189 research outputs found
Proton pump inhibitors display antitumor effects in barrett's adenocarcinoma cells
Recent evidence has reported that proton pump inhibitors (PPIs) can exert antineoplastic effects through the disruption of pH homeostasis by inhibiting vacuolar ATPase (H+-VATPase), a proton pump overexpressed in several tumor cells, but this aspect has not been deeply investigated in EAC yet. In the present study, the expression of H+-VATPase was assessed through the metaplasia-dysplasia-adenocarcinoma sequence in Barrett''s esophagus (BE) and the antineoplastic effects of PPIs and cellular mechanisms involved were evaluated in vitro. H+-VATPase expression was assessed by immunohistochemistry in paraffined-embedded samples or by immunofluorescence in cultured BE and EAC cell lines. Cells were treated with different concentrations of PPIs and parameters of citotoxicity, oxidative stress, and autophagy were evaluated. H+-VATPase expression was found in all biopsies and cell lines evaluated, showing differences in the location of the pump between the cell lines. Esomeprazole inhibited proliferation and cell invasion and induced apoptosis of EAC cells. Production of reactive oxygen species (ROS) seemed to be involved in the cytotoxic effects observed since the addition of N-acetylcysteine significantly reduced esomeprazole-induced apoptosis in EAC cells. Esomeprazole also reduced intracellular pH of tumor cells, whereas only disturbed the mitochondrial membrane potential in OE33 cells. Esomeprazole induced autophagy in both EAC cells, but also triggered a blockade in autophagic flux in the metastatic cell line. These data provide in vitro evidence supporting the potential use of PPIs as novel antineoplastic drugs for EAC and also shed some light on the mechanisms that trigger PPIs cytotoxic effects, which differ upon the cell line evaluated
A combined IRAM and Herschel/HIFI study of cyano(di)acetylene in Orion KL: tentative detection of DC3N
We present a study of cyanoacetylene (HC3N) and cyanodiacetylene (HC5N) in
Orion KL, through observations from two line surveys performed with the IRAM
30m telescope and the HIFI instrument on board the Herschel telescope. The
frequency ranges covered are 80-280 GHz and 480-1906 GHz. We model the observed
lines of HC3N, HC5N, their isotopologues (including DC3N), and vibrational
modes, using a non-LTE radiative transfer code. To investigate the chemical
origin of HC3N and DC3N in Orion KL, we use a time-dependent chemical model. We
detect 40 lines of the ground state of HC3N and 68 lines of its 13C
isotopologues. We also detect 297 lines of six vibrational modes of this
molecule (nu_7, 2nu_7, 3nu_7, nu_6, nu_5, and nu_6+nu_7) and 35 rotational
lines of the ground state of HC5N. We report the first tentative detection of
DC3N in a giant molecular cloud with a DC3N/HC3N abundance ratio of 0.015. We
provide column densities and isotopic and molecular abundances. We also perform
a 2x2" map around Orion IRc2 and we present maps of HC3N lines and maps of
lines of the HC3N vibrational modes nu_6 and nu_7. In addition, a comparison of
our results for HC3N with those in other clouds allows us to derive
correlations between the column density, the FWHM, the mass, and the luminosity
of the clouds. The high column densities of HC3N obtained in the hot core, make
this molecule an excellent tracer of hot and dense gas. In addition, the large
frequency range covered reveals the need to consider a temperature and density
gradient in the hot core in order to obtain better line fits. The high D/H
ratio (comparable to that obtained in cold clouds) that we derive suggests a
deuterium enrichment. Our chemical models indicate that the possible deuterated
HC3N present in Orion KL is formed during the gas-phase. This fact provides new
hints concerning the processes leading to deuteration.Comment: 50 pages, 33 figures, 13 tables. Accepted for publication in A&
Gas phase Elemental abundances in Molecular cloudS (GEMS) VI. A sulphur journey across star-forming regions: study of thioformaldehyde emission
In the context of the IRAM 30m Large Program GEMS, we present a study of
thioformaldehyde in several starless cores located in star-forming filaments of
Taurus, Perseus, and Orion. We investigate the influence of the environmental
conditions on the abundances of these molecules in the cores, and the effect of
time evolution. We have modelled the observed lines of H2CS, HDCS, and D2CS
using the radiative transfer code RADEX. We have also used the chemical code
Nautilus to model the evolution of these species depending on the
characteristics of the starless cores. We derive column densities and
abundances for all the cores. We also derive deuterium fractionation ratios,
Dfrac, to determine and compare the evolutionary stage between different parts
of each star-forming region. Our results indicate that the north region of the
B213 filament in Taurus is more evolved than the south, while the north-eastern
part of Perseus presents an earlier evolutionary stage than the south-western
zone. Model results also show that Dfrac decreases with the cosmic-ray
ionisation rate, while it increases with density and with the degree of sulphur
depletion. In particular, we only reproduce the observations when the initial
sulphur abundance in the starless cores is at least one order of magnitude
lower than the solar elemental sulphur abundance. The progressive increase in
HDCS/H2CS and D2CS/H2CS with time makes these ratios powerful tools for
deriving the chemical evolutionary stage of starless cores. However, they
cannot be used to derive the temperature of these regions, since both ratios
present a similar evolution at two different temperature ranges (7-11 K and
15-19 K). Regarding chemistry, (deuterated) thioformaldehyde is mainly formed
through gas-phase reactions (double-replacement and neutral-neutral
displacement reactions), while surface chemistry plays an important role as a
destruction mechanism.Comment: 31 pages, 26 figure
Linking the dust and chemical evolution: Taurus and Perseus -- New collisional rates for HCN, HNC, and their C, N, and H isotopologues
HCN, HNC, and their isotopologues are ubiquitous molecules that can serve as
chemical thermometers and evolutionary tracers to characterize star-forming
regions. Despite their importance in carrying information that is vital to
studies of the chemistry and evolution of star-forming regions, the collision
rates of some of these molecules have not been available for rigorous studies
in the past. We perform an up-to-date gas and dust chemical characterization of
two different star-forming regions, TMC 1-C and NGC 1333-C7, using new
collisional rates of HCN, HNC, and their isotopologues. We investigated the
possible effects of the environment and stellar feedback in their chemistry and
their evolution. With millimeter observations, we derived their column
densities, the C and N isotopic fractions, the isomeric ratios, and the
deuterium fractionation. The continuum data at 3 mm and 850 m allowed us
to compute the emissivity spectral index and look for grain growth as an
evolutionary tracer. The HCN/HNC ratio is anticorrelated with the
deuterium fraction of HCN, thus it can readily serve as a proxy for the
temperature. The spectral index shows a tentative
anticorrelation with the HCN/HNC ratio, suggesting grain growth
in the evolved, hotter, and less deuterated sources. Unlike TMC 1-C, the
south-to-north gradient in dust temperature and spectral index observed in NGC
1333-C7 suggests feedback from the main NGC 1333 cloud. With this up-to-date
characterization of two star-forming regions, we found that the chemistry and
the physical properties are tightly related. The dust temperature, deuterium
fraction, and the spectral index are complementary evolutionary tracers. The
large-scale environmental factors may dominate the chemistry and evolution in
clustered star-forming regions.Comment: 25 pages, 20 figure
Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis
Peer reviewedPublisher PD
Attenuation of lung inflammation and fibrosis in CD69-deficient mice after intratracheal bleomycin
<p>Abstract</p> <p>Background</p> <p>Cluster of differentiation 69 (CD69), an early activation marker antigen on T and B cells, is also expressed on activated macrophages and neutrophils, suggesting that CD69 may play a role in inflammatory diseases. To determine the effect of CD69 deficiency on bleomycin(BLM)-induced lung injury, we evaluated the inflammatory response following intratracheal BLM administration and the subsequent fibrotic changes in wild type (WT) and CD69-deficient (CD69<sup>-/-</sup>) mice.</p> <p>Methods</p> <p>The mice received a single dose of 3 mg/kg body weight of BLM and were sacrificed at 7 or 14 days post-instillation (dpi). Lung inflammation in the acute phase (7 dpi) was investigated by differential cell counts and cytokine array analyses of bronchoalveolar lavage fluid. In addition, lung fibrotic changes were evaluated at 14 dpi by histopathology and collagen assays. We also used reverse transcription polymerase chain reaction to measure the mRNA expression level of transforming growth factor β1 (TGF-β1) in the lungs of BLM-treated mice.</p> <p>Results</p> <p>CD69<sup>-/- </sup>mice exhibited less lung damage than WT mice, as shown by reductions in the following indices: (1) loss of body weight, (2) wet/dry ratio of lung, (3) cytokine levels in BALF, (4) histological evidence of lung injury, (5) lung collagen deposition, and (6) TGF-β1 mRNA expression in the lung.</p> <p>Conclusion</p> <p>The present study clearly demonstrates that CD69 plays an important role in the progression of lung injury induced by BLM.</p
GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis
Dysregulated hematopoiesis occurs in several chronic inflammatory diseases, but it remains unclear how hematopoietic stem cells (HSCs) in the bone marrow (BM) sense peripheral inflammation and contribute to tissue damage in arthritis. Here, we show the HSC gene expression program is biased toward myelopoiesis and differentiation skewed toward granulocyte-monocyte progenitors (GMP) during joint and intestinal inflammation in experimental spondyloarthritis (SpA). GM-CSF-receptor is increased on HSCs and multipotent progenitors, favoring a striking increase in myelopoiesis at the earliest hematopoietic stages. GMP accumulate in the BM in SpA and, unexpectedly, at extramedullary sites: in the inflamed joints and spleen. Furthermore, we show that GM-CSF promotes extramedullary myelopoiesis, tissue-toxic neutrophil accumulation in target organs, and GM-CSF prophylactic or therapeutic blockade substantially decreases SpA severity. Surprisingly, besides CD4+ T cells and innate lymphoid cells, mast cells are a source of GM-CSF in this model, and its pathogenic production is promoted by the alarmin IL-33
Microbial Reprogramming Inhibits Western Diet-Associated Obesity
A recent epidemiological study showed that eating âfast foodâ items such as potato chips increased likelihood of obesity, whereas eating yogurt prevented age-associated weight gain in humans. It was demonstrated previously in animal models of obesity that the immune system plays a critical role in this process. Here we examined human subjects and mouse models consuming Westernized âfast foodâ diet, and found CD4[superscript +] T helper (Th)17-biased immunity and changes in microbial communities and abdominal fat with obesity after eating the Western chow. In striking contrast, eating probiotic yogurt together with Western chow inhibited age-associated weight gain. We went on to test whether a bacteria found in yogurt may serve to lessen fat pathology by using purified Lactobacillus reuteri ATCC 6475 in drinking water. Surprisingly, we discovered that oral L. reuteri therapy alone was sufficient to change the pro-inflammatory immune cell profile and prevent abdominal fat pathology and age-associated weight gain in mice regardless of their baseline diet. These beneficial microbe effects were transferable into naĂŻve recipient animals by purified CD4[superscript +] T cells alone. Specifically, bacterial effects depended upon active immune tolerance by induction of Foxp3[superscript +] regulatory T cells (Treg) and interleukin (Il)-10, without significantly changing the gut microbial ecology or reducing ad libitum caloric intake. Our finding that microbial targeting restored CD4[superscript +] T cell balance and yielded significantly leaner animals regardless of their dietary âfast foodâ indiscretions suggests population-based approaches for weight management and enhancing public health in industrialized societies.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant RO1CA108854)National Institutes of Health (U.S.) (Grant P01 AI045757)National Institutes of Health (U.S.) (Grant U19 AI046130)National Institutes of Health (U.S.) (Grant U19 AI070352)National Institutes of Health (U.S.) (Grant P01 AI039671)National Institute of Neurological Disorders and Stroke (U.S.) (Jacob Javits Merit Award NS2427)The Penates FoundationNancy Taylor Foundation for Chronic Diseases, Inc
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