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COMMON AND DIFFERENTIAL ROLES OF INDUCIBLE NO SYNTHASE AND POLY (ADP-RIBOSE) POLYMERASE IN ALLERGEN-INDUCED INFLAMMATION AND AIRWAY HYPERRESPONSIVENESS: A POTENTIAL CONNECTION TO NO LEVELS
Get PDFAsthma is a chronic disease of the airways characterized by inflammation, structural and functional changes that are responsible for bronchial hyperresponsiveness (AHR) and limitation in airflow. While asthma symptoms can be controlled in the majority of patients, in around 5-10% of asthmatics, the disease remains symptomatic and inadequately controlled. For these reasons, additional therapeutic approaches are urgently required to provide better life conditions for these individuals.
The present study is focused on the role of inducible Nitric Oxide Synthase (iNOS) and poly(ADP-ribose) polymerase-1 (PARP-1) in the pathophysiology of asthma and their potential interaction and cooperation.
The role of iNOS in asthma has been examined in numerous studies with conflicting results. Its potential as a viable therapeutic target for the treatment of the disease was severely hampered by the negative results of a clinical trial showing that a selective iNOS inhibitor, although reducing effectively exhaled Nitric Oxide (eNO), did not affect AHR or airway inflammation after allergen challenge in human subjects with asthma. We believe that such conclusion is premature and that more careful studies are necessary to fully understand the role of iNOS in asthma and whether the enzyme can be adequately targeted at least as an adjuvant therapy for the treatment of this disease.
In the current study I report that iNOS inhibition, pharmacologically, using the relatively selective inhibitor L-NIL or by gene knockout, in our animal experimental models provides an excellent protection against AHR upon an acute, but not upon a chronic, exposure to allergens (OVA or HDM) as assessed using full body plethysmography. These results correlate with the differential protection provided by iNOS inhibition against airway inflammation observed in a previous study.
Considering all known beneficial effects of NO through its contribution to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium, I speculate that complete inhibition of iNOS, achieved by L-NIL administration or even more efficiently by gene knockout may be deleterious for some aspects of asthma such as AHR, which highly involve one of the major targets of NO, the smooth muscle cells. The fascinating aspect of my study is that the loss of protection observed in the chronic asthma model after L-NIL treatment was reversed by NO supplementation through administration of nitrite, a moderate NO source. The anion nitrite (NO2–) can be reduced to NO upon a reaction with deoxyhemoglobin.
Our group, in previous studies, also established a reciprocal relationship between iNOS and PARP-1 with a special connection to oxidative DNA damage and IL-5 in the process of eosinophilia during allergen-induced lung inflammation. Such relationship is also based on the fact that PARP-1 exerts a decisive role on the interaction between p65 NF-κB and the exportin protein Crm1. PARP-1 activity, decrease the interaction between the transcription factor and Crm1, increasing the quantity of p65 NF-κB detectable in the nuclei of cells upon TLR4 stimulation. This increase leads to an upregulation of NF-κB–dependent gene expression, which includes iNOS.
PARP inhibition, pharmacologically by Olaparib (AZD2281) or by gene knockout, protects against inflammation and AHR both upon single and multiple exposures to OVA. Similar protection was observed upon chronic exposure to HDM, demonstrating that the protective effect is not limited to the type of allergen used. Such protection may occur as a consequence that iNOS expression is markedly reduced upon PARP inhibition. However, it is interesting that PARP-1 inhibition does not completely abrogate expression of iNOS leaving the possibility that the protective effect of PARP inhibition against inflammation and AHR may be associated with the reduction but not the complete inhibition of iNOS and with consequent production of moderate levels of NO. A further confirmation of our hypothesis is that administration of iNOS inhibitor (L-NIL) to chronically HDM-exposed mice that received a PARP inhibitor (Olaparib-AZD2281) reversed the protection against AHR provided by PARP inhibition.
Overall, our results may explain why clinical studies focused on the complete inhibition of iNOS failed to protect against different aspects of asthma. However, further efforts to investigate the exact role of the enzyme in asthma may provide a clearer view on how to utilize iNOS as a therapeutic target. But what seems to be plausible is that moderate levels of NO achieved through partial inhibition of iNOS could represent a good therapeutic strategy at least against some aspect of the disease, such as AHR. Additionally, our results revealed that targeting PARP-1 may constitute a better alternative therapeutic approach. Such strategy seems to be very efficient at reducing the most important asthma traits (e.g. Th2 cytokines, mucus, and IgE production) but also partially reduces expression of iNOS with a consequent moderate production of NO that provides protections against AHR. It is important to note that the beneficial effects of PARP inhibition could be correlated with the capacity of PARP-1 to positively influence GATA3, the mast regulator of Th2 population, the paramount cells in the manifestation of the allergic disease. This is, of course, without omitting the potential impact of PARP inhibition on the T-reg population, which is responsible for the control and reduction of inflammation. Finally, it is noteworthy that L-NIL (L-N6-(1-Iminoethyl)lysine dihydrochloride) and AZD2281 (olaparib) are two clinically tested iNOS and PARP inhibitors, respectively, which increases considerably the clinical relevance of this study
Thiazolides elicit anti-viral innate immunity and drastically reduce HIV replication in vitro
No full textBackground: Nitazoxanide (Alinia®, NTZ) and tizoxanide (TIZ), its active circulating metabolite, belong to a new class of agents known as thiazolides (TZD) that are endowed with a broad anti-infective activity. TIZ and RM-4848, the active circulating metabolite of the new generation thiazolide RM-5038, were also recently shown to potently stimulate innate immunity in vitro. Because natural resistance to HIV-1 infection in HIV-exposed seronegative (HESN) individuals is associated with strong innate immune responses, we verified whether TIZ and RM4848 could reduce in vitro susceptibility to HIV-1.
Methods: Peripheral blood mononuclear cells (PBMCs) from 20 healthy donors were infected in vitro with HIV-1BaL in the presence/absence of TIZ or RM-4848. HIV-1 p24 was measured 7 and 10 days post infection. The immunomodulatory abilities of TZD and RM-4848 were evaluated by examining the expression of genes that are part of the type I IFN pathway and are stimulated by IFN (ISGs), as well as the downstream production of cytokines and chemokines.
Results: TIZ and RM-4848 drastically (>87%) and consistently inhibited in vitro HIV-1 replication. This was associated with the activation of innate immune responses and with the up-regulation of several ISGs, including those involved in cholesterol metabolism and efflux and in particular cholesterol-25 hydroxylase (CH25H).
Conclusions: Thiazolides inhibit HIV-1 replication in vitro possibly as a result of their ability to stimulate potent and multifaceted antiviral immune responses. These data warrant the exploration of thiazolides as preventive/therapeutic agent in HIV infection
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
koamabayili/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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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