An initial association between vitamin A supplementation and reduced childhood mortality due to measles and diarrhea led to the assumption that vitamin A was crucial in the fitness of the immune system. This finding sparked curiosity about the mechanisms through which vitamin A could modulate the immune response. Today, it is recognized that vitamin A, through its metabolite retinoic acid, is able to induce gut homing receptors on T and B cells, allowing the trafficking of these cells to the intestine (and probably also to the inflamed tissues) to perform their effector functions and maintain an appropriate gastrointestinal balance between immunity and tolerance. Moreover, exposure to vitamin A in the womb is an important determinant for the development of secondary lymphoid organs during embryogenesis and after birth through induction of lymphoid tissue-inducer cells. In addition, vitamin A has shown to be essential for T cell activation and differentiation into different T helper subsets, such as Th1, Th2 and Th17 cells. On the other hand, in vitro studies have shown that RA is able to induce regulatory T cells, however the role of vitamin A in promoting oral tolerance has not yet been fully established. A far more complex picture has emerged for the role of retinoic acid in gut immunity since there is contradictory evidence for several of aspects of T cell differentiation. Such discrepancies could be explained by the fact that RA can mediate different effects depending on the dose used in different experimental settings and the context in which an immune response is occurring. Accordingly, it has been proposed that RA may have a dual effect, modulating regulatory T cell differentiation in the steady state while promoting T cell activation and Th1 and Th17 cell responses during an ongoing immune response. In addition, results in VAD mice should be interpreted with caution; taking into consideration that VAD mice present important alterations in intestinal epithelial cells, which affects the resident microbiota. The gut microbiota has an important effect on the differentiation of T helper subsets and Tregs in the gut. Therefore, the effects observed in VAD mice could be the consequence of an altered gut microbiota rather than a direct effect of RA on T cells. Although the development of better models and experimental techniques has allowed significant progress in the discovery of the mechanisms through which vitamin A broadly impacts the immune response, further studies are needed to fully unravel the role of vitamin A in T cell-mediated immunity.
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We then developed a co-culture technique of IsO cells and F9-1.8 re- porter cells to detect the production of RA by the former (Figs. 2A and 3). In order to test basal b -galactosidase ac- tivity, we co-cultured these two cell types with a chemically deﬁned me- dium; few F9-1.8 blue cells (Fig. 3A; see also Fig. 3F for a plotted compari- son with other co-culture conditions) were seen, suggesting that in the ab- sence of E-CSF, IsO cells are not self- sufﬁcient to synthesize retinoic acid. Conversely, when F9-1.8 and IsO cells were co-cultured in a deﬁned medium supplemented with E-CSF (Fig. 3B and F), the number of F9-1.8 blue cells signiﬁcantly increased, suggest- ing that E-CSF contains factors that activate the synthesis of retinoic acid by the IsO cells.
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components of RA, but as monotherapy often they are insuffi- cient to achieve remission or adequate control of the disease activity (Smolen et al., 2017). This circumstance has motivated the common use of drug combinations, with the most frequent including methotrexate together with a targeted biologic drug as one of the monoclonal anti – tumor necrosis factor (TNF) antibodies (Smolen et al., 2017). A sizable fraction of patients does not reach adequate response even with these drug combinations. Therefore, there is a growing interest in developing treatments aimed to revert the activated pheno- type of RA FLS (Niedermeier et al., 2010). Recently, we found that a transporter of retinoids, cellular retinoic acid binding protein 2, is a candidate drug target of this type because cellular retinoic acid binding protein 2 suppression reverts RA FLS resistance to apoptosis (Mosquera et al., 2018). In the same study, we observed unconventional responses of RA FLS to the main biologic retinoid, all-trans retinoic acid. These results prompted us to investigate further the effects of all- trans retinoic acid (ATRA) on the activated phenotype of RA FLS (Mosquera et al., 2018).
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Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been success- fully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and hom- ing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the num- ber of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-spe- cific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells. a1111111111
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Background: Membranous nephropathy (MN) is one of the causes of nephrotic syndrome in adults that lead to end-stage renal disease with an unknown molecular signature. The current diagnosis is based on renal biopsy, which is an invasive meth- od and has several complications and challenges. Thus, identification of the novel biomarker candidates, as well as impaired pathways, will be helpful for non-invasive molecular-based diagnosis. Objectives: We aimed to study the molecular signature of MN and facilitate the systematic discovery of diagnostic candidate biomarkers, molecular pathway, and potential therapeu- tic targets using bioinformatics predictions. Methods: The protein-protein interaction (PPI) network of an integrated list of downloaded microarray data, differential proteins from a published proteomic study, and a list of retrieved scientific literature mining was constructed and analyzed in terms of functional modules, enriched biological pathways, hub genes, master regula- tor, and target genes. Results: These network analyses revealed several functional modules and hub genes including Vitamin D3 receptor, retinoic acid receptor RXR-alpha, interleukin 8, and SH3GL2. TEAD4 and FOXA1 were identified as the regulatory master molecules. LRP1 and ITGA3 were identified as the important target genes. Extracellular matrix organization, cell surface receptor signaling pathway, and defense and inflammatory response were found to be impaired in MN using functional analyses. A specific subnetwork for MN was suggested using PPI approach. Discussion: Omics data integration and systems biology analysis on the level of interaction networks provide a powerful approach for identification of pathway-specific biomarkers for MN. (REV INVES CLIN. 2018;70:184-91)
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The goals of our study were to determine the possible association of interleukin (IL)-31 with Th17 cytokine profile in serum and to quantify retinoic acid-related orphan receptor C (RORC) mRNA expression in psoriatic arthritis (PsA) patients. This cross-sectional study was conducted in 50 patients with PsA and 30 control subjects (CS) matched by age and gender. The cytokine serum levels were quantified by magnetic bead–based assay using the Bio-Plex MAGPIX system, and RORC mRNA expression was determined by quantitative polymerase chain reaction (qPCR). As a result, significant differences in IL-31 were observed between study groups (77.23 pg/mL in PsA vs 64.4 pg/mL in CS, P < 0.001) and Th17 cytokine profile serum levels (IL-17A: 6.36 pg/mL in PsA vs 2.97 pg/mL in CS, P = 0.02; IL-17F: 44.15 pg/mL in PsA vs 23.36 pg/mL in PsA, P = 0.01; IL-17E: 3.03 pg/mL in PsA vs 0.82 pg/mL in CS, P < 0.001; IL-21: 36.45 pg/mL in PsA vs 12.44 pg/mL in CS, P = 0.02); however, significant differences were not observed for IL-23 (31.2 pg/mL in PsA vs 53.26 pg/ mL in CS, P = 0.58). Furthermore, positive correlations between IL-31 and Th17 cytokine profile serum levels were found (IL-17A: r s = 0.64, P < 0.001; IL-17F: r s = 0.73, P < 0.001; IL-17E: r s = 0.70, P < 0.001; IL-21: r s = 0.54, P = 0.002; IL-23: r s = 0.5, P < 0.01). Regarding RORC gene expression, the PsA group showed an increase of 6.85-fold compared to the CS group. We did not find any association between the serum levels of cytokines and RORC gene expression. In conclusion, in PsA, there are increased serum levels of IL-31, IL-17A, IL-17F, IL-17E, and IL-21, but not IL-23. Moreover, there was a positive correlation of IL-31 with the Th17 cytokine profile and a high RORC gene expression. Altogether, these findings suggest a proinflammatory contribution of IL-31 in close association with the Th17 cytokine profile in PsA.
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injections were made using a Rheodyne Injectable valve (20 μL loop). The detector wavelength was set at 254 nm. The chromatographic separations were performed at ambient temperature on a Gracesmart RP18, 5μ (250 mm x 4.6 mm). The mobile phase was a mixture of acetonitrile, water and concentrated phosphoric acid (400:600:5), filtered and degassed prior to use and flowing at the rate of 0.8ml/min. The measurements were performed at room temperature. The duration of each analysis was 37.5min. The data were collected and analyzed with analyst & crystal software in a computer system. About 2g of selected extracts of this plant was placed into a 50mL flask and extracted with 70% aqueous methanol solution (50mL) by boiling with reflux for 2h on a water bath. After cooling, the extract was filtered through a paper filter into a 100mL measuring flask and was subsequently made up to the mark with the same solvent and sonicated for 15 min. Then the solution was filtered through 0.45 μ filter porosity membrane filter prior to injection. The sample components were identified by comparison of their retention times to those observed in the chromatograms of reference solutions which were collected from the library data. The relative content of each component was determined by measuring the area under the corresponding peak and using the method of internal normalization 10 .
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Wieland, H. and O. Schlichting (1924). "Analysis concerning gallic acid. XX. Announcement. The breakdown of a tricarboxylic acid C13H20O6." Hoppe-Seylers Zeitschrift Fur Physiologische Chemie 134(4/6): 276-289. Wieland, H. and A. Wingler (1924). "The oxydation process mechanism VII, 1 The
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The stimulatory activity of pyridine-3-suIfonic acid upon the oxidátion of glucose by S. Jomzei was not surprising since MIZUNO and NOJIMA ( 14) found that this substance was a growth accessory factor for S. dYJenteriae. Fur thermore, MIZlJNO and TA M A R A ( 1 5 ) found that pyridine-3-sulfonic acid could
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series, G1316A COLCOM, serial # DE43646850) under the following conditions: 20μL of ethanol extract were injected for 20 minutes at 25° C, pressure at 95 bar and a flow of 1mL/min. A second characterization of the phenolic compounds was done using a reversed-phase high performance liquid chromatographic (RP- HPLC, LaChrom serie 7000 Merck-Hitachi (Darmstadt, Germany), a Symmetry C18 Waters (Ireland), 4,6x250mm, 5mM, Pre- column: Symmetry C18 3.9 x 20 mm,5 μm,) under the following conditions: 20μL of ethanol extract were injected for 31 minutes at 40ºC, using phase mixture A:2% formic acid mixture B: 3 2% formic acid: Methanol, 1:1 v/v mixture C: Methanol UV-wave Detection at 280nm, 310nm and 360nm. Compounds were quantified using peak area calculation, and partially identified using correlations between retention times.
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Acrylic acid 12.3 13.9 Isobutyl alcohol 7.1 18.0 Allyl alcohol 10.2 14.3 Isobutyric acid 12.2 14.4 Allyl bromide 14.4 9.6 Isopropyl alcohol 8.2 16.0 Allyl iodide 14.0 11.7 Isopropyl bromide 14.1 9.2 Ammonia, 100% 12.6 2.0 Isopropyl chloride 13.9 7.1 Ammonia, 26% 10.1 13.9 Isopropyl iodide 13.7 11.2
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manica showed to act as an aggregation attractant cue, the cuticular hydrocarbons were detected as the major com- ponent responsible for this pheromone . In the desert locust Schistocerca gregaria, the aggregation behavior of larvae is modulated by three sets of pheromonal com- pounds: aldehydes and acids emitted by the larvae them- selves, and phenols associated with their feces . In Heteroptera, the aggregation behavior of immature pen- tatomid bugs was investigated using cuticular extracts of six different pentatomid bug species, two aldehyde iso- mers elicited opposite responses, whereas the major cutic- ular hydrocarbon showed the highest attractiveness . Research on model species from Blattodea, Coleoptera, Diptera, and Lepidoptera orders showed that many phe- romones arise from modifications of fatty acid metabo- lism. For instance, the ketone contact sex pheromone of the female German cockroach, Blattella germanica, derives from elongation of a methyl-branched fatty acyl-CoA moiety followed by decarboxylation, hydroxylation, and oxidation [28,29]. The aggregation pheromone of Tribo- lium castaneum arises from a fatty acid precursor . Also the major components of the sex pheromones in Diptera (e.g. Drosophila and Muscidae) are derived from elongation of fatty acyl-CoA moieties followed by loss of the carbonyl carbon and the formation of the corresponding hydrocar- bon . Lepidopteran sex pheromones are also derived from fatty acids, with diverse combinations of desatura- tion, chain-shortening, and modification of the carbonyl carbon [32,33]. Chemical communication activity has been reported for several esters of C16 and C18 fatty acids in the honeybee . However, very few studies are avail- able describing the aggregation role of insect fatty acids, among them; FFA components were reported as aggrega- tion cues in the coleopteran Trogodermes granarium , and in social insects . Also, endogenous free fatty acids were reported to be involved in conspecific attrac- tion and food recognition in Protaphorura armata (Colle- mbola) .
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Ghrelin produces the phosphorylation of AMPK and pAMPK becomes active and phosphorylates and inactivates ACC, causing a decrease in malonyl-CoA levels, the physiological inhibitor of CPT1 enzymes. This action produces disinhibition of the CPT1A enzyme, an increase in fatty acid oxidation, and an accumulation of ROS, which are mainly buffered by UCP2. Previous studies demonstrated that all these metabolic changes occur in the VMN (López et al., 2008; Gao et al., 2013), and although not fully understood, they ultimately activate transcriptional events by eliciting increased levels or activation of key transcription factors, such as pCREB, FoxO1, and BSX. These transcription factors are responsible, in part, for the increase of orexigenic neuropeptides AgRP and NPY in the ARC. CPT1C is more expressed in the brain than CPT1A. Although it has very low CPT1 activity it is known to bind malonyl-CoA as CPT1A does. Thus, we proceeded to analyze the ghrelin signaling pathway in the hypothalamus of CPT1C KO mice to determine if CPT1C plays a role in this pathway.
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Both phytic acid (PA) and catechin (CA) are well known antioxidants of natural origin. They were fre- quently tried on experimental level as hepatopro- tectants, relying only on their antioxidant properties. The present study was conducted mainly to outline the other biochemical pathways underlying the hepato- therapeutic potential of both drugs and to check a pos- sible synergistic action if prescribed concomitantly. As both materials are frequently taken on a daily basis in food and drinks, it will be helpful to pursue their possi- ble utility and/or to check if their value is really of medical importance. For this purpose, CCl 4 was used as a hepatotoxin, we evaluated plasma total sialic acid (TSA), serum ascorbic acid (AA) levels, liver tissue thiobarbituric acid reactive species (TBARS) as a marker for lipid peroxidation and total protein (TP) content as a rough marker to measure hepatic synthet- ic capability in 80 male Wistar rats as experimental models. Animals were classified into 8 groups (10 rats each), the first as control, the second as PA treated (0.3 mg kg -1 ), orally, the third as CA treated (30 mg kg -1 ),
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exothermic peak appears in the range 200–350°C after the departure of the remaining water molecule at ca. 120°C. The formation temperature of the oxide prepared ranges from 300 to 400°C. The exothermic effect corresponds to the combustion of carboxylic acid and nitrate/acetate ions. More than half of the weight loss occurs during this stage because of a violent oxidation-decomposition reaction. During the combustion process, the solution turned into brownish black powder. Assuming that complexing agents provide combustion heat for calcination in the synthesis of oxide powders, it appeared that these carboxylic acids act as fuels during the pyrolysis of the precursor, accelerating the decomposition of nitrate/acetate ions in the process. Eventhough crystallization started below 400°C, well-crystallized and pure phases were obtained at 600°C. While pyrolysis procedures at this stage were very complicated, it could be presumed that the last weak exothermic peaks at ca. 380–398°C in the DTA curves of citric acid- and glycine-assisted methods correspond to the crystallization of the LiNi 0.5 Co 0.5 O 2 phase.
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The influence of the reaction temperature on the extent of the controlled depolymerization of cellulose was assessed in the temperature range from 70 to 150 C, using two types of mineral acids as catalysts: sulfuric and hydrochloric acid (Table 1, entries 2e7). The addition of these catalysts was adjusted to get the same concentration of protons in the re- action media in order to properly compare their influence on the depolymerization of the catalysts. Reactions were per- formed in presence of a stoichiometric amount of water to get a theoretical complete cellulose hydrolysis. For this purpose, the amount of water accompanying the mineral acid was taken into account. A blank reaction test was also carried out for comparison purposes (Table 1, entry 1). In this experiment no mineral acid was added to the reaction media, but per- formed at 100 C and keeping constant the rest of the exper- imental conditions, including de addition of water. The first observed difference found in this experiment with regards to the rest of the tests performed in presence of mineral acid, is the readily precipitation of cellulose during the addition of water. This different behavior impossibilities the hydrolytic attack to the 1,4 glucoside bondings of cellulose, leading to a negligible yield towards glucose or any other by-product. These results suggest that simple presence of the ionic liquid species is not able to provide cellulose depolymeriza- tion, while revealing the needing of mineral acid to effectively maintain the cellulose in solution.
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The propylene is fed from a storage tank. Air is compressed as a source of oxygen. Steam is used to provide thermal ballast for the exothermic heat of reaction. After being mixed, the feeds enter the reactor. Reactor effluent proceeds to a quench tower (T-301) where the reaction is rapidly quenched, to avoid further oxidation, with a cool acrylic acid recycle stream. Additional recovery of acrylic acid and acetic acid occurs in an absorber, T-302. The stream leaving the absorption section is a dilute, aqueous acid mixture. It then proceeds to an extraction unit, X- 301, which contains and extractor and a solvent recovery tower. This unit was designed and is operated under contract by ExtractoCorp. Stream 15 contains virtually all of the acrylic acid and acetic acid fed to X-301. Final purification occurs in T-303, where 99.9 mole% acrylic acid is produced as the bottom product, and 95 mole% acetic acid is produced as the top product. The acrylic acid product is cooled prior to being sent to storage. The acrylic acid temperature should never exceed 90°C in order to avoid spontaneous polymerization.
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Only one continuous culture could be found for O. oeni (Zhang & Lovitt, 2006). In this study, the growth performance of the strain NCIMB 11648 was assessed at dilution rates between 0.007 and 0.052 . The authors determined dry cell weight, substrate uptake (fructose and glucose) and product formation (lactate, acetate, mannitol and ethanol) rates, as well as yields (maximum growth rate, maximun cell productivity, biomass yield and maintenance coefficient). Nevertheless, this study was carried out in the absence of ethanol, malic acid and citric acid, which could have significantly affected the physiology of the microorganism. Additionally, considering the high genotypic and phenotypic variation between strains (Borneman et al., 2012), we preferred to employ experimental data from the strain PSU-1 to refine our model and not use this data.
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BAs belong to a family of closely related acidic sterols synthesized from cholesterol, and represent the main catabolic pathway of cholesterol metabolism in humans. BAs are classified as soluble amphiphiles because of the ionized carboxylate or sulfonate group on the side chain that makes BAs water-soluble. In general, BAs possess a steroid nucleus of four fused hydrocarbon rings with po- lar hydroxyl functions. De novo BA biosynthesis occurs in the liver as the “primary” BAs, i.e., cholic acid (CA) and chenodeoxycholic acid (CDCA). Afterwards, the water solubility of BAs is increased by conjugation to either taurine or glycine, followed by hepatic secretion of BAs into bile and release by the gallbladder into the duode-
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According to the results obtained during the anaerobic batch assays, most suitable pH for produce VFAs was 8, since at this pH the highest concentration of VFAs was obtained (5276 mg/L). The VFAs obtained were mostly acetic (1652 COD mg/L) and butyric (2928 COD mg/L) acids. Also, propionic acid was obtained, but in a lower concentration (697 COD mg/L). The higher concentration was obtained at 8 days of operation, after which the concentration of VFAs decreased suggesting that VFAs were converted to other products. The increase of CH4 production after day 8, confirm the decrease on VFAs concentration due to their conversion into CH4 thus completing the cycle of anaerobic digestion.
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