Effects of La+++, Mn++ and ruthenium red on Mg-Ca-ATPase activity and ATP-dependent Ca-binding of the synaptic plasma membrane.
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The effects of La+++, Mn++ and ruthenium red (R.R.) on Ca-uptake of synaptic plasma membranes (S.P.M.) were investigated. La+++ (0.1 mM), Mn++ (0.2 mM) and R.R. (0.1 mM) selectively inhibited Mg-Ca-ATPase but did not significantly affect Mg-ATPase activity. The apparent Ki values of La+++, Mn++ and R.R. for Mg-Ca-ATPase were 0.05, 0.06 and 0.03 mM, respectively. La+++, Mn++ and R.R. did not affect Ca-uptake at concentrations which strongly inhibited Mg-Ca-ATPase activity. These results indicate that Ca-uptake by S.P.M. differ from that by sarcoplasmic reticulum. (+info)
Stereochemical control of skeletal diversity.
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[reaction: see text]. Substrates having appendages that pre-encode skeletal information (sigma-elements) can be converted into products having distinct skeletons using a common set of reaction conditions. The sequential use of the Ugi 4CC-IMDA reaction, followed by allylation, hydrolysis, and acylation of a chiral amino alcohol appendage (sigma-element), leads to substrates for a ROM/RCM or RCM reaction. The stereochemistry of the sigma-element and not its constitution controls the outcome of the pathway selected. This work illustrates the potential of linking stereochemical control to the challenging problem of skeletal diversity. (+info)
Synthesis, anticancer and antibacterial activity of some novel mononuclear Ru(II) complexes.
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In search of potential anticancer drug candidates in ruthenium complexes, a series of mononuclear ruthenium complexes of the type [Ru(phen)(2)(nmit)]Cl(2) (Ru1), [Ru(bpy)(2)(nmit)]Cl(2) (Ru2), [Ru(phen)(2)(icpl)]Cl(2) (Ru3), Ru(bpy)(2)(icpl)]Cl(2) (Ru4) (phen=1,10-phenanthroline; bpy=2,2'-bipyridine; nmit=N-methyl-isatin-3-thiosemicarbazone, icpl=isatin-3-(4-Cl-phenyl)thiosemicarbazone) and [Ru(phen)(2)(aze)]Cl(2) (Ru5), [Ru(bpy)(2)(aze)]Cl(2) (Ru6) (aze=acetazolamide) and [Ru(phen)(2)(R-tsc)](ClO(4))(2) (R=methyl (Ru7), ethyl (Ru8), cyclohexyl (Ru9), 4-Cl-phenyl (10), 4-Br-phenyl (Ru11), and 4-EtO-phenyl (Ru12), tsc=thiosemicarbazone) were prepared and characterized by elemental analysis, FTIR, (1)H-NMR and FAB-MS. Effect of these complexes on the growth of a transplantable murine tumor cell line (Ehrlich Ascites Carcinoma) and their antibacterial activity were studied. In cancer study the effect of hematological profile of the tumor hosts have also been studied. In the cancer study, the complexes Ru1-Ru4, Ru10 and Ru11 have remarkably decreased the tumor volume and viable ascitic cell count as indicated by trypan blue dye exclusion test (p<0.05). Treatment with the ruthenium complexes prolonged the lifespan of Ehrlich Ascites Carcinoma (EAC) bearing mice. Tumor inhibition by the ruthenium chelates was followed by improvements in hemoglobin, RBC and WBC values. All the complexes showed antibacterial activity, except Ru5 and Ru6. Thus, the results suggest that these ruthenium complexes have significant antitumor property and antibacterial activity. The results also reflect that the drug does not adversely affect the hematological profiles as compared to that of cisplatin on the host. (+info)
Intratumoral NAMI-A treatment triggers metastasis reduction, which correlates to CD44 regulation and tumor infiltrating lymphocyte recruitment.
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Intratumor (i.t.) injection of 35 mg/kg/day NAMI-A for six consecutive days to CBA mice bearing i.m. implants of MCa mammary carcinoma reduces primary tumor growth and particularly lung metastasis formation, causing 60% of animals to be free of macroscopically detectable metastases. The i.t. treatment allows study of the effects of NAMI-A on in vivo tumor cells exposed to millimolar concentrations for a relatively prolonged time. Under these conditions, NAMI-A reduces the number of CD44+ tumor cells and changes tumor cell phenotype to a lower aggressive behavior, as shown by scanning electron microscopy analysis. On primary tumor site, NAMI-A causes unbalance between 2n and aneuploid cells in favor of lymphocytes. Furthermore, in tumor tissue, nitric oxide production is increased and active matrix metalloproteinase 9 is decreased, and these effects are accompanied by a reduced hemoglobin concentration. These data are in agreement with the reduction of tumor invasion and metastasis and suggest the therapeutic usefulness of NAMI-A in neoadjuvant or tumor reduction treatments for preventing metastasis formation. These data further stress the usefulness of intratumor treatments as experimental preclinical model for studying in vivo the mechanism of tumor cell interactions after prolonged exposure to ruthenium-based compounds to be developed for metastasis inhibition. (+info)
Mechanisms involved in the increase in intracellular calcium following hypotonic shock in bovine articular chondrocytes.
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The extracellular osmotic environment of chondrocytes fluctuates during joint loading as fluid is expressed from and reimbibed by the extracellular matrix. Matrix synthesis by chondrocytes is modulated by joint loading, possibly mediated by variations in intracellular composition. The present study has employed the Ca2+-sensitive fluoroprobe Fura-2 to determine the effects of hypotonic shock (HTS) on intracellular Ca2+ concentration ([Ca2+]i) and to characterise the mechanisms involved in the response for isolated bovine articular chondrocytes. In cells subjected to a 50% dilution, [Ca2+]i rapidly increased by approximately 250%, a sustained plateau being achieved within 300 s. The effect was inhibited by thapsigargin or by removal of extracellular Ca2+, indicating that the rise in [Ca2+]i reflects both influx from the extracellular medium and release from intracellular stores. Inhibition of the response by neomycin implicates activation of PLC and IP3 synthesis in the mobilisation of Ca2+ from intracellular stores. The rise was insensitive to inhibitors of L-type voltage-activated Ca2+ channels (LVACC) or reverse mode Na+/Ca2+ exchange (NCE) but could be significantly attenuated by ruthenium red, an inhibitor of transient receptor potential vanilloid (TRPV) channels and by Gd3+, a blocker of stretch-activated cation (SAC) channels. The HTS-induced rise in [Ca2+]i was almost completely absent in cells treated with Ni2+, a non-specific inhibitor of Ca2+ entry pathways. We conclude that in response to HTS the opening of SACC and a member of TRPV channel family leads to Ca2+ influx, simultaneously with the release from intracellular stores. (+info)
Crosslinking of and coupling to viral capsid proteins by tyrosine oxidation.
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Cowpea mosaic virus is composed of 60 identical copies of a two-subunit protein organized in pentameric assemblies around the icosahedral 5-fold symmetry axis. Treatment of the virus with the Ni(II) complex of the tripeptide GGH and a peroxide oxidant, or irradiation in the presence of Ru(bpy)(3)(2+) and persulfate generates covalent crosslinks across the pentameric subunit boundaries, effectively stitching the subunits together. Intersubunit crosslinking was found to occur exclusively at adjacent tyrosine residues (Y52-Y103), as predicted from the X-ray crystal structure of the capsid, and to be more extensive with the photochemical ruthenium system. The Ni/GGH oxidative procedure was also used to make covalent attachments to the virion by trapping with a functionalized disulfide reagent. (+info)
A Phase I and pharmacological study with imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a novel ruthenium anticancer agent.
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PURPOSE: NAMI-A [H(2)Im[trans-RuCl(4)(DMSO)HIm] or imidazolium-trans-DMSO-imidazole-tetrachlororuthenate] is a novel ruthenium-containing compound that has demonstrated antimetastatic activity in preclinical studies. This Phase I study was designed to determine the maximum-tolerated dose (MTD), profile of adverse events, and dose-limiting toxicity of NAMI-A in patients with solid tumors. Furthermore, the ruthenium pharmacokinetics (PK) after NAMI-A administration and preliminary antitumor activity were evaluated. PATIENTS AND METHODS: Adult patients with solid tumors received NAMI-A as an i.v. infusion over 3 h daily for 5 days every 3 weeks. PK of total and unbound ruthenium was determined during the first and second treatment using noncompartmental pharmacokinetic analysis. The total accumulation of ruthenium in WBCs was also quantified. RESULTS: Twenty-four patients were treated at 12 dose levels (2.4-500 mg/m(2)/day). At 400 mg/m(2)/day, blisters developed on the hands, fingers, and toes. At 500 mg/m(2)/day, blisters persisted from weeks to months and slowly regressed. Although no formal common toxicity criteria (CTC) grade 3 developed, painful blister formation was considered dose limiting. Because the first signs developed at 400 mg/m(2)/day, the advised dose for further testing of NAMI-A was determined to be 300 mg/m(2)/day on this schedule. PK analysis revealed a linear relationship between dose and area under the concentration-time curve (AUC) of total and unbound ruthenium (R(2) = 0.75 and 0.96, respectively) over the whole dose range. Plasma clearance of total ruthenium was 0.17 +/- 0.09 liter/h, and terminal half-life was 50 +/- 19 h. The volume of distribution at steady state of total ruthenium was 10.1 +/- 2.8 liters. The accumulation of ruthenium in WBC was not directly proportional to the increasing total exposure to ruthenium. One patient with pretreated and progressive nonsmall cell lung cancer had stable disease for 21 weeks. CONCLUSION: NAMI-A can be administered safely as a 3-h i.v. infusion at a dose of 300 mg/m(2)/day for 5 days, every 3 weeks. (+info)
Charge equilibration between two distinct sites in double helical DNA.
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DNA assemblies containing a pendant dipyridophenazine complex of Ru(II) along with two oxidative traps, a site containing the nucleoside analog methylindole (5'-GMG-3') and a 5'-GGG-3' site, have been constructed to explore long-range charge transport through the base pair stack. With these chemically well defined assemblies, in combination with the flash/quench technique, formation of the methylindole cation radical and the neutral guanine radical is monitored directly by using transient absorption spectroscopy, and yields of oxidative damage are quantitated biochemically by gel electrophoresis. In these assemblies the base radicals form with a rate of > or =10(7) s(-1). The rate of base radical formation does not change upon the addition of a second radical trap, the 5'-GGG-3' site; however, the yield of methylindole oxidation is significantly lower. This observation indicates that the 5'-GGG-3' site is effective in competing for the migrating charge and provides a second trapping site. Switching the orientation of the two trapping sites does not affect the yield of oxidized products at either site. Therefore, in DNA both forward and reverse charge transport occur so as to provide equilibration across the duplex on a timescale that is fast compared with trapping at a particular site. Further evidence of charge equilibration results from incorporating an intervening base-stacking perturbation and monitoring the fate of the injected charge. These experiments underscore the dynamic nature of DNA charge transport and reveal the importance of considering radical propagation in both directions along the DNA duplex. (+info)