Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of ...reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective β1-adrenoreceptor (β1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 μM), epinephrine (1 μM), or both compounds. Metoprolol prevented both the HG-induced reduction of cell viability (MTT assays) and the modulation of the angiogenic potential of HREC (tube formation assays) reducing the TNF-α, IL-1β, and VEGF mRNA levels (qRT-PCR). Moreover, metoprolol prevented the increase in phospho-ERK1/2, phospho-cPLA
, COX2, and protein levels (Western blot) as well as counteracting the translocation of ERK1/2 and cPLA
(high-content screening). Metoprolol reduced ROS accumulation in HG-stimulated HREC by activating the anti-oxidative cellular response mediated by the Keap1/Nrf2/HO-1 pathway. In conclusion, metoprolol exerted a dual effect on HG-stimulated HREC, decreasing the activation of the pro-inflammatory ERK1/2/cPLA
/COX2 axis, and counteracting ROS accumulation by activating the Keap1/Nrf2/HO-1 pathway.
Bradykinin drives normal lung fibroblasts into myofibroblasts, induces fibroblast proliferation and activates mitogen activated protein kinase pathways (MAPK) but its effects on bronchial fibroblasts ...from asthmatics (HBAFb) have not been yet studied. We studied bradykinin-induced fibroblast proliferation and differentiation and the related intracellular mechanisms in HBAFb compared to normal bronchial fibroblasts (HNBFb). Bradykinin-stimulated HBAFb and HNBFb were used to assess: bradykinin B2 receptor expression by Western blot analysis; cell proliferation by 3H thymidine incorporation; α-smooth muscle actin (SMA) expression/polymerization by Western blot and immunofluorescence; epidermal growth factor (EGF) receptor, extracellular-regulated kinase (ERK) 1/2 and p38 MAPK activation by immunoprecipitation and Western blot, respectively.
Constitutive bradykinin B2 receptor and α-SMA expression was higher in HBAFb as compared to HNBFb. Bradykinin increased bradykinin B2 receptor expression in HBAFb. Bradykinin, via bradykinin B2 receptor, significantly increased fibroblast proliferation at lower concentration (10−11M) and α-SMA expression/polymerization at higher concentration (10−6M) in both cells. Bradykinin increased ERK1/2 and p38 phosphorylation via bradykinin B2 receptor; EGF receptor inhibitor AG1478 and panmetalloproteinase inhibitor GM6001 blocked bradykinin-induced ERK1/2 activation but not p38 phosphorylation. Bradykinin, via bradykinin B2 receptor, induced EGF receptor phosphorylation that was suppressed by AG1478. In HBAFb AG1478, GM6001, the ERK1/2-inhibitor U0126 and the p38 inhibitor SB203580 suppressed bradykinin-induced cell proliferation, but only SB203580 reduced myofibroblast differentiation.
These data indicate that bradykinin is actively involved in asthmatic bronchial fibroblast proliferation and differentiation, through MAPK pathways and EGF receptor transactivation, by which bradykinin may contribute to airway remodeling in asthma, opening new horizons for potential therapeutic implications in asthmatic patients.
As David J. Chalmers claims, “virtual reality is a sort of genuine reality, virtual objects are real objects, and what goes on in virtual reality is truly real.” In this paper, I will suggest that ...the philosophical hypothesis that we might live in a simulation can be considered to be the last and most nihilistic episode in the series of narrations about the true and apparent worlds that Nietzsche sketched in The Twilight of the Idols. I will argue that Nietzsche’s prediction about the obliteration of the apparent world has actually been fulfilled by Chalmers, and I will show why his theory must be considered one of the many fables that humans have been producing in order to organise the world according to their own ends.
Glucose induces corneal epithelial dysfunctions characterized by delayed wound repair. Nuclear erythroid 2-related factor 2 (Nrf2) mediates cell protection mechanisms even through the Heme ...oxygenase-1 (HO-1) up-regulation. Here, we synthesized new HO-1 inducers by modifying dimethyl fumarate (DMF) and used docking studies to select VP13/126 as a promising compound with the best binding energy to Kelch-like ECH-associated protein 1 (keap1), which is the the regulator of Nrf2 nuclear translocation. We verified if VP13/126 protects SIRC cells from hyperglycemia compared to DMF. SIRC were cultured in normal (5 mM) or high glucose (25 mM, HG) in presence of DMF (1–25 μM) or VP13/126 (0.1–5 μM) with or without ERK1/2 inhibitor PD98059 (15 μM). VP13/126 was more effective than DMF in the prevention of HG-induced reduction of cell viability and proliferation. Reduction of wound closure induced by HG was similarly counteracted by 1 μM VP13/126 and 10 μM DMF. VP13/126 strongly increased phospho/total ERK1/2 and restored HO-1 protein in HG-treated SIRC; these effects are completely counteracted by PD98059. Moreover, high-content screening analysis showed a higher rate of Nrf2 nuclear translocation induced by VP13/126 than DMF in HG-stimulated SIRC. These data indicate that VP13/126 exerts remarkable pro-survival properties in HG-stimulated SIRC, promoting the Nrf2/HO-1 axis.
The infinite judgement has long been forgotten and yet, as I am about to demonstrate, it may be urgent to revive it for its critical and productive potential. An infinite judgement is neither ...analytic nor synthetic; it does not produce logical truths, nor true representations, but it establishes the genetic conditions of real objects and the concepts appropriate to them. It is through infinite judgements that we reach the principle of transcendental logic, in the depths of which all reality can emerge in its material and sensible singularity, making possible all generalization and formal abstraction. KEYWORDS: Hegel; Kant; Deleuze; Maimon; Maimonides; Dialectics
Resumen. L'articolo invita all'ascolto di brani musicali soprattutto pianistici, creando connessioni con altri linguaggi (pittura e architettura). Viene dato un risalto all'aspetto numerico. In ...particolare viene ad essere sviluppato un focus sul numero sei. L'interdisciplinarità è vista a tutti gli effetti come una risorsa per la conoscenza.
This work describes the preliminary analysis of Fricke gels dosimeters
characterized by a new formulation making use of a matrix of polyvinyl
alcohol cross-linked by adding glutaraldehyde and ...analyzed by means of
nuclear magnetic resonance relaxometry. In previous optical studies, these
gels have shown promising dosimetric features in terms of photon sensitivity
and low diffusion of ferric ions produced after irradiation. In this work, we
used a portable nuclear magnetic resonance relaxometer to measure the
relaxation times (which are important for dosimetric applications) of these
gel materials. For this purpose, we performed a study for optimizing the
acquisition parameters with a nuclear magnetic resonance relaxometer. Gel
samples were exposed to clinical 6 MV photons in the dose range between 0 and
20 Gy. Nuclear magnetic resonance relaxometry measurements were per- formed
and the sensitivity to photon beams was measured for various values of the
Fe2+ ion concentration. The analyses pointed out that the MR signal increases
as the Fe2+ content in- creases and the increase is about 75 % when the
concentration of Fe2+ ions is increased from 0.5 mM to 2.5 mM. Furthermore,
the sensitivity improvement achieved with increasing the Fe2+ concentration
is about 60 %. This paper shows that the portable nuclear magnetic resonance
relaxometer used for analysis of porous materials can be used for
characterization of these dosimetric gels and this study can be considered as
the first step for the characterization of these dosimeters which in future
could be used for 3-D dose mapping in clinical applications.
nema
The impairment of the blood retinal barrier (BRB) represents one of the main features of diabetic retinopathy, a secondary microvascular complication of diabetes. Hyperglycemia is a triggering factor ...of vascular cells damage in diabetic retinopathy. The aim of this study was to assess the effects of vitamin D
3
on BRB protection, and to investigate its regulatory role on inflammatory pathways. We challenged human retinal endothelial cells with high glucose (HG) levels. We found that vitamin D
3
attenuates cell damage elicited by HG, maintaining cell viability and reducing the expression of inflammatory cytokines such as IL-1β and ICAM-1. Furthermore, we showed that vitamin D
3
preserved the BRB integrity as demonstrated by trans-endothelial electrical resistance, permeability assay, and cell junction morphology and quantification (ZO-1 and VE-cadherin). In conclusion this
in vitro
study provided new insights on the retinal protective role of vitamin D
3
, particularly as regard as the early phase of diabetic retinopathy, characterized by BRB breakdown and inflammation.
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