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The Saxon granulites, the type granulite locality, were deeply buried, extremely heated and then rapidly exhumed during the Variscan Orogeny; thus their evolution differs from many granulites elsewhere. The peak-metamorphic assemblages of layered felsic-mafic granulites from a 500 m deep borehole consist of garnet, kyanite, rutile, ternary feldspar and quartz in felsic granulite, and garnet, omphacite, titanite, ternary feldspar and quartz in mafic granulite. A minimum temperature of 1000-1020degreesC, calculated from reintegrated hypersolvus feldspar in felsic and mafic granulites, is consistent with the highest temperature estimates from garnet-clinopyroxene equilibria. Various equilibria in felsic and mafic granulites record a peak pressure of about 23 kbar. Diffusion zoning and local homogenisation of minerals reflect near-isothermal decompression that preceded cooling and partial hydration at medium- to low-pressure. U-Pb dating of titanite yields an age of peak metamorphism at 340.7+/-0.8 Ma (2sigma). However, chemical inheritance from precursor rutile and post-peak Pb loss are also evident, suggesting a protolith age of 499+/-2 Ma (2sigma) and partial resetting down to an age of 333+/-2 Ma (2sigma). Rb-Sr mica ages of 333.2+/-3.3 Ma (2sigma) are interpreted as dating cooling through about 620degreesC. Hence the Saxon granulites were exhumed to the upper crust during the short period of 6-11 Ma, which corresponds to average exhumation and cooling rates of 10 mm/year and 50degreesC/Ma, respectively. Such rapid exhumation is inconsistent with recent numerical models that assume foreland- directed transport of the Saxon granulites in the lower crust followed by extensional unroofing. Instead, high-pressure rocks of the Saxon Granulite Massif and the nearby Erzgebirge experienced a buoyant rise to the middle crust and subsequent juxtaposition with structurally higher units along a series of medium- to low-pressure detachment faults
Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha (LXRalpha) have been linked to the regulation of these processes. It remains to be identified how activation of these receptors is connected and regulated by endogenous lipid molecules. We identified CYP27, a p450 enzyme, as a link between retinoid, PPARgamma, and LXR signaling. We show that the human CYP27 gene is under coupled regulation by retinoids and ligands of PPARs via a PPAR-retinoic acid receptor response element in its promoter. Induction of the enzyme's expression results in an increased level of 27-hydroxycholesterol and upregulation of LXR-mediated processes. Upregulated CYP27 activity also leads to LXR-independent elimination of CYP27 metabolites as an alternative means of cholesterol efflux. Moreover, human macrophage-rich atherosclerotic lesions have an increased level of retinoid-, PPARgamma-, and LXR- regulated gene expression and also enhanced CYP27 levels. Our findings suggest that nuclear receptor-regulated CYP27 expression is likely to be a key integrator of retinoic acid receptor-PPARgamma-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages
There is increasing evidence that reactive oxygen species (ROS) are mediators in growth factor and cytokine signaling pathways. Mechanisms by which ROS can interfere with signaling cascades may include regulation of protein activities by the modification of essential cysteines. Modification can be performed chemically or enzyme-catalyzed. Enzymes catalyzing a reversible thiol modification within proteins are to be able to react with both, ROS and protein thiols. If hydroperoxides are involved, promising candidates are peroxiredoxins and glutathione peroxidases (GPx), especially the phospholipid hydroperoxide GPx. Interleukin-1, one of the key players in inflammatory response, stimulates the production of ROS itself, but its signaling cascade can also be influenced by ROS and by thiol modifying agents. Targets are located in early, intermediate, and late events in the signaling cascade. We here summarize what is known about the effects of thiol modifying agents, selenium and glutathione peroxidases, on the assembly of the IL-1 receptor signaling complex as an early event, on the activation of NF-kappaB as an intermediate event, and on the expression of cell adhesion molecules as a late event in IL-1 signaling. (C) 2003 Elsevier Inc. All rights reserved
Measurement of total urinary proteins in individuals that tested positive by urinary dipstick is a typical method for assessing the presence of potentially serious renal disorders. In the absence of such overt proteinuria, however, measurement of specific urinary proteins may be useful in the diagnosis of nephropathies and may provide greater insight into the pathogenesis. The urine of 28 dogs (16 with renal disease and 12 healthy) was evaluated to determine whether specific low-molecular-weight proteins or the pattern of protein excretion could also be used as a marker of tubular dysfunction in dogs. Specific proteins were assessed by immunological methods, whereas protein profiles were determined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (MS). In particular, changes in the excretion of retinol-binding protein (RBP) and Tamm-Horsfall protein (THP) appear to be of clinical relevance in the diagnosis of canine kidney diseases. The pattern of urinary protein and peptides revealed specific changes in abundance in dogs with renal disease at molecular masses (kD) of 11.58, 12.41, 12.60, 14.58, 20.95 (RBP), 27.85, and 65.69 (albumin). In conclusion, comparable proteins as in humans might be used as urinary markers for proximal (RBP) and distal (THP) tubular dysfunction in dogs. Surface-enhanced laser desorption/ionization time-of-flight MS is a promising tool for the study of kidney physiology and pathophysiology and might aid in the discovery of new biomarkers of renal disease
Soluble, viscous, but not insoluble dietary fibre has been shown to lower serum cholesterol. Due to the high content of polyphenols, however, insoluble dietary fibre from carob pods may have physiological benefits beyond those of the usual insoluble dietary fibre preparations. Insoluble polyphenol-rich fibre preparations from carob pods have also been shown to significantly lower serum total and LDL cholesterol in cholesterol-fed rodents (hamsters, rats), while HDL and triglycerides remained unchanged. An increased fecal excretion of bile acids caused by binding to the fibre constituents is supposed to be responsible for this effect. In human studies, consumption of 15 g/d of a carob fibre preparation over 6 weeks lowered LDL cholesterol by 11.0% in hypercholesterolemic subjects. This suggests that carob fibre may be effective in the dietary treatment of hypercholesterolernia. Recent studies have also shown that dietary fiber rich in polyphenols may (1) lower the glycemic index of food and (2) have anti-inflammatory effect. If carob fibre shows similar effects, it may be of special interest in the treatment of the metabolic syndrome
Retinoids modulate many physiological processes such as the differentiation and growth of different cell types. including cells from the immune system. We have previously shown that retinoids modulate IgE production in vitro and in vivo. In the present study we investigated the effects of retinoids in non-sensitized and ovalbumin-sensitized mice that were fed for 11 weeks with three different vitamin A (VA) diets: a) VA-deficiency diet, b) base diet, and c) base diet supplemented with 0.5% all-trans-retinoic acid (ATRA). Phorbol-myristate-acetate (PMA)/ionomycin-stimulated SMC (splenic mononuclear cells) from mice fed with ATRA and the vitamin A-deficient diet group showed increased interleukin-4 (IL-4) responses in non-sensitized mice. After ovalbumin sensitization in the VA-deficient and the ATRA supplementation diet groups, no significant effects on IL-4 production were observed. By contrast, gamma interferon (IFN-gamma production from PMA/ionomycin-stimulated SMC was enhanced in the VA-deficient diet group in ovalbumin-sensitized mice, and also in non-sensitized mice compared to the base and the ATRA-supplemented diet group. The data indicate that VA and retinoid content in a diet influences the cytokine response in non-sensitized and also ovalbumin-sensitized mice. Therefore these molecules may serve as active modulators of cytokine production in vivo that are responsible for the induction and persistence of atopic diseases