergua (Juan Miguel); A. León (Angel); S. Negri (Silvia); M. González (Marcos); C. Rivas (Concha); J. Esteve (Jordi); G. Milone (Gustavo); E. Amutio (Elena); S. Brunet (Salut); J. García-Laraña; D. Colomer (Dolors); M.J. Calasanz (Maria); C. Chillón (Carmen); E. Barragán (Eva); P. Bolufer (Pascual); B. Löwenberg (Bob)

    2008-01-01

    textabstractA previous report of the Programa de Estudio y Tratamiento de las Hemopatfas Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic

  20. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: Further improvements in treatment outcome

    NARCIS (Netherlands)

    M.A. Sanz (Miguel Angel); P. Montesinos (Pau); C. Rayón (Chelo); A. Holowiecka (Aleksandra); J. De La Serna (Javier); G. Milone (Gustavo); E. de Lisa (Elena); S. Brunet (Salut); V. Rybio (Vicente); J.M. Ribera (Josep Maria); C. Rivas (Concha); I. Krsnik (Isabel); J.M. Bergua (Juan Miguel); J.D. González (José David); J. Díaz-Mediavilla (Joaquín); R. Rojas (Rafael); F. Manso (Félix); G.J. Ossenkoppele (Gert); B. Löwenberg (Bob)

    2010-01-01

    textabstractA risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMALPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements

  1. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all- trans retinoic acid and anthracycline chemotherapy: Characteristics, outcome, and prognostic factors

    NARCIS (Netherlands)

    P. Montesinos (Pau); J.M. Bergua (Juan Miguel); E. Vellenga (Edo); C. Rayón (Chelo); R. Parody (Ricardo); J. de Serna (Javier); A. León (Angel); J. Esteve (Jordi); G. Milone (Gustavo); G. Debén (Guillermo); C. Rivas (Concha); M. González (Marcos); M. Tormo (Mar); D.M. Joaquín; J.D. González (José David); S. Negri (Silvia); E. Amutio (Elena); S. Brunet (Salut); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)

    2009-01-01

    textabstractDifferentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all- trans retinoic acid (ATRA). Detailed knowl- edge about DS has remained limited. We present an analysis of the incidence, char-

  2. 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.

  3. All-trans-retinoic acid-induced pseudotumor cerebri in acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    T. M. Anoop

    2014-01-01

    Full Text Available All-trans-retinoic acid is an integral part in the treatment strategy of acute promyelocytic leukemia (APL. Here we describe a case of pseudotumor cerebri associated with all-trans-retinoic acid (ATRA during the induction therapy in an adult with acute promyelocytic leukemia (APL.

  4. All-trans retinoic acid promotes wound healing of primary amniocytes through the induction of LOXL4, a member of the lysyl oxidase family.

    Science.gov (United States)

    Rouzaire, Marion; Comptour, Aurélie; Belville, Corinne; Bouvier, Damien; Clairefond, Gaël; Ponelle, Flora; Sapin, Vincent; Gallot, Denis; Blanchon, Loïc

    2016-12-01

    Thirty percent of preterm births directly result from preterm premature rupture of fetal membranes (PPROM). Clinical management currently proposes using a collagen plug to mechanically stop loss of amniotic fluid. Vitamin A and its active metabolite (retinoic acid) have well-known pro-healing properties and could thus make good candidates as a proposable adjuvant to this mechanical approach. Here we investigate the molecular mechanisms involved in the pro-healing properties of all-trans retinoic acid (atRA) in fetal membranes via an approach using an in vitro primary amniocyte wound model and transcriptomics. The results demonstrate that atRA promotes migration in primary amniocytes, improving wound healing in vitro by up to 90%. This effect is mediated by the induction of LOXL4, which plays a crucial role in the dynamics of the extracellular matrix by regulating collagen reticulation. This new insight into how atRA exerts its pro-healing properties prompts us to propose using atRA as a candidate strategy to help prevent future PPROM. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy : characteristics, outcome, and prognostic factors

    NARCIS (Netherlands)

    Montesinos, Pau; Bergua, Juan M.; Vellenga, Edo; Rayon, Chelo; Parody, Ricardo; de la Serna, Javier; Leon, Angel; Esteve, Jordi; Milone, Gustavo; Deben, Guillermo; Rivas, Concha; Gonzalez, Marcos; Tormo, Mar; Diaz-Mediavilla, Joaquin; Gonzalez, Jose D.; Negri, Silvia; Amutio, Elena; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2009-01-01

    Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid ( ATRA). Detailed knowledge about DS has remained limited. We present an analysis of the incidence, characteristics,

  6. All-trans retinoic acid combined with 5-Aza-2 Prime -deoxycitidine induces C/EBP{alpha} expression and growth inhibition in MLL-AF9-positive leukemic cells

    Energy Technology Data Exchange (ETDEWEB)

    Fujiki, Atsushi [Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Imamura, Toshihiko, E-mail: imamura@koto.kpu-m.ac.jp [Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Sakamoto, Kenichi; Kawashima, Sachiko; Yoshida, Hideki; Hirashima, Yoshifumi; Miyachi, Mitsuru; Yagyu, Shigeki; Nakatani, Takuya [Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Sugita, Kanji [Department of Pediatrics, University of Yamanashi, Yamanashi (Japan); Hosoi, Hajime [Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan)

    2012-11-16

    Highlights: Black-Right-Pointing-Pointer We tested whether ATRA and 5-Aza affect AML cell differentiation and growth. Black-Right-Pointing-Pointer Cell differentiation and growth arrest were induced in MLL-AF9-expressing cells. Black-Right-Pointing-Pointer Increased expression of C/EBP{alpha}, C/EBP{epsilon}, and PU.1 were also observed. Black-Right-Pointing-Pointer MLL-AF4/AF5q31-expressing cells are less sensitive to ATRA and 5-Aza. Black-Right-Pointing-Pointer Different MLL fusion has distinct epigenetic properties related to RA pathway. -- Abstract: The present study tested whether all-trans retinoic acid (ATRA) and 5-Aza-2 Prime -deoxycitidine (5-Aza) affect AML cell differentiation and growth in vitro by acting on the CCAAT/enhancer binding protein {alpha} (C/EBP{alpha}) and c-Myc axis. After exposure to a combination of these agents, cell differentiation and growth arrest were significantly higher in human and murine MLL-AF9-expressing cells than in MLL-AF4/AF5q31-expressing cells, which were partly associated with increased expression of C/EBP{alpha}, C/EBP{epsilon}, and PU.1, and decreased expression of c-Myc. These findings indicate that MLL-AF9-expressing cells are more sensitive to ATRA and 5-Aza, indicating that different MLL fusion proteins possess different epigenetic properties associated with retinoic acid pathway inactivation.

  7. A Study on the Factors Influencing the Growth and Survival of ...

    African Journals Online (AJOL)

    The aim of the present study was to investigate the influence environmental factors such as salinity and temperature and biological factors such as stocking density and feed type on the growth and survival of juvenile sea cucumbers Holothuria atra. The study was conducted from mid-October 2006 to end of January 2007 ...

  8. Synergistic effect of all-trans-retinoic acid and arsenic trioxide on growth inhibition and apoptosis in human hepatoma, breast cancer, and lung cancer cells in vitro

    OpenAIRE

    Lin, Le-Min; Li, Bao-Xin; Xiao, Jian-Bing; Lin, Dan-Hua; Yang, Bao-Feng

    2005-01-01

    AIM: To investigate the effect of all-trans-retinoic acid (ATRA) on arsenic trioxide (As2O3)-induced apoptosis of human hepatoma, breast cancer, and lung cancer cells in an attempt to find a better combination therapy for solid tumors.

  9. Physiological changes during the ovarian cycle of the female rock ...

    African Journals Online (AJOL)

    Seasonal morphometric and physiological changes associated with vltellogenesis in the female agamid lizard, Agama atra are described. Vitellogenic activity during August - September marked the onset of the breeding season. It is suggested that at least two clutches were ovulated during the breeding season.

  10. Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Hilde Kvestad

    2014-01-01

    Full Text Available The combined use of the histone deacetylase inhibitor valproic acid (VPA, the retinoic acid receptor-α agonist all-trans retinoic acid (ATRA, and the deoxyribonucleic acid polymerase-α inhibitor cytarabine (Ara-C is now considered for disease-stabilizing treatment of acute myeloid leukemia (AML. Leukemogenesis and leukemia cell chemoresistance seem to be supported by neighbouring stromal cells in the bone marrow, and we have therefore investigated the effects of these drugs on primary human endothelial cells and the osteoblastic Cal72 cell line. The results show that VPA and Ara-C have antiproliferative effects, and the antiproliferative/cytotoxic effect of Ara-C was seen at low concentrations corresponding to serum levels found during low-dose in vivo treatment. Furthermore, in functional assays of endothelial migration and tube formation VPA elicited an antiangiogenic effect, whereas ATRA elicited a proangiogenic effect. Finally, VPA and ATRA altered the endothelial cell release of angiogenic mediators; ATRA increased levels of CXCL8, PDGF-AA, and VEGF-D, while VPA decreased VEGF-D and PDGF-AA/BB levels and both drugs reduced MMP-2 levels. Several of these mediators can enhance AML cell proliferation and/or are involved in AML-induced bone marrow angiogenesis, and direct pharmacological effects on stromal cells may thus indirectly contribute to the overall antileukemic activity of this triple drug combination.

  11. Novel retinoic acid receptor alpha agonists for treatment of kidney disease.

    Directory of Open Access Journals (Sweden)

    Yifei Zhong

    Full Text Available Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs: RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1 in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN. Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN.

  12. University of Mauritius Research Journal - Vol 14, No 1 (2008)

    African Journals Online (AJOL)

    A Study on the Factors Influencing the Growth and Survival of Juvenile Sea Cucumber, Holothuria atra, under Laboratory Conditions · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Ramlochun Seeruttun, Chandani Appadoo, A. Laxminaraya, B Codabaccus, 1-15 ...

  13. Retinoic acid affects calcium signaling in adult molluscan neurons

    Science.gov (United States)

    Vesprini, Nicholas D.; Dawson, Taylor F.; Yuan, Ye; Bruce, Doug

    2014-01-01

    Retinoic acid, the active metabolite of vitamin A, is important for nervous system development, regeneration, as well as cognitive functions of the adult central nervous system. These central nervous system functions are all highly dependent on neuronal activity. Retinoic acid has previously been shown to induce changes in the firing properties and action potential waveforms of adult molluscan neurons in a dose- and isomer-dependent manner. In this study, we aimed to determine the cellular pathways by which retinoic acid might exert such effects, by testing the involvement of pathways previously shown to be affected by retinoic acid. We demonstrated that the ability of all-trans retinoic acid (atRA) to induce electrophysiological changes in cultured molluscan neurons was not prevented by inhibitors of protein synthesis, protein kinase A or phospholipase C. However, we showed that atRA was capable of rapidly reducing intracellular calcium levels in the same dose- and isomer-dependent manner as shown previously for changes in neuronal firing. Moreover, we also demonstrated that the transmembrane ion flux through voltage-gated calcium channels was rapidly modulated by retinoic acid. In particular, the peak current density was reduced and the inactivation rate was increased in the presence of atRA, over a similar time course as the changes in cell firing and reductions in intracellular calcium. These studies provide further evidence for the ability of atRA to induce rapid effects in mature neurons. PMID:25343782

  14. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer

    Science.gov (United States)

    Wei, Shuo; Kozono, Shingo; Kats, Lev; Nechama, Morris; Li, Wenzong; Guarnerio, Jlenia; Luo, Manli; You, Mi-Hyeon; Yao, Yandan; Kondo, Asami; Hu, Hai; Bozkurt, Gunes; Moerke, Nathan J.; Cao, Shugeng; Reschke, Markus; Chen, Chun-Hau; Rego, Eduardo M.; LoCoco, Francesco; Cantley, Lewis; Lee, Tae Ho; Wu, Hao; Zhang, Yan; Pandolfi, Pier Paolo; Zhou, Xiao Zhen; Lu, Kun Ping

    2015-01-01

    A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency. Using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but its drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RARα and treats APL in cell and animal models and human patients. ATRA-induced Pin1 ablation also inhibits triple negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors. PMID:25849135

  15. Antagonistic and synergistic effects of bone morphogenetic protein 2/7 and all-trans retinoic acid on the osteogenic differentiation of rat bone marrow stromal cells

    NARCIS (Netherlands)

    Bi, W.; Gu, Z.; Zheng, Y.; Wang, L.; Guo, J.; Wu, G.

    2013-01-01

    The osteogenesis of bone marrow stromal cells (BMSCs) is of paramount importance for the repair of large-size bone defects, which may be compromised by the dietary-accumulated all-trans retinoic acid (ATRA). We have shown that heterodimeric bone morphogenetic protein 2/7 (BMP2/7) could induce bone

  16. Ultrastructural examination of the pycnidia and conidia of the genus Opegrapha (Arthoniales, Ascomycota

    Directory of Open Access Journals (Sweden)

    Anetta Wieczorek

    2013-12-01

    Full Text Available The paper presents a summary of examinations on the variation of pycnidia and conidia of the following Opegrapha species occurring in Poland: O. atra, O. calcarea, O. dolomitica, O. gyrocarpa, O. niveoatra, O. rupestris, O. varia, O. vermicellifera, O. viridis and O. vulgata.

  17. 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.

  18. Phosphatidylinositol 3-kinases are involved in the all-trans retinoic acid-induced upregulation of CD38 antigen on human haematopoietic cells.

    Science.gov (United States)

    Lewandowski, Daniel; Linassier, Claude; Iochmann, Sophie; Degenne, Michel; Domenech, Jorge; Colombat, Philippe; Binet, Christian; Hérault, Olivier

    2002-08-01

    All-trans retinoic acid (ATRA) is a specific inducer of CD38 antigen on marrow CD34+ cells as well as on blast cells in acute promyelocytic and myeloblastic leukaemia. The CD38 antigen contributes to the control of blast cell proliferation, and the upregulation of CD38 might constitute an element in the pathogenesis of retinoic acid syndrome. The aim of this study was to determine whether phosphoinositide 3-kinase (PI3-K) is involved in the modification of CD38 antigen expression on myeloid cells, as PI3-K plays a major role in the ATRA-induced granulocytic differentiation of HL-60 cells. We evaluated the effects of PI3-K inhibitors (wortmannin and LY294002) on the levels of CD38 antigen and mRNA in HL-60 and normal marrow CD34+ cells exposed to ATRA (1 micromol/l). The inhibitors prevented increase in CD38 mRNA expression and the overexpression of membrane CD38 antigen, without modification of the cytoplasmic level of this antigen. Interestingly, PI3-K activity was also necessary for CD38 expression on normal marrow CD34+ cells and for the ATRA-induced upregulation of CD157, a CD38-related antigen. In conclusion, PI3-K activity plays an essential role in the regulation of CD38 expression on human haematopoietic cells, and might constitute an interesting therapeutic target in haematological disorders involving CD38 overexpression.

  19. Treatment of newly diagnosed acute promyelocytic leukemia (APL) : a comparison of French-Belgian-Swiss and PETHEMA results

    NARCIS (Netherlands)

    Ades, Lionel; Sanz, Miguel A.; Chevret, Sylvie; Montesinos, Pau; Chevallier, Patrice; Raffoux, Emmanuel; Vellenga, Edo; Guerci, Agnbs; Pigneux, Arnaud; Huguet, Francoise; Rayon, Consuelo; Stoppa, Anne Marie; de la Serna, Javier; Cahn, Jean-Yves; Meyer-Monard, Sandrine; Pabst, Thomas; Thomas, Xavier; de Botton, Stephane; Parody, Ricardo; Bergua, Juan; Lamy, Thierry; Vekhoff, Anne; Negri, Silvia; Ifrah, Norbert; Dombret, Herve; Ferrant, Augustin; Bron, Dominique; Degos, Laurent; Fenaux, Pierre

    2008-01-01

    All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para

  20. The impact of medical education and networking on the outcome of leukemia treatment in developing countries. The experience of International Consortium on Acute Promyelocytic Leukemia (IC-APL)

    NARCIS (Netherlands)

    E.M. Rego (Eduardo); H.T. Kim (Haesook); G. Ruiz-Argüelles (Guillermo); M.R. Uriarte (Maria del Rosario); R.H. Jacomo (Rafael); H. Gutiérrez-Aguirre (Homero); R.A. Melo (Raul); H.N.S. Bittencourt (Henrique); R. Pasquini (Ricardo); K. Pagnano (Katia); E.M. Fagundes (Evandro); M.d.L. Chauffaille (Maria de Lourdes); C.S. Chiattone (Carlos); L. Martinez (Lem); L.A. Meillón (Luis); D. Gómez-Almaguer (David); H.C. Kwaan (Hau); J. Garcés-Eisele (Javier); R. Gallagher (Robert); C.M. Niemeyer (Charlotte); B. Löwenberg (Bob); R.C. Ribeiro (Raul); F. Lo-Coco (Francesco); M.A. Sanz (Miguel Angel)

    2012-01-01

    textabstractObjectives: Several clinical trials conducted in Europe and US reported favorable outcomes of patients with APL treated with the combination of all trans retinoic acid (ATRA) and anthracyclines. Nevertheless, the results observed in developing countries with the same regimen was poorer,

  1. Anticancer Activity from Active Fraction of Sea Cucumber

    Directory of Open Access Journals (Sweden)

    Nurul Mutia Putram

    2017-05-01

    Full Text Available Sea Cucumber Holothuria atra is one of marine organisms has been used as a new source of novel bioactive compounds. Many of them have been used as the lead compounds in discovery of new anticancer drugs. The objective of this study was to determine the active fractions of sea cucumber (H. atra which have anticancer activity. H. atra was macerated using ethanol and the extract was freezedried using a freeze dryer. The crude extract was partitioned using n-hexane, ethyl acetate, and methanol-water (3:1:1:1. Cytotoxicity test was performed using HeLa (cervic cancer cell line and MCF-7 (breast cancer cell line based on the MTT assay. The crude extract of H. atra showed the best cytotoxic activity against HeLa cells (IC50 = 12.48 µg/mL and MCF-7 cells (IC50 = 17.90 µg/mL. The toxicity tests showed the IC50 value of the n-hexane fraction, ethyl acetate fraction, and methanol-water fraction against HeLa cells HeLa (IC50 = 76.45 µg/mL; 77.95 µg/mL;  14.27 µg/mL and MCF-7 cells (IC50 = 58.50 µg/mL; 59.59 µg/mL; 14.33 µg/mL.

  2. Nuclear Medicine Imaging

    Science.gov (United States)

    ... radiofármacos, que son atraídos a órganos, huesos o tejidos espe- cíficos. Cuando el radiofármaco viaja a través ... detecta estas emisiones en el órgano, hueso o tejido que se están estu- diando y después registra ...

  3. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes

    NARCIS (Netherlands)

    Arts, R.J.W.; Blok, B.A.; Crevel, R. van; Joosten, L.A.B.; Aaby, P.; Benn, C.S.; Netea, M.G.

    2015-01-01

    Epidemiologic studies suggest that VAS has long-lasting immunomodulatory effects. We hypothesized that ATRA inhibits inflammatory cytokines in a model of trained immunity in monocytes by inducing epigenetic reprogramming through histone modifications. We used an previously described in vitro model

  4. 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

  5. All-trans retinoic acid protects against arsenic-induced uterine toxicity in female Sprague-Dawley rats

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, A.; Chatterji, U., E-mail: urmichatterji@gmail.com

    2011-12-15

    Background and purpose: Arsenic exposure frequently leads to reproductive failures by disrupting the rat uterine histology, hormonal integrity and estrogen signaling components of the rat uterus, possibly by generating reactive oxygen species. All-trans retinoic acid (ATRA) was assessed as a prospective therapeutic agent for reversing reproductive disorders. Experimental approach: Rats exposed to arsenic for 28 days were allowed to either recover naturally or were treated simultaneously with ATRA for 28 days or treatment continued up to 56 days. Hematoxylin-eosin double staining was used to evaluate changes in the uterine histology. Serum gonadotropins and estradiol were assayed by ELISA. Expression of the estrogen receptor (ER{alpha}), an estrogen responsive gene vascular endothelial growth factor (VEGF), and cell cycle regulatory proteins, cyclin D1 and CDK4, was assessed by RT-PCR, immunohistochemistry and western blot analysis. Key results: ATRA ameliorated sodium arsenite-induced decrease in circulating estradiol and gonadotropin levels in a dose- and time-dependent manner, along with recovery of luminal epithelial cells and endometrial glands. Concomitant up regulation of ER{alpha}, VEGF, cyclin D1, CDK4 and Ki-67 was also observed to be more prominent for ATRA-treated rats as compared to the rats that were allowed to recover naturally for 56 days. Conclusions and implications: Collectively, the results reveal that ATRA reverses arsenic-induced disruption of the circulating levels of gonadotropins and estradiol, and degeneration of luminal epithelial cells and endometrial glands of the rat uterus, indicating resumption of their functional status. Since structural and functional maintenance of the pubertal uterus is under the influence of estradiol, ATRA consequently up regulated the estrogen receptor and resumed cellular proliferation, possibly by an antioxidant therapeutic approach against arsenic toxicity. Highlights: Black-Right-Pointing-Pointer Arsenic

  6. 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

  7. Effect of differentiating agents (all-trans retinoic acid and phorbol 12-myristate 13-acetate on drug sensitivity of HL60 and NB4 cells in vitro.

    Directory of Open Access Journals (Sweden)

    Jadwiga Mirecka

    2008-12-01

    Full Text Available In vitro studies have shown that human myeloid leukemia cell lines: HL60 and NB4 can be stimulated to differentiation by various agents, for example, all-trans retinoic acid (ATRA and phorbol 12-myristate 13-acetate (PMA. The purpose of this study was to investigate whether differentiation of HL60 and NB4 leukemia cell lines induced by ATRA and PMA alters their drug sensitivity. The differentiation along the neutrophil lineage (upon stimulation with ATRA and along the monocyte/macrophage lineage (upon stimulation with PMA was proved by decreased proliferative potential of cells, changes in their morphology, increased ability for NBT reduction and increased expression of CD11b and CD14 cell surface markers. The effect of drugs: cytosine arabinoside, daunorubicin, mitoxantrone and etoposide was examined by Alamar Blue test (proliferation and survival rates, as well as by evaluation of cell smears stained with Hoechst 33342 (apoptotic index. Differentiation resulted in the change of drug sensitivity in both cell lines: the differentiation along the neutrophil pathway (after stimulation with ATRA increased sensitivity to cytosine arabinoside and mitoxantrone but decreased sensitivity to etoposide; the differentiation along the monocyte/macrophage pathway (induced by PMA resulted in the decreased sensitivity of both cell lines to all drugs tested. In conclusion, we have shown that ATRA- and PMA-mediated differentiation of HL60 and NB4 cell lines results in the changes of their drug sensitivity. Our data may provide a contribution to a strategy aimed at a rational combination of differentiating agents and conventional anticancer drugs.

  8. All-trans retinoic acid stimulates gene expression of the cardioprotective natriuretic peptide system and prevents fibrosis and apoptosis in cardiomyocytes of obese ob/ob mice.

    Science.gov (United States)

    Manolescu, Daniel-Constantin; Jankowski, Marek; Danalache, Bogdan A; Wang, Donghao; Broderick, Tom L; Chiasson, Jean-Louis; Gutkowska, Jolanta

    2014-10-01

    In hypertensive rodents, retinoic acid (RA) prevents adverse cardiac remodelling and improves myocardial infarction outcome, but its role in obesity-related changes of cardiac tissue are unclear. We hypothesized that all-trans RA (ATRA) treatment will improve the cardioprotective oxytocin-natriuretic peptides (OT-NP) system, preventing apoptosis and collagen accumulation in hearts of ob/ob mice, a mouse model of obesity and insulin resistance. Female 9-week-old B6.V-Lep/J ob/ob mice (n = 16) were divided into 2 groups: 1 group (n = 8) treated with 100 μg of ATRA dissolved in 100 μL of corn oil (vehicle) delivered daily (∼2 μg·g body weight(-1)·day(-1)) by stomach intubation for 16 days, and 1 group (n = 8) that received the vehicle alone. A group of nonobese littermate mice (n = 9) served as controls. Ob/ob mice exhibited obesity, hyperglycaemia, and downregulation of the cardiac OT-NP system, including the mRNA for the transcription factor GATA4, OT receptor and brain NP, and the protein expression for endothelial nitric oxide synthase. Hearts from ob/ob mice also demonstrated increased apoptosis and collagen accumulation. ATRA treatment induced weight loss and decreased adipocytes diameter in the visceral fat, thus reducing visceral obesity, which is associated with a high risk for cardiovascular disease. RA treatment was associated with a reduction in hyperglycemia and a normalization of the OT-NP system's expression in the hearts of ob/ob mice. Furthermore, ATRA treatment prevented apoptosis and collagen accumulation in hearts of ob/ob mice. The present study indicates that ATRA treatment was effective in restoring the cardioprotective OT-NP system and in preventing abnormal cardiac remodelling in the ob/ob mice.

  9. Combined chemotherapy for acute promyelocytic leukemia: a meta-analysis.

    Science.gov (United States)

    Li, Xueliang; Wang, Chao; Chen, Guanglong; Ji, Buqiang; Xu, Yongchang

    2017-09-01

    This study evaluates the efficacy of combined chemotherapy for the management of acute promyelocytic leukemia (APL). Literature search was carried out in several electronic databases. Meta-analyses were performed to achieve weighted effect sizes of overall survival (OS), disease-free survival (DFS), complete remission (CR) rate, and relapse rate. Metaregression analyses were performed to evaluate the factors affecting CR and relapse rates. Data from 37 studies (7566 patients) were used for meta-analysis. Median follow-up was 49.24 [95% confidence interval (CI): 41.33, 57.16] months. Five-year OS and DFS were 86.41 [83.97, 88.85] % and 75.42 [67.44, 83.40] %, respectively (pooled effect size [95% CI]). Following induction therapy, 89.77 [87.04, 92.50] % patients achieved CR in 38.25[37.84, 38.65] days and 6.34 [5.98, 6.70] % of the patients died during induction. Induction with all-trans retinoic acid (ATRA), arsenic trioxide (ATO), and daunorubicin (DNR) combination was associated with the highest rate of CR (96.16 [89.92, 92.40] %), followed by ATRA-DNR (94.29 [93.15, 95.43] %), ATRA-DNR-cytarabine (92.04 [88.38, 95.71] %), and ATRA-idarubicin (91.16 [89.92, 92.40] %). Overall relapse rate in the study population was 14.42 [11.97, 16.86] %. Baseline leukocyte count was inversely related to the CR rate. Combined chemotherapy for APL is associated with 90% CR, 14.4% relapse rate, 86% 5-year OS, and 75% 5-year DFS. Induction with ATRA-DNR-ATO is found better than other combinations with respect to CR and relapse rates. Initial leukocyte count may affect prognosis.

  10. PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia.

    Science.gov (United States)

    Bräuer-Hartmann, Daniela; Hartmann, Jens-Uwe; Wurm, Alexander Arthur; Gerloff, Dennis; Katzerke, Christiane; Verga Falzacappa, Maria Vittoria; Pelicci, Pier Giuseppe; Müller-Tidow, Carsten; Tenen, Daniel G; Niederwieser, Dietger; Behre, Gerhard

    2015-08-15

    In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3'-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell-cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL. ©2015 American Association for Cancer Research.

  11. Economic evaluation of arsenic trioxide compared to all-trans retinoic acid + conventional chemotherapy for treatment of relapsed acute promyelocytic leukemia in Canada.

    Science.gov (United States)

    Lachaine, Jean; Mathurin, Karine; Barakat, Stéphane; Couban, Stephen

    2015-09-01

    Acute promyelocytic leukemia (APL) is an uncommon type of acute leukemia characterized by high early mortality. Current first-line treatments include all-trans retinoic acid (ATRA), anthracyclines, and other conventional chemotherapies (CTs). Although APL is generally associated with a good prognosis, about 20% of patients who achieve remission subsequently relapse and are resistant to the previously administrated treatment. The objective of this study was to assess, from a Canadian perspective, the economic impact of arsenic trioxide (ATO) compared to ATRA+CT for treatment of patients with relapsed/refractory APL. The cost-effectiveness of ATO compared to ATRA+CT for treating patients with relapsed/refractory APL was assessed over a lifetime horizon using a Markov model. The model considers five health states: induction, second remission, treatment failure or relapse, postfailure, and death. Markov cycle length was 1 month for the first 24 months and 1 yr thereafter. The model also takes into account the incidence of grade 3-4 adverse events reported in clinical trials. Analyses were conducted from a Canadian Ministry of Health (MoH) and a societal perspective. Compared to ATRA+CT, ATO was associated with incremental cost-effectiveness ratios of $ 20,551/quality-adjusted life year (QALY) from a MoH perspective and $ 22,219/QALY from a societal perspective. Results of the probabilistic sensitivity analysis indicated that ATO is a cost-effective strategy in 99.27% and 98.98% of the simulations from a MoH and a societal perspective, respectively. This economic evaluation demonstrates that ATO is a cost-effective strategy compared to ATRA+CT for treatment of patients with relapsed/refractory APL in Canada. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors.

    Science.gov (United States)

    Sun, Bin; Liu, Kai; Han, Jing; Zhao, Li-yu; Su, Xiao; Lin, Bin; Zhao, Dong-Mei; Cheng, Mao-Sheng

    2015-10-15

    All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents. Herein, we describe the design, synthesis and biological evaluation of a series of new amide imidazole derivatives as retinoic acid metabolism blocking agents (RAMBAs) toward CYP26A1 enzyme. First, based on the recent theoretical models (Sun et al., J. Mol. Graph. Model., 2015, 56, 10-19) a series of RAMBAs with novel scaffolds were designed using fragment-based drug discovery approach. Subsequently, the new RAMBAs were synthesized and evaluated for their biological activities. All the compounds demonstrated appropriate enzyme activities and cell activities. The promising inhibitors 20 and 23 with IC50 value of 0.22 μM and 0.46 μM toward CYP26A1, respectively, were further evaluated for CYP selectivity and the metabolic profile of ATRA. Both compounds 20 and 23 showed higher selectivity for CYP26A1 over other CYPs (CYP2D6, CYP3A4) when compared to liarozole. They also showed better inhibitory activities for the metabolism of ATRA when also compared to liarozole. These studies further validated the pharmacophore and structure-activity relationship models obtained about CYP26A1 inhibitors and highlighted the promising activities of the new series of CYP26A1 inhibitors designed from such models. They also paved the way for future development of those candidates as potential drugs. Published by Elsevier Ltd.

  13. Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS.

    Science.gov (United States)

    Kane, Maureen A; Chen, Na; Sparks, Susan; Napoli, Joseph L

    2005-05-15

    We report a sensitive LC (liquid chromatography)/MS/MS assay using selected reaction monitoring to quantify RA (retinoic acid), which is applicable to biological samples of limited size (10-20 mg of tissue wet weight), requires no sample derivatization, provides mass identification and resolves atRA (all-trans-RA) from its geometric isomers. The assay quantifies over a linear range of 20 fmol to 10 pmol, and has a 10 fmol limit of detection at a signal/noise ratio of 3. Coefficients of variation are: instrumental, 0.5-2.9%; intra-assay, 5.4+/-0.4%; inter-assay 8.9+/-1.0%. An internal standard (all-trans-4,4-dimethyl-RA) improves accuracy by confirming extraction efficiency and revealing handling-induced isomerization. Tissues of 2-4-month-old C57BL/6 male mice had atRA concentrations of 7-9.6 pmol/g and serum atRA of 1.9+/-0.6 pmol/ml (+/-S.E.M.). Tissue 13-cis-RA ranged from 2.9 to 4.2 pmol/g, and serum 13-cis-RA was 1.2+/-0.3 pmol/ml. CRBP (cellular retinol-binding protein)-null mouse liver had atRA approximately 30% lower than wild-type (Pquantification of atRA in animal brain and in CRBP-null mice. Direct measurements of endogenous RA should have a substantial impact on investigating target tissues of RA, mechanisms of RA action, and the relationship between RA and chronic disease.

  14. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab.

    Science.gov (United States)

    Abaza, Yasmin; Kantarjian, Hagop; Garcia-Manero, Guillermo; Estey, Elihu; Borthakur, Gautam; Jabbour, Elias; Faderl, Stefan; O'Brien, Susan; Wierda, William; Pierce, Sherry; Brandt, Mark; McCue, Deborah; Luthra, Rajyalakshmi; Patel, Keyur; Kornblau, Steven; Kadia, Tapan; Daver, Naval; DiNardo, Courtney; Jain, Nitin; Verstovsek, Srdan; Ferrajoli, Alessandra; Andreeff, Michael; Konopleva, Marina; Estrov, Zeev; Foudray, Maria; McCue, David; Cortes, Jorge; Ravandi, Farhad

    2017-03-09

    The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m2 on day 1) added to high-risk patients (white blood cell count, >10 × 109/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen. © 2017 by The American Society of Hematology.

  15. Regulatory CD8{sup +} T cells induced by exposure to all-trans retinoic acid and TGF-{beta} suppress autoimmune diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Kishi, Minoru [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Yasuda, Hisafumi, E-mail: yasuda@med.kobe-u.ac.jp [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Abe, Yasuhisa; Sasaki, Hirotomo; Shimizu, Mami; Arai, Takashi; Okumachi, Yasuyo; Moriyama, Hiroaki; Hara, Kenta; Yokono, Koichi; Nagata, Masao [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan)

    2010-03-26

    Antigen-specific regulatory CD4{sup +} T cells have been described but there are few reports on regulatory CD8{sup +} T cells. We generated islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8{sup +} T cells from 8.3-NOD transgenic mice. CD8{sup +} T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-{beta}, and all-trans retinoic acid (ATRA) for 5 days. CD8{sup +} T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-{beta} and ATRA had low Foxp3{sup +} expression (1.7 {+-} 0.9% and 3.2 {+-} 4.5%, respectively). In contrast, CD8{sup +} T cells induced by exposure to IGRP, SpDCs, TGF-{beta}, and ATRA showed the highest expression of Foxp3{sup +} in IGRP-reactive CD8{sup +} T cells (36.1 {+-} 10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8{sup +} T cells cultured with IGRP, SpDCs, TGF-{beta}, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8{sup +} T cells suppressed the proliferation of diabetogenic CD8{sup +} T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-{beta} induces CD8{sup +}Foxp3{sup +} T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo.

  16. MicroRNA mediates DNA demethylation events triggered by retinoic acid during neuroblastoma cell differentiation.

    Science.gov (United States)

    Das, Sudipto; Foley, Niamh; Bryan, Kenneth; Watters, Karen M; Bray, Isabella; Murphy, Derek M; Buckley, Patrick G; Stallings, Raymond L

    2010-10-15

    Neuroblastoma is an often fatal pediatric cancer arising from precursor cells of the sympathetic nervous system. 13-Cis retinoic acid is included in the treatment regimen for patients with high-risk disease, and a similar derivative, all-trans-retinoic acid (ATRA), causes neuroblastoma cell lines to undergo differentiation. The molecular signaling pathways involved with ATRA-induced differentiation are complex, and the role that DNA methylation changes might play are unknown. The purpose of this study was to evaluate the genome-wide effects of ATRA on DNA methylation using methylated DNA immunoprecipitation applied to microarrays representing all known promoter and CpG islands. Four hundred and two gene promoters became demethylated, whereas 88 were hypermethylated post-ATRA. mRNA expression microarrays revealed that 82 of the demethylated genes were overexpressed by >2-fold, whereas 13 of the hypermethylated genes were underexpressed. Gene ontology analysis indicated that demethylated and re-expressed genes were enriched for signal transduction pathways, including NOS1, which is required for neural cell differentiation. As a potential mechanism for the DNA methylation changes, we show the downregulation of methyltransferases, DNMT1 and DNMT3B, along with the upregulation of endogenous microRNAs targeting them. Ectopic overexpression of miR-152, targeting DNMT1, also negatively affected cell invasiveness and anchorage-independent growth, contributing in part to the differentiated phenotype. We conclude that functionally important, miRNA-mediated DNA demethylation changes contribute to the process of ATRA-induced differentiation resulting in the activation of NOS1, a critical determinant of neural cell differentiation. Our findings illustrate the plasticity and dynamic nature of the epigenome during cancer cell differentiation.

  17. PML-RARa modulates the vascular signature of extracellular vesicles released by acute promyelocytic leukemia cells.

    Science.gov (United States)

    Fang, Yi; Garnier, Delphine; Lee, Tae Hoon; D'Asti, Esterina; Montermini, Laura; Meehan, Brian; Rak, Janusz

    2016-01-01

    Oncogenic transformation is believed to impact the vascular phenotype and microenvironment in cancer, at least in part, through mechanisms involving extracellular vesicles (EVs). We explored these questions in the context of acute promyelocytic leukemia cells (NB4) expressing oncogenic fusion protein, PML-RARa and exquisitely sensitive to its clinically used antagonist, the all-trans retinoic acid (ATRA). We report that NB4 cells produce considerable numbers of EVs, which are readily taken up by cultured endothelial cells triggering their increased survival. NB4 EVs contain PML-RARa transcript, but no detectable protein, which is also absent in endothelial cells upon the vesicle uptake, thereby precluding an active intercellular trafficking of this oncogene in this setting. ATRA treatment changes the emission profile of NB4-related EVs resulting in preponderance of smaller vesicles, an effect that occurs in parallel with the onset of cellular differentiation. ATRA also increases IL-8 mRNA and protein content in NB4 cells and their EVs, while decreasing the levels of VEGF and tissue factor (TF). Endothelial cell uptake of NB4-derived EVs renders these cells more TF-positive and procoagulant, and this effect is diminished by pre-treatment of EV donor cells with ATRA. Profiling angiogenesis-related transcripts in intact and ATRA-treated APL cells and their EVs reveals multiple differences attributable to cellular responses and EV molecular packaging. These observations point to the potential significance of changes in the angiogenic signature and activity associated with EVs released from tumor cells subjected to targeted therapy.

  18. 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

  19. Induction of CYP26A1 by Metabolites of Retinoic Acid: Evidence That CYP26A1 Is an Important Enzyme in the Elimination of Active Retinoids

    Science.gov (United States)

    Topletz, Ariel R.; Tripathy, Sasmita; Foti, Robert S.; Shimshoni, Jakob A.; Nelson, Wendel L.

    2015-01-01

    All-trans-retinoic acid (atRA), the active metabolite of vitamin A, induces gene transcription via binding to nuclear retinoic acid receptors (RARs). The primary hydroxylated metabolites formed from atRA by CYP26A1, and the subsequent metabolite 4-oxo-atRA, bind to RARs and potentially have biologic activity. Hence, CYP26A1, the main atRA hydroxylase, may function either to deplete bioactive retinoids or to form active metabolites. This study aimed to determine the role of CYP26A1 in modulating RAR activation via formation and elimination of active retinoids. After treatment of HepG2 cells with atRA, (4S)-OH-atRA, (4R)-OH-atRA, 4-oxo-atRA, and 18-OH-atRA, mRNAs of CYP26A1 and RARβ were increased 300- to 3000-fold, with 4-oxo-atRA and atRA being the most potent inducers. However, >60% of the 4-OH-atRA enantiomers were converted to 4-oxo-atRA in the first 12 hours of treatment, suggesting that the activity of the 4-OH-atRA was due to 4-oxo-atRA. In human hepatocytes, atRA, 4-OH-atRA, and 4-oxo-atRA induced CYP26A1 and 4-oxo-atRA formation was observed from 4-OH-atRA. In HepG2 cells, 4-oxo-atRA formation was observed even in the absence of CYP26A1 activity and this formation was not inhibited by ketoconazole. In human liver microsomes, 4-oxo-atRA formation was supported by NAD+, suggesting that 4-oxo-atRA formation is mediated by a microsomal alcohol dehydrogenase. Although 4-oxo-atRA was not formed by CYP26A1, it was depleted by CYP26A1 (Km = 63 nM and intrinsic clearance = 90 μl/min per pmol). Similarly, CYP26A1 depleted 18-OH-atRA and the 4-OH-atRA enantiomers. These data support the role of CYP26A1 to clear bioactive retinoids, and suggest that the enzyme forming active 4-oxo-atRA may be important in modulating retinoid action. PMID:25492813

  20. Development of a validated UPLC method for simultaneous estimation of both free and entrapped (in solid lipid nanoparticles) all-trans retinoic acid and cholecalciferol (vitamin D3) and its pharmacokinetic applicability in rats.

    Science.gov (United States)

    Kumar, Manoj; Sharma, Gaurav; Singla, Dinesh; Singh, Sukhjeet; Sahwney, Sudhir; Chauhan, Anurag S; Singh, Gagandeep; Kaur, Indu Pal

    2014-03-01

    A sensitive ultra-performance liquid chromatography (UPLC) method was developed for simultaneous estimation of all-trans retinoic acid (ATRA) and cholecalciferol (vitamin D3) in rat plasma. The method was validated over the linear range of 1.0-5000ng/ml (r(2)=0.999) for both vitamins with a limit of detection of 0.5ng/ml. Chromatographic separation was achieved using liquid-liquid extraction (LLE) on an Acquity BEH RP 18 column (2.1mm×50mm, I.D. 1.7μm), with mobile phase comprising of acetonitrile:methanol:water (90:8:2, v/v/v), at a flow rate of 0.20ml/min and a total run time of 5min. Intra and inter-day variability (RSD) was ≤3.1%, and the accuracy varied between 95.4-99.9% and 95.3-101.1% respectively, for ATRA and 98.5-100.8% and 99.3-101.7%, respectively for vitamin D3. High recovery of ≥96.0% for ATRA and ≥87.80% for vitamin D3 was achieved. ATRA and vitamin D3 were stable in plasma under different storage and processing conditions. The method was applied to estimate the total drug content and entrapment efficiency of ATRA and vitamin D3 loaded solid lipid nanoparticles (SLNs). Concentration of these two agents was determined in rat plasma after simultaneous subcutaneous administration in free form or when loaded into SLNs thus establishing pharmacokinetic application of the developed procedure. Results indicated an improvement in AUC0-∞ by 5.4 times and 29.4 times for ATRA and vitamin D3, respectively, upon their incorporation into SLNs. Simultaneous administration of these two vitamins and their improved and prolonged bioavailability has scope for their use in treatment and control of tuberculosis. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Inhibitory effects of retinoic acid on invasiveness of human thyroid carcinoma cell lines in vitro.

    Science.gov (United States)

    Lan, L; Cui, D; Luo, Y; Shi, B Y; Deng, L L; Zhang, G Y; Wang, H

    2009-10-01

    The prognosis of patients with metastasized thyroid carcinoma is not optimistic, necessitating the search for new treatment options. Beneficial effects of retinoic acid (RA) have been suggested in thyroid cancer differentiation and the present study was performed to investigate the anti-metastatic potential of RA in respect of important determinants of metastatic behavior in thyroid carcinoma, focusing on the role of invasion-associated proteins. Differentiated thyroid carcinoma cell lines FTC- 133 and XTC.UC1, and anaplastic thyroid cancer cell lines C643 and HTH74 were studied. All cell lines were cultured with alltrans- RA (ATRA) or the solvent ethanol. Invasion and adhesion potency in vitro was studied by transwell experiment and short-term adhesion assay. The involvement of invasion-associated proteins, urokinase type plasminogen activator (uPA), uPA receptor (uPAR), matrix metalloproteinase-2 (MMP-2) and E-cadherin, were investigated by semi-quantitative RT-PCR and Western blot. In vitro invasion assay revealed that ATRA treatment could reduce the invasive potency in all the thyroid cancer cell lines, with the most significant effect in anaplastic cancer cells. Short-term adhesion assay suggested that ATRA increases cancer cell adhesion to extracellular matrix (ECM) in C643, HTH74 and XTC.UC1, probably through a transcriptional and translational regulation of some attachment molecules. RT-PCR andWestern blot both revealed diminished expression of uPAR in all four carcinoma cell lines. In C643 and HTH74 cell lines, the expression of uPA was reduced and the expression of E-cadherin was increased, whereas the MMP-2 expression was not significantly down-regulated in ATRA-treated group. In ATRA-treated FTC-133 and XTC.UC1 cell lines, MMP-2 expression was decreased, but no significant changes in uPA and E-cadherin expression were observed. The present study demonstrates the influence of ATRA on both important determinants of metastatic behavior ("de-adhesion" and

  2. Subsidized optimal ART for HIV-positive temporary residents of Australia improves virological outcomes: results from the Australian HIV Observational Database Temporary Residents Access Study

    Directory of Open Access Journals (Sweden)

    Kathy Petoumenos

    2015-02-01

    Full Text Available Introduction: HIV-positive (HIV+ temporary residents living in Australia legally are unable to access government subsidized antiretroviral treatment (ART which is provided via Medicare to Australian citizens and permanent residents. Currently, there is no information systematically being collected on non-Medicare eligible HIV+ patients in Australia. The objectives of this study are to describe the population recruited to the Australian HIV Observational Database (AHOD Temporary Residents Access Study (ATRAS and to determine the short- and long-term outcomes of receiving (subsidized optimal ART and the impact on onwards HIV transmission. Methods: ATRAS was established in 2011. Eligible patients were recruited via the AHOD network. Key HIV-related characteristics were recorded at baseline and prospectively. Additional visa-related information was also recorded at baseline, and updated annually. Descriptive statistics were used to describe the ATRAS cohort in terms of visa status by key demographic characteristics, including sex, region of birth, and HIV disease status. CD4 cell count (mean and SD and the proportion with undetectable (<50 copies/ml HIV viral load are reported at baseline, 6 and 12 months of follow-up. We also estimate the proportion reduction of onward HIV transmission based on the reduction in proportion of people with detectable HIV viral load. Results: A total of 180 patients were recruited to ATRAS by June 2012, and by July 2013 39 patients no longer required ART via ATRAS, 35 of whom became eligible for Medicare-funded medication. At enrolment, 63% of ATRAS patients were receiving ART from alternative sources, 47% had an undetectable HIV viral load (<50 copies/ml and the median CD4 cell count was 343 cells/µl (IQR: 222–479. At 12 months of follow-up, 85% had an undetectable viral load. We estimated a 75% reduction in the risk of onward HIV transmission with the improved rate of undetectable viral load. Conclusions: The

  3. All-Trans Retinoic Acid Promotes an M1- to M2-Phenotype Shift and Inhibits Macrophage-Mediated Immunity to Leishmania major

    Directory of Open Access Journals (Sweden)

    Natália S. Vellozo

    2017-11-01

    Full Text Available As key cells, able to host and kill Leishmania parasites, inflammatory monocytes/macrophages are potential vaccine and therapeutic targets to improve immune responses in Leishmaniasis. Macrophage phenotypes range from M1, which express NO-mediated microbial killing, to M2 macrophages that might help infection. Resistance to Leishmaniasis depends on Leishmania species, mouse strain, and both innate and adaptive immunity. C57BL/6 (B6 mice are resistant and control infection, whereas Leishmania parasites thrive in BALB/c mice, which are susceptible to develop cutaneous lesions in the course of infection with Leishmania major, but not upon infection with Leishmania braziliensis. Here, we investigated whether a deficit in early maturation of inflammatory monocytes into macrophages in BALB/c mice underlies increased susceptibility to L. major versus L. braziliensis parasites. We show that, after infection with L. braziliensis, monocytes are recruited to peritoneum, differentiate into macrophages, and develop an M1 phenotype able to produce proinflammatory cytokines in both B6 and BALB/c mice. Nonetheless, more mature macrophages from B6 mice expressed inducible NO synthase (iNOS and higher NO production in response to L. braziliensis parasites, whereas BALB/c mice developed macrophages expressing an incomplete M1 phenotype. By contrast, monocytes recruited upon L. major infection gave rise to immature macrophages that failed to induce an M1 response in BALB/c mice. Overall, these results are consistent with the idea that resistance to Leishmania infection correlates with improved maturation of macrophages in a mouse-strain and Leishmania-species dependent manner. All-trans retinoic acid (ATRA has been proposed as a therapy to differentiate immature myeloid cells into macrophages and help immunity to tumors. To prompt monocyte to macrophage maturation upon L. major infection, we treated B6 and BALB/c mice with ATRA. Unexpectedly, treatment with ATRA

  4. Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Stephen E. Langabeer

    2017-01-01

    Full Text Available Several variant RARA translocations have been reported in acute promyelocytic leukemia (APL of which the t(11;17(q23;q21, which results in a ZBTB16-RARA fusion, is the most widely identified and is largely resistant to therapy with all-trans retinoic acid (ATRA. The clinical course together with the cytogenetic and molecular characterization of a case of ATRA-unresponsive ZBTB16-RARA APL is described. Additional mutations potentially cooperating with the translocation fusion product in leukemogenesis have been hitherto unreported in ZBTB16-RARA APL and were sought by application of a next-generation sequencing approach to detect those recurrently found in myeloid malignancies. This technique identified a solitary, low level mutation in the CEBPA gene. Molecular profiling of additional mutations may provide a platform to individualise therapeutic management in patients with this rare form of APL.

  5. Acute Promyelocytic Leukemia Presenting as Focal Neurologic Findings and Deteriorating Mental Status.

    Science.gov (United States)

    Dolan, Matthew; Ngaruiya, Christine

    2017-01-01

    Acute promyelocytic leukemia (APL) is a rare but particularly malignant form of acute leukemia that is characterized by a rapid progression to fatal hemorrhage. Survival rates of patients with APL have increased with the introduction of all-trans retinoic acid (ATRA), but early deaths caused by hemorrhage still persist. A man with undiagnosed APL presenting with focal neurologic findings and deteriorating altered mental status caused by an intracranial hemorrhage is discussed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important to consider APL when diagnosing etiologies for intracranial hemorrhage. In addition to standard care, early administration of ATRA is recommended upon clinical suspicion of the disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. AcEST: BP921136 [AcEST

    Lifescience Database Archive (English)

    Full Text Available 04|PA2N_NAJAT Phospholipase A2 natratoxin OS=Naja atra Align length 87 Score (bit) 36.2 E-value 0.099 Report...NAJAT Phospholipase A2 natratoxin OS=Naja atra PE... 36 0.099 sp|Q9I900|PA2D_NAJSP Phospholipase A2, acidic D OS=Naja... sputatri... 36 0.099 sp|Q92086|PA2C_NAJSP Phospholipase A2, acidic C OS=Naja sputatri... 36 0.099 ...sp|Q92085|PA2B_NAJSP Phospholipase A2, neutral B OS=Naja sputatr... 36 0.13 sp|Q9...2084|PA2A_NAJSP Phospholipase A2, neutral A OS=Naja sputatr... 36 0.13 sp|P00596|PA21_NAJKA Phospholipase A2 isozyme 1 OS=Naja

  7. Therapy-related myeloid neoplasms as a concerning complication in acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    María del Carmen Vicente-Ayuso

    2017-09-01

    Full Text Available Acute promyelocytic leukemia (APL has become a highly curable malignant disease after the introduction of all transretinoic acid (ATRA to chemotherapy treatment. However, the risk to develop therapy-related myeloid neoplasms (t-MN has become a matter of concern, as APL patients are otherwise expected to have a good prognosis. We report a patient with APL who achieved complete remission after chemotherapy induction with anthracycline and ATRA, followed by consolidation and maintenance chemotherapy. Two years later, the patient developed t-AML, with MLL rearrangements, without any evidence of relapse of the APL original clone. The increasing incidence of t-MN in oncohematological patients is partly due to the development of safer, more efficient or targeted therapies, which allow better outcomes and lengthened survival amongst treated patients. The identification of genetic factors, mechanisms or prognostic biomarkers in t-MN might open new windows for the development of personalized targeted therapy regimes in this underserved patient population.

  8. Concordancia interobservador de hallazgos en radiografía de tórax pediátrica

    OpenAIRE

    Venera, Amalfi D.; Rincón, David A.; Torres, Liliana I.; Arango, Magnolia

    2014-01-01

    Antecedentes. La radiografía de tórax es unaprueba diagnóstica útil, por la alta incidencia yprevalencia de enfermedades respiratorias enla población pediátrica.Objetivo. Evaluar la concordancia entre médicoscon diferentes niveles de experiencia enla interpretación de estudios radiográficos detórax.Material y métodos. Se evaluó la concordanciade seis médicos (tres residentes de pediatría,un pedíatra, un neumólogo pedíatra yun radiólogo) en cuanto a la presencia de buenatécnica radiológica, at...

  9. Cotylenin A--a plant growth regulator as a differentiation-inducing agent against myeloid leukemia.

    Science.gov (United States)

    Honma, Yoshio

    2002-06-01

    Acute myeloid leukemia (AML) is characterized by the arrest of differentiation leading to the accumulation of immature cells. This maturation arrest can be reversed by certain agents. Although differentiation therapy for patients with acute promyelocytic leukemia (APL) using all-trans retinoic acid (ATRA) has been established, the clinical response of AML patients other than those with APL to ATRA is limited. We must consider novel therapeutic drugs against other forms of AML for the development of a differentiation therapy for leukemia. Regulators that play an important role in the differentiation and development of plants or invertebrates may also affect the differentiation of human leukemia cells through a common signal transduction system, and might be clinically useful for treating AML. Cotylenin A, a plant growth regulator, is a potent and novel inducer of the monocytic differentiation of human myeloid leukemia cell lines and leukemia cells freshly isolated from AML patients.

  10. Activation of retinoic acid receptor signaling coordinates lineage commitment of spontaneously differentiating mouse embryonic stem cells in embryoid bodies.

    Science.gov (United States)

    Simandi, Zoltan; Balint, Balint Laszlo; Poliska, Szilard; Ruhl, Ralph; Nagy, Laszlo

    2010-07-16

    Retinoid signaling has been implicated in embryonic stem cell differentiation. Here we present a systematic analysis of gene expression changes in mouse embryonic stem cells (mESCs), during their spontaneous differentiation into embryoid bodies and the effect of all-trans retinoic acid (ATRA) on this process. We show that retinoic acid is present in the serum and is sufficient to activate retinoid signaling at a basal level in undifferentiated mESCs. This signal disappears during embryoid body formation. However exogenously added ATRA resets the spontaneous differentiation programs in embryoid bodies and initiates a distinct genetic program. These data suggest that retinoid signaling not only promotes a particular pathway but also acts as a context dependent general coordinator of the differentiation states in embryonic stem cells. Copyright 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  11. Acute promyelocytic leukemia mutated to radioresistance suppressed monocyte lineage differentiation by phorbol 12-myristate 13-acetate.

    Science.gov (United States)

    Monzen, Satoru; Takimura, Kodai; Kashiwakura, Ikuo; Hosokawa, Yoichiro

    2013-09-01

    Induction of myeloid differentiation in radioresistant HL60 cells (Res-HL60) was examined to clarify the developmental mechanism of radioresistant leukemia. Compared to wild-type HL60 cells (Wt-HL60), Res-HL60 were smaller and strongly expressed CD38. Under all-trans retinoic acid (ATRA) stimulation, Res-HL60 continued to proliferate slowly and with similar level of CD11b expression to Wt-HL60. Phorbol 12-myristate 13-acetate (PMA) strongly suppressed proliferation of Res-HL60, downregulated CD14, and affected mRNA expression. These results suggested that the specific myeloid differentiation of Res-HL60 suppressed monocyte lineage by ATRA and PMA occurred through regulation of mRNA expression. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Successful Control of Disseminated Intravascular Coagulation by Recombinant Thrombomodulin during Arsenic Trioxide Treatment in Relapsed Patient with Acute Promyelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Motohiro Shindo

    2012-01-01

    Full Text Available Disseminated intravascular coagulation (DIC frequently occurs in patients with acute promyelocytic leukemia (APL. With the induction of therapy in APL using all-trans retinoic acid (ATRA, DIC can be controlled in most cases as ATRA usually shows immediate improvement of the APL. However, arsenic trioxide (ATO which has been used for the treatment of relapse in APL patients has shown to take time to suppress APL cells, therefore the control of DIC in APL with ATO treatment is a major problem. Recently, the recombinant soluble thrombomodulin fragment has received a lot of attention as the novel drug for the treatment of DIC with high efficacy. Here, we present a relapsed patient with APL in whom DIC was successfully and safely controlled by rTM during treatment with ATO.

  13. Estímulos olfativos envolvidos no comportamento sexual e na seleção hospedeira de Diabrotica speciosa (Germar) (Coleoptera: Chrysomelidae)

    OpenAIRE

    Cristiane Nardi

    2010-01-01

    Neste trabalho foi caracterizado o comportamento de Diabrotica speciosa, quando submetida a estímulos químicos de atração sexual ou de localização hospedeira. As atividades desenvolvidas foram: (i) Determinação da idade, horário, duração, número de cópulas, sexo responsável pela atração sexual e sequência de atividades envolvidas no comportamento sexual; (ii) investigação sobre o padrão de resposta dos machos ao feromônio sexual das fêmeas em olfatômetro e em eletroantenograma; (iii) investig...

  14. Effect of all-trans retinoic acid on newly diagnosed acute promyelocytic leukemia patients: results of a Brazilian center

    Directory of Open Access Journals (Sweden)

    B.C. de-Medeiros

    1998-12-01

    Full Text Available Thirty-seven patients with acute promyelocytic leukemia (APL were treated with all-trans retinoic acid (ATRA. Patients received 45 mg m-2 day-1 po of ATRA until complete remission (CR was achieved, defined as: a presence of less than 5% blasts in the bone marrow, with b white blood cells >103/mm3, c platelets >105/mm3 and d hemoglobin concentration >8 g/dl, with no blood or platelet transfusions. Thirty-one (83.7% patients achieved CR by day 50, and 75% of these before day 30. Correction of the coagulopathy, achieved between days 2 and 10 (mean, 3 days, was the first evidence of response to treatment. Only one patient had been previously treated with chemotherapy and three had the microgranular variant M3 form. Dryness of skin and mucosae was the most common side effect observed in 82% of the patients. Thrombosis, hepatotoxicity and retinoid acid syndrome (RAS were observed in 7 (19%, 6 (16% and 4 (11% patients, respectively. Thirteen (35% patients had to be submitted to chemotherapy due to hyperleukocytosis (above 40 x 103/mm3 and six of these presented with new signs of coagulopathy after chemotherapy. Four (11% patients died secondarily to intracerebral hemorrhage (IH and two (5.4% dropped out of the protocol due to severe ATRA side effects (one RAS and one hepatotoxicity. RAS and IH were related strictly to hyperleukocytosis. The reduced use of platelets and fresh frozen plasma probably lowered the total cost of treatment. We conclude that ATRA is an effective agent for inducing complete remission in APL patients.

  15. Validation of a Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry Method for Determination of All-Trans Retinoic Acid in Human Plasma and Its Application to a Bioequivalence Study

    Directory of Open Access Journals (Sweden)

    Jing-Bo Peng

    2014-01-01

    Full Text Available A sensitive, reliable and specific LC-MS-MS method was developed and validated for the identification and quantitation of all-trans retinoic acid (ATRA in human plasma. Acitretin was used as the internal standard (IS. After liquid-liquid extraction of 500 μL plasma with methyl tert-butyl ether (MTBE, ATRA and the IS were chromatographed on a HyPURITY C18 column (150 mm × 2.1 mm, 5 μm with the column temperature set at 40 °C. The mobile phase was consisted of 40% phase A (MTBE–methanol–acetic acid, 50:50:0.5, v/v and 60% phase B (water–methanol–acetic acid, 50:50:0.5, v/v with a flow rate of 0.3 mL/min. The API 4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM mode via the positive electrospray ionization interface using the transition m/z 301.4 → 123.1 for ATRA and m/z 326.9 → 177.1 for IS, respectively. The calibration curve was linear over the range of 0.45–217.00 ng/mL (r ≥ 0.999 with a lower limit of quantitation (LLOQ of 0.45 ng/mL. The intra- and inter-day precisions values were below 8% relative standard deviation and the accuracy was from 98.98% to 106.19% in terms of relative error. The validated method was successfully applied in a bioequivalence study of ATRA in Chinese healthy volunteers.

  16. Presence of plastic particles in waterbirds faeces collected in Spanish lakes

    OpenAIRE

    Gil-Delgado, J.A.; Guijarro, Daniel; Gosálvez, Rafael U.; López-Iborra, Germán; Ponz, A.; Velasco García, Ángel

    2016-01-01

    Plastic intake by marine vertebrates has been widely reported, but information about its presence in continental waterfowl is scarce. Here we analyzed faeces of waterbirds species (European coot, Fulica atra, mallard, Anas platyrhynchos and shelduck, Tadorna tadorna) for plastic debris in five wetlands in Central Spain. We collected 89 faeces of shelduck distributed in four lakes, 43.8% of them presented plastic remnants. Sixty percent of 10 faeces of European coot and 45% of 40 faeces of mal...

  17. Page 1 The Fungicide Kitazin and the Mycoflora of Rice 301 TABLE ...

    Indian Academy of Sciences (India)

    D. halodes (Drechs.) Subram. 'É. and Jain * 曦... 1 1 施○ 影编| 1 1. D. hawaiiensis (Bugnicourt). Subram. and Jain ... 3 . . 磁蟾1 1. 噬命○ 岭1. Alternaria tenuis Nees ... 2 * * ○ ○ 1 2 2 . . 1. Humicola fusco-atra Traaen 4 2 3 ... 1 3 1. 2 2. Sepedonium chrysospermum. (Bulliard) Fries .. * * * * 学瓷歌够1. Trichoderma viride Pers.

  18. 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.

  19. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients.

    Science.gov (United States)

    Testa, Ugo; Lo-Coco, Francesco

    2016-04-01

    All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.

  20. Impacto ambiental da apicultura

    OpenAIRE

    Leticia M. Estevinho

    1999-01-01

    A cultura da abelha doméstica Apis. mellifera L. ou apicultura é conhecida desde a antiguidade, sendo o mel uni alimento natural corrente entre os povos primitivos. Pinturas rupestres mostram que desde o neolítico o homem era atraído pelo mel, pois tentava recolher ninhos de abelhas selvagens e instalava-os em cavidades naturais das rochas, muito perto da sua habitação.

  1. The all-trans retinoic acid (atRA)-regulated gene Calmin (Clmn) regulates cell cycle exit and neurite outgrowth in murine neuroblastoma (Neuro2a) cells

    Energy Technology Data Exchange (ETDEWEB)

    Marzinke, Mark A. [Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706-1544 (United States); Clagett-Dame, Margaret, E-mail: dame@biochem.wisc.edu [Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706-1544 (United States); Pharmaceutical Science Division, University of Wisconsin-Madison, Madison, WI 53705-2222 (United States)

    2012-01-01

    The vitamin A metabolite all-trans retinoic acid (atRA) functions in nervous system development and regulates cell proliferation and differentiation. Neuroblastoma cells (SH-SY5Y and Neuro2a or N2A) exposed to atRA undergo growth inhibition and neuronal differentiation, both of which are preceded by an increase in Clmn mRNA. Treatment of N2A cells with atRA produces a reduction in phosphohistone 3 immunostaining and BrdU incorporation, both indicators of a reduction in cell proliferation. These effects are nearly eliminated in atRA-treated shClmn knockdown cells. Loss of Clmn in the mouse N2A cell line also results in a significant reduction of atRA-mediated neurite outgrowth, a response that can be rescued by reintroduction of the Clmn sequence. In contrast, ectopic overexpression of Clmn produces an increase in the cyclin dependent kinase inhibitor, p21{sup Cip1}, a decrease in cyclin D1 protein and an increase in hypophosphorylated Rb, showing that Clmn participates in G{sub 1}/S arrest. Clmn overexpression alone is sufficient to inhibit N2A cell proliferation, whereas both Clmn and atRA must be present to induce neurite outgrowth. This study shows that the atRA-responsive gene Clmn promotes exit from the cell cycle, a requisite event for neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer Calmin is a retinoic acid-responsive gene. Black-Right-Pointing-Pointer Calmin promotes cell cycle exit in N2A cells. Black-Right-Pointing-Pointer Calmin overexpression increases p21Cip1 and decreases cyclin D1. Black-Right-Pointing-Pointer Calmin is required for RA-induced growth inhibition and neurite outgrowth.

  2. Materialidad y espacio

    OpenAIRE

    Lelli, Gabriele

    2017-01-01

    [ES] El espacio es el protagonista de la arquitectura de Kazunori Fujimoto. En términos de su esencia, el espacio está arraigado a la profunda e intensa espiritualidad japonesa que tanto atrae a los arquitectos occidentales y que influye en sus arquitecturas. Lelli, G. (2017). Materialidad y espacio. EN BLANCO. Revista de Arquitectura. 9(22):5-9. doi:10.4995/eb.2017.7594. 5 9 9 22

  3. Differential expression of neuronal dopamine and serotonin transporters DAT and SERT in megakaryocytes and platelets generated from human MEG-01 megakaryoblasts.

    Science.gov (United States)

    Hohmann, Sarah; Schweinfurth, Nina; Lau, Thorsten; Deuschle, Michael; Lederbogen, Florian; Banaschewski, Tobias; Schloss, Patrick

    2011-11-01

    In the central nervous system, serotonergic and dopaminergic signaling is terminated by the activity of specialized transporter proteins for serotonin (SERT) and dopamine (DAT). These transporter proteins are found both on the cell surface and in intracellular transport vesicles. Trafficking between these subcellular domains regulates the efficiency of removal of extracellular neurotransmitters and hence the efficacy of neuronal signaling. Therefore, it is of high interest to gain more insight into the regulatory mechanisms of the human DAT and SERT cell surface expression in their natural surroundings, i.e., in human cells. Because it is not possible to cultivate human neuronal cells expressing these transporter proteins, there is a need to find other human cells expressing these neuronal proteins. Here, we have investigated the expression of human SERT and DAT on developing megakaryocytes and platelet-like particles derived from the megakaryocyte progenitor cell line MEG-01 upon differentiation by valproic acid (VPA) and all-trans retinoic acid (ATRA). Our results show that MEG-01 cells express SERT and DAT and that VPA and ATRA induce a significant increase of transporter expression on developing megakaryocytes and platelets. As compared to ATRA, VPA more efficiently induced SERT expression but not DAT expression. Comparable to naïve platelets and neurons, SERT was localized to both the cell surface and intracellular compartments. Hence, VPA and ATRA-treated MEG-01 cells provide a model well-suited to studying neuronal monoamine transporter expression, not only during transcription and translation but also with respect to protein trafficking to and from the cell surface.

  4. DEVOTEES, WANNABES Y PRETENDERS: PARAFILIAS VINCULADAS A LA DISCAPACIDAD

    OpenAIRE

    Carolina Mora

    2016-01-01

    Con el desarrollo de internet se ha ido haciendo evidente la vinculación entre discapacidad y sexualidad, en la que las designaciones “devotees”, “pretedenders” y “wannabes” (DPW) juegan un rol central. Los devotees son individuos sanos que se sienten atraídos sexualmente hacia personas con discapacidad, generalmente con problemas de movilidad. Los pretenders son personas que actúan como si tuvieran una discapacidad imitando sus movimientos, usando muletas, sillas de ruedas, escayola...

  5. Investigation of Turbo Machinery and Jet Noise of the V2500 Engine During Ground Tests with an A320 Aircraft

    OpenAIRE

    Siller, Henri; Bassetti, Alessandro; Funke, Stefan

    2015-01-01

    The noise emission of a V2500 engine during ground operation was investigated with the A320 research aircraft ATRA of the German aerospace center DLR. Acoustic measurements with a microphone array parallel to the engine shaft axis were performed with the engines running at different speeds between idle and maximum continuous thrust. The main measurements took place in a noise-protection hangar, because optical measurents with laser devices were performed in parallel. In order t...

  6. Growth inhibition of Tax-activated human Jurkat leukemia T cells by all-trans retinoic acid requires JNK-1 inhibition.

    Science.gov (United States)

    Parra, Eduardo; Gutiérrez, Luis

    2013-01-01

    Retinoids, including vitamin A (retinol) and its analogues, are critical for a variety of biological functions. In this study, we report that all-trans retinoic acid (ATRA) decreases Jun N-terminal kinase 1 (JNK-1) activity, antagonizing the effect of the Tax protein in Jurkat leukemia T cells transiently transfected for expressing the Tax protein. The Tax protein is one of the products of the human T-cell leukemia virus type 1 (HTLV-1) which is the etiologic agent of adult T-cell leukemia (ATL), an aggressive neoplasia of CD4+ T cells. The decrease in JNK-1 activity was followed by a marked decrease in the expression of interleukin (IL)-2 and a weak increase in interferon (IFN)-γ in Jurkat cells treated with ATRA in a dose-dependent manner, suggesting a correlation between the expression of JNK-1 and the activity of the Tax protein. However, the expression levels of IL-4 and IL-10 were enhanced in cells transfected with Tax, compared with the levels in untransfected cells, but the expression levels were not affected following ATRA treatment. In transfection studies using a luciferase reporter construct expressing the IL-2 promoter or a tandem repeat of AP-1 or NF-κB, the inhibitory effect of ATRA on the IL-2 promoter and AP-1 construct was confirmed at the transcriptional level. However, the inhibitory effect in the NF-κB reporter construct was only marginal. In addition, our data demonstrated that JNK-1 is constitutively activated in Jurkat leukemia T cells expressing the Tax protein, suggesting that JNK-1 is required for Tax-induced proliferation of Jurkat leukemia cells.

  7. Graphene samples preparation and some possible uses in developing optical communication devices/Preparación de muestras de grafeno y algunos posibles usos en el desarrollo de dispositivos en comunicaciones ópticas

    National Research Council Canada - National Science Library

    Juan Diego Zapata-Caro; Ana María Cárdenas-Soto; Rodrigo Henao-Henao; Eunezio Antonio Thoroh de Souza

    2015-01-01

    ... spectroscopy, flakes and exfoliation method Resumen El grafeno es un material bidimensional que ha atraído la atención de toda la comunidad científica alrededor del mundo; este interés es motivado por sus propiedades ópticas y electrónicas. Existen diferentes métodos para obtener grafeno, sin embargo el proceso más simple para su obtención es exfoliación m...

  8. Mode of Action of Membrane Perturbing Agents: Snake Venom Cardiotoxins and Phospholipases A

    Science.gov (United States)

    1989-07-15

    phospholipids preradiolabeled by feeding the cells 1.4C-fatty acids overnight. To develop potential prophylactic and therapeutic agents, pharmacological studies...PLAz neurotoxins. Experimental Methods: Materials. Vencm from 1 nAjA atra, CTX from Naja n9ja kaouthia venom (Lots 125F-4007), bee venom PLAz ( Apis ... mellifera ), melittin, B-bungarotoxin, Tris base, Hepes (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid), Mes (4- morpholineethanesulfonic acid), bovine

  9. El boom de la comunicación en español en Estados Unidos

    OpenAIRE

    Prado, Emili

    2007-01-01

    Los medios de comunicación en español en EEUU viven un periodo expansivo. Este Cuaderno Central propone suministrar un mapa sobre el estado del arte de la comunicación hispana, así como algunas claves que nos permitan interpretar la trascendencia de un fenómeno que atrae más atención de inversores y políticos que de estudiosos.

  10. Inorganic Carbon Turnover caused by Digestion of Carbonate Sands and Metabolic Activity of Holothurians

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, Kenneth; Silverman, Jacob; Kravitz, Benjamin S.; Rivlin, Tanya; Schneider-Mor, Aya; Barbosa, Sergio; Byrne, Maria; Caldeira, Ken

    2013-11-20

    Recent measurements have shown that holothurians (sea cucumbers) play an important role in the cycling of CaCO3 in tropical coral reef systems through ingestion and processing of carbonate sediment. In this study inorganic additional aspects of carbon turnover were determined in laboratory incubations of Holothuria atra, H. leucospilota and Stichopus herrmanni from One Tree Reef, Great Barrier Reef. The pH values of the gut lumen ranged from 6.1 to 6.7 in animals with empty digestive tracts as opposed to 7.0 to 7.6 when digestive tracts were filled with sediment. Empty gut volume estimates for H. atra and S. herrmanni were 36 ± 4 mL and 151 ± 14 mL, respectively. Based on these measurements it is estimated that these species process 19 ± 2kg and 80 ± 7kg CaCO3 sand yr-1 per individual, respectively. The annual dissolution rates of H. atra and S. herrmanni of 6.5±1.9g and 9.6±1.4g, respectively, suggest that 0.05±0.02% and 0.1±0.02% of the CaCO3 processed through their gut annually is dissolved. During the incubations the CaCO3 dissolution was 0.07±0.01%, 0.04±0.01% and 0.21±0.05% of the fecal casts for H. atra, H. leucospilota and S. herrmanni, respectively. The CaCO3 saturation state for both aragonite and calcite minerals during laboratory incubations decreased markedly due to a greater increase in dissolved inorganic carbon (DIC) relative to total alkalinity (AT) as a result of respiration by the animals. Our results support the hypothesis that deposit feeders such as sea cucumbers play an important ecological role in the coral reef CaCO3 cycle.

  11. Microbial modification of host long-distance dispersal capacity

    OpenAIRE

    Hutchings Linda; Bonte Dries; Martin Oliver Y; Goodacre Sara L; Woolley Chris; Ibrahim Kamal; George Thomas CF; Hewitt Godfrey M

    2009-01-01

    Abstract Background Dispersal plays a key role in shaping biological and ecological processes such as the distribution of spatially-structured populations or the pace and scale of invasion. Here we have studied the relationship between long-distance dispersal behaviour of a pest-controlling money spider, Erigone atra, and the distribution of maternally acquired endosymbionts within the wider meta-population. This spider persists in heterogeneous environments because of its ability to recoloni...

  12. Raspberry ketone promotes the differentiation of C3H10T1/2 stem cells into osteoblasts.

    Science.gov (United States)

    Takata, Tomoyo; Morimoto, Chie

    2014-03-01

    The decrease in the bone mass associated with osteoporosis caused by ovariectomy, aging, and other conditions is accompanied by an increase in bone marrow adipose tissue. The balance between osteoblasts and adipocytes is influenced by a reciprocal relationship. The development of modalities to promote local/systemic bone formation by inhibiting bone marrow adipose tissue is important in the treatment of fractures or metabolic bone diseases such as osteoporosis. In this study, we examined whether raspberry ketone [4-(4-hydroxyphenyl)butan-2-one; RK], which is one of the major aromatic compounds of red raspberry and exhibits anti-obesity action, could promote osteoblast differentiation in C3H10T1/2 stem cells. Confluent C3H10T1/2 stem cells were treated for 6 days with 10-100 μg/mL of RK in culture medium containing 10 nM all-trans-retinoic acid (ATRA) or 300 ng/mL recombinant human bone morphogenetic protein (rhBMP)-2 protein as an osteoblast-differentiating agent. RK in the presence of ATRA increased alkaline phosphatase (ALP) activity in a dose-dependent manner. RK in the presence of rhBMP-2 also increased ALP activity. RK in the presence of ATRA also increased the levels of mRNAs of osteocalcin, α1(I) collagen, and TGF-βs (TGF-β1, TGF-β2, and TGF-β3) compared with ATRA only. RK promoted the differentiation of C3H10T1/2 stem cells into osteoblasts. However, RK did not affect the inhibition of early-stage adipocyte differentiation. Our results suggest that RK enhances the differentiation of C3H10T1/2 stem cells into osteoblasts, and it may promote bone formation by an action unrelated to adipocyte differentiation.

  13. The proteosome inhibitor MG132 attenuates Retinoic Acid Receptor trans-activation and enhances trans-repression of Nuclear Factor κB. Potential relevance to chemo-preventive interventions with retinoids

    Directory of Open Access Journals (Sweden)

    Rosier Randy N

    2004-03-01

    Full Text Available Abstract Background Nuclear factor kappa B (NFκB is a pro-malignant transcription factor with reciprocal effects on pro-metastatic and anti-metastatic gene expression. Interestingly, NFκB blockade results in the reciprocal induction of retinoic acid receptors (RARs. Given the established property of RARs as negative regulators of malignant progression, we postulated that reciprocal interactions between NFκB and RARs constitute a signaling module in metastatic gene expression and malignant progression. Using Line 1 tumor cells as a model for signal regulation of metastatic gene expression, we investigated the reciprocal interactions between NFκB and RARs in response to the pan-RAR agonist, all-trans retinoic acid (at-RA and the pan-RAR antagonist, AGN193109. Results At-RA [0.1–1 μM] dose-dependently activated RAR and coordinately trans-repressed NFκB, while AGN193109 [1–10 μM] dose-dependently antagonized the effects of at-RA. At-RA and AGN193109 reciprocally regulate pro-metastatic matrix metalloprotease 9 (MMP 9 and its endogenous inhibitor, the tissue inhibitor of metalloprotease 1 (TIMP 1, in a manner consistent with the putative roles of NFκB and RAR in malignant progression. Activation of RAR concurs with its ubiquitination and proteosomal degradation. Accordingly, the proteosome inhibitor, MG132 [5 μM], blocked RAR degradation, quelled RAR trans-activation and enhanced RAR trans-repression of NFκB. Conclusion We conclude that reciprocal interactions between NFκB and RARs constitute a signaling module in metastatic gene expression and malignant progression and propose that the dissociative effect of proteosome inhibitors could be harnessed towards enhancing the anticancer activity of retinoids.

  14. Recent advances in the diagnosis and management of childhood acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Eun Sun Yoo

    2011-03-01

    Full Text Available Since the successful introduction of all-trans-retinoic acid (ATRA and its combination with anthracycline-containing chemotherapy, the prognosis for acute promyelocytic leukemia (APL has markedly improved. With ATRA and anthracycline-based-chemotherapy, the complete remission rate is greater than 90%, and the long-term survival rate is 70&#8210;89%. Moreover, arsenic trioxide (ATO, which was introduced for APL treatment in 1994, resulted in excellent remission rates in relapsed patients with APL, and more recently, several clinical studies have been designed to explore its role in initial therapy either alone or in combination with ATRA. APL is a rare disease in children and is frequently associated with hyperleukocytosis, which is a marker for higher risk of relapse and an increased incidence of microgranular morphology. The frequency of occurrence of the promyelocytic leukemia/ retinoic acid receptor-alpha (PML/RAR?#6752;isoforms bcr 2 and bcr 3 is higher in children than in adults. Although recent clinical studies have reported comparable long-term survival rates in patients with APL, therapy for APL in children is challenging because of the risk of early death and the potential long-term cardiac toxicity resulting from the need to use high doses of anthracyclines. Additional prospective, randomized, large clinical trials are needed to address several issues in pediatric APL and to possibly minimize or eliminate the need for chemotherapy by combining ATRA and ATO. In this review article, we discuss the molecular pathogenesis, diagnostic progress, and most recent therapeutic advances in the treatment of children with APL.

  15. Crotoxin: Structural Studies, Mechanism of Action and Cloning of Its Gene

    Science.gov (United States)

    1987-03-01

    with these same antisera, while cross-reactivity with B3-bungarotoxin was very slight. Neurophysin and phospholipase A2 from N. n. atra and honey bee ...other venoms and examine their toxin neutral- izing ability. The amino acid sequences of both crotoxin subunits were determined Is a prelude to cloning...of crotoxin from the venom of C.d. terrificus has been de rmined. Sequence comparison data suggest that the non-toxic, acidic subunit was derived

  16. Energy Metabolism Regulates Retinoic Acid Synthesis and Homeostasis in Physiological Contexts

    OpenAIRE

    Obrochta, Kristin Marie

    2014-01-01

    Mounting evidence supports a regulated and reciprocal relationship between retinoid homeostasis and energy metabolism, with a physiologically relevant consequence of disrupted energy balance. This research was motivated by an observation that all-trans-retinoic acid (atRA), and biosynthetic precursors, were responsive to acute shifts in energy status, in wild type animals with normal body weight and glucose tolerance, i.e. not consequent to metabolic syndrome. My dissertation was designed to ...

  17. RARα2 and PML-RAR similarities in the control of basal and retinoic acid induced myeloid maturation of acute myeloid leukemia cells

    Science.gov (United States)

    Gianni, Maurizio; Fratelli, Maddalena; Bolis, Marco; Kurosaki, Mami; Zanetti, Adriana; Paroni, Gabriela; Rambaldi, Alessandro; Borleri, Gianmaria; Rochette-Egly, Cecile; Terao, Mineko; Garattini, Enrico

    2017-01-01

    Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) is the first example of targeted therapy. In fact, the oncogenic fusion-protein (PML-RAR) typical of this leukemia contains the retinoid-nuclear-receptor RARα. PML-RAR is responsible for the differentiation block of the leukemic blast. Besides PML-RAR, two endogenous RARα proteins are present in APL blasts, i.e. RARα1 and RARα2. We developed different cell populations characterized by PML-RAR, RARα2 and RARα1 knock-down in the APL-derived NB4 cell-line. Unexpectedly, silencing of PML-RAR and RARα2 results in similar increases in the constitutive expression of several granulocytic differentiation markers. This is accompanied by enhanced expression of the same granulocytic markers upon exposure of the NB4 blasts to ATRA. Silencing of PML-RAR and RARα2 causes also similar perturbations in the whole genome gene-expression profiles of vehicle and ATRA treated NB4 cells. Unlike PML-RAR and RARα2, RARα1 knock-down blocks ATRA-dependent induction of several granulocytic differentiation markers. Many of the effects on myeloid differentiation are confirmed by over-expression of RARα2 in NB4 cells. RARα2 action on myeloid differentiation does not require the presence of PML-RAR, as it is recapitulated also upon knock-down in PML-RAR-negative HL-60 cells. Thus, relative to RARα1, PML-RAR and RARα2 exert opposite effects on APL-cell differentiation. These contrasting actions may be related to the fact that both PML-RAR and RARα2 interact with and inhibit the transcriptional activity of RARα1. The interaction surface is located in the carboxy-terminal domain containing the D/E/F regions and it is influenced by phosphorylation of Ser-369 of RARα1. PMID:27419624

  18. The Effects of Quercetin and Retinoic acid on Skeletal System of Rat Embryos in Prenatal Period

    OpenAIRE

    Nahid Gohari-Behbahani; Mahmood Khaksary-Mahabady; Reza Ranjbar; Hossein Najafzadeh-Varzi; Babak Mohammadian3. Department of Pathology, Faculty of Veterinary Medicine, Shahid Cha

    2014-01-01

    Background: Prenatal rat embryo exposure to retinoid induces some malformations in various organs, the most active and teratogenic metablolite is all-trans-retinoic acid (atRA). The teratogenic effects of some drugs can be prevented by the application of antioxidant drugs and stimulation of the maternal immune system. Also, quercetin, a naturally occurring flavonoid has excellent antioxidant properties. Therefore, in this study, the prophylactic effect of quercetin on teratogenic effects of a...

  19. Induction of retinoic acid receptor-alpha by granulocyte macrophage colony-stimulating factor in human myeloid leukemia cell lines.

    Science.gov (United States)

    Shimizu, T; Takeda, K

    2000-08-15

    We reported previously that treatment with all-trans retinoic acid (ATRA) and granulocyte macrophage colony-stimulating factor (GM-CSF) induces differentiation of human myeloblastic leukemia ML-1 cells to granulocytes, whereas treatment with ATRA alone induces practically no differentiation of these cells. To investigate the mechanism of the synergistic effect of these factors, we examined the effect of GM-CSF on retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in ML-1 cells. We reveal that GM-CSF induces the expression of RAR alpha mRNA and protein and stimulates the binding of nuclear proteins to direct repeat 5, a consensus sequence with high affinity for RAR-RXR heterodimers. Furthermore, expression of CD38 mRNA mediated through RAR alpha is induced synergistically by treatment with ATRA + GM-CSF. These results suggest that GM-CSF stimulates transcriptional activity mediated via RAR alpha in ML-1 cells. The induction of RAR alpha by GM-CSF may therefore be a mechanism for stimulation by GM-CSF. The induction of RAR alpha by GM-CSF was also detected in other myeloid leukemia cell lines (THP-1 and KG-1) that showed a synergistic effect similar to that seen in ML-1 cells in response to ATRA + GM-CSF. We also found that GM-CSF induced the expression of RAR alpha in blood cells obtained from patients with acute myeloid leukemia. This activity of GM-CSF may serve as a useful adjunct to differentiation therapy for retinoic acid-nonresponsive leukemias.

  20. A Novel Molecular Target for Breast Cancer Prevention and Treatment

    Science.gov (United States)

    2004-06-01

    trichostatin A; CAT, chloramphenicol transferase; Chemicals (Ann Arbor, MI). All reagents were dissolved in a 1:1 ratio of 13-gal, 0-galactosidase; MTS...RARP BY RXR AND PPARy LIGANDS T-47D ATRA - + servation that ciglitazone synergized with SRI 1237 in inducing SR11237 - - + - + RAR)3 expression...from restrained electrostatic an AHPN analogue or retinoid. Chloramphenicol acetyl trans- potential fits derived from DFT computations at ligand ferase

  1. HISTORICKÝ VÝVOJ TECHNIKY PLAVECKÝCH ZPŮSOBŮ V SOUVISLOSTI SE ZMĚNAMI PRAVIDEL

    OpenAIRE

    Šatra, Michal

    2012-01-01

    Bibliographic identification ŠATRA, Michal: The historical development of the technique of swimming styles in connection with changes in the rules [Diploma thesis]. Charles University in Prague. Faculty of Physical Education and Sport. Department of Swimming. Supervisor: Mgr. Babeta Chrzanowská. Prague: FTVS UK, 2012. Abstract The aim of this thesis is to describe the development of the techniques of each individual swimming style on the basis of all available materials and to discover its co...

  2. Lutzomyia gasparviannai Martins, Godoy & Silva, 1962, probable vector of Leishmania mexicana ssp. in Viana municipality, Espírito Santo State, Brazil

    Directory of Open Access Journals (Sweden)

    Aloísio Falqueto

    1985-12-01

    Full Text Available Dos flebótomos atraídos pelo Proechimys iheringi numa área onde esse roedor foi achado naturalmente infectado por Leishmania mexicana ssp., 98,1% foram Lutzomyia gasparviannai, o que sugere que essa espécie não antropofílica seja o transmissor entre os roedores mas não habitualmente ao homem.

  3. Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

    OpenAIRE

    Armstrong, J. L.; Ruiz, M.; Boddy, A V; Redfern, C P F; Pearson, A D J; Veal, G J

    2005-01-01

    Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid bi...

  4. Acute promyelocytic leukemia.

    Science.gov (United States)

    Lemons, R S; Keller, S; Gietzen, D; Dufner, J; Rebentisch, M; Feusner, J; Eilender, D

    1995-08-01

    Significant advances have occurred in the diagnosis, treatment, and long-term outcome of patients with acute promyelocytic leukemia (APL). The purpose of this review is to describe the molecular genetics of this disease, the use of all-trans retinoic acid (ATRA) in clinical trials of APL, and the clinical and basic research questions for future