1,721,062 research outputs found
GREEN TEA EPIGALLOCATECHIN AFFECTS COX1-1-MEDIATED PROSTACYCLIN PRODUCTION BY ENDOTHELIUM
No full textPolarization in patterns of human monocyte-derived macrophages in relation to estrogen treatment and menopausal status
Full text linkMononuclear phagocytes respond to environmental cues with the acquisition of distinct functional phenotypes, M1 (classical) or M2 (alternative), which in turn are involved in different pathological conditions. 17β-estradiol (E2), the major female sex hormone, is known to mediate profound effects on monocyte and macrophage immune function acting through estrogen receptors (ER). We hypothesized that estrogen-dependent effects on the monocyte/macrophage system protect postmenopausal women from cardiovascular disease. To test our hypothesis, we first investigated the effects of E2 on human monocyte-derived macrophage subsets in resting state (M0) and after M1 or M2 polarized activation. Human monocytes were isolated from buffy coats by density gradient centrifugation and monocyte-to-macrophage differentiation occurred within 7 days in the absence of any stimulating factors other than serum. We demonstrated that spontaneously differentiated human macrophages polarized to M1/M2 phenotypes by 48h-stimulation with LPS/IFN-γ or IL-4/IL-13, respectively. Polarized macrophages showed specific gene expression profiles different cytokine production (TNFα, IL-1β, IL-10, CCL22) and surface markers. In particular, the M1 phenotype was characterized by flow cytometry as percentage of CD68+, CD68+/CCR2+, CD14+/CD16-/CD68+ or CD80+ cells and the M2 phenotype was identified as CD163+, CD206+, CX3CR1+ cells. We also demonstrated that M1 activation with LPS/IFN-γ down-regulated the M2 immunophenotype. Similarly to dexamethasone, used as a reference drug, E2 promoted a M2 macrophage signature counteracting the negative regulation by pro-inflammatory stimuli of both M2 surface marker expression and cytokine production. Overall, these data suggest that differences in the functional status of macrophages are critical to investigate pharmacological macrophage targeting. Given that the pro-inflammatory activity of monocyte-macrophages plays a role in the development and progression of CVD, we subsequently investigated if an imbalance in the M1/M2 ratio of macrophages derived from peripheral blood monocytes menopausal women could be detected in relation to menopausal status. In the resting state, macrophages from post-menopausal women displayed similar M1/M2 phenotype with respect to macrophages from pre-menopausal women. However, among post-menopausal women, the M2 phenotype was enhanced and M1 was attenuated by ongoing statin therapy with respect to non statin-treated patients. Moreover, macrophages from post-menopausal women after polarized activation displayed similar M1 response but impaired alternative activation (M2) with respect to those from pre-menopausal women. In the attempt to identify a biomarker linking menopause to cardiovascular risk, the M1/M2 ratio in circulating monocytes from pre- and post-menopausal women was measured and found unchanged. In conclusion, estrogenic pathways modulate the phenotypes and function of human macrophages and represent a possible pharmacological intervention in inflammatory disease. Future perspectives include investigating monocyte-macrophage polarization in women in relation to menstrual cycle and endocrine disease such as polycystic ovary syndrome
On natural language generation of formal argumentation
No full textIn this paper we provide a first analysis of the research questions that arise when dealing with the problem of communicating pieces of formal argumentation through natural language interfaces. It is a generally held opinion that formal models of argumentation naturally capture human argument, and some preliminary studies have focused on justifying this view. Unfortunately, the results are not only inconclusive, but seem to suggest that explaining formal argumentation to humans is a rather articulated task. Graphical models for expressing argumentation-based reasoning are appealing, but often humans require significant training to use these tools effectively. We claim that natural language interfaces to formal argumentation systems offer a real alternative, and may be the way forward for systems that capture human argument.</p
A tool to highlight weaknesses and strengthen cases: CISpaces.org
No full textWe demonstrate CISpaces.org, a tool to support situational understanding in intelligence analysis that complements but not replaces human expertise, for the first time applied to a judicial context. The system combines argumentationbased reasoning and natural language generation to support the creation of analysis and summary reports, and to record the process of forming hypotheses from relationships among information.</p
Dialectical models of deliberation, problem solving and decision making
No full textHamblin distinguished between formal and descriptive dialectic. Formal normative models of deliberation dialogue have been strongly emphasized as argumentation frameworks in computer science. But making such models of deliberation applicable to real natural language examples has reached a point where the descriptive aspect needs more interdisciplinary work. The new formal and computational models of deliberation dialogue that are being built in computer science seem to be closely related to some already existing and very well established computing technologies such as problem solving and decision making, but whether or how dialectical argumentation can be helpful to support these systems remains an open question. The aim of this paper is to examine some real examples of argumentation that seem to hover on the borderlines between deliberation, problem solving and decision making
Pharmacological modulation of macrophage activation phenotypes: the paradigm of dexamethasone
No full textPhenotypes of human macrophage polarized activation: role of dexamethasone
No full textIn response to various signals, macrophages undergo classical M1 activation (stimulated by toll-like receptor ligands and IFN-γ) or alternative M2 activation (stimulated by IL-4/IL-13). Functional polarization of macrophages has been observed in vivo under physiological and pathological conditions, and may represent an attractive target for pharmacological modulation. Given the lack of gold standards for M1/M2 activation in vitro, we polarized human monocyte-derived macrophages using different protocols and performed extensive characterization including the modulation of specific markers by dexamethasone. Human monocytes were obtained from healthy donor buffy coats by 2-step gradient centrifugation, and macrophages were obtained by culturing monocytes for 7 days in RPMI 1640 medium with 10% FCS. While virtually 100% of macrophages specifically stained for the intracellular glycoprotein CD68 on immunocytochemistry, only 10% showed surface expression as measured by flow cytometry, indicating a low basal activation state. When resting macrophages were incubated with LPS/IFN-γ (M1) for 4 h, no change was observed in the percentage of cells expressing the M1 surface markers CD68 and CCR2. After longer stimulation (48 h), the number of CD68- but not CCR2-positive cells doubled as compared with resting macrophages. This polarization protocol concomitantly down-regulated the expression of M2 markers CD206, CD163 and CX3CR1. In contrast, none of these markers were affected by alternative (M2) polarization with IL-4/IL-13 for 48 h whereas CD206 was up-regulated after 7 days. Q-PCR phenotyping after M1 polarization for 6-48 h showed increased TNF-α, IL-1β, COX-2, IL-10 and VEGF transcript levels with decreased CD206 and COX-1 expression. Finally, overnight pretreatment with 10 nM dexamethasone enhanced surface expression of CD163 in resting and M2-polarized macrophages, and reversed M1-induced CD163 down-regulation. We conclude that the phenotypic characterization of polarized macrophages is required and provides a basis for pharmacological macrophage targeting
COX-1 AND PROSTACYCLIN PRODUCTION BY ENDOTHELIAL CELLS IN THE PRESENCE OF MILD OXIDATIVE STRESS
No full textPrenylated and Geranylated Flavonoids Increase Production of Reactive Oxygen Species in Mouse Macrophages but Inhibit the Inflammatory Response
No full textIn this study, four prenylated and geranylated flavonoids, cudraflavone B (1), pomiferin (2), osajin (3), and diplacone (4), were tested for their antioxidant and anti-inflammatory effects and to identify any potential relationships between chemical structure and antioxidant or anti-inflammatory properties. The selected flavonoids were examined in cell-free models to prove their ability to scavenge superoxide radicals, hydrogen peroxide, and hypochlorous acid. Further, the ability of the flavonoids to influence the formation of reactive oxygen species in the murine macrophage cell line J774.A1 was tested in the presence and absence of lipopolysaccharide (LPS). The ability of flavonoids to inhibit LPS-induced IκB-α degradation and COX-2 expression was used as a model for the inflammatory response. The present results indicated that the antioxidant activity was dependent on the chemical structure, where the catechol moiety is especially crucial for this effect. The most potent antioxidant activities in cell-free models were observed for diplacone (4), whereas cudraflavone B (1) and osajin (3) showed a pro-oxidant effect in J774.A1 cells. All flavonoids tested were able to inhibit IκB-α degradation, but only diplacone (4) also down-regulated COX-2 expression
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