Inflammatory joint diseases are characterized by enhanced extracellular matrix degradation which is predominantly mediated by cytokine-stimulated upregulation of matrix metalloproteinase (MMP) ...expression. Besides tumour necrosis factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta) produced by articular chondrocytes and synovial macrophages, is the most important cytokine stimulating MMP expression under inflammatory conditions. Blockade of these two cytokines and their downstream effectors are suitable molecular targets of antirheumatic therapy. Hox alpha is a novel stinging nettle (Urtica dioica/Urtica urens) leaf extract used for treatment of rheumatic diseases. The aim of the present study was to clarify the effects of Hox alpha and the monosubstance 13-HOTrE (13-Hydroxyoctadecatrienic acid) on the expression of matrix metalloproteinase-1, -3 and -9 proteins (MMP-1, -3, -9). Human chondrocytes were cultured on collagen type-II-coated petri dishes, exposed to IL-1beta and treated with or without Hox alpha and 13-HOTrE. A close analysis by immunofluorescence microscopy and western blot analysis showed that Hox alpha and 13-HOTrE significantly suppressed IL-1beta-induced expression of matrix metalloproteinase-1, -3 and -9 proteins on the chondrocytes in vitro. The potential of Hox alpha and 13-HOTrE to suppress the expression of matrix metalloproteinases may explain the clinical efficacy of stinging nettle leaf extracts in treatment of rheumatoid arthritis. These results suggest that the monosubstance 13-HOTrE is one of the more active antiinflammatory substances in Hox alpha and that Hox alpha may be a promising remedy for therapy of inflammatory joint diseases.
The third hypervariable (V3) loop of the HIV-1 envelope glycoprotein gp120 plays an essential role in the process of viral entry. It contributes to the tropism, coreceptor usage and immune-escape of ...the virus. We generated a monovalent plasmid DNA and demonstrated the expression of HIV-1 clade B subtype NL4-3 gp120 and gp160 in comparison to a multivalent plasmid DNA encoding for a variety of V3-variants. In contrast to the membrane-anchored gp160, preliminary data demonstrate the monovariant gp120 is expressed in and presented on a human dendritic cell (DC) line, due to a HIV
env-specific re-stimulation of naïve T-cells detected by IFNγ-ELISPOT assay.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We determine the metallicity distribution function (MDF) of the Galactic halo by means of a sample of 1638 metal-poor stars selected from the Hamburg/ESO objective-prism survey (HES). The sample was ...corrected for minor biases introduced by the strategy for spectroscopic follow-up observations of the metal-poor candidates, namely “best and brightest stars first”. Comparison of the metallicities Fe/H of the stars determined from moderate-resolution (i.e., $R\sim 2000$) follow-up spectra with results derived from abundance analyses based on high-resolution spectra (i.e., $R>20\,000$) shows that the Fe/H estimates used for the determination of the halo MDF are accurate to within 0.3 dex, once highly C-rich stars are eliminated. We determined the selection function of the HES, which must be taken into account for a proper comparison between the HES MDF with MDFs of other stellar populations or those predicted by models of Galactic chemical evolution. The latter show a reasonable agreement with the overall shape of the HES MDF for ${\rm Fe/H} > -3.6$, but only a model of Salvadori et al. (2007) with a critical metallicity for low-mass star formation of $Z_{\rm cr}=10^{-3.4}~Z_{\odot}$ reproduces the sharp drop at ${\rm Fe/H} \sim -3.6$ present in the HES MDF. Although currently about ten stars at ${\rm Fe/H} < -3.6$ are known, the evidence for the existence of a tail of the halo MDF extending to ${\rm Fe/H} \sim -5.5$ is weak from the sample considered in this paper, because it only includes two stars ${\rm Fe/H} < -3.6$. Therefore, a comparison with theoretical models has to await larger statistically complete and unbiased samples. A comparison of the MDF of Galactic globular clusters and of dSph satellites to the Galaxy shows qualitative agreement with the halo MDF, derived from the HES, once the selection function of the latter is included. However, statistical tests show that the differences between these are still highly significant.
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FMFMET, NUK, UL, UM, UPUK
Plant cysteine proteinases (CPs) from papaya (Carica papaya) are capable of killing parasitic nematode worms in vitro and have been shown to possess anthelmintic effects in vivo. The acute damage ...reported in gastrointestinal parasites has not been found in free-living nematodes such as Caenorhabditis elegans nor among the free-living stages of parasitic nematodes. This apparent difference in susceptibility might be the result of active production of cysteine proteinase inhibitors (such as cystatins) by the free-living stages or species. To test this possibility, a supernatant extract of refined papaya latex (PLS) with known active enzyme content was used. The effect on wild-type (Bristol N2) and cystatin null mutant (cpi-1⁻/⁻ and cpi-2⁻/⁻) C. elegans was concentration-, temperature- and time-dependent. Cysteine proteinases digested the worm cuticle leading to release of internal structures and consequent death. Both cystatin null mutant strains were highly susceptible to PLS attack irrespective of the temperature and concentration of exposure, whereas wild-type N2 worms were generally resistant but far more susceptible to attack at low temperatures. PLS was able to induce elevated cpi-1 and cpi-2 cystatin expression. We conclude that wild-type C. elegans deploy cystatins CPI-1 and CPI-2 to resist CP attack. The results suggest that the cpi-1 or cpi-2 null mutants (or a double mutant combination of the two) could provide a cheap and effective rapid throughput C. elegans-based assay for screening plant CP extracts for anthelmintic activity.
Activation of transcription factor NF-κB is elevated in several chronic inflammatory diseases and is responsible for the enhanced expression of many proinflammatory gene products. Extracts from ...leaves of stinging nettle (
Urtica dioica) are used as antiinflammatory remedies in rheumatoid arthritis. Standardized preparations of these extracts (IDS23) suppress cytokine production, but their mode of action remains unclear. Here we demonstrate that treatment of different cells with IDS23 potently inhibits NF-κB activation. An inhibitory effect was observed in response to several stimuli, suggesting that IDS23 suppressed a common NF-κB pathway. Inhibition of NF-κB activation by IDS23 was not mediated by a direct modification of DNA binding, but rather by preventing degradation of its inhibitory subunit IκB-α. Our results suggests that part of the antiinflammatory effect of
Urtica extract may be ascribed to its inhibitory effect on NF-κB activation.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pulmonary emphysema impairs lung and respiratory muscle function leading to restricted physical capacity and accelerated morbidity and mortality consequent to respiratory muscle failure. In the ...absence of direct evidence, an O2 supply-demand imbalance within the diaphragm and other respiratory muscles in emphysema has been considered the most likely explanation for this failure. To test this hypothesis, we utilized phosphorescence quenching techniques to measure mean microvascular PO2 (PO2m) within the medial costal diaphragm of control (C, n = 10) and emphysematous (E, elastase instilled, n = 7) hamsters. PO2m and mean arterial pressure (MAP) were measured in the spontaneously breathing anesthetized hamster at inspired O2 percentages of 10, 21, and 100, and across a range of mean MAPs from 40 to 115 mm Hg. At each inspired O2, diaphragm PO2m was significantly (p < 0.05) lower in E animals (10%: C, 19 +/- 3; E, 9 +/- 2; 21%: C, 32 +/- 2; E, 21 +/- 2; 100%: C, 60 +/- 8; E, 36 +/- 9 mm Hg). At 21% inspired O2, the PO2m decrease was correlated with reduced MAP in both C (r = 0.968) and E (r = 0.976) animals. We conclude that diaphragmatic PO2m (and therefore microvascular O2 content) is decreased in emphysematous hamsters reflecting a greater diaphragmatic O2 utilization at rest and a lower O2 extraction reserve. According to Fick's law, this lower PO2m will mandate an exaggerated fall in intramyocyte PO2, which is expected to accelerate muscle glycogen depletion and consequently fatigue. This provides empirical evidence in support of one possible mechanism for respiratory muscle failure in emphysema.
There is some indirect evidence that the pineal hormone melatonin can suppress plasma levels of cholesterol in hypercholesterolemic rats. We have examined the effects of the hormone on cellular ...cholesterol metabolism in freshly isolated human mononuclear leukocytes. Incubation of cells for up to 20 h in a lipid-free medium resulted in an increase in the rate of cholesterol synthesis from 14Cacetate and the high affinity accumulation and degradation of 125Ilabeled low density lipoprotein (LDL). Addition of melatonin in increasing concentrations to the incubation medium at zero time inhibited cholesterol synthesis and the specific accumulation and degradation of 125Ilabeled LDL; at a concentration of 100 microM, the inhibitions were 38%, 42%, and 48%, respectively. Similar results were obtained using 14Cmevalonate as precursor. Fatty acid synthesis was not altered under these conditions. In contrast to cholesterol, the synthesis of the first cyclic compound lanosterol was not affected by the pineal hormone. These results implicate that melatonin inhibits this pathway between lanosterol and cholesterol. The action of melatonin on LDL receptor activity appeared to be mediated by a decrease in the number of LDL receptors and not by a change in binding affinity. Pharmacological characterization of the potential melatonin receptor site using several analogs like tryptamine, 5-hydroxytryptamine,N-acetyl-5-hydroxytryptamine, 5-methoxytryptamine, and 6-chloromelatonin indicated that the 5-methoxy group is indispensible for the hormone action on cholesterol synthesis. The data provide evidence that melatonin can modulate cholesterol metabolism in human cells.
In response to an elevated metabolic rate , increased microvascular bloodâmuscle O 2 flux is the product of both augmented O 2 delivery and fractional O 2 extraction. Whole body and exercising limb ...measurements demonstrate that and fractional O 2 extraction increase as linear and hyperbolic functions, respectively, of . Given the presence of disparate vascular control mechanisms among different muscle fibre types, we tested the hypothesis
that, in response to muscle contractions, would be lower and fractional O 2 extraction (as assessed via microvascular O 2 pressure, P mvO 2 ) higher in fast- versus slow-twitch muscles. Radiolabelled microsphere and phosphorescence quenching techniques were used to measure and P mvO 2 , respectively at rest and across the transition to 1 Hz twitch contractions at low (Lo, 2.5 V) and high intensities (Hi,
4.5 V) in rat ( n
= 20) soleus (Sol, slow-twitch, type I), mixed gastrocnemius (MG, fast-twitch, type IIa) and white gastrocnemius (WG,
fast-twitch, type IIb) muscle. At rest and for Lo and Hi (steady-state values) transitions, P mvO 2 was lower (all P < 0.05) in MG (mmHg: rest, 22.5 ± 1.0; Lo, 15.3 ± 1.3; Hi, 10.2 ± 1.6) and WG (mmHg: rest, 19.0 ± 1.3; Lo, 12.2 ± 1.1; Hi,
9.9 ± 1.1) than in Sol (rest, 33.1 ± 3.2 mmHg; Lo, 19.0 ± 2.3 mmHg; Hi, 18.7 ± 1.8 mmHg), despite lower and in MG and WG under each set of conditions. These data suggest that during submaximal metabolic rates, the relationship between
and O 2 extraction is dependent on fibre type (at least in the muscles studied herein), such that muscles comprised of fast-twitch
fibres display a greater fractional O 2 extraction (i.e. lower P mvO 2 ) than their slow-twitch counterparts. These results also indicate that the greater sustained P mvO 2 in Sol may be important for ensuring high bloodâmyocyte O 2 flux and therefore a greater oxidative contribution to energetic requirements.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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