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PubMed2000

Vasopressin-induced neurotrophism in cultured neurons of the cerebral cortex: dependency on calcium signaling and protein kinase C activity.

Neuronal process outgrowth has been postulated to be one of the fundamental steps involved in neuronal development. To test whether vasopressin can influence neuronal development by acting on the outgrowth of neuronal processes, we determined the neurotrophic action of the memory-enhancing peptide, vasopressin, in neurons derived from the cerebral cortex, a site of integrative cognitive function and long-term memory. Exposure to V(1) receptor agonist significantly increased multiple features of nerve cell morphology, including neurite length, number of branches, branch length, number of branch bifurcation points and number of microspikes. The dose-response profile of V(1) receptor agonist-induced neurotrophism exhibited a biphasic function, with lower concentrations inducing a significant increase while higher concentrations generally induced no significant effect. The neurotrophic effect of V(1) receptor activation did not require growth factors present in serum. Analysis of the regional selectivity of the vasopressin-induced neurotrophic effect revealed significant V(1) receptor agonist-induced neurotrophism in occipital and parietal neurons, whereas frontal and temporal neurons were unresponsive. Results of experiments to determine the mechanism of vasopressin-induced neurotrophism demonstrated that vasopressin-induced neurotrophism is dependent on V(1)a receptor activation, requires L-type calcium channel activation and activation of both pathways of the phosphatidylinositol signaling cascade, inositol trisphosphate and protein kinase C. These studies are the first to describe a functional cellular response for vasopressin in the cerebral cortex. The findings are discussed with respect to their implications for understanding the role of vasopressin-induced neurotrophism, the associated signaling pathways required for this response, and the ability of vasopressin to enhance memory function.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Acute and chronic alterations in calcium homeostasis in 3-nitropropionic acid-treated human NT2-N neurons.

3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, induced ATP depletion and both necrosis and apoptosis in human NT2-N neurons. Necrosis occurred predominantly within the first two days, and increased in a dose-dependent fashion with the concentration of 3-NP, whereas apoptosis was observed after 24 h or later at a similar rate in 0.1 mM and 5 mM 3-NP. We focused our efforts on intracellular calcium homeostasis during the first 48 h in 1 mM 3-NP, a period during which 10% of the neurons died by necrosis and 3% by apoptosis. All NT2-N neurons showed a stereotyped [Ca(2+)](i) rise, from 48+/-2 to 140+/-12 nM (mean +/-S.E.M.), during the first 2 h in 3-NP. Despite severe ATP depletion, however, [Ca(2+)](i) remained above 100 nM in only 17% and 25% of the NT2-N neurons after 24 and 48 h in 3-NP, respectively, indicating that most neurons were able to recover from acute [Ca(2+)](i) rise, and suggesting that chronic [Ca(2+)](i) dysregulation is a better indicator of subsequent necrosis. Blockade of N-methyl-D-aspartate-glutamate receptor by MK-801 substantially ameliorated 3-NP-induced ATP depletion, subsequent chronic [Ca(2+)](i) elevation, and survival. Moreover, xestospongin C, an inhibitor of endoplasmic reticulum Ca(2+) release, enhanced the capacity of NT2-N neurons to maintain [Ca(2+)](i) homeostasis and resist necrosis while subjected to sustained energy deprivation. As far as we know, this report is the first to employ human neurons to study the pathophysiology of 3-NP neurotoxicity.

Adenosine Triphosphate↗
PubMed2003

Contribution of intracellular calcium stores to an increase in cytosolic calcium concentration induced by Mannheimia haemolytica leukotoxin.

The contribution of intracellular calcium stores to Mannheimia haemolytica leukotoxin (LKT)-induced increase in cytosolic calcium concentration was studied by pharmacologically inhibiting transport of calcium across the plasma and endoplasmic reticulum membranes of bovine neutrophils exposed to LKT. Active intracellular storage of calcium by sarcoplasmic/endoplasmic reticulum calcium ATPase, influx of extracellular calcium across the plasma membrane, and release of stored calcium via inositol triphosphate receptors and ryanodine-sensitive calcium channels were inhibited using thapsigargin, lanthanum chloride, xestospongin C, and magnesium chloride, respectively. Pre-incubation with thapsigargin attenuated the increase in cytosolic calcium concentration produced by LKT, thus confirming the involvement of intracellular calcium stores. Inhibitory effects of lanthanum chloride, xestospongin C, and magnesium chloride indicated that the increase in cytosolic calcium concentration induced by LKT resulted from both influx of calcium across the plasma membrane and release of calcium from intracellular stores.

Animals↗
PubMed2002

Transmitter release from Rana pipiens vestibular hair cells via mGluRs: a role for intracellular Ca(++) release.

The response of the semicircular canal (SCC) to the group I mGluR-selective agonist dihydroxyphenylglycine (DHPG; 300 microM) - facilitation of afferent discharge rate - was dose-dependently reduced by the phospholipase C inhibitor U-73122 (1-100 microM; IC(50): 22 microM), the smooth endoplasmic reticulum Ca(++) ATPase inhibitor thapsigargin (100 nM-3 microM; IC(50): 500 nM), and xestospongin C (100 pM-1 microM; IC(50): 11 nM), an inositol trisphosphate receptor (IP(3)R) antagonist. Ryanodine, a modulator of Ca(++)-induced Ca(++) release, biphasically facilitated, then suppressed this response (1 nM-1 mM; approximate IC(50): 50 microM). 5 mM caffeine increased the amplitude (34.6+/-13.4%) and duration (453+/-169.8%; n=4) of the response of the SCC to DHPG, while 50 mM caffeine eliminated this response (n=2). The protein kinase C inhibitor bisindolylmaleimide I-HCl (10-100 microM; n=3) and the cyclic-ADP ribose antagonist 8-Br-cyclic-ADP ribose (1-10 microM; n=3) had no effect on the response of the SCC to DHPG. These data suggest that the increase in transmitter release following activation of group I mGluRs on vestibular hair cells is associated with intracellular Ca(++) release from both IP(3)-sensitive and ryanodine/caffeine-sensitive intracellular Ca(++) stores. Such positive feedback on transmitter release may serve to enhance the contrast between the spontaneous and stimulus-evoked modes of hair cell transmitter release, thereby optimizing signal discrimination at the synapse between hair cells and vestibular afferent fibers.

Animals↗
PubMed1997

Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor.

Xestospongins (Xe's) A, C, D, araguspongine B, and demethylxestospongin B, a group of macrocyclic bis-1-oxaquinolizidines isolated from the Australian sponge, Xestospongia species, are shown to be potent blockers of IP3-mediated Ca2+ release from endoplasmic reticulum vesicles of rabbit cerebellum. XeC blocks IP3-induced Ca2+ release (IC50 = 358 nM) without interacting with the IP3-binding site, suggesting a mechanism that is independent of the IP3 effector site. Analysis of Pheochromocytoma cells and primary astrocytes loaded with Ca2+-sensitive dye reveals that XeC selectively blocks bradykinin- and carbamylcholine-induced Ca2+ efflux from endoplasmic reticulum stores. Xe's represent a new class of potent, membrane permeable IP3 receptor blockers exhibiting a high selectivity over ryanodine receptors. Xe's are a valuable tool for investigating the structure and function of IP3 receptors and Ca2+ signaling in neuronal and nonneuronal cells.

Alkaloids↗
PubMed2004

Influence of intracellular Ca2+ release modulating drugs on bupivacaine infiltration anesthesia in mice.

The endoplasmic reticulum inside neurons can provide enormous amounts of releasable Ca2+ to increase cytosolic Ca2+ levels through the activation of endoplasmic membrane ion channels. Ryanodine (RyR) channels release Ca2+ into the cytosol when activated by Ca2+ influx through voltage-gated channels, or by cyclicADP ribose. Inositol tris-phosphate (IP3) channels are stimulated by phospolipid metabolism and the release of IP3. The hypothesis was tested that drugs that bind RyR or IP3 channels would affect the anesthetic potency of bupivacaine. The radiant heat tail-flick test was used to assess for anesthesia following subcutaneous infiltration of bupivacaine and Ca2+ modulating drugs in the tails of mice. No musculature is contained in the tail that could result in motor block. The RyR channel agonists 4-chloro-m-cresol and poly-L-lysine significantly reduced the anesthetic potency of bupivacaine. The plant alkaloid ryanodine elicited a bi-phasic effect, with low concentrations blocking bupivacaine anesthesia, and a high concentration enhancing anesthesia. Alternatively, the RyR channel antagonist dantrolene sodium dose-dependently increased bupivacaine's potency. However, the IP3 channel drugs were inactive. The IP3 agonist adenophostin A failed to affect bupivacaine anesthesia. Furthermore, bupivacaine was unaffected by the IP3 channel antagonists xestospongin C or low molecular weight heparin. Our results indicate that only the RyR channel drugs modulated the anesthetic effects of bupivacaine. Electrophysiological and molecular studies of sensory dorsal root ganglia neurons, the source of Adelta and C-fiber nociceptors, have demonstrated the presence of RyR3 Ca2+ release channels. This provides the first evidence that RyR channels might affect bupivacaine anesthesia in some fashion.

Anesthesia, Local↗
PubMed1999

Antibiotic inhibitors of organellar protein synthesis in Plasmodium falciparum.

Elongation factor Tu (EF-Tu) is encoded by the tuf gene of the plastid organelle of the malaria parasite Plasmodium falciparum. A range of structurally unrelated inhibitors of this GTP-dependent translation factor was shown to have antimalarial activity in blood cultures. The most active was the cyclic thiazolyl peptide amythiamicin A with an IC50 = 0.01 microM. Demonstrable complexes were formed in vitro between a recombinant version of P. falciparum EF-Tu(pl) and inhibitors that bind to different sites on EF-Tu; these included the antibiotics kirromycin, GE2270A and enacyloxin IIa.

Animals↗
PubMed2006

The chain-length dependence test.

Trends obtained from systematic studies based on chain-length variation have provided valuable insight and understanding into the behavior of m-phenylene ethynylene foldamers. The generalization of this experimental approach, the chain-length dependence test, is useful for studying solution conformation, packing in the solid state, specific intrachain interactions, and the contributions of end groups to a particular property.

Macrocyclic Compounds↗
PubMedDate not supplied

Pyridine-containing 6-hydrazinonicotinamide derivatives as potential bifunctional chelators for 99mTc-labeling of small biomolecules.

As a continuation of our interest in novel 99mTc chelating systems, several pyridine-containing HYNIC (6-hydrazinonicotinamide) derivatives (L1-L5) have been synthesized and characterized by NMR (1H and 13C) and LC-MS. 99mTc complexes of L1-L5 were prepared by the reaction of the HYNIC derivative with 99mTcO4- in the presence of excess tricine and stannous chloride. Results from this study show that the attachment site of the linker is critical for the formation of macrocyclic 99mTc complexes. For example, the pyridine-N in L3 is not able to bond to the Tc, because the lysine linker is attached to the 4-position. When the linker is at the 2-position, L1 forms the macrocyclic complex [99mTc(L1)(tricine)], but the radiochemical purity is relatively low. If the linker is attached to the 3-position of the pyridine ring, the HYNIC derivatives form macrocyclic complexes [99mTc(L)(tricine)] (L2, L4, and L5) in high yield (>95%). The HPLC data suggest that the macrocyclic complex [(99m)Tc(L2)(tricine)] exists in solution as four isomers: two diastereomers and two conformational isomers. Diastereomers are due to a combination of the chirality of the lysine linker and of the Tc chelate. Replacing lysine with a pentamethylenediamine linker results in the macrocyclic complex [99mTc(L4)(tricine)] with two conformational isomers, which interconvert rapidly at room temperature. Changing the linker from pentamethylenediamine to hexamethylenediamine did not eliminate the minor isomer; but the percentage of the minor isomer was reduced from approximately 10% for [99mTc(L4)(tricine)] to only 6% for [99mTc(L5)(tricine)]. The linker length is an important parameter to minimize the minor isomer. LC-MS data of complexes [99mTc(L)(tricine)] (L2, L4, and L5) are completely consistent with their proposed compositions. On the basis of these data, it is concluded that pyridine-containing HYNIC derivatives have the potential as bifunctional chelators for 99mTc-labeling of small biomolecules if the linker is attached to the 3-position of the pyridine ring.

Benzenesulfonates↗
PubMedDate not supplied

RNAi silencing of exogenous and endogenous reporter genes using a macrocyclic octaamine as a "compact" siRNA carrier. Studies on the nonsilenced residual activity.

A macrocyclic octaamine 1 having a covalently linked lipid-bundle structure was introduced as a new type of siRNA carrier. Gel electrophoresis, DLS, and SPR results indicate that it strongly binds to a luciferase-targeting 21-mer (42P) siRNA with a ratio of 1/P congruent with 0.3 (1/N congruent with 2.4) to give remarkably compact 1-siRNA complexes with an average size of approximately 10 nm. The 1-mediated siRNA silencing of the exogenous luciferase gene occurs with a 90-95% efficiency. The overall suppression-[siRNA] profile with a 5-10% residual activity in the saturation region is commonly observed irrespective of the cell type (HeLa, HepG2, or HEK293), the order, or timing (stepwise or simultaneous) of supply of the siRNA and that of the luciferase-encoding plasmid, the level of mRNA transcribed, or the type of carriers (1 vs lipofectamine 2000). The silencing of the endogenous DsRed2 gene stably incorporated in the genome of HeLa cells also has a similar overall profile. These results suggest that (1) the cellular uptake of the plasmid and that of the siRNA are basically independent of each other and (2) the incomplete silencing is not due to insufficient siRNA delivery. Implication of item 2 is briefly discussed.

Cell Line↗
PubMed2006

PAR-1-stimulated factor IXa binding to a small platelet subpopulation requires a pronounced and sustained increase of cytoplasmic calcium.

We previously reported that only a subpopulation of PAR-1-stimulated platelets binds coagulation factor IXa, since confirmed by other laboratories. Since calcium changes have been implicated in exposure of procoagulant aminophospholipids, we have now examined calcium fluxes in this subpopulation by measuring fluorescence changes in Fura Red/AM-loaded platelets following PAR-1 stimulation. While fluorescence changes in all platelets indicated calcium release from internal stores and influx of external calcium, a subpopulation of platelets displayed a pronounced increase in calcium transients by 15 s and positive factor IXa binding by 2 min, with calcium transients sustained for 45 min. Pretreatment of platelets with Xestospongin C to inhibit IP3-mediated dense tubule calcium release, and the presence of impermeable calcium channel blockers nifedipine, SKF96365, or LaCl3, inhibited PAR-1-induced development of a subpopulation with pronounced calcium transients, factor IXa binding, and platelet support of FXa generation, suggesting the importance of both release of calcium from internal stores and influx of extracellular calcium. When platelets were stimulated in EDTA for 5-20 min before addition of calcium, factor IXa binding sites developed on a smaller subpopulation but with unchanged rate, indicating sustained opening of calcium channels and continued availability of signaling elements required for binding site exposure. While pretreatment of platelets with 100 microM BAPTA/AM (Kd 160 nM) had minimal effects, 100 microM 5,5'-dimethylBAPTA/AM (Kd 40 nM) completely inhibited the appearance and function of the platelet subpopulation, indicating the importance of minor increases of cytoplasmic calcium. We conclude that PAR-1-stimulated development of factor IXa binding sites in a subpopulation of platelets is dependent upon release of calcium from internal stores leading to sustained and pronounced calcium transients.

Blood Platelets↗
PubMedDate not supplied

Chemiluminescence-based inhibition kinetics of alkaline phosphatase in the development of a pesticide biosensor.

The use and application of the enzyme alkaline phosphatase in a chemiluminescence assay are discussed. The enzyme catalyzes the hydrolysis of a macrocyclic phosphate compound generating a chemiluminescence signal. On the basis of inhibition of this signal, a methodology for the detection and quantitation of organophosphorus-based pesticides has been developed. The methodology is studied with alkaline phosphatase in the bulk aqueous phase, and detection of the signal is accomplished by a simple optical setup. Parts per billion level detection of paraoxon and methyl parathion in bulk solutions is achieved. The technique is rapid and sensitive and is applicable to the detection of most organophosphorus-based pesticides. The results from kinetic studies indicate a mixed type of inhibition of the enzyme by paraoxon and methyl parathion. The detection methodology forms an integral part of a biosensor under development and is adaptable to incorporating optical fibers for remote detection of pesticides.

Adamantane↗
PubMed2004

Bolaamphiphiles.

Explore the source record for details and available documents.

Macrocyclic Compounds↗
PubMed2004

Self-assembly using dynamic coordination chemistry and hydrogen bonding: mercury(II) macrocycles, polymers and sheets.

The self-assembly of extended metal-containing arrays is described based on dynamic coordination chemistry at mercury(II) with bis(amidopyridyl) ligands to form macrocycles, polymers, or sheets which can be further organized by hydrogen bonding between amide substituents. The ligands 1,2-C6H4[NHC(O)-4-C5H4N]2, 1, 1,2-C(6)H(4)[C(O)NHCH(2)-4-C(5)H(4)N](2), 2, and 1,2-C(6)H(4)[CH(2)C(O)NHCH(2)-4-C(5)H(4)N]2, 3 can adopt polar conformations and so can confer helicity in their complexes. Several macrocycles of formula [(HgX(2))(2)(micro-LL)(2)] (LL = 1, 2), with tetrahedral mercury(II) centers, were prepared in which individual molecules are further self-assembled via hydrogen bonding in the solid state to form one- or two-dimensional polymers or sheets. In one case, a one-dimensional polymer [((HgX2)-(mu-3))n] was formed. It is shown that the mercury(II) centers can be six-coordinate in forming the sheet structure [((HgX2)(mu-2)2)n], in which there are particularly large pores.

Benzamides↗
PubMed2004

Zn(II) coordination to polyamine macrocycles containing dipyridine units. New insights into the activity of dinuclear Zn(II) complexes in phosphate ester hydrolysis.

Zn(II) binding by the dipyridine-containing macrocycles L1-L3 has been analyzed by means of potentiometric measurements in aqueous solutions. These ligands contain one (L1, L2) or two (L3) 2,2'-dipyridine units as an integral part of a polyamine macrocyclic framework having different dimensions and numbers of nitrogen donors. Depending on the number of donors, L1-L3 can form stable mono- and/or dinuclear Zn(II) complexes in a wide pH range. Facile deprotonation of Zn(II)-coordinated water molecules gives mono- and dihydroxo-complexes from neutral to alkaline pH values. The ability of these complexes as nucleophilic agents in hydrolytic processes has been tested by using bis(p-nitrophenyl) phosphate (BNPP) as a substrate. In the dinuclear complexes the two metals play a cooperative role in BNPP cleavage. In the case of the L2 dinuclear complex [Zn(2)L2(OH)(2)](2+), the two metals act cooperatively through a hydrolytic process involving a bridging interaction of the substrate with the two Zn(II) ions and a simultaneous nucleophilic attack of a Zn-OH function at phosphorus; in the case of the dizinc complex with the largest macrocycle L3, only the monohydroxo complex [Zn(2)L3(OH)](3+) promotes BNPP hydrolysis. BNPP interacts with a single metal, while the hydroxide anion may operate a nucleophilic attack. Both complexes display high rate enhancements in BNPP cleavage with respect to previously reported dizinc complexes, due to hydrophobic and pi-stacking interactions between the nitrophenyl groups of BNPP and the dipyridine units of the complexes.

2,2'-Dipyridyl↗
PubMed2005

Synthesis and crystal structure of unprecedented oxo/hydroxo-bridged polynuclear gallium(III) aqua complexes.

Two new polynuclear oxo/hydroxo-bridged polynuclear gallium(III) aqua complexes are obtained upon treatment of Ga(3+)(aq) with pyridine: the supramolecular compound of macrocyclic cavitand cucurbit[6]uril with gallium complex containing 32 metal atoms [Ga(32)(mu(4)-O)(12)(mu(3)-O)(8)(mu(2)-O)(7)(mu(2)-OH)(39)(H(2)O)(20)](PyH subsetC(36)H(36)N(24)O(12))(3)(NO(3))(6).53H(2)O (1) and the tridecanuclear complex [Ga(13)(mu(3)-OH)(6)(mu(2)-OH)(18)(H(2)O)(24)](NO(3))(15).12H(2)O (2). It follows that two modes of nucleation exist when Ga(3+)(aq) is hydrolyzed: one around the tetrahedral GaO(4) units (complex 1) and the other around the octahedral GaO(6) units (complex 2). This is the first time that polynuclear oxo/hydroxo-bridged aqua complexes of Ga(III) have been isolated without the use of other ligands to control or block olygomerization.

Journal Article↗
PubMed2005

Calix[4]pyrrole Schiff base macrocycles: novel binucleating ligands for Cu(I) and Cu(II).

New bimetallic copper(I) and copper(II) complexes of dipyrromethane-derived Schiff base macrocycles are reported. Two different structural motifs were identified, providing support for the notion that ligands of this type can support a variety of coordination modes. In the case of the Cu(I) complexes, the metal centers were found to have a distorted tetrahedral geometry and be coordinated to two imine nitrogens on each side of the ligand, with the exact structure depending on the choice of Schiff base macrocycle. In contrast to what is seen for Cu(I), with Cu(II) as the coordinated cation the Cu(II) metal centers assumed distorted square planar geometries, and both pyrrole N-Cu and imine N-Cu interactions were confirmed by single-crystal X-ray diffraction analysis. This structural analysis revealed a copper-copper distance of 3.47 A, while SQUID magnetic susceptibility data provided evidence for antiferromagnetic coupling between the two metal centers.

Copper↗