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A 16 year old boy presenting with features of myocarditis and pulmonary oedema following scorpion sting developed hemiplegia with patchy vasculitic lesions on CT scan. The possible pathogenic mechanism is discussed.
In search for the toxic components constituting the venom of the southern African scorpion Parabuthus transvaalicus we compared and optimized several chromatographic separation protocols resulting in an efficient venom purification strategy. We found that the sequential combination of gelfiltration (Superdex) together with reversed phase chromatography (C2/C18)-but not cation exchange (Mono S)-stood surety for the best purification.
The effect of long-term natural stimulation resulting in prolonged fatigue and structural disorders as well as the black scorpion poison influence on these processes were studied in gold fish Mauthner neurons (MN). The poison previously applied to MN significantly protects their function and structure from the stimulatory effect and subsequently allows the neurons to recover more fast. Appearance of numerous desmosome-like (actin-containing) contacts and proliferation of subsurface cisterns, the accumulators of calcium ions was noted immediately after the poison action and stimulation and one day later in afferent synapse ultrastructure. The poison interaction with neuronal actin, mediated by alteration of calcium-accumulating systems is probably one of the mechanisms of its protective effect.
The syntheses and structures of complexes of the fifth period elements indium and antimony, and the sixth period element bismuth with the soft scorpionate ligand, hydrotris(methimazolyl)borate (Tm(Me)) are reported. A considerable variety of structural motifs were obtained by reaction of the main-group element halide and NaTm(Me). The indium(III) complexes took the form [In(kappa(3)-Tm(Me))(2)](+). This motif could not, however, be isolated for antimony(III), the dominant product being [Sb(kappa(3)-Tm(Me))(kappa(1)-Tm(Me))X] (X = Br, I). An iodo-bridged species [Sb(kappa(3)-Tm(Me))I(mu(2)-I)](2), analogous to a previously reported bismuth complex, was also isolated. Reaction of antimony(III) acetate with NaTm(Me) results in a remarkable species in which three different ligand binding modes are observed. In each antimony complex the influence of the nonbonded electron pair is observed in the structure. Bismuth halides form complexes analogous to those of antimony, with directional lone pairs, but in addition, reaction of Bi(NO(3))(3) with NaTm(Me) results in a complex with a regular S(6) coordination sphere and a nonstereochemically active lone pair. Comparisons are drawn with known Tm(Me) complexes of As, Sn, and Bi in which the stereochemical influence of the lone pairs is negligible and with Tm(Me) complexes of Te and Bi in which the lone pairs are stereochemically active. This study highlights the ability of Tm(Me) to coordinate in a variety of modes as dictated by the metal centre with no adverse effects on the stability of the complexes formed.
Uncovering the relationship between the generation of alternative transcripts and cellular processes is of crucial importance in the exploration of a gene's biology. The description and quantification of the spatiotemporal splicing pattern can be one method to select the most interesting transcripts for future studies. Fluorescence-based real-time quantitative RT-PCR has recently revolutionized the possibilities for transcriptional quantification studies. In this report, Molecular Beacon and Scorpion probes have been tested as new possibilities for determining the expression level of alternative transcripts. We validated these systems by analyzing alternative splicing of exons 6, 15, and 16 of the calpain 3 gene with tissues containing large variation in the ratio of the different transcripts. We determined conditions that demonstrated that boundary probes are useful tools and good alternatives to boundary primers, when developing a system to quantify specific transcripts. We suggest that the choice of a quantification system should depend in part on the structure and base composition of the gene and may have to be determined experimentally.
A novel real-time quantitative method for detecting HCV in serum was established in which the duplex scorpion primer was used to provide a unimolecular probing mechanism for hybridizing the highly conserved 5' noncoding region (5' NCR) of the HCV genome specifically. Through methodological evaluation, we found this new method had a wide linearity, high sensitivity, repeatability and specificity. Compared to the commercial TaqMan method, this method was found to be more sensitive and less costly, and the final results were obtained more quickly. Therefore, it could be applied to diagnose and monitor HCV infection in clinical practice.
Receptor sites for some of the most important toxins known to be specific for voltage-sensitive Na+ channel in the mammalian nervous system have been identified in a purified membrane preparation of house fly brain. Very high affinities have been found for the association of tetrodotoxin or tetrodotoxin derivatives with the insect Na+ channel (Kd = 0.03 - 0.08 nM). The gamma toxin from the Brazilian scorpion Tityus serrulatus forms a complex with the Na+ channel having a Kd of 6.1 pM. The Kd value for toxin II from the sea anemone Anemonia sulcata is 0.12 microM. These results show a high degree of conservation of the pharmacological properties of the brain Na+ channels between insects and mammals.
The distribution of alpha scorpion toxin (alpha-ScTx) receptors was examined in differentiated mouse neuroblastoma cell cultures (N IE 115 clone) by electron microscope autoradiography using [125I]alpha-ScTx. This neurotoxin binds specifically to voltage-sensitive sodium channels, slowing down the inactivation of the sodium permeability. Quantitative analysis demonstrated that only plasma membranes were labelled. The alpha-ScTx receptors seemed to be randomly dispersed on both cell bodies and cell processes. Microvilli protruding from the cell bodies carried more sodium channels than other parts of the membrane. The specific binding site density for alpha-ScTx varied from 4 (cell body membrane) to 13 (cell process membrane) per square micrometer.
Purified neurotoxin II from the scorpion Androctonus australis Hector (alpha-ScTx) has previously been shown to bind specifically to the voltage-sensitive Na+ channels of excitable cells. Recent studies, using high specific activity 125I-labeled alpha-ScTx, demonstrated specific binding to neuronal cells derived from fetal mouse brains. In the present study, 125I-labeled alpha-ScTx was used to localize the voltage-sensitive Na+ channels in cultured fetal mouse brain cells. By quantitative electron microscope autoradiography we demonstrate that specific alpha-ScTx binding sites are selectively located at the plasma membrane. Estimates of their density revealed that neurites at 13 days in vitro carry at least 6 X more specific alpha-ScTx sites than cell body membrane.
Voltage-dependent potassium channels belong to a family of structurally related cation channels that underlie the electrical activity of excitable cells. Many potassium channels are blocked with high affinity by scorpion toxins, whereas others are completely insensitive. We transferred toxin sensitivity from the highly sensitive Kv1.3 (KV3) to the insensitive Kv2.1 (DRK1) potassium channel by transferring the stretch of amino acids between transmembrane domains 5/6. We provide evidence that this S5-S6 linker, which has been shown to comprise the pore-forming region, is probably the only part of the ion channel that directly interacts with bound toxin. Using site-directed mutagenesis, we identified specific residues in the S5-S6 linker that are responsible for the acquisition of toxin sensitivity by Kv2.1.
BACKGROUND: Real-time quantitative TRAP assays for detection of telomerase activity have been recently developed to eliminate complex post-PCR procedures. However, all of them use the conventional TRAP assay that possesses an unpredictable cascade of events in PCR amplification caused by stagger annealing, which may affect the accuracy of quantitation. METHODS: A novel RTQ-TRAP method was developed by combining the duplex scorpion with modified TP-TRAP assay that has high fidelity PCR amplification of the telomerase product (DS/TP-TRAP). The synthesized oligonucleotide that represents telomerase products is used to set up a standard curve. RESULTS: The DS/TP-TRAP method gives the standard curve a dynamic range of 6 orders of magnitude (R(2)=0.9992). It optimizes PCR amplification efficiency and determines telomerase activity in a lower threshold cycle number (Ct value). The method is both accurate and reproducible to measure telomerase activity in human tumor cell lines, and linearity from 1 to 1000 cells could be obtained (R(2)=0.9926). For tumor samples, the results determined by the DS/TP-TRAP assay are comparable to the data obtained with the conventional TRAP method. CONCLUSIONS: The DS/TP-TRAP assay provides a high sensitive and accurate method for real-time quantitative detection of telomerase activity. It is thus a potential robust tool for application in cancer molecular diagnostics.
Using the classical emulsified system and the monomolecular film technique, we compared the interfacial properties of the scorpion digestive lipase (SDL) with those of higher animals'. In the absence of bile slats, SDL does not hydrolyse efficiently pure tributyrin, as well as dicaprin films maintained at low surface pressure. The preincubation of bile salts with tributyrin seems to be a better substrate for SDL than the pure tributyrin. A kinetic study on the surface pressure dependency, stereospecificity and regioselectivity of SDL was performed using monomolecular films of either three dicaprin isomers or three pairs of didecanoyl-deoxyamino-O-methyl glycerol enantiomers (DDG) containing a single hydrolysable decanoyl ester bond. With all diacylglycerol isomers, SDL has a surface pressure threshold of about 15 m Nm(-1), below which enzymatic activity is undetectable. SDL seems to prefer vicinal ester groups of the diacylglycerol isomers, with preference for sn-1 position at both 15 and 23 m Nm(-1). Furthermore, the maximum SDL activity is measured with DDG having a primary ester bond (1,3DDG, SII). This shows that SDL has a preference for the sn-1 position of this diacylglycerol analogue. Moreover, this was in line with the fact that SDL is inactive on sn-2 position of both DDG isomers and a triacylglycerol. With diacylglycerol analogue isomers, SDL shows a preference for distal isomers contrary to what has been observed with diacylglycerol isomers. SDL interacts with egg-phosphatidyl choline (egg-PC) monomolecular films. The critical surface pressure value (13 m Nm(-1)) is comparable to those of pancreatic lipases.
Voltage-activated sodium channels in central neurons of larval and adult Heliothis virescens were characterized using whole-cell patch clamp techniques. Macroscopic currents showing rapid activation and inactivation kinetics were uniformly sensitive to tetrodotoxin (IC(50)=1.9nM). Currents began to activate at voltage steps to -45mV and reached half maximal at -30mV. Fast inactivation was evident at voltages as negative as -75mV and reached half maximal at -50mV. Full recovery from inactivation occurred within 1 to 2ms. Currents in larval neurons exhibited similar properties to those of adult neurons, except for the rate of fast inactivation (t(1)), which was significantly slower in larval neurons. The biophysical properties of sodium channels remained unchanged for up to 3days in culture. Two insecticidal neurotoxins, LqhalphaIT and AaIT, produced distinctly different modifications of H. virescens sodium channels. LqhalphaIT slowed channel inactivation, while AaIT specifically shifted voltage-dependent activation to more negative potentials. Overall, the results indicate that sodium channels in H. virescens neurons exhibit biophysical characteristics similar to those of vertebrates, yet possess pharmacological uniqueness with respect to scorpion toxin modification.
New copper(I) complexes have been synthesised from the reaction of CuCl with 4-(diphenylphosphane)benzoic acid and lithium tris(1H-pyrazol-1-yl)methanesulfonate, Li(SO(3))C(pz)(3), sodium hydrotris(3-trifluoromethyl-1H-pyrazol-1-yl)borate, NaHB[3-(CF(3))pz](3), potassium dihydrobis(1H-1,2,4-triazol-1-yl)borate, KH(2)B(tz)(2), hydrotris(1H-1,2,4-triazol-1-yl)borate, KHB(tz)(3), sodium hydrotris(1H-pyrazol-1-yl)borate, NaHB(pz)(3), potassium hydrotris(3,5-dimethyl-1H-pyrazol-1-yl)borate KHB(3,5-Me(2)Pz)(3) or potassium hydrotris(4-bromo-1H-pyrazol-1-yl)borate KHB(4-Brpz)(3). The complexes obtained have been characterized by elemental analyses and FT-IR in the solid state, and by NMR (1H and 31P[(1)H]) spectroscopy and conductivity measurements in solution. The solution data are consistent with partial dissociation of the sterically hindered complexes by way of breaking of Cu-P and Cu-N bonds. Electrospray mass spectrometry has been used to investigate the relative properties of the 4-(diphenylphosphane)benzoic acid and of the "scorpionate" ligands towards copper(I) ions. Chemiluminescence technique was used to evaluate the superoxide scavenging activity of these new copper complexes.
To improve the targeting properties of receptor-directed drug-peptide conjugates, a multiligand approach was proposed and a model "scorpion" conjugate (6, Figure 1), consisting of two peptide "claws" and a paclitaxel (PTX) "tail", was synthesized. The cell surface receptor-directed peptide used in this single-drug multiligand (SDML) model was a segment of the amphibian peptide bombesin (BBN) which had the Y6Q7W8A9V10G11H12L13M14-NH2 sequence, designated here as BBN[6-14] (2, Figure 2). Due to the lipophilic nature of both PTX and BBN[6-14], compound 6 had a low water solubility. To enhance the solubility, PEG derivatives of this conjugate were prepared with the polymer inserted either in the claws or in the tail regions. In a preliminary random screening, conjugate 6 showed superior cytotoxic activity in several GRPR-positive human cancer cell lines as compared to free PTX and two single-drug single-ligand (SDSL) conjugates. In a receptor blocking experiment, addition of excess unconjugated BBN[6-14] ligand reduced the cytotoxicity of conjugate 6, indicating the receptor-mediated mechanism of drug delivery. The PEG-derived conjugates showed activities which were intermediate between SDSL and the SDML congeners. Also, an increase in the number of the PEG segments lowered cytotoxicity, possibly due to steric hindrance against ligand-receptor binding. Taken together, these results demonstrate the potential of the multiligand approach in the design of receptor-targeting conjugates for tumor-specific drug delivery.
The preparation of new "scorpionate" ligands in the form of the lithium derivatives [(Li(bdmpzdta)(H(2)O))(4)] (1) [bdmpzdta = bis(3,5-dimethylpyrazol-1-yl)dithioacetate], [Li(bdphpza)(H(2)O)(THF)] (2) [bdphpza = bis(3,5-diphenylpyrazol-1-yl)acetate], and [Li(bdphpzdta)(H(2)O)(THF)] (3) [bdphpzdta = bis(3,5-diphenylpyrazol-1-yl)dithioacetate] has been carried out. Furthermore, a series of titanium complexes has been prepared by reaction of TiCl(4)(THF)(2) with the lithium reagents [(Li(bdmpza)(H(2)O))(4)] (4) [bdmpza = bis(3,5-dimethylpyrazol-1-yl)acetate] and 1. Under the appropriate experimental conditions neutral complexes, namely [TiCl(3)(kappa(3)-bdmpza)] (5), [TiCl(3)(kappa(3)-bdmpzdta)] (6), and [TiCl(2)(kappa(2)-bdmpzdta)(2)] (7), and cationic complexes, namely [TiCl(2)(THF)(kappa(3)-bdmpza)]Cl (8) and [TiCl(2)(THF)(kappa(3)-bdmpzdta)]Cl (9), were isolated. Complexes 8 and 9 undergo an interesting nucleophilic THF ring-opening reaction to give the corresponding alkoxide-containing species [TiCl(2)(kappa(3)-bdmpza)(O(CH(2))(4)Cl)] (10) and [TiCl(2)(kappa(3)-bdmpzdta)(O(CH(2))(4)Cl)] (11). A family of alkoxide-containing complexes of general formulas [TiCl(2)(kappa(3)-bdmpza)(OR)] [R = Me (12); R = Et (14); R = (i)Pr (16); R = (t)Bu (18)] and [TiCl(2)(kappa(3)-bdmpzdta)(OR)] [R = Me (13); R = Et (15); R = (i)Pr (17)] was also prepared. The structures of these complexes have been determined by spectroscopic methods, and in addition, the X-ray crystal structures of 3, 7, 10, and 11 were also established.
The preparation and structure of the first scorpionate complex of a group 16 element, [Te(kappa(2)-Tm(Me))(2)], is reported. It displays square planar geometry at the Te atom and two distinct ligand conformations. In addition, the first pyrazolylborate complex of a group 15 element, [Bi(Tp)(2)(pzH)Cl], has been synthesized and characterized.
A dissymmetric 1,10-phenanthroline chelate (N-phen-S) bearing two polyether chains terminated by two monodentate ligands of the benzonitrile (N) and dialkylesulfoxide (S) types was synthesized, characterized, and coordinated to ruthenium. The corresponding Ru(terpy)(N-phen-S)2+ complexes (terpy = 4'-(3,5-ditertiobutylphenyl)-2,2';6',2' '-terpyridine) were fully characterized as being two coordination isomers of the scorpionate type with one of the two tails occupying the sixth position on the coordination sphere. Photoexpulsion of the coordinated tail led to opening of the ruthena-macrocycle and subsequent rearrangement of the bidentate chelate. This rearrangement consisted of a 90 degrees rotation of the phenanthroline around the ruthenium atom. Selective irradiation of one isomer in a mixture of the two was undertaken using band-pass filters; this resulted in an enrichment of the nonirradiated isomer in the mixture. Thermal back-coordination of the tail was investigated in the dark. It took place quantitatively from the corresponding ruthenium chloride complex by trapping of the anion with silver salts.