The Role of the BMP Signaling Antagonist Noggin in the Development of Prostate Cancer Osteolytic Bone Metastasis

Members of the BMP and Wnt protein families play a relevant role in physiologic and pathologic bone turnover. Extracellular antagonists are crucial for the modulation of their activity. Lack of expression of the BMP antagonist noggin by osteoinductive, carcinoma-derived cell lines is a determinant of the osteoblast response induced by their bone metastases. In contrast, osteolytic, carcinoma-derived cell lines express noggin constitutively. We hypothesized that cancer cell-derived noggin may contribute to the pathogenesis of osteolytic bone metastasis of solid cancers by repressing bone formation. Intra-osseous xenografts of PC-3 prostate cancer cells induced osteolytic lesions characterized not only by enhanced osteoclast-mediated bone resorption, but also by decreased osteoblast-mediated bone formation. Therefore, in this model, uncoupling of the bone remodeling process contributes to osteolysis. Bone formation was preserved in the osteolytic lesions induced by noggin-silenced PC-3 cells, suggesting that cancer cell-derived noggin interferes with physiologic bone coupling. Furthermore, intra-osseous tumor growth of noggin-silenced PC-3 cells was limited, most probably as a result of the persisting osteoblast activity. This investigation provides new evidence for a model of osteolytic bone metastasis where constitutive secretion of noggin by cancer cells mediates inhibition of bone formation, thereby preventing repair of osteolytic lesions generated by an excess of osteoclast-mediated bone resorption. Therefore, noggin suppression may be a novel strategy for the treatment of osteolytic bone metastases

Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called 'stress reactivity' (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors.In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD

The Problem of Religious Evil: Does Belief in God Cause Evil?

Daniel Kodaj has recently developed a pro-atheistic argument that he calls "the problem of religious evil." This first premise of this argument is "belief in God causes evil." Although this idea that belief in God causes evil is widely accepted, certainly in the secular West, it is sufficiently problematic as to be unsuitable as a basis for an argument for atheism, as Kodaj seeks to use it. In this paper I shall highlight the problems inherent in it in three ways: by considering whether it is reasonable to say that "belief in God" causes evil; whether it is reasonable to say that belief in God "causes" evil; and whether it is reasonable to say that belief in God causes "evil." In each case I will argue that it is problematic to make such claims, and accordingly I will conclude that the premise "belief in God causes evil" is unacceptable as it stands, and consequently is unable to ground Kodaj's pro-atheistic argument

Synthesis of 2-azidoethyl α-d-mannopyranoside orthogonally protected and selective deprotections

4 páginas, 1 figura, 2 esquemas.We present the synthesis of a fully orthogonally protected mannosyl glycoside 1 and the corresponding methods for selective deprotections. Mannosyl glycoside 1 contains a functionalized linker at the anomeric position to allow for the attachment of carbohydrate units to scaffolds in order to prepare carbohydrate multivalent systems.We would like to thank FIS (PI030093), for financial supportPeer reviewe

Identification and quantitative determination of mercapturic acids formed from Z- and E-1,3-dichloropropene by the rat, using gas chromatography with three different detection techniques

Z- and E-1,3-dichloropropene, mutagenic geometric isomers and major constituents of commercial soil fumigants, were found to be metabolized to mercapturic acid derivatives by the rat. Extremely small quantities of mixtures of the parent compounds were administered intraperitoneally to the rat and the isomeric urinary mercapturic acids were quantified in three ways. Gas chromatographic procedures with nitrogen selective, sulphur selective and mass spectrometric detection, using negative chemical ionization with single ion detection, were evaluated with respect to selectivity and sensitivity. Applying the former two techniques, urinary mercapturic acids could still be quantified following 5 micrograms doses of each of the dichloropropene isomers. With gas chromatography-negative chemical ionization mass spectrometry, only mercapturic acid metabolites arising from 25 micrograms doses and higher could be quantified because of interference from endogenous compounds. These results suggest that all three analytical methods can be used to determine exposure of men to soil fumigants containing low levels of 1,3-dichloropropene

Biotransformation and quantitative determination of sulfur-containing metabolites of 1,4-dibromobutane in the rat

Two stable sulfur-containing metabolites were isolated from rat urine following administration of the mutagenic 1,4-dibromobutane. They were identified as tetrahydrothiophene and 3-hydroxysulfolane by gas chromatography and gas chromatography-mass spectrometry and were found to be excreted in 48-hr urine, representing 5.8 +/- 1.1 and 57 +/- 15% of the dose of 1,4-dibromobutane, respectively. When urines of rats treated with 1,4-dibromobutane were collected in a buffer of pH 1.0, however, only 3-hydroxysulfolane was found. It was indirectly shown that an N-acetyl-S-(beta-alanyl)tetrahydrothiophenium salt was present in urine and that this metabolite is probably the precursor of tetrahydrothiophene. The latter product is only formed at higher pH values and quantified after addition of NaOH to buffered urines. Tetrahydrothiophene is probably also formed under physiological conditions in vivo from the N-acetyl-S-(beta-alanyl)-tetrahydrothiophenium salt, but in this case it is subsequently transformed to 3-hydroxysulfolane. Based on these findings, a biotransformation scheme of 1,4-dibromobutane in the rat is proposed. The extensive metabolism via glutathione conjugation resulted in efficient detoxification of 1,4-dibromobutane

Identification and quantitative determination of four different mercapturic acids formed from 1,3-dibromopropane and its 1,1,3,3-tetradeutero analogue by the rat

1,3-Dibromopropane (1,3-DBP) was administered i.p. in doses ranging from 5.6 to 54 mg to male Wistar rats. Four different mercapturic acids, viz. N-acetyl-S-3-bromopropyl-(MA I), N-acetyl-S-3-chloropropyl-(MA II), N-acetyl-S-2-carboxyethyl-(MA III) and N-acetyl-S-3-hydroxypropyl(-1-)cysteine (MA IV) were synthesized and identified as metabolites in urine by g.l.c.-mass spectrometry. 1,1,3,3-Tetradeutero-1,3-dibromopropane was used to study the mechanism of formation of the mercapturic acids in more detail. It was found that in the formation of MA IV a reactive episulphonium ion could be involved. Gas chromatographic quantification of the mercapturic acids (mercapturic acid assay) was correlated with a spectrophotometric thioether determination of the metabolites (thioether test). At doses up to 30 mg of 1,3-DBP, excretion of mercapturic acids was virtually complete in 24 h urine and amounted to about 19% of the dose (11.3% MA I, 4.9% MA II, 2.6% MA III and 0.2% MA IV). From excretion rate curves a half-time t1/2 was calculated as being about 4.5 h. A plateau in the dose-excretion curve was observed at 1,3-DBP doses higher than 40 mg, probably caused by glutathione depletion