Excellent correlation between cathepsin B inhibition and cytotoxicity for a series of palladacycles

The reaction of the five- or six-membered C,N or C,S-palladacycles [(L)PdCl](2) with PTA (1,3,5-triaza-7-phosphaadamantane) led to the monomeric complexes [(L)Pd(PTA)Cl] 6a, 6b and 7 where LH= N,N-dimethyl-1-phenylmethanamine, benzyl(methyl)sulfane or 1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one respectively. Dimeric complexes have also been synthesised: [Pd(2)L(2)(mu-dppe)Cl(2)], where LH = 1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (1a), (R)- or (S)-3-isopropyl-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (1b, 1c), [Pd(2)L(2)(mu-dppf)Cl(2)], where L= 1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (4a) or (R)-3-isopropyl-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (4b), respectively, and dppe = 1,2-bis(diphenylphosphino)ethane, dppf = 1,1'-bis(diphenylphosphino)ferrocene. The complexes were characterised in solution, by (1)H and (31)P NMR spectroscopy, and single crystals of complexes 6b and 7 were studied in the solid state by X-ray crystallography. The palladacycles were evaluated for in vitro activity as cytotoxic agents on A2780/S cells and also as cathepsin B inhibitors, an enzyme implicated in a number of cancer related events.

Antioxidant and cytoprotective activity of leaves of Peltiphyllum peltatum (Torr.) Engl.

The antioxidant potential of fresh leaves of Peltiphyllum peltatum (Torr.) Engl. (Saxfragaceae) was analysed by measuring scavenging potential against l,l'-diphenyl-2-picrylhydrazyl (DPPH center dot) and hydroxyl radicals (W), reducing power, inhibition of lipid peroxidation and protection of cultured cells from a lethal dose of hydrogen peroxide (H2O2). In all chemical assays used, the crude ethanolic extract of leaves of P. peltatum, which contained 21.8 +/- 1.7% (w/w, n = 3) of total phenols, was as effective as the standard antioxidant compound, rutin. Fractionation of the crude extract with solvent of increasing polarity (namely, petroleum ether, chloroform, ethyl acetate, butanol and water) led to identification of the active fractions (ethyl acetate and butanol fractions). The crude extract and its active fractions, but not rutin, protected cultured RAW 264.7 macrophages from a lethal dose Of H2O2.

Heat Dissipation And Energetic Efficiency In Animal Anoxibiosis - Economy Contra Power

This survey on calorimetry and thermodynamics of anoxibiosis applies classical and irreversible thermodynamics to interpret experimental, direct calorimetric results in order to elucidate the sequential activation of various biochemical pathways. First, the concept of direct and indirect calorimetry is expanded to incorporate the thermochemistry of aerobic and anoxic metabolism in living cells and organisms. Calorimetric studies done under normoxia as well as under physiological and environmental anoxia are presented and assessed in terms of ATP turnover rate. Present evidence suggests that unknown sources of energy in freshwater and marine invertebrates under long-term anoxia may be important. During physiological hypoxia, thermodynamically grossly inefficient pathways sustain high metabolic rates for brief periods. On the contrary, under long-term environmental anoxia, low steady-state heat dissipation is linked to the more efficient succinate, propionate, and acetate pathways. In the second part of this paper these relationships are discussed in the context of linear, irreversible thermodynamics. The calorimetric and biochemical trends during aerobic-anoxic transitions are consistent with thermodynamic optimum functions of catabolic pathways. The theory predicts a decrease of rate with an increase of thermodynamic efficiency; therefore maximum rate and maximum efficiency are mutually exclusive. Cellular changes of pH and adenylate phosphorylation potential are recognized as regulatory mechanisms in the energetic switching to propionate production. While enzyme kinetics provides one key for understanding metabolic regulation, our insight remains incomplete without a complementary thermodynamic analysis of kinetic control in energetically coupled pathways.

Pathophysiology of feline hyperadrenocorticism clinical. Case presentation

Hyperadrenocorticism is a rare endocrine disease in the cat; it is characterized by elevated blood cortisol level that generates numerous clinical signs including hyperglycemia, polyuria, polydipsia, polyphagia and skin diseases. The average age of onset is around 10 years. This disease usually occurs link with other endocrine disorders such as diabetes mellitus.The disease can be produced by functional alteration of the pituitary gland or the adrenal. A case report, with differential diagnosis and review of the literature, is presented.

Creación de una filmoteca de prácticas para la Facultad de Ciencias de la Información de la UCM: Adecuación de espacio y estrategias de catalogación

En el presente trabajo se da el primer paso para la creación de una Filmoteca de Prácticas en la facultad de Ciencias de la Información de la Universidad Complutense de Madrid. El Patrimonio Fílmico se ve gravemente expuesto al paso del tiempo y el abandono por lo que se necesita un rescate urgente. Mediante un riguroso trabajo de investigación, en el que se estudian diferentes propuestas y normativas expuestas por organismos especializados, se redacta un manual de inicio. Se han investigado, diseñado y propuesto las herramientas básicas y útiles para poner en funcionamiento la primera Filmoteca de Prácticas en el ámbito universitario español.

A dynamic mechanical method for determining the silicone elastomer solubility of drugs and pharmaceutical excipients in silicone intravaginal drug delivery rings

The silicone elastomer solubilities of a range of drugs and pharmaceutical excipients employed in the development of silicone intravaginal drug delivery rings (polyethylene glycols, norethisterone acetate, estradiol, triclosan, oleyl alcohol, oxybutynin) have been determined using dynamic mechanical analysis. The method involves measuring the concentration-dependent decrease in the storage modulus associated with the melting of the incorporated drug/excipient, and extrapolation to zero change in storage modulus. The study also demonstrates the effect of drug/excipient concentrations on the mechanical stiffness of the silicone devices at 37°C.

Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings

The in vitro release characteristics of eight low-molecular-weight drugs (clindamycin, 17beta-estradiol, 17beta-estradiol-3-acetate, 17beta-estradiol diacetate, metronidazole, norethisterone, norethisterone acetate and oxybutynin) from silicone matrixtype intravaginal rings of various drug loadings have been evaluated under sink conditions. Through modelling of the release data using the Higuchi equation, and determination of the silicone solubility of the drugs, the apparent silicone elastomer diffusion coefficients of the drugs have been calculated. Furthermore, in an attempt to develop a quantitative model for predicting release rates of new drug substances from these vaginal ring devices, it has been observed that linear relationships exist between the log of the silicone solubility of the drug (mg ml(-1)) and the reciprocal of its melting point (K-1) (y = 3.558x - 9.620, R = 0.77), and also between the log of the diffusion coefficient (cm(2) s(-1)) and the molecular weight of the drug molecule (g mol(-1)) (y = - 0.0068x - 4.0738, R = 0.95). Given that the silicone solubility and silicone diffusion coefficient are the major parameters influencing the permeation of drugs through silicone elastomers, it is now possible to predict through use of the appropriate mathematical equations both matrix-type and reservoir-type intravaginal ring release rates simply from a knowledge of drug melting temperature and molecular weight. (C) 2003 Elsevier Science B.V. All rights reserved.

Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide

TMC 120 (Dapivirine) is a potent non-nucleoside reverse transcriptase inhibitor that is presently being developed as a vaginal HIV microbicide. To date, most vaginal microbicides under clinical investigation have been formulated as single-dose semi-solid gels, designed for application to the vagina before each act of intercourse. However, a clear rationale exists for providing long-term, controlled release of vaginal microbicides in order to afford continuous protection against heterosexually transmitted HIV infection and to improve user compliance. In this study we report on the incorporation of various pharmaceutical excipients into TMC 120 silicone, reservoir-type intravaginal rings (IVRs) in order to modify the controlled release characteristics of the microbicide. The results demonstrate that TMC 120 is released in zero-order fashion from the rings over a 28-day period and that release parameters could be modified by the inclusion of release-modifying excipients in the IVR. The hydrophobic liquid excipient isopropyl myristate had little effect on steady-state daily release rates, but did increase the magnitude and duration of burst release in proportion to excipient loading in the IVR. By comparison, the hydrophobic liquid poly(dimethylsiloxane) had little effect on TMC 120 release parameters. A hydrophilic excipient, lactose, had the surprising effect of decreasing TMC 120 burst release while increasing the apparent steady-state daily release in a concentration-dependent manner. Based on previous cell culture data and vaginal physiology, TMC120 is released from the various ring formulations in amounts potentially capable of maintaining a protective vaginal concentration. It is further predicted that the observed release rates may be maintained for at least a period of 1 year from a single ring device. TMC 120 release profiles and the mechanical properties of rings could be modified by the physicochemical nature of hydrophobic and hydrophilic excipients incorporated into the IVRs.

Enhanced inflammatory responses in alpha-tocopherol transfer protein null mice

The liver preferentially secretes alpha-tocopherol into plasma under the control of the hepatic alpha-tocopherol transfer protein (alpha-TTP). alpha-TTP-null mice (Ttpa(-/-) mice) are vitamin E deficient, therefore were used for investigations of in vivo responses to sub-normal tissue alpha-tocopherol concentrations during inflammation. Increased basal oxidative stress in Ttpa(-/-) mice was documented by increased plasma lipid peroxidation, and superoxide production by bone marrow-derived neutrophils stimulated in vitro with phorbol 12-myristate 13-acetate. Lipopolysaccharide (LPS) injected intraperitoneally induced increases in lung and liver HO-1 and iNOS, as well as plasma NO(x) in Ttpa(+/+) mice. LPS induced more modest increases in these markers in Ttpa(-/-) mice, while more marked increases in plasma IL-10 and lung lavage TNF alpha were observed. Taken together, these results demonstrate that alpha-tocopherol is important for proper modulation of inflammatory responses and that sub-optimal alpha-tocopherol concentrations may derange inflammatory-immune responses.

Regulation of the Gene Encoding Thrombin-Activable Fibrinolysis Inhibitor in Non-Hepatic Cells

Thrombin-activable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like pro-enzyme that, once activated, attenuates fibrinolysis. TAFIa also possesses anti-inflammatory properties. Although liver is the main source of plasma TAFI, platelet-derived TAFI has also been reported. An alternatively spliced TAFI variant resulted from the skipping of exon 6 and a 52-base deletion in exon 10 of CPB2 mRNA (∆6+10) was described to be brain specific. This TAFI variant is reputed to possess a secretase-like activity that cleaves β-amyloid precursor protein to form β-amyloid, a process involved in the onset of Alzheimer's disease. In this thesis, we report the identification of CPB2 mRNA and TAFI protein in various vascular and inflammatory cells. Specifically, we describe the expression of CPB2 mRNA in the megakaryocytic cell lines MEG-01 and Dami, the monocytic cell line THP-1, and peripheral blood mononuclear cells. TAFI protein was detected in differentiated Dami and THP-1 cells. We next describe the effect of external stimuli such as phorbol myristate acetate (PMA) on CPB2 expression in Dami and THP-1 cells. We found that PMA treatment increases both CPB2 mRNA abundance and promoter activity in Dami cells, and decreases both CPB2 mRNA abundance and promoter activity in THP-1 cells. Deletion analysis of the CPB2 promoter indicated cell-type specific regulation of CPB2 gene expression. Finally, we evaluated the expression of alternatively spliced CPB2 mRNA variants in hepatic and non hepatic cells. We found that exon 6 skipping variants are expressed in all cell types of interest. The variant previously reported to be brain specific was also found to be expressed in platelets. We found that the alternatively spliced TAFI variants accumulated inside the cells in a non-secretable, hypoglycosylated form and showed no carboxypeptidase activity. Taken together, this thesis provides further evidence supporting the hypothesis that platelet-derived TAFI is originated from CPB2 gene expression in megakaryocytes. Moreover, our data imply a potential for site-specific anti-inflammatory control provided by macrophage-derived TAFI. Alternative splicing of the CPB2 mRNA may give rise to variants with an intracellular role, perhaps as a peptidase chaperone, and may modulate the synthesis of secretable TAFI.

Diabetes-induced activation of protein kinase C inhibits store-operated Ca2+ uptake in rat retinal microvascular smooth muscle.

AIMS/HYPOTHESIS: To assess the effects of diabetes-induced activation of protein kinase C (PKC) on voltage-dependent and voltage-independent Ca2+ influx pathways in retinal microvascular smooth muscle cells. METHODS: Cytosolic Ca2+ was estimated in freshly isolated rat retinal arterioles from streptozotocin-induced diabetic and non-diabetic rats using fura-2 microfluorimetry. Voltage-dependent Ca2+ influx was tested by measuring rises in [Ca2+]i with KCl (100 mmol/l) and store-operated Ca2+ influx was assessed by depleting [Ca2+]i stores with Ca2+ free medium containing 5 micromol/l cyclopiazonic acid over 10 min and subsequently measuring the rate of rise in Ca2+ on adding 2 mmol/l or 10 mmol/l Ca2+ solution. RESULTS: Ca2+ entry through voltage-dependent L-type Ca2+ channels was unaffected by diabetes. In contrast, store-operated Ca2+ influx was attenuated. In microvessels from non-diabetic rats 20 mmol/l D-mannitol had no effect on store-operated Ca2+ influx. Diabetic rats injected daily with insulin had store-operated Ca2+ influx rates similar to non-diabetic control rats. The reduced Ca2+ entry in diabetic microvessels was reversed by 2-h exposure to 100 nmol/l staurosporine, a non-specific PKC antagonist and was mimicked in microvessels from non-diabetic rats by 10-min exposure to the PKC activator phorbol myristate acetate (100 nmol/l). The specific PKCbeta antagonist LY379196 (100 nmol/l) also reversed the poor Ca2+ influx although its action was less efficacious than staurosporine. CONCLUSION/INTERPRETATION: These results show that store-operated Ca2+ influx is inhibited in retinal arterioles from rats having sustained increased blood glucose and that PKCbeta seems to play a role in mediating this effect.

A group contribution method for viscosity estimation of ionic liquids

Based on experimental viscosity data collected from the literature and using density data obtained from a predictive method previously proposed by the authors, a group contribution method is proposed to estimate viscosity of imidazolium-, pyridinium-, and pyrrolidinium-based ILs containing hexafluorophosphate (PF6), tetrafluoroborate (BF4), bis(trifluoromethanesulfonyl) amide (Tf2N), chloride (Cl), acetate (CH3COO), methyl sulfate (MeSO4), ethyl sulfate (EtSO4), and trifluoromethanesulfonate (CF3SO3) anions, covering wide ranges of temperature, 293–393 K and viscosity, 4–21,000 cP. It is shown that a good agreement with literature data is obtained. For circa 500 data points of 29 ILs studied, a mean percent deviation (MPD) of 7.7% with a maximum deviation smaller than 28% was observed. 71.1% of the estimated viscosities present deviations smaller than 10% of the experimental values while only 6.4% have deviations larger than 20%. The group contribution method here developed can thus be used to evaluate the viscosity of new ionic liquids in wide ranges of temperatures at atmospheric pressure and, as data for new groups of cations and anions became available, can be extended to a larger range of ionic liquids.

Color preferences in gorillas (Gorilla gorilla gorilla) and chimpanzees (Pan troglodytes)

Color plays an important biological role in the lives of many animals, with some species exhibiting preferences for certain colors over others. This study explored the color preferences of two species of ape, which, like humans, possess trichromatic color vision. Six western lowland gorillas, and six chimpanzees, housed in Belfast Zoological Gardens, were exposed to three stimuli (cloths, boxes, sheets of acetate) in red, blue, and green. Six stimuli of the same nature, in each of the three colors, were provided to both species for 5 days per stimulus. The amount of interest that the animals showed toward each stimulus of each color was recorded for 1 hr. Results showed that the apes, both when analyzed as two separate groups, and when assessed collectively, showed significant color preferences, paying significantly less attention to the red-, than to the blue- or green-colored stimuli. The animals' interest in the blue- and green-colored stimuli did not differ significantly. Overall, the findings suggest that gorillas and chimpanzees, our closest living relatives, may harbor color preferences comparable to those of humans and other species. © 2008 American Psychological Association.


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A surface plasmon resonance biosensor assay for the simultaneous determination of thiamphenicol, florefenicol, florefenicol amine and chloramphenicol residues in shrimps

A rapid and sensitive screening qualitative method using a surface plasmon resonance (SPR) biosensor was developed which can detect of all fenicol antibiotic residues in shrimps from a single sample extract. This method requires ethyl acetate extraction followed by a single wash with isooctane/chlorofonrm. Each sample extract is injected over the surfaces of two biosensor chip flow cells, one surface having the capability to detect florefenicol amine (FF amine), florefenicol (FF), and thiamphenicol (TAP) and the second surface for chloramphenicol (CAP) detection. The estimated detection capabilities (CC beta) were 0. 1, 0.2, 250, and 0.5 ppb for CAP, FF, FF amine, and TAP, respectively. This quick, simple test allowed the detection of CAP residues in shrimps at the minimum required performance limit (MRPL) of 0.1 mu g kg(-1) for this compound and of FF, FF amine, and TAP below their maximum residue limits (MRLs). (c) 2006 Elsevier B.V. All rights reserved.

Pharmacological characterisation of neuropeptide F (NPF)-induced effects on the motility of Mesocestoides corti (syn. Mesocestoides vogae) larvae

Neuropeptide F is the most abundant neuropeptide in parasitic flatworms and is analogous to vertebrate neuropeptide Y. This paper examines the effects of neuropeptide F on tetrathyridia of the cestode Mesocestoides vogae and provides preliminary data on the signalling mechanisms employed. Neuropeptide F ( greater than or equal to 10 muM) had profound excitatory effects on larval motility in vitro. The effects were insensitive to high concentrations (I mM) of the anaesthetic procame hydrochloride suggesting extraneuronal sites of action. Neuropeptide F activity was not significantly blocked by a FMRFamide-related peptide analog (GNFFRdFamide) that was found to inhibit GNFFRFamide-induced excitation indicating the occurrence of distinct neuropeptide F and FMRFamide-related peptide receptors. Larval treatment with guanosine 5'-O-(2-thiodiphosphate) trilithium salt prior to the addition of neuropeptide F completely abolished the excitatory effects indicating the involvement of G-proteins and a G-protein coupled receptor in neuropeptide F activity. Addition of guanosine 5'-O-(2-thiodiphosphate) following neuropeptide F had limited inhibitory effects consistent with the activation of a signalling cascade by the neuropeptide. With respect to Ca2+ involvement in neuropeptide F-induced excitation of M. vogae larvae, the L-type Ca2+-channel blockers verapamil and nifedipine both abolished neuropeptide F activity as did high Mg+ concentrations and drugs which blocked sarcoplasmic reticulum Ca2+-activated Ca2+-channels (ryanodine) and sarcoplasmic reticulum Ca2+ pumps (cyclopiazonic acid). Therefore, both extracellular and intracellular Ca2+ is important for neuropeptide F excitation in M. vogae. With resepct to second messengers, the protein kinase C inhibitor chelerythrine chloride and the adenylate cyclase inhibitor MDL-2330A both abolished neuropeptide F-induced excitation. The involvement of a signalling pathway that involves protein kinase C was further supported by the fact that phorbol-12-myristate-13-acetate,known to directly activate protein kinase C, had direct excitatory effects on larval motility. Although neuropeptide F is structurally analogous to neuropeptide Y, its mode-of-action in flatworms appears quite distinct from the common signalling mechanism seen in vertebrates. (C) 2003 on behalf of Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.