A mechanistic view of mitochondrial death decision pores

Mitochondria increase their outer and inner membrane permeability to solutes, protons and metabolites in response to a variety of extrinsic and intrinsic signaling events. The maintenance of cellular and intraorganelle ionic homeostasis, particularly for Ca2+, can determine cell survival or death. Mitochondrial death decision is centered on two processes: inner membrane permeabilization, such as that promoted by the mitochondrial permeability transition pore, formed across inner membranes when Ca2+ reaches a critical threshold, and mitochondrial outer membrane permeabilization, in which the pro-apoptotic proteins BID, BAX, and BAK play active roles. Membrane permeabilization leads to the release of apoptogenic proteins: cytochrome c, apoptosis-inducing factor, Smac/Diablo, HtrA2/Omi, and endonuclease G. Cytochrome c initiates the proteolytic activation of caspases, which in turn cleave hundreds of proteins to produce the morphological and biochemical changes of apoptosis. Voltage-dependent anion channel, cyclophilin D, adenine nucleotide translocase, and the pro-apoptotic proteins BID, BAX, and BAK may be part of the molecular composition of membrane pores leading to mitochondrial permeabilization, but this remains a central question to be resolved. Other transporting pores and channels, including the ceramide channel, the mitochondrial apoptosis-induced channel, as well as a non-specific outer membrane rupture may also be potential release pathways for these apoptogenic factors. In this review, we discuss the mechanistic models by which reactive oxygen species and caspases, via structural and conformational changes of membrane lipids and proteins, promote conditions for inner/outer membrane permeabilization, which may be followed by either opening of pores or a rupture of the outer mitochondrial membrane.

TMEM16 proteins: the long awaited calcium-activated chloride channels?

Currents mediated by calcium-activated chloride channels (CaCCs), observed for the first time in Xenopus oocytes, have been recorded in many cells and tissues ranging from different types of neurons to epithelial and muscle cells. CaCCs play a role in the regulation of excitability in neurons including sensory receptors. In addition, they are crucial mediators of chloride movements in epithelial cells where their activity regulates electrolyte and fluid transport. The roles of CaCCs, particularly in epithelia, are briefly reviewed with emphasis on their function in secretory epithelia. The recent identification by three independent groups, using different strategies, of TMEM16A as the molecular counterpart of the CaCC is discussed. TMEM16A is part of a family that has 10 other members in mice. The discovery of the potential TMEM16 anion channel activity opens the way for the molecular investigation of the role of these anion channels in specific cells and in organ physiology and pathophysiology. The identification of TMEM16A protein as a CaCC chloride channel molecule represents a great triumph of scientific perseverance and ingenuity. The varied approaches used by the three independent research groups also augur well for the solidity of the discovery.

Análise interactômica da VDAC (voltage-dependent anion selective channel) nos cérebros aviar, bovino e murino

A VDAC é a proteína mais abundante na membrana mitocondrial externa. Exerce o controle da atividade desta organela através da regulação da troca de metabólitos e tem função crucial no mecanismo de apoptose. Em nosso caso, os estudos dos complexos protéicos, das interações entre a VDAC e outras proteínas presentes no interior do neurônio que auxiliam na manutenção das funções das organelas e da célula, fazem parte da chamada interactômica. O presente estudo determinou o interactoma do complexo protéico Hexoquinase-VDAC-ANT presente em cérebros murino, bovino e aviar. Nosso objetivo foi identificar se as expressões diferenciadas da VDAC1 e VDAC2 verificadas nos cérebros murino, aviar e bovino, estão associadas a diferenças nos interactomas dessas proteínas. Este estudo revelou que as espécies aviar e bovina apresentaram o maior número de complexos protéicos contendo VDACs (5) quando comparadas com os neurônios de rato (1), o que é indicativo de uma cinética diferencial de montagem ou desmontagem do complexo. Além disso, a VDAC mitocondrial neuronal aviar também interage com mais proteínas em relação à VDAC mitocondrial neuronal bovina, o que é resultado de uma composição de subunidades diferenciada. Tais resultados indicam diferenças significativas quanto ao metabolismo energético e apoptótico no cérebro aviar, bovino e murino, existindo interações diferenciais da VDAC no cérebro aviar.

Population biology of Eudendrium caraiuru (Cnidaria, Anthoathecata, Eudendriidae) from São Sebastião Channel, Southeastern Brazil

The ecology of Eudendrium spp. from the Brazilian coast is poorly known, although it already proved to be useful and important as a tool to solve some taxonomical problems of the genus. The seasonality and reproduction patterns of a population of Eudendrium caraiuru Marques & Oliveira, 2003 were studied. Data were sampled from test panels immersed in the water off Cabelo Gordo de Dentro beach, in São Sebastião Channel, Southeastern Brazil, from July 1999 to July 2000, every three months. Eudendrium caraiuru was active throughout the study period. Reproductive peaks of the species were regulated by cold and low-salinity water, although part of the population always bore mature gonophores. In addition to morphological differences, ecological differences between E. caraiuru and its similar species, E. glomeratum Picard, 1951, especially from well known populations of the Mediterranean Sea, corroborated that these species are diverse lineages of a unique ancestor.

Space-time variation of the relative abundance of Limnoperna fortunei in deep zones of São Gonçalo Channel, Rio Grande do Sul, Brazil

This work describes the spatial-temporal variation of the relative abundance and size of Limnoperna fortunei (Dunker, 1857) collected in São Gonçalo Channel through bottom trawl with a 0.5 cm mesh, at depths between 3 and 6 m. The estimative of mean relative abundance (CPUE) ranged from 2,425.3 individuals per drag (ind./drag) in the spring to 21,715.0 ind./drag in the fall, with an average of 9,515.3 ind./drag throughout the year. The estimated mean density of L. fortunei for the deep region of São Gonçalo Channel ranged from 1.2 to 10.3 ind./m², and it was recorded a maximum density of 84.9 ind./m² in the fall of 2008. The method of sampling using bottom trawl enabled the capture of L. fortunei under the soft muddy bottom of the channel, in different sizes ranging from 0.4 to 3.2 cm. This shows that the structure of the L. fortunei adult population under the bottom of the São Gonçalo Channel is composed mostly of small individuals (<1.4 cm), which represent up to 74% of the population collected.

Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs

The need for drug combinations to treat visceral leishmaniasis (VL) arose because of resistance to antimonials, the toxicity of current treatments and the length of the course of therapy. Calcium channel blockers (CCBs) have shown anti-leishmanial activity; therefore their use in combination with standard drugs could provide new alternatives for the treatment of VL. In this work, in vitro isobolograms of Leishmania (Leishmania) chagasi using promastigotes or intracellular amastigotes were utilised to identify the interactions between five CCBs and the standard drugs pentamidine, amphotericin B and glucantime. The drug interactions were assessed with a fixed ratio isobologram method and the fractional inhibitory concentrations (FICs), sum of FICs (ΣFICs) and the overall mean ΣFIC were calculated for each combination. Graphical isobologram analysis showed that the combination of nimodipine and glucantime was the most promising in amastigotes with an overall mean ΣFIC value of 0.79. Interactions between CCBs and the anti-leishmanial drugs were classified as indifferent according to the overall mean ΣFIC and the isobologram graphic analysis.

Antischistosomal activity of a calcium channel antagonist on schistosomula and adult Schistosoma mansoni worms

Current schistosomiasis control strategies are largely based on chemotherapeutic agents and a limited number of drugs are available today. Praziquantel (PZQ) is the only drug currently used in schistosomiasis control programs. Unfortunately, this drug shows poor efficacy in patients during the earliest infection phases. The effects of PZQ appear to operate on the voltage-operated Ca2+channels, which are located on the external Schistosoma mansoni membrane. Because some Ca2+channels have dihydropyridine drug class (a class that includes nifedipine) sensitivity, an in vitro analysis using a calcium channel antagonist (clinically used for cardiovascular hypertension) was performed to determine the antischistosomal effects of nifedipine on schistosomula and adult worm cultures. Nifedipine demonstrated antischistosomal activity against schistosomula and significantly reduced viability at all of the concentrations used alone or in combination with PZQ. In contrast, PZQ did not show significant efficacy when used alone. Adult worms were also affected by nifedipine after a 24 h incubation and exhibited impaired motility, several lesions on the tegument and intense contractility. These data support the idea of Ca2+channels subunits as drug targets and favour alternative therapeutic schemes when drug resistance has been reported. In this paper, strong arguments encouraging drug research are presented, with a focus on exploring schistosomal Ca2+channels.

Whole-body MRI: comprehensive evaluation on a 48-channel 3T MRI system in less than 40 minutes. Preliminary results

OBJECTIVE: To evaluate a comprehensive MRI protocol that investigates for cancer, vascular disease, and degenerative/inflammatory disease from the head to the pelvis in less than 40 minutes on a new generation 48-channel 3T system. MATERIALS AND METHODS: All MR studies were performed on a 48-channel 3T MR scanner. A 20-channel head/neck coil, two 18-channel body arrays, and a 32-channel spine array were employed. A total of 4 healthy individuals were studied. The designed protocol included a combination of single-shot T2-weighted sequences, T1-weighted 3D gradient-echo pre- and post-gadolinium. All images were retrospectively evaluated by two radiologists independently for overall image quality. RESULTS: The image quality for cancer was rated as excellent in the liver, pancreas, kidneys, lungs, pelvic organs, and brain, and rated as fair in the colon and breast. For vascular diseases ratings were excellent in the aorta, major branch vessel origins, inferior vena cava, portal and hepatic veins, rated as good in pulmonary arteries, and as poor in the coronary arteries. For degenerative/inflammatory diseases ratings were excellent in the brain, liver and pancreas. The inter-observer agreement was excellent. CONCLUSION: A comprehensive and time efficient screening for important categories of disease processes may be achieved with high quality imaging in a new generation 48-channel 3T system.

Models for the estimation of thermodynamic properties of layered double hydroxides: application to the study of their anion exchange characteristics

Several models for the estimation of thermodynamic properties of layered double hydroxides (LDHs) are presented. The predicted thermodynamic quantities calculated by the proposed models agree with experimental thermodynamic data. A thermodynamic study of the anion exchange process on LDHs is also made using the described models. Tables for the prediction of monovalent anion exchange selectivities on LDHs are provided. Reasonable agreement is found between the predicted and the experimental monovalent anion exchange selectivities.

The saccharinate anion: a versatile and fascinating ligand in coordination chemistry

The saccharinate anion, obtained by deprotonation of the N-H moiety of saccharin (o-sulfobenzimide) is a very versatile and polyfunctional ligand in coordination chemistry. In this review the different forms of metal-to-ligand interactions involving this anion and some other coordination peculiarities are briefly discussed on the basis of some selected examples.

Electrical and magnetic properties of new compounds of the conductor anion [Ni(dmit)2]- and nitronyl nitroxide magnetic radicals

Three compounds have been synthesized with formulae [3-MeRad][Ni(dmit)2] (1), [4-MeRad][Ni(dmit)2] (2) and [4-PrRad][Ni(dmit)2] (3) where [Ni(dmit)2]- is an anionic pi-radical (dmit = 1,3-dithiol-2-thione-4,5-dithiolate) and [3-MeRad]+ is 3-N-methylpyridinium alpha-nitronyl nitroxide, [4-MeRad]+ is 4-N-methylpyridinium alpha-nitronyl nitroxide and [4-PrRad]+ is 4-N-propylpyridinium alpha-nitronyl nitroxide. The temperature-dependent magnetic susceptibility of 1 revealed that an antiferromagnetic interaction operates between the 3-MeRad+ radical cations with exchange coupling constants of J1 = - 1.72 cm-1 and antiferromagnetism assigned to the spin ladder chains of the Ni(dmit)2 radical anions. Compound 1 exhibits semiconducting behavior and 3 presents capacitor behavior in the temperature range studied (4 - 300 K).

ANION-BINDING AND SENSING PROPERTIES OF NOVEL RECEPTORS BASED ON N-(INDOL-3-YLGLYOXYLYL)BENZYLAMINE

Indole-based receptors such as biindole, carbazole, and indolocarbazole are regarded as some of the most favorable anion receptors in molecular recognition. This is because indole groups possess N–H groups as hydrogen-bonding donors. The introduction of amide groups in the indole framework can induce strong binding properties and good water solubility. In this study, we designed and synthesized a series of N-(indol-3-ylglyoxylyl)benzylamine derivatives as novel and simple anion receptors. The receptors derived by aryl and aliphatic amines can selectively recognize F– based on a color change from colorless-to-yellow in DMSO. The receptors derived by hydrazine hydrate can recognize F–, AcO–, and H2PO4– by similar color changes in DMSO and can even enable the selective recognition of F– in a DMSO–H2O binary solution by the naked eye. Spectrographic data indicate that complexes are formed between receptors and anions through multiple hydrogen-bonding interactions in dual solutions.

Extraction and spectrophotometric determination of Hg2+ as complex anion HgI3-

A method has been developed for the extraction and spectrophotometric determination of Hg2+ in a concentration range of 0.2-1.0 mg L-1; following the Lambert-Beer's law using high molecular weight quaternary ammonium salts dissolved in chloroform. The metal complex anion was determined in the extract in the region UV (260 nm).

Flow injection spectrophotometric determination of adrenaline using a solid-phase reactor containing triiodide ions immobilized in an anion-exchange resin

A flow injection spectrophotometric procedure with on-line solid-phase reactor containing ion triiodide immobilized in an anion-exchange resin is proposed for the determination of adrenaline (epinephrine) in pharmaceutical products. Adrenaline is oxidized by triiodide ion immobilized in an anionic-exchange resin yielding adrenochrome which is transported by the carrier solution and detected at a wavelength of 488 nm. Adrenaline was determined in three pharmaceutical products in the 6.4 x 10-6 to 3.0 x 10-4 mol L-1 concentration range with a detection limit of 4.8 x 10-7 mol L-1. The recovery of this analyte in three samples ranged from 96.0 to 105 %. The analytical frequency was 80 determinations per hour and the RSDs were less than 1 % for adrenaline concentrations of 6.4 x 10-5 and 2.0 x 10-4 mol L-1 (n=10). A paired t-test showed that all results obtained for adrenaline in commercial formulations using the proposed flow injection procedure and a spectrophotometric batch procedure agree at the 95% confidence level.