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ATRA
Terms modified by ATRA Selected AbstractsPre-activation of retinoid signaling facilitates neuronal differentiation of mesenchymal stem cellsDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 5 2010Yang Bi Mesenchymal stem cells (MSCs) can differentiate into neurons in an appropriate cellular environment. Retinoid signaling pathway is required in neural development. However, the effect and mechanism through retinoid signaling regulates neuronal differentiation of MSCs are still poorly understood. Here, we report that all-trans-retinoic acid (ATRA) pre-induction improved neuronal differentiation of rat MSCs. We found that, when MSCs were exposed to different concentrations of ATRA (0.01,100 ,mol/L) for 24 h and then cultured with modified neuronal induction medium (MNM), 1 ,mol/L ATRA pre-induction significantly improved neuronal differentiation efficiency and neural-cell survival. Compared with MNM alone induced neural-like cells, ATRA/MNM induced cells expressed higher levels of Nestin, neuron specific enolase (NSE), microtubule-associated protein-2 (MAP-2), but lower levels of CD68, glial fibrillary acidic protein (GFAP), and glial cell line-derived neurotrophic factor(GDNF), also exhibited higher resting membrane potential and intracellular calcium concentration, supporting that ATRA pre-induction promotes maturation and function of derived neurons but not neuroglia cells from MSCs. Endogenous retinoid X receptors (RXR) RXR, and RXR, (and to a lesser extent, RXR,) were weakly expressed in MSCs. But the expression of RAR, and RAR, was readily detectable, whereas RAR, was undetectable. However, at 24 h after ATRA treatment, the expression of RAR,, not RAR, or RAR,, increased significantly. We further found the subnuclear redistribution of RAR, in differentiated neurons, suggesting that RAR, may function as a major mediator of retinoid signaling during neuronal differentiation from MSCs. ATRA treatment upregulated the expression of Vimentin and Stra13, while it downregulated the expression of Brachyury in MSCs. Thus, our results demonstrate that pre-activation of retinoid signaling by ATRA facilitates neuronal differentiation of MSCs. [source] An efficient therapeutic approach to patients with acute promyelocytic leukemia using a combination of arsenic trioxide with low-dose all-trans retinoic acidHEMATOLOGICAL ONCOLOGY, Issue 2 2004Guanjun Wang Abstract The use of arsenic trioxide (As2O3, ATO) combined with all-trans retinoic acid (ATRA) has recently been reported to induce remission in patients with acute promyelocytic leukemia (APL). However, its efficiency remains inconclusive mainly due to the small number of the available cases. In this study, therefore, we present a clinical study using a combination of ATO with low-dose ATRA (LD-ATRA) to treat 108 APL patients (80 newly diagnosed patients, 28 relapsed patients). Therapeutic outcomes using the ATO/LD-ATRA approach were compared with those of APL patients treated either with ATO alone (65 patients) or ATRA alone (51 patients). The results showed that the ATO/LD-ATRA approach provided significantly better therapeutic outcomes as compared to either ATO or ATRA alone, as evidenced by lower mortality, a higher CR rate and a reduced period to CR. In addition, the toxic side-effects have been no worse with the combined ATO/LD-ATRA treatment than with either ATO or ATRO alone and in some cases have been reduced. These data suggest that the ATO/LD-ATRA regimen is superior to either regimen given alone to patients with APL. Copyright © 2004 John Wiley & Sons, Ltd. [source] Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoidsHEPATOLOGY, Issue 1 2004Karine Hellemans Activation of hepatic stellate cells (HSC) is a central event in the pathogenesis of liver fibrosis during chronic liver injury. We examined the expression of retinoic acid (RAR) and retinoid X receptors (RXR) during HSC activation and evaluated the influence of natural and synthetic retinoic acids (RA) on the phenotype of culture-activated HSC. The expression of the major RAR/RXR subtypes and isoforms was analyzed by Northern hybridization. Presence of functional receptor proteins was established by gel shift analysis. Retinoic acids, RAR, and RXR selective agonists and an RAR antagonist were used to evaluate the effects of retinoid signalling on matrix synthesis by Northern blotting and immunoprecipitation, and on cell proliferation by BrdU incorporation. The 9- cisRA and synthetic RXR agonists reduced HSC proliferation and synthesis of collagen I and fibronectin. All- trans RA and RAR agonists both reduced the synthesis of collagen I, collagen III, and fibronectin, but showed a different effect on cell proliferation. Synthetic RAR agonists did not affect HSC proliferation, indicating that ATRA inhibits cell growth independent of its interaction with RARs. In contrast, RAR specific antagonists enhance HSC proliferation and demonstrate that RARs control proliferation in a negative way. In conclusion, natural RAs and synthetic RAR or RXR specific ligands exert differential effects on activated HSC. Our observations may explain prior divergent results obtained following retinoid administration to cultured stellate cells or to animals subjected to fibrogenic stimuli. (HEPATOLOGY 2004;39:97,108.) [source] PLC-,2 monitors the drug-induced release of differentiation blockade in tumoral myeloid precursorsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Federica Brugnoli Abstract The differentiation therapy in treatment of acute promyelocytic leukemia (APL), based on the administration of all-trans retinoic acid (ATRA), is currently flanked with the use of As2O3, a safe and effective agent for patients showing a resistance to ATRA treatment. A synergy between ATRA and As2O3 was also reported in inducing granulocytic differentiation of APL-derived cells. We have demonstrated that phospholipase C-,2 (PLC-,2), highly expressed in neutrophils and nearly absent in tumoral promyelocytes, largely increases during ATRA treatment of APL-derived cells and strongly correlates with the responsiveness of APL patients to ATRA-based differentiating therapies. Here we report that, in APL-derived cells, low doses of As2O3 induce a slight increase of PLC-,2 together with a moderate maturation, and cooperate with ATRA to provoke a significant increase of PLC-,2 expression. Remarkably, the amounts of PLC-,2 draw a parallel with the differentiation levels reached by both ATRA-responsive and -resistant cells treated with ATRA/As2O3 combinations. PLC-,2 is not necessary for the progression of tumoral promyelocytes along the granulocytic lineage and is unable to overcome the differentiation block or to potentiate the agonist-induced maturation. On the other hand, since its expression closely correlates with the differentiation level reached by APL-derived cells induced to maturate by drugs presently employed in APL therapies, PLC-,2 represents indeed a specific marker to test the ability of differentiation agents to induce the release of the maturation blockade of tumoral myeloid precursors. J. Cell. Biochem. 98: 160,173, 2006. © 2006 Wiley-Liss, Inc. [source] Differential regulation of protein expression, growth and apoptosis by natural and synthetic retinoidsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2003M.A. Christine Pratt Abstract All- trans retinoic acid (ATRA) can down regulate the anti-apoptotic protein Bcl-2 and the cell cycle proteins cyclin D1 and cdk2 in estrogen receptor-positive breast cancer cells. We show here that retinoids can also reduce expression of the inhibitor of apoptosis protein, survivin. Here we have compared the regulation of these proteins in MCF-7 and ZR-75 breast cancer cells by natural and synthetic retinoids selective for the RA receptors (RARs) ,, ,, and , then correlated these with growth inhibition, induction of apoptosis and chemosensitization to Taxol. In both cell lines ATRA and 9- cis RA induced the most profound decreases in cyclin D1 and cdk2 expression and also mediated the largest growth inhibition. The RAR, agonist, Ro 40-6055 also strongly downregulated these proteins although did not produce an equivalent decrease in S-phase cells. Only ATRA induced RAR, expression. ATRA, 9- cis RA and 4-HPR initiated the highest level of apoptosis as determined by mitochondrial Bax translocation, while only ATRA and 9- cis RA strongly reduced Bcl-2 and survivin protein expression. Enumeration of dead cells over 96 h correlated well with downregulation of both survivin and Bcl-2. Simultaneous retinoid-mediated reduction of both these proteins also predicted optimal Taxol sensitization. 4-HPR was much weaker than the natural retinoids with respect to Taxol sensitization, consistent with the proposed requirement for reduced Bcl-2 in this synergy. Neither the extent of cell cycle protein regulation nor AP-1 inhibition fully predicted the antiproliferative effect of the synthetic retinoids suggesting that growth inhibition requires regulation of a spectrum of RAR-regulated gene products in addition even to pivotal cell cycle proteins. © 2003 Wiley-Liss, Inc. [source] Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell linesJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2004William F. Holmes Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis. It has been reported that many tumors and tumor cell lines have dysfunctional apoptosis signaling, causing these tumors to escape immune monitoring and internal cellular control mechanisms. One potential cause of this dysfunctional apoptosis is the tumor suppressor p53, an important regulator of growth arrest and apoptosis that is mutated in over 50% of all cancers. Retinoids have great potential in the areas of cancer therapy and chemoprevention. While some tumor cells are sensitive to the growth inhibitory effects of natural retinoids such as all- trans -retinoic acid (ATRA), many ovarian tumor cells are not. 6-[3-(1-Admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and fenretinide N -[4-hydroxyphenyl] retinamide (4-HPR) are conformationally restricted synthetic retinoids that induce growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. Recently, we have identified the molecular pathways of apoptosis induced by treatment of ovarian carcinoma cells with mutated p53 by CD437 and 4-HPR. © 2004 Wiley-Liss, Inc. [source] p27/Kip1 mediates retinoic acid-induced suppression of ovarian carcinoma cell growthJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2004Scott Vuocolo We have investigated the mechanisms by which all-trans retinoic acid (ATRA) causes growth inhibition of ovarian carcinoma cells. As a model, we have studied the CAOV3 cell line, which is sensitive to ATRA, and the SKOV3 cell line, which is resistant. We have found that treatment of CAOV3 cells with ATRA causes a 5,10 fold increase in the protein level of the cyclin dependent kinase inhibitor p27/Kip1. p27/Kip1 protein upregulation is important in ovarian carcinoma as primary tumors are frequently found lacking this protein. The increase in p27/Kip1 is detected by day 3 of ATRA treatment of CAOV3 cells, and is maximal by day 5. Messenger RNA levels of p27/Kip1 do not change in CAOV3 cells following ATRA treatment, however, we have shown that p27/Kip1 mRNA is more stable in ATRA treated CAOV3 cells. Conversely, the ATRA resistant cell line SKOV3 fails to show p27/Kip1 accumulation. Interestingly, the SCF component protein SKP2 appears to be decreased in CAOV3 cells treated with ATRA. We have also shown that the ATRA dependent increase in p27/kip1 protein in CAOV3 cells leads to a decrease in the kinase activity of cyclin dependent kinase 4 (CDK4) following ATRA treatment. Finally, we found that CAOV3 cells stably transfected with a p27/kip1antisense construct, which express lower levels of p27/kip1 following ATRA treatment, and have a higher CDK4 kinase activity are less sensitive to ATRA induced growth suppression. Taken together our data suggest ATRA-induced growth inhibition in CAOV3 ovarian carcinoma cells involves modulation of the CDK inhibitor p27/kip1. J. Cell. Physiol. 199: 237,243, 2004© 2004 Wiley-Liss, Inc. [source] Evaluation of the pharmacokinetics of All- Trans -Retinoic Acid (ATRA) in wistar rats after intravenous administration of ATRA loaded into tributyrin submicron emulsion and its cellular activity on caco-2 and HepG2 cell linesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2008Jie Su Abstract The pharmacokinetics of all- trans -retinoic acid (ATRA), an anti-cancer drug was highly variable due to its poor aqueous solubility. In this study, we investigated the pharmacokinetics of ATRA in male Wistar rats following intravenous administration of the ATRA loaded tributyrin emulsion. In vitro, the ATRA emulsion was proved binding to apolipoprotein(s). In vivo, the clearance of ATRA was significantly reduced by formulating into the tributyrin emulsion, leading to higher AUCs. Co-administration with 17,-ethynylestradiol, a compound known to upregulate the activity of low-density lipoprotein receptors in tissues, significantly increased the Ke, V, and CL of ATRA. The variation of plasma AUCs after administering the ATRA emulsion to the healthy rats was two times less than that after the ATRA solution. The IC50 in ATRA of the ATRA emulsion for the Caco-2 carcinoma cells was 3.8 µg/mL lower than 6 µg/mL of the ATRA solution. The IC50 of the emulsion for the HepG2 carcinoma cells was 2.8 µg/mL, while IC50 was not achieved with the ATRA solution over the test concentration range. The finding indicated that the tributyrin emulsion could be used as a carrier for ATRA and enhances the drug effect by reducing the clearance and increasing the in vitro activity. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2844,2853, 2008 [source] Biodistribution characteristics of all- trans retinoic acid incorporated in liposomes and polymeric micelles following intravenous administrationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2005Shigeru Kawakami Abstract The aim of this study was to investigate the biodistribution characteristics of all- trans retinoic acid (ATRA) incorporated in liposomes and polymeric micelles following intravenous administration. [3H] ATRA were incorporated in distearoylphosphatidylcholine (DSPC)/cholesterol (6:4) liposomes. Two types of block copolymers, poly (ethylene glycol)-b-poly-(aspartic acid) derivatives with benzyl (Bz-75) groups, were synthesized to prepare the polymeric micelles for [3H]ATRA incorporation. ATRA were dissolved in mouse serum to analyze their inherent distribution. After intravenous administration, the blood concentration of [3H] ATRA in liposomes and polymeric micelles (Bz-75) was higher than that of inherent [3H]ATRA, suggesting that liposomes and polymeric micelles (Bz-75) control the distribution of ATRA. Pharmacokinetic analysis demonstrated that [3H]ATRA incorporated in polymeric micelles (Bz-75) exhibit the largest AUCblood and lowest hepatic clearance of ATRA, suggesting that polymeric micelles (Bz-75) are an effective ATRA carrier system for acute promyelocytic leukemia (APL) therapy. These results have potential implications for the design of ATRA carriers for APL patients. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2606,2615, 2005 [source] Andrographolide inhibits growth of acute promyelocytic leukaemia cells by inducing retinoic acid receptor-independent cell differentiation and apoptosisJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2009Shiamala T. Manikam Abstract Objectives The growth inhibiting potential of andrographolide was evaluated in three acute promyelocytic leukaemia cell line models (HL-60, NB4 and all- trans retinoic acid (ATRA)-resistant NB4-R2). Methods In elucidating the mechanisms of growth inhibition, a special emphasis was placed on assessing the induction of differentiation and apoptosis by andrographolide in the primary acute promyelocytic leukaemia NB4 cells. Key findings The compound was 2- and 3-fold more active in inhibiting the growth of HL-60 and NB4-R2 cells compared with NB4 cells, respectively. At IC50 (concentration at which growth of 50% of the cells (compared with medium only treated control cells) is inhibited; 4.5 ,M) the compound exhibited strong cell-differentiating activity in NB4 cells, similar to ATRA (IC50 1.5 ,M). In the presence of a pure retinoic acid receptor antagonist AGN193109, the growth inhibition of NB4 cells by ATRA was reversed, whereas the activity of andrographolide was not affected. This clearly suggested that andrographolide's cell differentiating activity to induce growth inhibition of NB4 cells most likely occurred via a retinoic acid receptor-independent pathway. At higher concentration (2 × IC50), andrographolide was an efficient inducer of apoptosis in NB4 cells. Conclusions Taken together, these results suggest andrographolide and its derivatives, apparently with a novel cell differentiating mechanism and with ability to induce apoptosis, might be beneficial in the treatment of primary and ATRA-resistant acute promyelocytic leukaemia. [source] Retinoids and retinoic acid receptors regulate growth arrest and apoptosis in human mammary epithelial cells and modulate expression of CBP/p300MICROSCOPY RESEARCH AND TECHNIQUE, Issue 1 2002Eric C. Dietze Abstract Retinoids and retinoic acid receptors (RARs) are important mediators of normal epithelial cell homeostasis. To assess the role of retinoids and RARs in regulating growth arrest and apoptosis in benign and malignant mammary epithelial cells, two model systems were developed: 1) RAR function was suppressed in retinoid-sensitive normal human mammary epithelial cells (HMECs) by the dominant-negative retinoic acid receptor, RAR,403 (DNRAR), and 2) retinoid-resistant MCF-7 breast cancer cells were transduced with a functional RAR,2. Inhibition of RAR function by the DNRAR in HMECs resulted in retinoid-resistance, increased proliferation, and dysregulated growth when cells were cultured in reconstituted extracellular matrix (rECM). Expression of RAR,2 in MCF-7 cells resulted in sensitivity to retinoid-induced growth arrest and apoptosis. The CREB-binding protein (CBP) and the homologous protein p300 are tightly regulated, rate-limiting integrators of diverse signaling pathways and are recruited during retinoid-mediated transcriptional activation. The relationship between retinoid receptor expression, growth regulation, and transcriptional regulation of CBP/p300 is poorly understood. Inhibition of RAR function in HMECs by DNRAR suppressed expression of CBP/p300 and expression of RAR,2 in MCF-7 cells promoted induction of CBP/p300 when cells were treated with 1.0 ,M all- trans -retinoic acid (ATRA). These results suggest that ATRA and RARs regulate growth arrest of HMECs and modulate CBP/p300 protein expression. Since CBP and p300 are normally present in limiting amounts, their regulation by ATRA and RARs may be an important element in the control of transcriptional activation of genes regulating growth arrest and apoptosis. Microsc. Res. Tech. 59:23,40, 2002. © 2002 Wiley-Liss, Inc. [source] Secondary clonal cytogenetic abnormalities following successful treatment of acute promyelocytic leukemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 11 2009Crisoula Batzios To identify patients who developed secondary clonal cytogenetic aberrations (CCA) following therapy for acute promyelocytic leukemia (APL), we retrospectively analyzed cytogenetic results from 123 patients diagnosed with APL between 1995 and 2007, who had ongoing cytogenetic analysis undertaken in our laboratory. During follow-up for APL we identified 12 patients (9.8%) who developed CCA, not detected at diagnosis of APL and unrelated to their original APL karyotype. All patients had received all-trans retinoic acid (ATRA) and chemotherapy and were in complete remission for APL when secondary CCA were identified. The median latency period between diagnosis of APL and emergence of secondary CCA was 27.5 months (range: 2,54 months). To date, four patients with CCA have been diagnosed with therapy-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (t-AML), giving a median t-MDS/AML free survival of 78 months, with follow-up ranging between 20 and 136 months from APL diagnosis. Three patients have died: two patients died of t-AML and another developed relapsed APL with persistence of his secondary clone but no diagnosis of t-MDS/AML and died from transplant-related complications. Two patients are alive with t-MDS. Seven patients with CCA are alive with no morphological evidence of MDS at the time of their last known follow-up; thus median survival has not been reached. The appearance of these abnormalities in the absence of morphological evidence of MDS in the majority of patients is unusual, and highlights the importance of continued cytogenetic follow-up in these patients. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] A phase 2 trial of all- trans -retinoic acid in combination with interferon-,2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group StudyPEDIATRIC BLOOD & CANCER, Issue 5 2007Peter C. Adamson MD Abstract Background The combination of the antiproliferative and differentiation-inducing effects of retinoids together with the antiproliferative, immunostimulatory, and differentiation-potentiating effects of interferon-, (IFN-,) were the basis for the development of this combination in pediatric patients with refractory neuroblastoma or Wilms tumor. Procedure A phase 2 trial of all- trans -retinoic acid (ATRA), administered orally at a dose of 90 mg/m2/day in three divided doses for 3 consecutive days per week, and IFN-,2a, administered subcutaneously daily at a dose of 3,×,106 U/m2/day for 5 consecutive days per week, in 4 week cycles was performed. A two-stage design was used for each disease stratum. Results Seventeen patients (16 evaluable) with neuroblastoma, median age 9 years, and 15 patients (14 evaluable) with Wilms tumor, median age 6 years, were enrolled. Overall, the combination was well tolerated, with headache being the most common toxicity observed. There were no complete or partial responses. The median number of cycles administered was 1 (range 1,9). Four patients with neuroblastoma had stable disease for 12 or more weeks. Conclusions The combination of ATRA and IFN-,2a was inactive in children with relapsed or refractory neuroblastoma and Wilms tumor. The lack of activity with this combination in children with refractory neuroblastoma is similar to the disappointing phase 2 results of single agent 13- cis -retinoic-acid (13cRA) and does not support further development of ATRA for children with relapsed neuroblastoma. Pediatr Blood Cancer 2007;49:661,665. © 2006 Wiley-Liss, Inc. [source] All-trans retinoic acid affects subcellular localization of a novel BmNIF3l protein: functional deduce and tissue distribution of NIF3l gene from silkworm (Bombyx mori),ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 4 2010Jianqing Chen Abstract A novel cDNA sequence encoding a predicted protein of 271 amino acids containing a conserved NIF3 domain was found from a pupal cDNA library of silkworm. The corresponding gene was named BmNIF3l (Bombyx mori NGG1p interacting factor 3-like). It was found by bioinformatics that BmNIF3l gene consisted of five exons and four introns and BmNIF3l had a high degree of homology to other NIF3-like proteins, especially in the N-terminal and C-terminal regions. A His-tagged BmNIF3l fusion protein with a molecular weight of approximately 33.6,kDa was expressed and purified to homogeneity. We have used the purified fusion protein to produce polyclonal antibodies against BmNIF3l for histochemical analysis. Subcellular localization revealed that BmNIF3l is a cytoplasmic protein that responds to all-trans retinoic acid (ATRA). Western blotting and real-time reverse transcription polymerase chain reaction showed that the expression level of BmNIF3l is higher in tissues undergoing differentiation. Taken together, the results suggest that BmNIF3l functions in transcription. © 2010 Wiley Periodicals, Inc. [source] Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic jointARTHRITIS & RHEUMATISM, Issue 6 2009Mark R. Davies Objective Vitamin A derivatives, including all- trans -retinoic acid (ATRA), have a well-established role during skeletal development and limb formation and have been shown to have profound effects on chondrocyte phenotype. The aim of this study was to elucidate the effects of retinoids and components of the retinoid metabolic pathway on chondrocyte phenotype in the tibiofemoral joints of patients with osteoarthritis (OA), to show that the retinoids can have multiple effects relevant to the OA disease process. Methods Human explant tissue and a chondrocyte-like cell line were treated with ATRA, and the responses of 4 key markers of chondrocyte phenotype were analyzed. In addition, the effects of ATRA on a number of novel genes associated with OA were assessed using a low-density microarray containing 80 disease marker genes. Results Vitamin A metabolite levels were elevated in synovial fluid, serum, and cartilage from patients with OA. Expression profiling of a retinoic acid receptor , coactivator protein, P/CAF, demonstrated elevated expression in patients with OA, suggesting the potential for increased signaling via the retinoid receptors in the disease. ATRA increased the levels of matrix metalloproteinase 13 and aggrecanase activity in human cartilage explants and in a human chondrocyte cell line. Furthermore, ATRA altered the expression of a wide range of relevant genes, including the types I, II, IX, and XI collagen genes, toward a nonchondrogenic and OA-like phenotype. Conclusion These results suggest that retinoid signaling could have a central role in OA, and that components of the pathway may provide potential disease biomarkers or targets for therapeutic intervention. [source] Synergic effect of retinoic acid and extremely low frequency magnetic field exposure on human neuroblastoma cell line BE(2)CBIOELECTROMAGNETICS, Issue 6 2010Pamela Marcantonio Abstract The aim of the present study was to assess whether exposure to a sinusoidal extremely low frequency magnetic field (ELF-MF; 50,Hz, 1,mT) can affect proliferation and differentiation in the human neuroblastoma cell line BE(2)C, which is representative of high risk neuroblastomas. Cells were subjected to ELF-MF exposure in the presence or absence of a neuronal differentiating agent (all-trans-retinoic acid, ATRA) for 24,72,h. In each experiment, ELF-MF-exposed samples were compared to sham-exposed samples. Cells exposed to ELF-MF combined with retinoic treatment showed a decreased cellular proliferation and an increased proportion of G0/G1 phase cells compared to cells exposed to either treatment alone. Moreover, ELF-MF- and ATRA-treated cells showed more differentiated morphological traits (a higher neurite number/cell, an increased neurite length), together with a significant increase of mRNA levels of p21WAF1/CIP1 and cdk5 genes, both involved in neuronal differentiation. In addition, the expression of cyp19 gene, which is involved both in neuronal differentiation and stress response, was evaluated; cyp19 gene expression was enhanced by ATRA treatment and significantly enhanced further by ELF-MF exposure combined with ATRA. In conclusion, our data suggest that ELF-MF exposure can strengthen ATRA effects on neuroblastoma cells. Bioelectromagnetics 31:425,433, 2010. © 2010 Wiley-Liss, Inc. [source] Epigallocatechin-3-gallate induces cell death in acute myeloid leukaemia cells and supports all- trans retinoic acid-induced neutrophil differentiation via death-associated protein kinase 2BRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2010Adrian Britschgi Summary Acute promyelocytic leukaemia (APL) patients are successfully treated with all- trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 (DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover, combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and potentiated differentiation. EGCG toxicity of primary AML blasts correlated with 67 kDa laminin receptor (67LR) expression. Pretreatment of AML cells with ATRA, causing downregulation of 67LR, rendered these cells resistant to EGCG-mediated cell death. In summary, it was found that (i) DAPK2 is essential for EGCG-induced cell death in AML cells, (ii) ATRA and EGCG cotreatment significantly boosted neutrophil differentiation, and 67LR expression correlates with susceptibility of AML cells to EGCG. We thus suggest that EGCG, by selectively targeting leukaemic cells, may improve differentiation therapies for APL and chemotherapy for other AML subtypes. [source] The synthetic furanonaphthoquinone induces growth arrest, apoptosis and differentiation in a variety of leukaemias and multiple myeloma cellsBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2005Julian C. Desmond Summary 2-Methyl-naphtho[2,3- b]furan-4,9-dione (FNQ3), a synthetic analogue of the quinone kigelinone, has demonstrated a real potential for use in the treatment of a variety of solid tumours. Unlike other quinones, such as mitomycin-C and adriamycin, the cytotoxicity of FNQ3 is often 10- to 14-fold more potent towards the tumour cells than their normal counterparts. We report, for the first time, that the drug had activity against a broad spectrum of leukaemias and multiple myeloma cells. It decreased the growth of acute myeloid leukaemia (AML) and multiple myeloma cell lines in a dose-dependent fashion (50% inhibitory concentration ,1·25 ,g/ml against most of the leukaemia cell lines). This dose apparently initiated mitochondrial collapse as measured by depolarisation of the mitochondrial membrane. FNQ3 potentiated the differentiation of HL-60 myeloid cells in the presence of either 1,, 25(OH)2 dihydroxyvitamin D3 [1,,25(OH)2D3] or all- trans -retinoic acid (ATRA). FNQ3 inhibited the proliferation of primary AML cells while inducing apoptosis. Eleven of 14 (79%) AML marrow samples had a prominent decrease in their clonogenic growth when cultured in the presence of the drug. In summary, this drug has growth inhibitory, apoptotic and differentiative effects against myeloid leukaemias and multiple myeloma cells. FNQ3 may represent a new therapeutic approach to these malignancies. [source] Characterization of apoptosis induced by protein kinase C inhibitors and its modulation by the caspase pathway in acute promyelocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 3 2000Hesham M. Amin Acute promyelocytic leukaemia (APL;M3) is a unique form of acute myelogenous leukaemia characterized by t(15;17) translocation. The induction of apoptosis via inhibiting protein kinase C (PKC) has been recently viewed as a promising tool for the eradication of several malignant disorders. In the present study, we investigated the effect of two different protein kinase C inhibitors, Gö6976 and safingol, on the induction of apoptosis in the APL cell line NB4 and its all trans retinoic acid (ATRA)-resistant variant NB4.306. The effect of the PKC inhibitors on leukaemic cells obtained from three APL patients was also studied. We also evaluated the possible involvement of the caspases in apoptosis induced by PKC inhibitors. Significant time- and concentration-dependent apoptotic changes were demonstrated using Gö6976 and safingol. In addition, our results demonstrated that the caspases were involved in the apoptosis induced by the PKC inhibitors. In conclusion, our study illustrates that the PKC inhibitors Gö6976 and safingol induce apoptosis in APL and hence could be potential therapeutic agents for the treatment of this disease. [source] Arachidonic acid-mediated cooxidation of all- trans -retinoic acid in microsomal fractions from human liverBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000Louise Nadin The quantitative importance of prostaglandin H synthase (PGHS)-mediated cooxidation of all- trans -retinoic acid (ATRA) was evaluated in human liver microsomes (n=17) in relation to CYP-dependent ATRA 4-hydroxylation. Observed rates of ATRA cooxidation (4.6,20 pmol mg protein,1 min,1) and 4-hydroxylation (8.7,45 pmol mg protein,1 min,1) were quantitatively similar and exhibited similar individual variation (4 and 5 fold, respectively). From kinetic studies cooxidation was an efficient process in human hepatic microsomes (VmaxKm,1=0.25) compared with NADPH- and NADH-mediated 4-hydroxylation by CYP (VmaxKm,1=0.14 and 0.02, respectively). The capacity of lipid hydroperoxide metabolites of arachidonic acid to mediate ATRA oxidation was established directly, but downstream products (D, E, F and I-series prostaglandins) were inactive. cDNA-expressed CYPs supported ATRA oxidation by lipid hydroperoxides. Whereas CYPs 2C8, 2C9 and 3A4, but not CYPs 1A2 or 2E1, were effective catalysts of the NADPH-mediated reaction, cooxidation supported by 15(S)-hydroperoxyeicosatetraenoic acid was mediated by all five CYPs. The cooxidation reaction in human hepatic microsomes was inhibited by the CYP inhibitor miconazole. These findings indicate that ATRA oxidation is quantitatively significant in human liver. Lipid hydroperoxides generated by intracellular enzymes such as prostaglandin synthase and lipoxygenases are sources of activated oxygen for CYP-mediated deactivation of ATRA to polar products. British Journal of Pharmacology (2000) 131, 851,857; doi:10.1038/sj.bjp.0703579 [source] Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acidCANCER, Issue 1 2005Chiara Pilatrino M.D. Abstract BACKGROUND The authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all-trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). METHODS Twenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45,100 ,g/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for , 2 months were considered evaluable. RESULTS Hematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63,550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone. CONCLUSIONS Differentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life. Cancer 2005;. © 2005 American Cancer Society. [source] Effects of retinoids and thiazolidinediones on proliferation, insulin release, insulin mRNA, GLUT 2 transporter protein and mRNA of INS-1 cellsCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2001J. Blumentrath Abstract Both 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (ATRA) are active metabolites of vitamin A (retinol). There exists an interaction between retinoid receptors and peroxisome proliferator-activated receptors (PPAR,). To define their functions in an insulin secreting system the effects of ATRA, 9cRA and the PPAR, agonist rosiglitazone on cell proliferation, insulin release and glucose transporter (GLUT) 2 of INS-1 cells were tested. Retinoic acid receptor (RAR-, and -,) and retinoid X receptor (RXR-, and -,) proteins are present (immunoblots). Both 9cRA and ATRA inhibit INS-1 cell proliferation ([3H]-thymidine assay) in a concentration dependent manner. Both 9cRA and ATRA increased insulin release, but only ATRA ralsed the GLUT 2 mRNA in a bell-shaped concentration response curve after 48,h. The insulinotropic effect of one compound is not significantly superimposed by the other indicating that the same binding sites are used by 9cRA and ATRA. The acute and chronic effects of the PPAR, agonist rosiglitazone on insulin release were additionally determined since glitazones act as transcription factors together with RXR agonists. At high concentrations (100,,m) rosiglitazone inhibited glucose (8.3,mm) stimulated insulin secretion (acute experiment over 60,min). Insulin secretion, however, was increased during a 24,h treatment at a concentration of 10,,m and again inhibited at 100,,m. Changes in preproinsulin mRNA expression were not observed. Rosiglitazone (100,,m) increased GLUT 2 mRNA paralleled by an increase of GLUT 2 protein, but only after 24,h of treatment. This data indicate that RAR and RXR mediate insulin release. The changes in GLUT 2 have no direct impact on insulin release; the inhibition seen at high concentrations of either compound is possibly the result of the observed inhibition of cell proliferation. Effects of rosiglitazone on preproinsulin mRNA and GLUT 2 (mRNA and protein) do not play a role in modulating insulin secretion. With the presence of an RXR receptor agonist the effect of rosiglitazone on insulin release becomes stimulatory. Thus the effects of RAR-, RXR agonists and rosiglitazone depend on their concentrations, the duration of their presence and are due to specific interactions. Copyright © 2001 John Wiley & Sons, Ltd. [source] Regulation of dHAND protein expression by all- trans retinoic acid through ET-1/ETAR signaling in H9c2 cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006Weixin Li Abstract dHAND is thought to be a cardiac-restricted transcription factor during embryonic development. Vertebrate heart development involves many transcription factors such as Nkx2.5, GATA, and tbx5. All- trans retinoic acid (AtRA), the oxidative metabolite of vitamin A, can regulate the expression of these factors to affect embryonic heart development. However, the action of atRA on the expression of dHAND is rarely reported. To clarify whether atRA regulate the dHAND expression, we exposed cultured H9c2 cells (rat embryonic cardiomyocytes) to atRA and detected the protein expression of dHAND by Western blot analysis. We observed atRA can regulate the dHAND expression in a dose- and time-dependent manner. AtRA also inhibited endothelin-1 (ET-1) expression in a time-dependent manner. Further studies revealed that pretreatment with 10 µM BQ-123, a selective endothelin-1 receptor (ETAR) antagonist, for 2 h can significantly counteract the inhibition of 5 µM atRA treatment for 2 h of dHAND mRNA and protein expression. Taken together, these results suggest that atRA regulates dHAND expression by ET-1/ETAR signal transduction pathway in H9c2 cells. The mechanism of ET-1/ETAR signaling in controlling the level of dHAND protein is to reduce the levels of dHAND mRNA. It is possible for atRA to exert its cardiac teratogenesis during vertebrate embryonic development in this way. J. Cell. Biochem. 99: 478,484, 2006. © 2006 Wiley-Liss, Inc. [source] 1,1-bis(3,-indolyl)-1-(p- substituted phenyl)methanes decrease mitochondrial membrane potential and induce apoptosis in endometrial and other cancer cell linesMOLECULAR CARCINOGENESIS, Issue 7 2008Jun Hong Abstract 1,1-Bis(3,-indolyl)-1-(p -substituted phenyl)methanes, containing p-t- butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) substituents, are peroxisome proliferator-activated receptor , (PPAR,) agonists; however, DIM-C-pPhtBu-induced growth inhibition and cell death in human HEC1A endometrial cancer cells is PPAR,-independent. DIM-C-pPhtBu decreased mitochondrial membrane potential (MMP) and promoted the release of cytochrome c and caspase activation and nuclear uptake of endonuclease G leading to apoptosis of HEC1A cells. DIM-C-pPhtBu specifically targeted the mitochondrial permeability transition pore complex (PTPC) because the DIM-C-pPhtBu-induced pro-apoptotic responses were inhibited by atractyloside (Atra), a compound that specifically interacts with the inner mitochondrial membrane adenine nucleotide transport (ANT) proteins. At the dose of Atra used in this study (300 µM), this compound alone did not alter the PTPC but inhibited the mitochondriotoxic effects of DIM-C-pPhtBu. DIM-C-pPhtBu/DIM-C-pPhC6H5 and Atra also differentially affected the ability of eosin-5-maleimide (EMA) to alkylate Cys160 in the ANT protein and Atra, but not DIM-C-pPhtBu, inhibited the exchange of ATP/ADP in isolated mitochondria suggesting that these pharmacophores act on different sites on the ANT protein. Results of this study show that the receptor-independent proapoptotic activity of DIM-C-pPhtBu and DIM-C-pPhC6H5 were related to novel mitochondriotoxic activities involving inner mitochondrial ANT proteins. © 2007 Wiley-Liss, Inc. [source] All- Trans Retinoic Acid (Atra) and Tranexamic Acid: A Potentially Fatal Combination In Acute Promyelocytic LeukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2000J. E. Brown First page of article [source] Augmentation of all- trans -retinoic acid concentration in plasma by preventing inflammation responses induced by atRA-loaded microspheres with concurrent treatment of dexamethasoneDRUG DEVELOPMENT RESEARCH, Issue 4 2004Kyeongsoon Park Abstract All- trans retinoic acid (atRA)-loaded microspheres severely induce inflammatory responses after microsphere implantation. Fibroblasts and a thick band of fibrous capsule resulting from the inflammatory responses could hamper drug permeation to the bloodstream because fibroblasts actively metabolize atRA into polar metabolites and the thick fibrous capsule acts as a diffusion barrier. In the present study, we investigated whether the fibroblast proliferation and collagen deposition induced by atRA released from microspheres might affect the atRA concentration in plasma and atRA metabolism with or without treatment of dexamethasone as an anti-inflammatory drug. After subcutaneous injection of atRA-loaded microspheres in rats, it was observed that atRA-loaded microspheres induced severe inflammatory responses and stimulated fibroblast proliferation and collagen deposition in fibrous capsules. On the other hand, the orally treated dexamethasone effectively prevented inflammatory responses in a dose-dependent manner and suppressed about 49% of the number of fibroblasts and collagen deposition in fibrous capsules at 14 days. In addition, after the treatment of dexamethasone, the atRA concentration in plasma was increased, and its metabolism was decreased approximately by 40% at 7 days, compared to the group treated alone with atRA-loaded microspheres. In conclusion, the concurrent treatment of dexmethasone with atRA-loaded microspheres could prevent inflammatory responses and metabolism of atRA, thereby maintaining the atRA concentration in plasma for longer periods in the therapeutic range. Drug Dev. Res. 61:197,206, 2004. © 2004 Wiley-Liss, Inc. [source] Regulation of dHAND protein expression by all- trans retinoic acid through ET-1/ETAR signaling in H9c2 cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006Weixin Li Abstract dHAND is thought to be a cardiac-restricted transcription factor during embryonic development. Vertebrate heart development involves many transcription factors such as Nkx2.5, GATA, and tbx5. All- trans retinoic acid (AtRA), the oxidative metabolite of vitamin A, can regulate the expression of these factors to affect embryonic heart development. However, the action of atRA on the expression of dHAND is rarely reported. To clarify whether atRA regulate the dHAND expression, we exposed cultured H9c2 cells (rat embryonic cardiomyocytes) to atRA and detected the protein expression of dHAND by Western blot analysis. We observed atRA can regulate the dHAND expression in a dose- and time-dependent manner. AtRA also inhibited endothelin-1 (ET-1) expression in a time-dependent manner. Further studies revealed that pretreatment with 10 µM BQ-123, a selective endothelin-1 receptor (ETAR) antagonist, for 2 h can significantly counteract the inhibition of 5 µM atRA treatment for 2 h of dHAND mRNA and protein expression. Taken together, these results suggest that atRA regulates dHAND expression by ET-1/ETAR signal transduction pathway in H9c2 cells. The mechanism of ET-1/ETAR signaling in controlling the level of dHAND protein is to reduce the levels of dHAND mRNA. It is possible for atRA to exert its cardiac teratogenesis during vertebrate embryonic development in this way. J. Cell. Biochem. 99: 478,484, 2006. © 2006 Wiley-Liss, Inc. [source] Patterns of interspecific associations of stem gallers on willowsDIVERSITY AND DISTRIBUTIONS, Issue 6 2003Jens-Peter Kopelke Abstract., The pattern of interspecific associations of three stem-galling sawfly species (Euura atra, E. elaeagnos, E. purpureae) and three stem-galling gallmidge species (Rabdophaga sp. 3,5) was investigated on five willow taxa (Salix alba, S. fragilis, S. × rubens, S. elaeagnos, S. purpurea) at five natural sites in Central Europe. The willow species harboured specific species associations of two stem gallers, each pair consisting of one Euura and one Rabdophaga species. The stem gallers were patchily distributed and their densities varied significantly among willow host plant species, host plant individuals, and host plant sexes. Four of the six species showed a significant increase in galling rate with shoot length. The other two species were the sawfly and cecidomyiid pair that induce galls on S. purpurea. The preference of stem gallers to longer shoots was generally not related to higher larval performance in terms of survival. Only one species, Rabdophaga sp. 5, was found to be more abundant on male plants. The correlation of densities of the species pairs of stem gallers was independent of willow sexes. Species pairs of stem gallers co-occurring on the same willow species tended to attack different shoots within the same host plant individual. When species pairs co-occurred on shoots they were usually found in similar densities as when occurring alone on shoots. The stem-galling sawflies usually formed galls at the basal part of a shoot, whereas the gallmidge R. sp. 5 (R. sp. 3 and R. sp. 4 showed no clear tendency) preferred the middle or distal part of a shoot. This is interpreted with differences of their phenology and oviposition period. [source] Repeatability of dispersal behaviour in a common dwarf spider: evidence for different mechanisms behind short- and long-distance dispersalECOLOGICAL ENTOMOLOGY, Issue 2 2009DRIES BONTE Abstract 1.,The response of dispersal towards evolution largely depends on its heritability for which upper limits are determined by the trait's repeatability. 2.,In the Linyphiid spider E. atra, we were able to separate long- and short-distance dispersal behaviours (respectively ballooning and rappelling) under laboratory conditions. By performing repeated behavioural trials for females, we show that average dispersal trait values decrease with increasing testing days. By comparing mated and unmated individuals during two periods (before and after mating for the mated group, and the same two periods for the unmated group), we show that mating has no effect on the mean displayed dispersal behaviour or its within-individual variation. Repeatabilities were high and consistent for ballooning motivation, but not for rappelling. 3.,Ballooning motivation can be regarded as highly individual-specific behaviour, while general pre-dispersal and rappelling behaviours showed more individual variation. Such difference in repeatability between long- and short-distance dispersal suggests that short- and long-distance dispersal events are triggered by different ecological and evolutionary mechanisms. [source] The potential role of waterbirds in dispersing invertebrates and plants in arid AustraliaFRESHWATER BIOLOGY, Issue 2 2008A. J. GREEN Summary 1. The role of waterbirds as vectors of plants and invertebrates within and between arid-zone wetlands is poorly understood. We present the first detailed study of passive dispersal by nomadic birds in Australasia. We investigated the numbers and types of invertebrate and plant propagules within freshly collected faecal samples as well as their viability. We compared dispersal among Grey Teal (Anas gracilis), Eurasian Coot (Fulica atra) and Black Swan (Cygnus atratus) in the Macquarie Marshes, a complex of temporary to semi-permanent wetlands in New South Wales. 2. When faecal samples (n = 60) were inundated in the laboratory and monitored over 3 weeks, ciliates (75% of samples), nematodes (22%), ostracods (13%) and rotifers (5%) were recorded, with higher taxon richness in coot samples. Faecal samples (n = 71) were also sieved to quantify intact propagules, and ostracod eggs (70% of samples), large branchiopod eggs (31%) and bryozoan statoblasts (31%) were the most abundant invertebrates. Diaspores of 19 plant taxa were recorded, 14 of which were germinated in the laboratory or shown to be viable at the end of germination trials. The abundance and diversity of invertebrate propagules was highest in coot samples, whereas the abundance and diversity of diaspores was highest in teal samples. 3. One Australian Pelican (Pelecanus conspicillatus) sample was obtained and found to contain more taxa and far more propagules than any sample from other waterbirds, suggesting that piscivorous birds might have an important role in the indirect dispersal of propagules ingested by fish. 4. Our results support a role for birds in explaining the distributions of cosmopolitan plant genera such as Lemna, Typha, Myriophyllum and Nitella. The alien plants Ranunculus sceleratus, Medicago polymorpha and Polygonum arenastrum were recorded, demonstrating the potential role of waterfowl in the spread of exotic species. As the frequency and duration of flooding of arid-zone wetlands decreases owing to human activities, the importance of waterbirds in facilitating recolonisation of temporary wetlands is likely to increase. [source] | |||||||||||||||||||||||||||||||