1,720,984 research outputs found
PDE4 inhibitors and oxidative stress
No full textPDE4 belongs to the PDE1-11 superfamily, specifically degrades cAMP and is present in almost all cells with the exception of platelets. Selective inhibition of PDE4 augments cellular cAMP content that improves chronic inflammation or tissue remodeling. Consequently, over almost three decades industry endeavored to develop PDE4 inhibitors. Roflumilast has now been approved in EU/US as the first PDE4 inhibitor for treatment in severe chronic obstructive pulmonary disease (COPD).
In COPD an enhanced burden of oxidative stress is likely promoting key disease mechanisms such as COPD-related inflammation, lung remodeling or mucociliary malfunction. Neutrophils, which are considered as primary effectors cells in COPD almost exclusively express PDE4. That PDE4 inhibitors such as rolipram or Ro20-1724 suppress fMLP-induced superoxide radical release from neutrophils was described in 1990. These findings were probably the first demonstration that PDE4 inhibitors may mitigate oxidative stress. Such initial observations in neutrophils were now extended to numerous other cells involved in COPD, specifically structural cells. Indeed, PDE4 inhibitors reduce ROS formation in airway epithelial cells, lung fibroblasts, endothelial cells or pulmonary artery smooth muscle cells. Mechanistically, PDE4 inhibitors may act by (i) reducing NADPH oxidase (NOX) activity secondary to inactivating Rac, (ii) attenuating the expression levels of some NOX isoforms. Cellular ROS levels may result from the balance between ROS formation mainly attributed to the NOX system and ROS quenching secondary to the Nrf2-dependent anti-oxidative machinery. Aside from its potential to reduce ROS formation more recently an increase in cAMP was related to enhanced Nrf2 nuclear accumulation, which may support the anti-oxidative machinery. Evidence for this concept was first generated in dermal fibroblasts. Preliminary data from human umbilical vein endothelial cells showed that inhibition of PDE4 (1μM roflumilast N-oxide) when PDE3 was blocked (10μM motapizone) resulted in an about 1.9-fold increase in nuclear Nrf2 following a 3 hours incubation time (roflumilast N-oxide or motapizone on their own were ineffective). Thus, the notion may be raised that PDE4 inhibitors potentially attack excessive ROS twofold, by inhibiting generation and accelerating degradation. More studies are required to further support such a concept.
Lung fibrotic remodeling has been related to oxidative stress and indeed N-acetyl cysteine (NAC) may have some clinical benefit in idiopathic pulmonary fibrosis. In vivo, NAC partly suppresses the bleomycin-induced lung fibrotic response indicating a critical role of ROS to mediate fibrosis. The PDE4 inhibitor roflumilast was shown to mitigate lung fibrosis following bleomycin in preventive but also therapeutic protocols in mice and rats that was paralleled by a partial reduction of lipid hydroperoxides (markers of oxidative stress) in BAL.
Taken together, there is firm evidence that PDE4 inhibitors suppress oxidative stress in vitro that is also reflected in vivo. One may postulate that reducing the burden of oxidative stress may be one of the mechanisms translating into the therapeutic success of roflumilast in severe COPD although this notion remains to be specifically addressed in clinical investigations
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Roflumilast N-oxide, a PDE4 inhibitor, curbs bleomycin-induced lung fibroblast activation in vitro
No full textkoamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Roflumilast N-oxide, a PDE4 inhibitor, inhibits fibrotic changes induced by isoprostanes in human lung fibroblasts
No full textOxidative stress plays an critical role in the pathogenesis of pulmonary fibrosis. Isoprostanes, the most proximal products of lipid peroxidation, are known mediators of important biological effects and have been found to be increased in fibrosis. Roflumilast, a PDE4 inhibitor, has been demonstrated to mitigate the oxidative stress-induced lung fibrotic response in vivo.
In this study we evaluated in vitro the effect of roflumilast N-oxide (RNO), the active metabolite of roflumilast, on oxidative stress and some markers of fibrotic response induced by isoprostanes. Human lung fibroblasts (HLF) were incubated in the absence or presence of RNO (2nM-1M) for 30 min and then treated with 8-epi-PGE2the most represented isomer of the species).
8-epi-PGE2 (10nM) induced a 1.3-fold increase of radical oxygen species (ROS) generation that was abolished by RNO both at the low (2nM) and at the high (1M) concentration (p<0.05). RNO did not change baseline ROS levels. The time course for total glutathione (GSH) levels showed that 8-epi-PGE2 (10nM) induced an increase (by 19% vs respective control, p<0.05) in total GSH levels after 6 h of incubation. RNO did not add to this effect. On the other hand, RNO (1μM) alone increased total GSH levels by 16% (p<0.05). Based on the latter findings the notion was raised that PDE4 inhibition may enhance total glutathione production possibly by inducing an increased expression of glutamate cysteine ligase (GCLC). In fact, RNO 1μM but also 8-epi-PGE2 (10nM) increased GCLC mRNA expression by 1.3 (p<0.05) and 1.2 fold (p<0.05), respectively. Furthermore, 8-epi-PGE2alpha (10nM) stimulated cell proliferation (+17%; p<0.05) and collagen synthesis (+27%; p<0.05) and RNO (2nM) completely abolished such an increase. Taken together, inhibition of PDE4 (by roflumilast N-oxide) curbs ROS formation, collagen synthesis and proliferation of human lung fibroblasts triggered by the isoprostane 8-epi-PGE2alpha. In addition, the PDE4 inhibitor enhanced total GSH
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