julilili42/papers huggingface dataset:
Rapid Assembly of Polyfunctional Structures Using a One‐Pot Five‐ and Six‐Component Sequential Groebke–Blackburn/Ugi/Passerini Process
2010-08-24

Abstract Sequential addition of up to six components under well‐defined conditions results in the formation of novel structures with amino acid, peptide, and heterocyclic components. This process forms up to eight new bonds under very mild conditions and tolerates a broad spectrum of functional groups. An orthogonal union of the Groebke–Blackburn three‐component reaction with the Ugi four‐component or Passerini three component reaction was adopted to synthesize polyfunctionalized heterocycles. In terms of diversity oriented synthesis, 10 positions on the basic polycyclic structure can be varied. Straightforward batch splitting provides a simple and efficient method for preparing structurally complex analogs.
Cytotoxic abietane diterpenes from Peltodon longipes and their mode of action
2010-08-24

Peltodon longipes (Labiatae), also known as „baicuru amarelo“ in south of Brazil, has been used in folk medicine as an anti-inflammatory and antiseptic remedy (1). The effective compounds responsible for these effects are still unknown. Here we report the isolation and structure elucidation of 12 diterpenes from the abietane type. 12,14-dihydroxy-11-methoxyabieta-8,11,13-trien-7-one was isolated for the first time, whereas the other diterpenes have already been known. Structure elucidation was based on 1D-(1H and 13C) and 2D NMR experiments (COSY, HMQC, HMBC and NOESY) as well as EIMS. Cytotoxic activity of these compounds was evaluated against two different cancer cell lines, MIA PaCa-2 (Human Pancreatic Carcinoma Cell Line) and MV-3 (Human Melanoma Cell Line). 7α acetoxyroyleanone, the major compound, showed the highest cytotoxic activity with an IC50 value of 4.7 and 7.5μM, respectively. Interestingly, some diterpenes preferentially inhibited topoisomerase-I in the relaxation assay and gave lower IC50 values (2.8 and 4.7μM) than the known classical topoisomerase-I inhibitor camptothecin (IC50 28μM). Docking experiments revealed that these diterpenes may target topoisomerase-I differenzially to camptothecin. While camptothecin stabilizes type I topoisomerase-DNA complexes, there is evidence that the diterpenes compete with DNA for topoisomerase binding through direct interaction. A new binding side is suggested which allows correlation with the experimental data. Additionally studies are in progress to give further insights in the mechanism of action.
In vitro and in vivo evaluation of the anti-inflammatory effects of Arzanol from Helichrysum italicum
2010-08-24

Eicosanoids derived from arachidonic acid, mainly prostaglandins (PGs) and leukotrienes (LTs) function as powerful lipid mediators in inflammatory reactions. The dual inhibition of the LT-producing enzyme 5-lipoxygenase (5-LO) and of microsomal PGE2 synthase-1 (mPGES-1, which forms pro-inflammatory PGE2 from COX-2 derived PGH2), is a novel and promising strategy for the therapy of inflammation. The acylphloroglucinol arzanol has recently been suggested as an active ingredient responsible for the anti-inflammatory effects of the plant Helichrysum italicum. Here we analysed the effect of arzanol on LT and PGE2 formation in cell-free and cell-based models as well as in an experimental model of inflammation in rats. We find that arzanol inhibits 5-LO and mPGES-1 (IC50=5μM and 0.5μM, respectively) in cell-free assays and efficiently reduces mPGES-1-derived PGE2 formation in LPS-stimulated human monocytes (at 3μM) and LPS-stimulated human whole blood (at 10μM) with a similar efficiency as the specific mPGES-1 inhibitor MD-52 (tested at 2 and 5μM). In human neutrophils arzanol inhibited 5-LO product formation with an IC50=5μM. The in vivo efficiency of arzanol (3.6mg/kg i.p.) was demonstrated by the reduction of exudate volume (59%), number of inflammatory cells (48%) and PGE2 (47%) and LTB4 (31%) levels, in the pleural exudates of rats in a model of carrageenan-induced pleurisy. Taken together arzanol is a potent inhibitor of 5-LO and mPGES-1 in both cell-free and cell-based assays with significant anti-inflammatory effects in vivo.
Catechin derivatives from Parapiptadenia rigida: biological studies and conformational analysis
2010-08-24

Parapiptadenia rigida (Benth.) Brenan (Fabaceae), popularly known in Brazil as „Angico vermelho“, is a perennial tree native in South America. Preparations from its bark are used in traditional medicine because of its astringent, expectorant, antiseptic and antihemorrhagic properties [1–2], but no detailed phytochemical analysis has yet been performed. To increase our knowledge on the biologically active compounds from P. rigida, the ethanolic extract of its bark was phytochemically analysed and 10 catechin derivatives were isolated and identified by 1D and 2D NMR (1H, 13C, COSY, HSQC, HMBC, NOESY, 2D-ROESY) and ESI-MS spectroscopy analyses. 3′′, 4′-O-methyl-apocynin (1), 3′′,4′-O-methyl-apocynin-B (2), epigallocatechin-(4β-8)-4′-O-methyl-gallocatechin (3), 4′-O-methyl-gallocatechin-(4α-8)-4′-O-methyl-gallocatechin (4) and (–)-epigallocatechin-3-O-ferulate (5) have been found for the first time and 4′-O-methyl-(–)-epigallocatechin-3-O-gallate (6) for the first time from natural sources, in addition to the four known compounds 4′-O-methyl-gallocatechin (7), 4′-O-methyl-epigallocatechin (8), 3′-O-methyl-(–)-epicatechin (9) and (–)-epigallocatechin-3-O-gallate (10). Comprehensive conformational analyses were performed for the dimeric procyanidins 3 and 4. Absolute configuration of 2 was determined by CD analysis. The extract and some of the catechin derivatives were studied for their wound healing effect in the scratch assay and gave promising results which suggest that plant preparations from P. rigida and their effective ingredients may have beneficial effects as a wound healing remedy.
Impulse Lecture: Elucidation of the molecular basis of anti-inflammatory natural compounds from traditional medicinal plants
2010-08-24

Although many traditional medicinal plants are used in the therapy of inflammatory disorders, the bioactive ingredients and/or the molecular basis underlying the anti-inflammatory action are often unclear. Numerous plant-derived natural products with anti-inflammatory properties have previously been reported to reduce the biosynthesis of eicosanoids, i.e., prostaglandins (PGs) and leukotrienes (LTs) and this has essentially been attributed to an interference with the respective key enzymes cyclooxygenase (COX) and 5-lipoxygenase (5-LO). The dual inhibition of 5-LO and of microsomal PGE2 synthase-1 (mPGES-1), which forms pro-inflammatory PGE2 from COX-2 derived PGH2, is a novel and promising strategy for the therapy of inflammation being superior over single inhibition in terms of higher anti-inflammatory efficacy but also may cause fewer side effects. We have investigated selected natural products for which either anti-inflammatory efficacy in vivo or inhibition of PG biosynthesis was described. Here we report that many of these compounds (e.g., hyperforin, epigallocatechin gallate, garcinol, curcumin, myrtucommulone, arzanol) are poor inhibitors of COX enzymes but instead efficiently inhibit mPGES-1. Hence, the previously observed reduced PGE2 levels are rather due to inhibition of mPGES-1 than COX-1/2. Of interest, the mPGES-1 inhibitiory effect is often associated with suppression of 5-LO. Finally, analysis of selected compounds in experimental models of inflammation confirm inhibition of PGE2 and LT biosynthesis in vivo and suggest a valuable therapeutic potential for intervention with inflammatory diseases.
Inhibition of histamine-induced inflammatory reactions in intestinal mucosa by STW 5
2010-08-24

Herbal medicine is a therapeutic option in the therapy of irritable bowel syndrome (IBS), a disease, for which an inflammatory etiology is discussed. In such inflammatory reactions in the gastrointestinal tract, histamine seems to be an important trigger. So the question raised, whether STW 5, a herbal medicine with clinically proven efficacy in the therapy of IBS (2), and consisting of a fixed combination of 9 herbal extracts, has anti-inflammatory and antioxidant effects (3). For the measurements of these effects a pharmacological model involving mucosa preparations from mouse ileum was developed. As a marker of inflammatory reactions, free radical production was measured via luminol-enhanced chemiluminescence. Histamine (5 to 100μmol/L) strongly increased this parameter. Similar to the antioxidant trolox, STW 5 had a significant inhibitory effect even in dilutions down to 0.1μl/ml). From the extracts contained in STW 5, those from peppermint and chamomile showed highest effects, that of greater celandine herb was least active. It can be concluded, that ileal mucosa preparations stimulated by histamine are a model with significant relevance in studies on diseases involving intestinal inflammation. The inhibitory effects exerted by STW 5 and its constituents in that reaction might be involved in its therapeutic effects.
Rosmarinic acid as the effective compound in Cordia americana
2010-08-24

In Brazil medicinal plants have been widely used for the treatment of diseases in folk medicine. However, the effective compounds responsible for the biological effects are widely unknown. The objective of this study was to characterize the phytochemical profile and to identify bioactive compounds in the leaves of Cordia americana (Boraginaceae) [1]. The biological activity of the constituents and the ethanolic extract were investigated for the inhibition of 5-lipoxygenase, p38α MAPK, TNFα release and fibroblast scratch assay, targeting different aspects of inflammatory and wound healing processes. The phytochemical studies (i.e., 1D, 2D NMR and MS) have led to the identification of flavonols, phenolic compounds and phytosterols. Quantification analysis showed that rosmarinic acid (RA) is the main compound with an amount of 8.44% in the ethanolic extract. RA as well as the ethanolic extract exhibited the highest inhibitory effects on 5-lipoxygenase (IC50=0.97 and 0.69μg/ml, resp.) and p38α MAPK (IC50=1.16 and 3.25μg/ml, resp.). Additionally, RA inhibited the release of TNFα to 36.75±1.55% at a concentration of 36.03μg/ml, which can be considered as moderately active. The ethanolic extract showed a lower inhibition of 30.3±0.75% at a concentration of 100μg/mL. RA also exhibited slight stimulatory activity on proliferation and migration of fibroblasts indicating that it may partially contribute to the wound healing effects of this plant. We demonstrated for the first time pharmacological effects of C. americana and we provided evidences for a crucial role of RA as the major player.
Lupeolic acid derivatives from Boswellia species as inhibitors of the cytosolic phospholipase A2α
2010-08-24

Resins derived from Boswellia species are traditionally used in chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel diseases or psoriasis. Recent data disclose a higher risk for patients suffering from these diseases to be affected by occlusive vascular events which partly can be attributed to an elevated activation state of blood platelets [1, 2, 3]. Here, we analyzed the impact of different triterpenic acids isolated from Boswellia carterii on the activity of cytosolic phospholipase (cPL)A2α. This enzyme plays a central role in inflammation by catalyzing the release of arachidonic acid (AA) from the sn-2 position of phospholipids in cellular membranes [4]. Using a cell-free assay of (cPL)A2α activity we found that two thus far unidentified lupeolic acid derivatives, that is 3α,28-dihydroxylup-20(29)-en-4β-oic acid (OH-LA) and 3α-acetoxy-28-hydroxylup-20(29)-en-4β-oic acid (Ac-OH-LA) act as potent (cPL)A2α inhibitors (IC50=5 and 12μM, respectively). Their inhibitory potential on AA release could also be observed in cell-based assays using A23187-stimulated blood cells. In stimulated human platelets the lupeolic acid derivatives also inhibited the formation of metabolites of AA which was restored by supplementation of exogenous AA, supporting selective impact of the compounds on PLA2 activity. Moreover, OH-LA and Ac-OH-LA inhibited platelet aggregation induced by collagen but not after stimulation with U46619, a thromboxane receptor agonist. Together, we identified two novel hydroxy-derivatives of lupeolic acid from Boswellia carterii which act as inhibitors of (cPL)A2α. These data suggest a potential of Boswellia extracts as anti-inflammatory remedy associated with possible cardiovascular protective functions in chronic inflammatory diseases.
Dispersal-Dormancy Relationships in Annual Plants: Putting Model Predictions to the Test
2010-08-25

Bet hedging is a means to increase fitness in environments that vary unpredictably in space and time. In such environments, models predict a trade-off between the bet-hedging strategies dispersal and dormancy, while the increasing importance of risk reduction with decreasing predictability should lead to an increase in dispersal and dormancy along gradients of environmental predictability. However, so far there has been no experimental study to test these predictions in the field. Here, we used a set of novel field experiments that enabled us to quantify and separate seedling recruitment from three sources: local reproduction, dormancy, and dispersal. The study included the entire plant community from five environments differing considerably in predictability. Evidence for both the existence of a trade-off between dispersal and dormancy within environments and their increased use in unpredictable environments was very weak. The importance of dispersal for population and community dynamics in our system was extremely low relative to dormancy and local reproduction. This indicates that the role of dispersal for buffering environmental variation may be negligible compared with other risk-reducing strategies. Our findings highlight the urgent need for multispecies and multisite experiments in empirical tests of theoretical predictions.
Ludwig Biermann Award Lecture:Pulsations and Planets: The Asteroseismology‐Extrasolar‐Planet Connection
2010-08-25

This chapter contains sections titled: Introduction Extrasolar planet detection methods Stellar oscillation - extrasolar planet links Hot subdwarf stars The EXOTIME program Sub-stellar companions of evolved stars Summary References
Chitosan/siRNA Nanoparticles Biofunctionalize Nerve Implants and Enable Neurite Outgrowth
2010-08-26

Microstructured 20 μm thick polymer filaments used as nerve implants were loaded with chitosan/siRNA nanoparticles to promote nerve regeneration and ensure local delivery of nanotherapeutics. The stable nanoparticles were rapidly internalized by cells and did not affect cell viability. Target mRNA was successfully reduced by 65-75% and neurite outgrowth was enhanced even in an inhibitory environment. This work, thus, supports the application of nanobiofunctionalized implants as a novel approach for spinal cord and nerve repair.
Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in Drosophila
2010-08-26

The most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (Rh(P23H)). Unlike the wild-type Rh, mutant Rh(P23H) exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded Rh(P23H) and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that Rh(P23H) is a substrate of the ER-associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1(P37H) (the equivalent of mammalian Rh(P23H)) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1(P37H) toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1(P37H) and further activated the Ire1/Xbp1 ER stress pathway in the Rh1(P37H) retina. Despite this, Rh1(P37H) flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1(P37H) retina. Pharmacological treatment of Rh1(P37H) flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration.
Audiovisual interactions in binocular rivalry
2010-08-26

When the two eyes are presented with dissimilar images, human observers report alternating percepts-a phenomenon coined binocular rivalry. These perceptual fluctuations reflect competition between the two visual inputs both at monocular and binocular processing stages. Here we investigated the influence of auditory stimulation on the temporal dynamics of binocular rivalry. In three psychophysics experiments, we investigated whether sounds that provide directionally congruent, incongruent, or non-motion information modulate the dominance periods of rivaling visual motion percepts. Visual stimuli were dichoptically presented random-dot kinematograms (RDKs) at different levels of motion coherence. The results show that directional motion sounds rather than auditory input per se influenced the temporal dynamics of binocular rivalry. In all experiments, motion sounds prolonged the dominance periods of the directionally congruent visual motion percept. In contrast, motion sounds abbreviated the suppression periods of the directionally congruent visual motion percepts only when they competed with directionally incongruent percepts. Therefore, analogous to visual contextual effects, auditory motion interacted primarily with consciously perceived visual input rather than visual input suppressed from awareness. Our findings suggest that auditory modulation of perceptual dominance times might be established in a top-down fashion by means of feedback mechanisms.
Multiplicity of Plasmodium falciparum infection following intermittent preventive treatment in infants
2010-08-26

Abstract Background Intermittent preventive treatment in infants with sulphadoxine-pyrimethamine (IPTi-SP) reduces malaria morbidity by 20% to 33%. Potentially, however, this intervention may compromise the acquisition of immunity, including the tolerance towards multiple infections with Plasmodium falciparum . Methods Plasmodium falciparum isolates were obtained from children participating in two Ghanaian IPTi-SP trials (Tamale, Afigya Sekyere) at 15 months of age, i.e., six months after they had received the second dose of IPTi-SP or placebo. By typing the polymorphic merozoite surface protein 1 ( msp1 ) and msp2 genes, multiplicity of infection (MOI) was assessed in 389 isolates. A total of additional 133 samples were collected in Tamale at 3, 6, 9, and 12 months of age. Comparisons of MOI between groups were done by non-parametric statistical tests. Results The number of distinguishable P. falciparum clones (MOI) ranged between one and six. Mean MOI in Tamale was stable at 2.13 - 2.17 during the first year of life, and increased to 2.57 at age 15 months ( P = 0.01). At no age did MOI differ between the IPTi-SP and placebo groups (each, P ≥ 0.5). At 15 months of age, i.e., six months after the second dose, MOI was very similar for children who had received IPTi or placebo (means, 2.25 vs . 2.33; P = 0.55) as was the proportion of polyclonal infections (69.6% vs. 69.7%; P = 0.99). Adjusting for study site, current and prior malaria, parasite density, and season did not change this finding. Conclusions IPTi-SP appears to have no impact on the multiplicity of infection during infancy and thereafter. This suggests that tolerance of multiple infections, a component of protective immunity in highly endemic areas, is not affected by this intervention.
DevT (Alr4674), resembling a Ser/Thr protein phosphatase, is essential for heterocyst function in the cyanobacterium Anabaena sp. PCC 7120
2010-08-26

Heterocyst-forming cyanobacteria are able to perform oxygenic photosynthesis and nitrogen fixation simultaneously in the same filament, by restricting the highly O(2)-sensitive nitrogenase to specialized cells, the heterocysts. A remarkable change in morphology and metabolism accompanies the differentiation of heterocysts, which only occurs when no source of combined nitrogen is available. In this study, we characterized DevT (Alr4674), a putative protein phosphatase from Anabaena PCC 7120. Mutants defective in devT are able to form morphologically mature heterocysts, which however cannot fix N(2), and the mutant cannot survive without a source of combined nitrogen. DevT shows homology to phosphatases of the PPP family and displays a Mn(2+)-dependent phosphatase activity that can be inhibited by phosphatase inhibitors and oxidizing conditions. DevT is constitutively expressed in both vegetative cells and heterocysts, and is not regulated by NtcA. The heterocyst regulator HetR may exert a certain inhibition on the expression of devT. Under diazotrophic growth conditions, DevT protein accumulates specifically in mature heterocysts. Therefore DevT plays a still unknown role in a late essential step of heterocyst differentiation.
POLG, but not PEO1, is a frequent cause of cerebellar ataxia in Central Europe
2010-08-27

Abstract Nuclear genes, in particular mitochondrial polymerase gamma ( POLG ) and PEO1 , have been increasingly recognized to cause mitochondrial diseases. Both genes assume a complementary role as part of the mitochondrial DNA (mtDNA) replication fork and, accordingly, seem to present with largely overlapping phenotypical spectra. We assessed the frequency and phenotypic spectrum of PEO1 compared to POLG mutations in a cohort of 80 patients with cerebellar ataxia for which common repeat expansion diseases had been excluded. Patients were selected to present additional features previously described for PEO1 mutations, namely early age of onset, progressive external ophthalmoplegia (PEO), or epilepsy. Whereas PEO1 mutations were not found in our cohort, POLG frequently caused ataxia with PEO (47%), psychiatric comorbidities (20%) and, more rarely, with epilepsy (14%). Thus, PEO1 is rare in Central Europe even in those patients displaying characteristic phenotypic features. In contrast, POLG is rather common in Central European ataxia patients. It should be particularly considered in ataxia patients with PEO, psychiatric comorbidities, and/or sensory neuropathy, even if characteristic mitochondrial extra‐CNS features are absent. © 2010 Movement Disorder Society.