1,721,004 research outputs found
Nitric oxide and inflammation.
No full textThere are several pre-clinical studies on the involvement of NO in inflammation. From this large amount of information it is clear that virtually every cell and many immunological parameters are modulated by NO. Thus, the final outcome is that NO cannot be rigidly classified as an anti-inflammatory or pro-inflammatory molecule. This peculiar aspect of the pathophysiology of NO has hampered the development of new drugs based on the concepts developed. Recent therapeutic approach are targeted to increase endogenous NO by activating the gene and some promising early data are available. At the present stage one of the most promising approach in the inflammation field is represented by a new class of NO-releasing compounds namely NO-NSAIDs that have recently enrolled in phase 2 clinical studies
Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders
No full textThe farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR)
are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism
of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/
activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion
by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction
in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on
hepatocyte’s basolateral transporters. Because these effects might worsen live injury in a subset of patients with obstructive
cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies
have shown that available FXR antagonists are poorly specific for FXR, however the recent discovery of selective antagonists
from marine sponges has ground the identification/development of specific FXR antagonists that are currently
used in pre-clinical models of liver injury. PXR agonists are endowed with a wide array of biological activities but their
effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development.
Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset
of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to
target subsets of genes in the intestine and liver avoid side-effects linked to FXR activation
Farnesoid-X-receptor from medicinal chemistry to clinical application
No full textThe farnesoid X receptor (FXR) is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps in bile acid uptake, metabolism and excretion. In addition, FXR is an ancillary receptor involved in lipid and glucose homeostasis. Steroidal and non-steroidal FXR ligands are currently available. Both groups have shown limitations in the preclinical studies regarding absorption, metabolism, specificity of target and intrinsic toxicity. FXR ligands endowed with agonistic activity are under development for the treatment of cholestatic liver diseases, including primary biliary cirrhosis and metabolic disorders linked to insulin resistance. Despite the fact that results from preclinical models are encouraging, targeting FXR holds potential for side effects (i.e., impaired cholesterol disposal and cholestasis). Thus, results from FXR gene-ablated mice and mice administered an FXR antagonist support a role for FXR antagonists or modulators (i.e., FXR agonists that selectively activate specific subsets of FXR target genes in a tissue) or co-regulator-specific manner
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
L-arginine Nitric-oxide Pathway Modulates Gastric-motility and Gallbladder Emptying Induced By Erythromycin and Liquid Meal In Humans
No full textThere is recent evidence that nitric oxide, a soluble gas produced from L-arginine, is released by the smooth muscle cells and neurons of the gastrointestinal tract where it exerts a myorelaxive action. However, little is known about the effects nitric oxide has on gastric and gallbladder motility during the inter- and postprandial phases in man. We therefore investigated the effects 200 mg/kg/hr L-arginine exerts on the gastric and gallbladder motility induced by 2 mg/kg erythromycin or a liquid meal in 21 subjects in a double-blind, placebo-controlled study. Gastric and gallbladder emptying were evaluated by sonography. Fasting antral motility was expressed as antral motility index (MI). In fasting subjects, L-arginine administration determined a threefold increase in plasma nitrite concentrations. Administration of erythromycin caused a significant rise in the antral MI, which was inhibited by L-arginine (P < 0.05). Ingestion of a liquid meal also significantly increased antral MI, but it returned to basal values 90 min after the end of the meal. Although L-arginine administration caused a significant reduction in the antral MI (P < 0.05), it did not inhibit gastric emptying. L-Arginine provoked an approximately 40% increase in basal gallbladder volume, completely blocked erythromycin-induced emptying, and partially, but significantly, prevented the emptying induced by a liquid meal (P < 0.01). Our study suggests that nitric oxide may be implicated in the physiological modulation of gastric and gallbladder motility during the inter- and postprandial phases in man
Evidence that 5-lipoxygenase and acetylated cyclooxygenase 2-derived eicosanoids regulate leukocyte-endothelial adherence in response to aspirin.
No full text(1) Unlike other nonsteroidal anti-inflammatory drugs that inhibit formation of cyclooxygenase (COX)-dependent eicosanoids, acetylation of COX-2 by aspirin switches eicosanoid biosynthesis from prostaglandin E(2) (PGE(2)) to 15-epi-lipoxin A(4) (15-epi-LXA(4) or aspirin-triggered lipoxin, ATL). ATL formation by activated leukocytes (PMN) requires the intervention of 5-lipoxygenase (5-LOX), an enzyme that is involved in leukotriene B(4) (LTB(4)) formation. (2) In the present study, we have examined the role of acetylated COX-2 and 5-LOX in modulating antiadhesive effects of aspirin on adhesion of PMN to endotoxin (LPS)-primed human umbilical endothelial cells (HUVEC). (3) Treating PMN/HUVEC cocultures with aspirin resulted in a concentration-dependent inhibition of cell-to-cell adhesion induced by LPS. Treating HUVEC with selective COX-2 inhibitors, celecoxib and rofecoxib, caused an approximately 70\% reversion of antiadhesive effect of aspirin. In contrast, inhibition of neutrophil's 5-LOX pathway with 1 micro M ZD2138, a selective 5-LOX inhibitor, 1 micro M BAY-X-1005, a FLAP inhibitor, or 100 micro M licofelone, a dual COX/5-LOX inhibitor, did not affect antiadhesive properties of aspirin. (4) Exposure to celecoxib (100 micro M) or rofecoxib (10 micro M) completely suppressed ATL formation caused by aspirin without affecting LTB(4) levels. ZD2138, licofelone and BAY-X-1005 inhibited ATL formation as well as LTB(4) generation. (5) Treatment with LXA(4) reduced PMN adhesion to HUVEC and counteracted the proadhesive effect of celecoxib. In contrast, exposure to Boc-1, an LXA(4) antagonist, counteracts the antiadhesive activities of aspirin. Exposure to U75302, an LTB(4) receptor antagonist, enhances the antiadesive effect of aspirin. (6) Reversal of antiadhesive activities of aspirin by celecoxib was associated with increased expression of LFA-1 on PMN and E-selectin on HUVEC. Addition of LXA(4), ZD2138 and U75302 inhibited these changes. (7) The present results support the notion that inhibition of ATL formation is mechanistically linked to the reversal of the antiadhesive activity of aspirin caused by selective COX-1 inhibitors and suggests that the LTB(4)/ATL balance modulates pro- and antiadhesive activity of nonsteroidal anti-inflammatory drugs at the leukocyte-endothelial cell interface
3-oxa-lipoxin A4 analog treats colitis induced by Dss by attenuating inflammation and immunity.
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