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At least 793 records · Page 44Linked to original sources
PubMed2000

[8-(Diethylamino)octyl-3,4,5-trimethoxybenzoate, HCl], the inhibitor of intracellular calcium mobilization, blocked mitogen-induced T cell proliferation by interfering with the sustained phase of protein kinase C activation.

The physiological role of IP(3)-dependent Ca(2+) release in T cell activation was in question due to the contradictory findings that [8-(Diethylamino)octyl-3,4,5-trimethoxybenzoate, HCl] (TMB-8), an inhibitor of intracellular Ca(2+) mobilization, blocked T cell proliferation, curtailing specifically the level of released Ca(2+) did not affect T cell activation and T cell line lacking IP(3) receptor was defective in IL-2 production in response to TCR/CD3 ligand. In the present study we found that TMB-8 inhibited Concanavalin A (Con A)- but not PMA/Ionomycin-induced T cell proliferation in a reversible and dose-dependent manner. The kinetic study revealed that TMB-8 exerted the inhibitory effect at a very early step of T cell activation. The Ca(2+) ionophore ionomycin augmented instead of overcoming the inhibitory effect of TMB-8, although the same doses of ionomycin alone had no effect on Con A-induced T cell proliferation. PMA the metabolically stable, but not diacylglycerol (DAG) the metabolically labile, activator of protein Kinase C (PKC) completely overcome the antiproliferative effect of TMB-8. A specific DAG lipase inhibitor RHC80267 also overcome the effect of TMB-8. Taken together, these results showed that the process of Ca(2+) release through IP(3) receptor, not the released Ca(2+), is essential for the sustained phase of PKC activation during T cell proliferation.

Animals↗
PubMed1998

Tyrosyl-phosphorylated proteins are involved in regulation of meiosis in the rat egg.

Fertilization in invertebrates results in tyrosine (Tyr) phosphorylation of several egg proteins. However, the involvement of Tyr phosphorylation in mediating mammalian egg activation has not yet been investigated. Using an antibody specific for phosphotyrosine (P-Tyr), immunoblotting, and densitometric analysis, we found that maturation of the oocyte is accompanied by a generalized increase in the P-Tyr content of almost all egg proteins detected. After sperm penetration, 5 of the 17 protein bands detected demonstrated a small increase in their P-Tyr content, while at the pronuclear (PN) stage the signal was markedly reduced. Ionomycin emulated the changes observed at fertilization in most protein bands detected, demonstrating a small increase in their P-Tyr content within 15 min of exposure. Analysis of the involvement of the tyrosyl-phosphorylated, mitogen-activated protein (MAP) kinase during meiosis revealed comigration of the phosphotyrosyl bands with the protein and a good correlation with its enzyme activity. Maturation was accompanied by an increase in MAP kinase activity. The activity dropped partially after sperm penetration and furthermore later at the PN stage. A larger quantity accompanied by a more significant change in the P-Tyr content implies for extracellular regulated kinase (ERK) 2 being the dominant isoform present in the rat egg. Our results indicate that fertilization in mammals involves changes in activity of protein tyrosine kinases (PTKs) or in the balance between PTKs and protein tyrosine phosphatases. The single, ionomycin-induced Ca2+ rise is sufficient to imitate fertilization-induced changes in MAP kinase activity, as well as in tyrosine phosphorylation of other proteins within the egg.

Animals↗
PubMed1997

Bovine parthenogenesis is characterized by abnormal chromosomal complements: implications for maternal and paternal co-dependence during early bovine development.

The present study was conducted to examine the karyotypes of parthenogenetic bovine embryos arising from the application of standard oocyte activation and diploidization methods. Bovine cumulusoocyte complexes were collected and matured in vitro for 24 hr prior to oocyte activation with either 5 microM ionomycin or 7% ethanol for 5 min. Groups of activated oocytes were further treated with 5 micrograms/ml cytochalasin D or 1.9 mM 6-dimethylaminopurine (DMAP) for 6 hr. Cleavage varied significantly (P < .05) among the treatment groups with 68.0% of the ethanol- and DMAP-treated oocytes dividing. Blastocyst development did not vary with 18.4 +/- 2.5% of all treated oocytes progressing to this stage. Blastocyst development did not occur in groups subjected to oocyte activation alone. Blastocysts displayed haploid (2.3%), diploid (11.4%), tetraploid (40.9%), octaploid (4.5%), and mixoploid chromosomal complements (40.9%). Two-cell stage parthenogenotes resulting from ethanol or ionomycin treatment alone displayed haploid (66.7%), diploid (16.7%), tetraploid (4.2%), and mixoploid (12.5%) complements. Our results demonstrate that diploid bovine parthenogenotes arising from these procedures are a minority, with the majority of parthenogenotes displaying polyploid and mixoploid chromosomal complements. The events contributing to these abnormal chromosomal complements occur as early as completion of the first cell cycle, possibly linking these events with the absence of a paternally supplied centrosome.

Adenine↗
PubMed2000

Effects on Rb(+)(K+) uptake of HeLa cells in a high K(+) medium of exposure to a switched 1.7 Tesla magnetic field.

Effects of a switched, time-varying 1.7 T magnetic field on Rb(+)(K+) uptake by HeLa S3 cells incubated in an isosmotic high K(+) medium were examined. The magnetic flux density was varied intermittently from 0.07-1.7 T at an interval of 3 s. K(+) uptake was activated by replacement of normal medium by high K(+) medium. A membrane-permeable Ca(2+) chelating agent (BAPTA-AM) and Ca(2+)-dependent K(+) channel inhibitors (quinine, charibdotoxin, and iberiotoxin) were found to reduce the Rb(+)(K+) uptake by about 30-40%. Uptake of K(+) that is sensitive to these drugs is possibly mediated by Ca(2+)-dependent K(+) channels. The intermittent magnetic field partly suppress ed the drug-sensitive K(+) uptake by about 30-40% (P < 0.05). To test the mechanism of inhibition by the magnetic fields, intracellular Ca(2+) concentration ([Ca(2+)]c) was measured using Fura 2-AM. When cells were placed in the high K(&plus;) medium, [Ca(2+)]c increased to about 1.4 times the original level, but exposure to the magnetic fields completely suppressed the increase (P < 0.01). Addition of a Ca(2+) ionophore (ionomycin) to the high K(+) medium increased [Ca(2+)]c to the level of control cells, regardless of exposure to the magnetic field. But the inhibition of K(+) uptake by the magnetic fields was not restored by addition of ionomycin. Based on our previous results on magnetic field-induced changes in properties of the cell membrane, these results indicate that exposure to the magnetic fields partly suppresses K(+) influx, which may be mediated by Ca(2+)-dependent K(+) channels. The suppress ion of K(+) fluxes could relate to a change in electric properties of cell surface and an inhibition of Ca(2+) influx mediated by Ca(2+) channels of either the cell plasma membrane or the inner vesicular membrane of intracellular Ca(2+) stores.

Calcium↗
PubMed1998

PMA/ionomycin induces Ig kappa 3' enhancer activity which is in part mediated by a unique NFAT transcription complex.

The Ig kappa 3' enhancer is required for high levels of Ig kappa gene expression. We now show that kappa 3' enhancer function increases five- to eightfold after stimulation of primary murine B cells with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin. In the presence of cyclosporin A this induction is almost halved, suggesting that transcription factors of the NFAT family contribute to kappa 3' enhancer induction. Indeed, we identify a novel NFAT binding site which is required for full enhancer function. We find that this site is transcriptionally active in stimulated B cells, T cells and fibroblasts and that both PMA and ionomycin are required for maximal induction. Time course analysis of the components of the protein-DNA complex in primary lymphocytes reveals that both NFATp and NFATc are present in the complex after 15 min, while only NFATc is detectable after 4 h. This suggests that NFATc plays the dominant role in controlling long-term responses of this transcription factor family. Furthermore, JunB, JunD, FosB and cFos form part of the DNA-protein complex in Bal-17 B cells. Complex formation as well as transcriptional activity can also be induced by crosslinking of surface Ig. We have, thus, identified a unique NFAT complex in B cells that contributes to Ig kappa gene expression.

Animals↗
PubMed1991

A morphometric and computer-assisted three-dimensional reconstruction study of neural tube formation in chick embryos.

The origin of the driving forces for neural tube formation remains uncertain but is currently thought to involve the participation of microfilament bundles situated in the apical ends of neuroepithelial cells. In the work presented here, we show how morphometric measurements that map local variations in the apical geometry of neuroepithelial cells (especially apical constriction) can provide information on the distribution of motive forces within the neuroepithelium during neural tube formation. When used in combination with computer-assisted, three-dimensional reconstruction, it becomes possible to analyze the morphometric data from a dynamic, three-dimensional perspective. As an example application of this method, we have used morphometry to evaluate the effects of ionomycin on the developing neuroepithelium. Treatment of early (stages 6-8) chick embryos with 5 microM ionomycin was found to cause rapid bending of the neuroepithelium within 1 min of exposure and a dramatic acceleration of the normal sequence of neural tube formation. Electron microscopy and morphometry revealed that this acceleration was coincident with a marked increase in the local degree of apical constriction of neuroepithelial cells, presumably a consequence of enhanced contractile activity of apical microfilament bundles. This work shows that transient elevation of free calcium levels can accelerate the usual sequential phases of NT formation. The rapidity of the response (hours of normal development reduced to minutes), increased prominence of apical microfilament bundles, and the enhanced degree of apical constriction strongly support a direct causal role for apical microfilament bundles and apical constriction of neuroepithelial cells in bending of the neuroepithelium.

Actin Cytoskeleton↗
PubMed1988

Deficient phytohemagglutinin-induced interleukin-2 activity in patients with inactive systemic lupus erythematosus is correctable by the addition of phorbol myristate acetate.

In systemic lupus erythematosus (SLE) patients, the production of interleukin-2 (IL-2) by blood T lymphocytes in response to stimulation with phytohemagglutinin (PHA) either alone or with phorbol myristate acetate (PMA) or ionomycin, a Ca2+ ionophore, was examined. Deficiency in PHA-stimulated IL-2 production by cells from SLE patients was repaired by the addition of PMA, but not ionomycin. PMA alone did not stimulate IL-2 production but, in concert with PHA, induced IL-2 synthesis. Moreover, PMA was effective in the repair of the deficiency of PHA-induced IL-2 production by both T4+ and T8+ subsets. Thus, for effective IL-2 production, SLE T cells required signals either distinct from or in addition to those supplied by PHA.

Adult↗
PubMed1987

Synergistic interaction between interleukin 4 and anti-Bp50 (CDw40) revealed in a novel B cell restimulation assay.

Highly purified resting B lymphocytes stimulated for 3 days to high-rate DNA synthesis by a synergistic combination of phorbol dibutyrate and ionomycin soon returned to quiescence once those signals had been removed. The maintenance of DNA synthesis in such cultures was found to provide a sensitive assay for revealing the factors that interact with cycling B cells. Whereas several activities-namely, interleukin 4, anti-Bp50 and a low molecular weight B cell growth factor-were, by themselves, capable of prolonging DNA synthesis over a further day or so, no single factor was capable of sustaining the replication cycle out to day 6 of culture. By contrast, certain combinations of activities displayed significant synergy in the restimulation assay. The most striking observed was that between interleukin 4 and anti-Bp50 where, by day 6, their combined effect on maintaining DNA synthesis in 3-day stimulated cells was the same as having kept phorbol dibutyrate and ionomycin in the culture system. The implications of these findings are discussed.

Antibodies, Monoclonal↗
PubMed1987

Selective effects of cholera toxin on the activation of mouse B cells by different polyclonal activators.

Murine B cells were stimulated in vitro with anti-immunoglobulin (Ig) antibodies, lipopolysaccharide, or with various combinations of phorbol dibutyrate and ionomycin. Very low concentrations (ca. 10(-14) M) of cholera toxin inhibited anti-Ig-stimulated DNA synthesis, while the response to LPS was only abrogated by 2 X 10(4)-10(5)-fold greater concentrations of the toxin. Earlier responses in anti-Ig-stimulated B cells, such as increases in Ia antigen levels, were not affected by the toxin. Protein kinase C-activating phorbol esters, together with Ca2+ ionophores, are believed to stimulate DNA synthesis in lymphocytes by mimicking the two second messengers resulting from ligation of the antigen receptors. However, concentrations of cholera toxin which totally abolish anti-Ig-induced B cell proliferation significantly enhanced DNA and RNA synthesis induced by phorbol dibutyrate plus ionomycin. The results are discussed in terms of possible effects of cholera toxin on guanine nucleotide-binding (G) proteins controlling receptor coupling to second messenger-generating systems in B cells.

Animals↗
PubMed1988

Interleukin 4 and soluble CD23 as progression factors for human B lymphocytes: analysis of their interactions with agonists of the phosphoinositide "dual pathway" of signalling.

Human B lymphocytes pre-activated for 24 h with a combination of phorbol dibutyrate [P(Bu)2] and ionomycin were found to provide excellent targets for assessing the detailed action of B cell progression factors. Both recombinant interleukin 4 (IL 4) and affinity-purified 25-kDa fragment of the CD23 molecule (sol-CD23) were shown to be active in this assay. While the progression activity of IL 4 was enhanced by continued co-culture with P(Bu)2, that of sol-CD23 was found to be more strictly dependent upon such a joint application with the phorbol ester. Similar requirements were observed for triggering cell-cycle progression in the pre-activated B cells when using a stimulating CD23 antibody. Ionomycin, in contrast to P(Bu)2, did not augment either IL 4 or sol-CD23 in these assays but did enhance significantly the progression activity of an anti-CDw40 antibody. When added to B cells concomitantly with, or prior to, a high dose of phorbol ester, IL 4 unexpectedly down-regulated the subsequent mitogenic response to this agent whereas, when added 24 h later, IL 4 up-regulated such stimulations. The latter sequence of additions resulted in a particularly dramatic induction of CD23 at the B cell surface, much more so than seen when B cells were incubated with either IL 4 alone or with IL 4 and P(Bu)2 together. This up-regulation of surface CD23 was, in turn, mirrored by the appearance of large amounts of the soluble form of the molecule in such cultures. The findings are discussed with reference to possible mechanisms through which IL 4 and CD23 interact to exert their multiple actions on B cell regulatory pathways.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1989

T lymphocyte heterogeneity in old and young mice: functional defects in T cells selected for poor calcium signal generation.

An increase in cytoplasmic free calcium ion concentration is thought to play a critical role in the entry of resting T lymphocytes into the mitotic cycle. Not all murine T cells, however, generate such a calcium signal when exposed to mitogenic doses of concanavalin A (Con A), and the proportion of nonresponsive cells increases with age in adult mice. Since the frequency of T cells able to generate cytotoxic or lymphokine-secreting cells in culture also declines in old age, we have speculated that the defect in changes in Ca2+ concentration might underlie this functional deficit. To examine the relationship between functional competence and the calcium signaling pathway, we performed limiting dilution analyses of T cells enriched (by a fluorescence-based cell-sorting method) for high or low calcium signal generation. We found that rapid Ca2+ signal generation after Con A exposure did indeed correlate well with functional competence in Con A-stimulated limiting dilution cultures. Furthermore, selection for Ca2+ signals induced by anti-CD3 antibody, or even by ionomycin, similarly enriched for the functionally competent set of T cells. The ionomycin result, in particular, suggests that the difference between the reactive and nonreactive sets of T cells is unlikely to result simply from alterations in receptor-linked signal transduction pathways. We discuss a model in which immune senescence involves an age-dependent increase in a subset of T cells in which changes in cytoplasmic Ca2+ concentration are relatively difficult to induce by either receptor-dependent mitogens or ionophores.

Aging↗
PubMed1989

Enumeration of cytokine-secreting cells at the single-cell level.

A sensitive assay utilizing enzyme-linked immunosorbent assay methodology has been developed for the quantitation of single cells secreting interferon (IFN)-gamma or tumor necrosis factor (TNF). Cloned T cells or cells from lymphoid organs were stimulated with antigen, concanavalin A, or phorbol myristate acetate and ionomycin in microwells coated with antibodies specific for IFN-gamma. Discrete "spots" overlying areas where cells secrete IFN-gamma were then developed by incubation with a second antibody to IFN-gamma, followed by an enzyme-labeled antibody conjugate and substrate. Similarly, using TNF-specific antibody reagents, TNF-secreting cells were detected and quantitated in cell populations obtained from normal lymphoid tissues, bone marrow and peripheral blood, following activation with phorbol myristate acetate and ionomycin. Provided specific antibodies are available, this method has the potential to measure the frequency of cells secreting any cytokine.

Animals↗
PubMed1989

Cyclic AMP can enhance mouse B cell activation by regulating progression into the late G1/S phase.

This study demonstrates that several substances which raise intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels in different ways were able to enhance both RNA and DNA synthesis in mouse purified B cells co-stimulated by the protein kinase C activator phorbol 12-myristate 13-acetate and the Ca2+ ionophore ionomycin, while earlier activation events were not modified. These included early changes in cell size and chromatin decondensing demonstrated by light scatter properties at narrow and 90 degrees angles, increase in Ia expression and loss of surface IgD. We concluded that cAMP can up-regulate mouse B cell activation by controlling progression into the late G1 (G1B)/S phase, but not transition from G0 to early G1 (G1A). Furthermore, because cAMP could synergize with ionomycin but not with phorbol 12-myristate 13-acetate to induce RNA and DNA synthesis, we proposed that the cAMP effects in this model may be related to the protein kinase C pathway.

Animals↗
PubMed1992

Regulation of immunoglobulin gene expression in normal lymphocytes. II. Mechanisms of down-regulation of immunoglobulin secretion after engagement of the B cell antigen receptor.

When B cells are stimulated with lipopolysaccharide (LPS) they start to proliferate and mature into immunoglobulin (Ig)-secreting cells. Co-stimulation with F(ab')2 fragments of antibodies directed against the B cell antigen receptor leads to an inhibition of Ig secretion but not of proliferation. This effect can be mimicked by phorbol esters alone or by a combination of phorbol esters and the Ca2+ ionophore ionomycin, which activate protein kinase C. Here we report that co-stimulation with phorbol esters and ionomycin differentially affects a group of genes normally up-regulated during the course of LPS-dependent B cell activation. Thus, the mRNA coding for the membrane-bound form of IgM and the interleukin 2 receptor (55-kDa protein) continue to be expressed at the levels typical of LPS-stimulated cells, while the mRNA coding for the secreted form of IgM (mu S) and for the J chain are reduced. The loss of mu S mRNA is attributable to an altered processing behavior with respect to the mu precursor and/or a decreased stability of the mRNA itself.

Animals↗
PubMed1995

The role of bcl-XL in CD40-mediated rescue from anti-mu-induced apoptosis in WEHI-231 B lymphoma cells.

The phenotypically immature B cell lymphoma WEHI-231 undergoes apoptotic cell death when cultured with anti-immunoglobulin (Ig) antibodies, via a bcl-2-independent mechanism. We have therefore studied the role of the bcl-2-related protein bcl-x in controlling cell death in WEHI-231. We find that overexpression of the long form of bcl-x (bcl-XL) renders these cells refractory to anti-Ig-induced cell death. Stimulation of WEHI-231 via CD40 has similar protective effects. We show here that ligation of CD40 rapidly induces the appearance of the bcl-XL protein in WEHI-231, while stimulation via sIgM, sIgD, CD5 or CD45 receptors, or with phorbol esters plus ionomycin does not. WEHI-231 cells also rapidly undergo massive apoptosis following culture with thapsigargin, a specific inhibitor of the Ca(2+)-ATPase of the endoplasmic reticulum: this is also reversed by anti-CD40, or by overexpression of bcl-XL. We, therefore, conclude that bcl-XL plays a key role in the regulation of antigen receptor-mediated apoptosis via CD40 in WEHI-231. In addition, the fact that this protein is not induced in WEHI-231 in response to phorbol dibutyrate plus ionomycin points to a fundamental signaling defect in these cells, which could conceivably be a reflection of their immature, apoptosis-susceptible phenotype.

Animals↗
PubMed1995

Identification of an ionomycin/cyclosporin A-responsive element within the human T cell receptor gamma enhancer.

Activation through the Ca2+/calcineurin pathway is essential to the transcription of many cytokine genes. The conserved cis-acting sequence, GGAAAA, and transcription factors binding to this sequence are involved in the response to increased intracellular Ca2+ concentrations. Here we report the identification and importance of the same sequence in a non-cytokine gene, the human T cell receptor gamma (TCRG) enhancer. Results from site-directed mutations and electrophoretic mobility shift assays strongly suggest that this sequence mediates the ionomycin-induced activation of the TCRG enhancer. Our studies provide an explanation for a previous observation that TCRG mRNA levels, but not mRNA levels for T cell receptor alpha and -beta, are increased by ionomycin treatment.

Base Sequence↗
PubMed1997

MRL/lpr CD4- CD8- and CD8+ T cells, respectively, mediate Fas-dependent and perforin cytotoxic pathways.

Autoimmune-prone MRL/lpr mice, homozygous for the lpr mutation, exhibit defective apoptosis and develop generalized lymphoproliferation with the accumulation of a double-negative (DN: CD4- CD8-) T cell population. The capacity of lpr T lymphocytes to effectuate Fas- and perforin-mediated cytotoxicity was investigated. Spleen and lymph nodes cells spontaneously lyse Fas- targets (thymocytes) through a Fas-mediated mechanism as a consequence of their overexpression of Fas ligand (FasL) confirmed by semiquantitative reverse transcription (RT)-PCR and immunoprecipitation analysis. This cytotoxicity was greatly increased after stimulation of the effectors by phorbol myristate acetate (PMA) + ionomycin. Under these conditions, MRL/lpr spleen and LN cells exhibited strong Fas-mediated Ca2+-independent cytotoxic activity against wild-type Fas+ (H-2 compatible or incompatible) thymocytes or lipopolysaccharide (LPS)-transformed blast cells. Such Fas-mediated cytotoxic activity was also observed with C57BL/6-lpr, but never with wild-type C57BL/6 or MLR+/+ effectors. Depletion experiments showed that the effector cells of this Fas-mediated cytotoxicity were DN T cells. This subset, which represent in vivo activated T cells, can spontaneously lyse Fas+ targets by a mechanism that does not need the interaction of the T cell receptor (TCR) with major histocompatibility complex molecule plus antigen. This lytic potential is increased by PMA + ionomycin, which sends a second activation signal to these primed T cells. Therefore, the small amounts of Fas receptor expressed on MRL/lpr tissues may account for their nonspecific autoimmune attack by DN cells. In Con A-containing medium, which allows detection of the perforin-mediated pathway against Fas targets, cytotoxic CD8+ effectors were detected that are able to kill lpr thymocytes via a Ca2+-dependent pathway. Thus, in MRL/lpr mice, these CD8+ cells could constitute potent cytotoxic effectors against cells presenting antigen to their TCR.

Animals↗
PubMed1993

Cross talk of dual-signal transduction systems in the regulation of DNA synthesis by parathyroid hormone in osteoblastic osteosarcoma cells.

There has been recent evidence that calcium/protein kinase C (Ca/PKC) messenger system as well as adenylate cyclase are involved in the signal transduction stimulated by PTH. We therefore examined the role of these dual-signal transduction systems and the interaction of these systems in the regulation of DNA synthesis by PTH in the osteoblastic osteosarcoma cells, UMR-106. As recently reported, 10(-4) M Sp-cAMPS, a direct activator of cAMP-dependent protein kinase (PKA), and 10(-4) M dibutyryl-cAMP, as well as hPTH-(1-34), caused the significant inhibition of [3H]thymidine incorporation (TdR). Both A23187 and ionomycin (10(-8)-10(-6) M) inhibited TdR in a dose-dependent manner, with a minimal effective dose at 10(-7) M. Although 10(-6) M phorbol 12-myristate 13-acetate (PMA) caused slight but significant stimulation of TdR by itself, it augmented not only dibutyryl-cAMP- but also Sp-cAMPS-induced inhibition of TdR. On the other hand, 4 alpha-phorbol 12,13-didecanoate, incapable of activating PKC, failed to augment these cAMP analogs-induced effects. Pretreatment with 50 microM H-7, an inhibitor of PKC, not only abolished the PMA-induced augmentation of effect by cAMP analogs but also significantly blocked the PTH-induced inhibitory effect on TdR. Pretreatment with 10(-6) M PMA, which downregulates PKC, significantly inhibited the PTH-induced suppression of TdR. Combined treatment with cAMP analog (dibutyryl-cAMP or Sp-cAMPS) and calcium ionophore (A23187 or ionomycin) caused additive effects on TdR, and PMA used in combination with both cAMP analog and calcium ionophore induced the further inhibition of TdR.(ABSTRACT TRUNCATED AT 250 WORDS)

Bucladesine↗