Medicinal applications of fullerenes

Fullerenes have attracted considerable attention in different fields of science since their discovery in 1985. Investigations of physical, chemical and biological properties of fullerenes have yielded promising information. It is inferred that size, hydrophobicity, three-dimensionality and electronic configurations make them an appealing subject in medicinal chemistry. Their unique carbon cage structure coupled with immense scope for derivatization make them a potential therapeutic agent. The study of biological applications has attracted increasing attention despite the low solubility of carbon spheres in physiological media. The fullerene family, and especially C60, has appealing photo, electrochemical and physical properties, which can be exploited in various medical fields. Fullerene is able to fit inside the hydrophobic cavity of HIV proteases, inhibiting the access of substrates to the catalytic site of enzyme. It can be used as radical scavenger and antioxidant. At the same time, if exposed to light, fullerene can produce singlet oxygen in high quantum yields. This action, together with direct electron transfer from excited state of fullerene and DNA bases, can be used to cleave DNA. In addition, fullerenes have been used as a carrier for gene and drug delivery systems. Also they are used for serum protein profiling as MELDI material for biomarker discovery. In this review we report the aspects of medicinal applications of fullerenes.     

Development of a new thiol-reactive prosthetic group for site-specific labeling of biomolecules with radioactive iodine

In this report, we describe the radiosynthesis of a new thiol-targeting prosthetic group for efficient radioactive iodine labeling of biomolecules. Radioiodination using the precursor 3 was performed to obtain ¹²⁵I-labeled tetrazole 4b with high radiochemical yield (73%) and radiochemical purity. Using the radiolabeled 4b, a single free cysteine containing peptide and human serum albumin were labeled with ¹²⁵I in modest-to-good radiochemical yields (65–99%) under mildly reactive conditions. A biodistribution study of [¹²⁵I]7 in normal ICR mice exhibited lower thyroid uptake values than those of ¹²⁵I-labeled human serum albumin prepared via a traditional radiolabeling method. Thus, [¹²⁵I]7 could be employed as an effective radiotracer for molecular imaging and biodistribution studies. The results clearly demonstrate that 4b has the potential to be effectively implemented as a prosthetic group in the preparation of radiolabeled biomolecules.     

Patterns of carbon allocation above ground in a deciduous (Vaccinium uliginosum) and an evergreen (Vaccinium vitis-idaea) dwarf shrub

The carbon allocation to current-year shoots of the deciduous Vaccinium uliginosum L. and the evergreen V. vitis-idaea L. was studied in a field experiment using ¹⁴C. During the first week after labelling, 0–50% and 30–80% of the initially assimilated ¹⁴C was lost in V. vitis-idaea and V. uliginosum respectively. Later on, the losses were smaller. After leaf fall in V. uliginosum , 30, 10 and 8% of the initially assimilated ¹⁴C was recovered in the abscised leaves, in plants labelled 1 July, 1 August and 1 September, respectively. The amounts found in the old V. vitis-idaea leaves the year after labelling were 33, 20 and 10%. Only traces of past-year assimilates were found in the current-year V. vitis-idaea leaves, while it was estimated that the V. uliginosum leaves contained 10–15% of the past-year label. It is concluded that V. vitis-idaea is mainly dependent on early summer assimilates - produced by leaves that have overwintered – for the current year shoot growth, while past-years' assimilates probably make an important contribution to the leaf expansion in V. uliginosum. When fruits occurred, a large fraction of the ¹⁴C assimilates was allocated to them.     

Pollen as a chronometer and sediment tracer,Burrinjuck Reservoir,Australia

Pollen analysis is widely used to reconstruct vegetation and land use histories, but can also provide sedimentological information. At Burrinjuck Reservoir, in south-eastern Australia, annual grass pollen peaks are used to distinguish each year's sediment, even when there are no visible laminations. In conjunction with other dating methods, this allows the determination of year by year influxes of all sediment components. Pollen grains in the Burrinjuck sediments are shown to be predominantly waterborne so that they can be used to trace sediment to its source in particular vegetation stands. Pollen concentration and the proportion of damaged pollen might also distinguish sediment eroded from topsoils and that from subsoils. Pollen analysis can thus be used to locate specific erosion events in both time and space.     

Efficiency of the monofunctionalized C60 fullerenes as membrane targeting agents studied by all-atom molecular dynamics simulations

Abstract

Transmembrane translocation of C₆₀ fullerenes functionalized by the single amino-derivative in neutral and charged forms was studies by extensive all-atom molecular dynamics simulations. It is shown that these complexes exhibit very strong affinity to the membrane core, but their spontaneous translocation through the membrane is not possible at practical time scale. In contrast, free amino derivatives translocate through the membrane much easier than their complexes with fullerenes, but do not have pronounced affinity to the membrane interior. Our results suggest that monofunctionalized C₆₀ could be extremely efficient membrane targeting agents, which facilitate accumulation of the water-soluble compounds in the hydrophobic core of lipid bilayer.     

Using C60 fullerenes for photodynamic inactivation of mosquito iridescent viruses

This article describes the photodynamic inactivation of mosquito iridescent virus (MIV) Aedes flavescens in the presence of water-soluble C₆₀ fullerenes. It has been observed that the photodynamic inactivation of MIV for about 1?h reduces the infectious titre of the virus in large wax-moth larvae Galleria mellonella to 4.5 lg ID₅₀/mL. The influence of the C₆₀ concentration on its anti-viral activity was tested in the concentration range from 1 to 0.001?mg/mL. It has been found that C₆₀ is able to inactivate the iridovirus even in low concentrations. Consequently, the findings of this work suggest that photoexcited C₆₀ fullerenes can be successfully used for the inactivation of iridoviruses in biological systems.     

Bromoform in the effluents of a nuclear power plant: a potential tracer of coastal water masses

Bromoform (tribromomethane, CHBr₃), one of the trihalomethanes, is a chlorination byproduct in cooling water of power plants and industrial complexes. We used the distribution of bromoform in seawater to monitor the movement of cooling water from the Youngkwang Nuclear Power Plant (YNPP) located on the West Coast of Korea. Bromoform concentrations were highest, 124 g l^–1, in surface water near the outlet of YNPP and decreased linearly with distance from the outlet, mimicking the dissipation of cooling water discharged from the power plant. This byproduct of chlorination is thus a potential tracer of coastal water masses, due to its conservative behavior in the cooling water, low natural background in seawater, and easy analytical detection.     

TFLUX: a general purpose program for the interpretation of radioactive tracer experiments.

TFLUX is a computer program which simulates radioactive tracer experiments using intact cells under steady-state conditions. It is designed for the naive computer user to use, providing English-like input. An example is described in which compartmentation and flux through the citric acid cycle in Dictyostelium discoideum are simulated.     

Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies

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Populations of strongyloid nematode infective stages in sheep pastures: Comparison between direct pasture sampling and tracer lambs as estimators of larval abundance

Waller P.J., Dobson R.J., Donald A.D. and Thomas R.J. 1981. Populations of strongyloid nematode infective stages in sheep pastures : comparison between direct pasture sampling and tracer lambs as estimators of larval abundance. International Journal for Parasitology11: 359–367. Over a 2-year period, numbers of infective larvae in samples of pasture herbage, and numbers of worms in previously worm-free “tracer” lambs allowed 4 weeks grazing, were compared as estimators of the abundance of infective larvae on pastures.Transformation of sample estimates of infective larval numbers per 100 g herbage dry matter (DM) and of worm numbers in tracer sheep, according to the expression y = log₁₀ (x+25), was effective in stabilizing variances. Estimates of error variance for each technique did not differ significantly among the genera Haemonchus, Ostertagia or Trichostrongylus and the pooled estimate for the tracer sheep method was 4 times greater than that for pasture sampling. From these results, more tracer sheep than pasture samples would be required to achieve the same level of precision with the two techniques. Using conventional statistical methods, the effects of numbers of pasture samples or tracer sheep on the size of the difference between two means which can be detected as significant and on the width of the confidence interval about a single mean, are illustrated. These can be used as a guide in the choice of sample sizes. Error variances for Nematodirus spp. were significantly less than for the other genera by pasture sampling, and greater by the tracer sheep technique. Possible reasons for this are discussed, but it is concluded that pasture sampling is likely to be much the more precise method for estimating Nematodirus spp. infective larval availability.Changes with time in infective larval abundance, for Haemonchus, Trichostrongylus and Nematodirus spp. which were present in moderate to low numbers, followed similar trends by both techniques. However, for Ostertagia spp. larvae, which were much more abundant, peak levels were defined more sharply and occurred earlier by pasture sampling than by the tracer method. It is suggested that worm counts from tracer sheep, especially those grazing for 4 weeks rather than shorter periods, may systematically underestimate the infective larval population on pasture at high levels of abundance owing to density-dependent worm loss.     

13N as a tracer for studying glutamate metabolism

This mini-review summarizes studies my associates and I carried out that are relevant to the topic of the present volume [i.e. glutamate dehydrogenase (GDH)] using radioactive ¹³N (t_1/2 9.96 min) as a biological tracer. These studies revealed the previously unrecognized rapidity with which nitrogen is exchanged among certain metabolites in vivo. For example, our work demonstrated that (a) the t_1/2 for conversion of portal vein ammonia to urea in the rat liver is ∼10-11 s, despite the need for five enzyme-catalyzed steps and two mitochondrial transport steps, (b) the residence time for ammonia in the blood of anesthetized rats is ≤7-8 s, (c) the t_1/2 for incorporation of blood-borne ammonia into glutamine in the normal rat brain is <3 s, and (d) equilibration between glutamate and aspartate nitrogen in rat liver is extremely rapid (seconds), a reflection of the fact that the components of the hepatic aspartate aminotransferase reaction are in thermodynamic equilibrium. Our work emphasizes the importance of the GDH reaction in rat liver as a conduit for dissimilating or assimilating ammonia as needed. In contrast, our work shows that the GDH reaction in rat brain appears to operate mostly in the direction of ammonia production (dissimilation). The importance of the GDH reaction as an endogenous source of ammonia in the brain and the relation of GDH to the brain glutamine cycle is discussed. Finally, our work integrates with the increasing use of positron emission tomography (PET) and nuclear magnetic resonance (NMR) to study brain ammonia uptake and brain glutamine, respectively, in normal individuals and in patients with liver disease or other diseases associated with hyperammonemia.     

Deinococcus misasensis and Deinococcus roseus, novel members of the genus Deinococcus, isolated from a radioactive site in Japan

Two gamma- and UV-radiation resistant, Gram-positive, red- or pink-pigmented, rod-shaped, strictly aerobic, oxidase- and catalase-positive bacterial strains, TDMA-25^T and TDMA-uv51^T, were isolated from fresh water collected at Misasa, a radioactive site in Japan. Phylogenetic analysis based on 16S rRNA gene sequences placed both in a distinct lineage in the family Deinococcaceae, and the highest degrees of sequence similarity determined belonged to Deinococcus maricopensis LB-34^T (88.8–89.3%), Deinococcus pimensis KR-235^T (86.4–86.7%) and Deinococcus yavapaiensis KR-236^T (86.1%). The DNA G+C content of the strains was 53–58 mol%. The major respiratory quinone was MK-8. The predominant fatty acids were C_15:0 iso, C_16:0 iso, C_13:0 iso, C_17:0 iso, C_16:0, C_13:0 anteiso, C_15:0 and C_12:0 iso. The strains degraded gelatin, casein, starch and Tween 80. Unique physiological characteristics, differences in their fatty acid profiles, and genotypic and phylogenetic features, differentiated strains TDMA-25^T and TDMA-uv51^T from closely related Deinococcus species. Hence, the two strains are described as novel species of the genus Deinococcus. The names Deinococcus misasensis sp. nov. (type strain TDMA-25^T=JCM 14369=NBRC 102116=CCUG 53610) and Deinococcus roseus sp. nov. (type strain TDMA-uv51^T=JCM 14370=NBRC 102117=CCUG 53611) are proposed.     

Lithium as a non-radioactive tracer for roots of intercropped species

Summary A technique is described for investigating the rooting pattern of species when intercropped, using Lithium as a non-radioactive tracer. The technique was tested on pure stands and mixtures of barley (Hordeum sativum) and field beans (Vicia faba), with 10% LiCl solution placed at depths of 0, 10, 25 and 62 cm.Pure stands of the two crops had similar patterns of Li uptake with depth. Growing the crops in mixture did not significantly change the pattern of Li uptake with depth, but did change total uptake. The Li uptake (m^–2) by both species was reduced in mixtures, and was further reduced when the observed species was sown later than the other.The value of non-radioactive tracers, especially Li, in intercropping studies is discussed.     

Binding of fibrinogen to platelet integrin αIIbβ3 in solution as monitored by tracer sedimentation equilibrium

Fibrinogen showed essentially no binding (K_D>1 mM ) to platelet αIIbβ3 integrin in solution in the presence of Triton or octylglucoside above critical micellar concentrations. Under these conditions the integrin was an αβ monomer. After removal of the detergent from the Triton containing buffer (25 mM Tris/HCl;, 150 mM NaCl, 1 mM CaCl₂, 1 mM MgCl₂, pH 7.4) the integrin formed aggregates with hexamers as the most prominent species, as demonstrated by analytical ultracentrifugation and electron microscopy. Tracer sedimentation equilibrium experiments indicate that fibrinogen binds to the integrin aggregates, but with a surprisingly large K_D (at least 3 μM ). This value is 10- to 100-fold higher than values determined by solid phase assays or with integrins reconstituted onto lipid bilayers.     

Estimating hydraulic conductivity of a sandy soil under different plant covers using minidisk infiltrometer and a dye tracer experiment

The objective of this study was to estimate the hydraulic conductivity of sandy soil under different plant cover at the locality Mláky II at Sekule (southwest Slovakia). Two sites were demarcated at the locality, with mainly moss species at glade site, and pine forest at forest site. The estimation of unsaturated hydraulic conductivity was conducted by (a) minidisk infiltrometer and (b) the analysis of a dye tracer total resident concentration. The latter approach assumed the applicability of the stochastic—convective flow theory in the sandy soil. In the dye tracer experiment, two plots (1 × 1 m each) were established in both sites, and 100 mm of dye tracer (Brilliant Blue FCF) solution was applied on the soil surface. Similar results were obtained in both plots, with more than 70 % area of horizons stained in the depth of 30–50 cm. In some cases, the predicted and measured hydraulic conductivity were found within an order of magnitude, thus revealing similar impact of different plant cover on hydraulic properties of sandy soil studied. In contrast to sandy soils used for agriculture, the influence of the plant/surface humus and topsoil interface extended in the form of a highly heterogeneous matrix flow to the depth of 50–60 cm, where it was dampened by horizontal layering.     

Synthesis of an acromelic acid A analog-based 11C-labeled PET tracer for exploration of the site of action of acromelic acid A in allodynia induction

A novel ¹¹C-labeled PET (positron emission tomography) tracer, which was designed based on the (phenylthio)pyrrolidine derivative that can competitively block the acromelic acid A-induced allodynia, was synthesized. A protocol in which methylation by palladium-mediated coupling of the boronate derivative with [¹¹C]CH₃I and deprotection of the protected amino acid moiety are successively performed in one-pot within 5 min was established for the synthesis of the tracer. The tracer is potentially useful as a tool to investigate the mode of action of acromelic acid A in the induction of allodynia.     

Investigation of copper-PTSM as a PET tracer for tumor blood flow

Copper-PTSM has been shown in previous studies to act as a fluid microsphere and to be useful in quantitating blood flow in brain, myocardium, and kidneys. In this study we have evaluated this agent as a PET tumor blood flow agent. ⁶⁴Cu- or ⁶⁷Cu-labeled Cu-PTSM was administered (i.v.) to Golden Syrian hamsters with colorectal carcinoma cell implants (GW39). One minute prior to sacrifice (10–60 min after Cu-PTSM was administered) ¹²⁵I-iodoantipyrine (¹²⁵I-IAP), an agent known to measure tumor blood flow, was administered intravenously by a 3-stage, 1 min ramp infusion. Following sacrifice, samples of tumor and brain were removed (within 40 s) and the tumor and brain levels of Cu-PTSM and iodoantipyrine determined. Since the brain uptake of both Cu-PTSM and IAP is perfusion rate limited, the brain was used as a reference organ to normalize tumor levels of the two tracers. The plot of Cu-PTSM versus ¹²⁵I-IAP tumor/brain ratios showed a good linear correlation (r value of 0.97), suggesting that Cu-PTSM could be used to quantify tumor blood flow. Since the mechanism of Cu-PTSM trapping is likely to be due to glutathione levels in the tissue, and because tumor tissue glutathione levels might vary, the temporal uptake of Cu-PTSM was investigated by PET imaging both the tumor-bearing hamsters and ~300 g Copenhagen rats bearing R3227 prostate tumors. The tumors were clearly visualized and the retained copper radioactivity in the tumor was constant over the 30 min imaging period.     

基于137Cs示踪技术的土壤侵蚀及养分流失特征评价

研究不同土地利用方式对小流域土壤侵蚀及其养分流失特征的影响有助于更好的理解土地利用方式变化引发的环境效应问题,对区域生态保护和高质量发展具有重要意义。选择陕北延安市湫沟小流域为研究对象,利用¹³⁷Cs示踪技术,定量评价了不同土地利用方式的土壤侵蚀和养分流失状况及其相互变化关系,结果表明：（1）土地利用方式显著影响小流域土壤侵蚀状况。土壤侵蚀模数介于-18.67-151.27 t km^-2 a^-1之间,大小顺序为沟道 > 苹果园 > 林地 > 草地 > 灌木,均为微度侵蚀。其中,除灌木地发生沉积以外,其它土地利用方式均发生了土壤侵蚀现象。（2）不同土地利用方式下的土壤侵蚀模数空间变异明显,除沟道为轻度变异以外,其它土地利用均为中等变异。（3）土壤全氮含量、有机质含量、N/P比和C/P比在不同土地利用方式下的变化特征表现一致,大小顺序均为灌木 > 草地 > 林地 > 沟道 > 苹果园,且在不同利用方式间均存在显著性差异。但全磷含量表现为灌木>苹果园>沟道>草地>林地,且与土壤全氮含量和有机质含量极显著正相关。同全国平均水平相比,土壤全氮含量偏低,全磷含量适中;C/N超过全国平均水平,而N/P和C/P远低于全国平均水平,小流域土壤氮限制严重。（4）土壤侵蚀是该小流域养分流失的重要诱因。不同土地利用方式土壤养分流失变化特征与土壤侵蚀模数表现一致,且两者呈极显著正相关关系;但与土壤全氮、全磷、有机质、N/P比及C/P比呈极显著负相关关系,与C/N比关系不显著。     

Enantiomerically Pure Bithiophene Diphosphine Oxides as Catalysts for Direct Double Aldol Reactions

The direct aldol reaction between aryl methyl ketones with aromatic aldehydes in the presence of tetrachlorosilane and a catalytic amount of a chiral bithiophene diphosphine oxide was studied; the product of double aldol addition was isolated as diacetate in good diastereoselectivity (up to 95:5) and enantioselectivities up to 91%. The reaction with heteroaromatic aldehydes was also investigated leading to the corresponding 1,3 diols, in some cases with excellent stereoselectivities. Chirality 25:643–647:, 2013. © 2013 Wiley Periodicals, Inc.