Analysis of Ranitidine-Associated N-Nitrosodimethylamine Production Under Simulated Physiologic Conditions.
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ABSTRACT:
SUBMITTER: Braunstein LZ
PROVIDER: S-EPMC7846938 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceA publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies.ObjectiveTo characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels.Design, setting, and participantsOne 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 μmol/L) to higher concentrations (10 000 μmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method.Main outcomes and measuresNDMA detected in simulated gastric fluid 2 hours after adding ranitidine.ResultsAt a supraphysiologic nitrite concentration (ie, 10 000 μmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 μmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 μmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 μmol/L) or 10-fold physiologic (1000 μmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 μmol/L).Conclusions and relevanceIn this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 μmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.
| S-EPMC8239951 | biostudies-literature
Project description:Human and mouse neutrophils are known to form tethers when rolling on selectins in vitro. Tethers are ∼0.2 μm thin, ∼5-10 μm-long structures behind rolling cells that can swing around to form slings that serve as self-adhesive substrates. Here, we developed a mouse intravital imaging method, where the neutrophil surface is labeled by injecting fluorescently labeled mAb to Ly-6G. Venules in the cremaster muscle of live mice were imaged at a high frame rate using a confocal microscope equipped with a fast resonant scanner. We observed 270 tethers (median length 3.5 μm) and 31 slings (median length 6.9 µm) on 186 neutrophils of 15 mice. Out of 199 tether break events, 123 were followed by immediate acceleration of the rolling cell, which shows that tethers are load-bearing structures in vivo. In venules with a high wall shear stress (WSS; > 12 dyn/cm2 ), median rolling velocity was higher (19 μm/s), and 43% of rolling neutrophils had visible tethers. In venules with WSS < 12 dyn/cm2 , only 26% of rolling neutrophils had visible tethers. We conclude that neutrophil tethers are commonly present and stabilize rolling in vivo.
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Project description:Several fluorescent proteins (FPs) are prone to forming low-affinity oligomers. This undesirable tendency is exacerbated when FPs are confined to membranes or when fused to naturally oligomeric proteins. Oligomerization of FPs limits their suitability for creating fusions with proteins of interest. Unfortunately, no standardized method evaluates the biologically relevant oligomeric state of FPs. Here, we describe a quantitative visual assay for assessing whether FPs are sufficiently monomeric under physiologic conditions. Membrane-associated FP-fusion proteins, by virtue of their constrained planar geometry, achieve high effective concentrations. We exploited this propensity to develop an assay to measure FP tendencies to oligomerize in cells. FPs were fused on the cytoplasmic end of an endoplasmic reticulum (ER) signal-anchor membrane protein (CytERM) and expressed in cells. Cells were scored based on the ability of CytERM to homo-oligomerize with proteins on apposing membranes and restructure the ER from a tubular network into organized smooth ER (OSER) whorl structures. The ratio of nuclear envelope and OSER structures mean fluorescent intensities for cells expressing enhanced green fluorescent protein (EGFP) or monomeric green fluorescent protein (mGFP) CytERM established standards for comparison of uncharacterized FPs. We tested three FPs and identified two as sufficiently monomeric, while a third previously reported as monomeric was found to strongly oligomerize.
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Project description:Pyruvate is an important "hub" metabolite that is a precursor for amino acids, sugars, cofactors, and lipids in extant metabolic networks. Pyruvate has been produced under simulated hydrothermal vent conditions from alkyl thiols and carbon monoxide in the presence of transition metal sulfides at 250 °C [Cody GD et al. (2000) Science 289(5483):1337-1340], so it is plausible that pyruvate was formed in hydrothermal systems on the early earth. We report here that pyruvate reacts readily in the presence of transition metal sulfide minerals under simulated hydrothermal vent fluids at more moderate temperatures (25-110 °C) that are more conducive to survival of biogenic molecules. We found that pyruvate partitions among five reaction pathways at rates that depend upon the nature of the mineral present; the concentrations of H2S, H2, and NH4Cl; and the temperature. In most cases, high yields of one or two primary products are found due to preferential acceleration of certain pathways. Reactions observed include reduction of ketones to alcohols and aldol condensation, both reactions that are common in extant metabolic networks. We also observed reductive amination to form alanine and reduction to form propionic acid. Amino acids and fatty acids formed by analogous processes may have been important components of a protometabolic network that allowed the emergence of life.
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Project description:The effectiveness of a simulated microgravity environment as a novel method for preserving the freshness of vegetables was investigated. Three types of vegetables were selected: vegetable soybean, mung bean sprouts, and white radish sprouts. These selected vegetables were fixed on a three-dimensional rotary gravity controller, rotated slowly. The selected vegetables were stored at 25°C and 66% of relative humidity for 9, 6, or 5 d while undergoing this process. The simulated microgravity was controlled utilizing a gravity controller around 0 m s-2. The mung bean sprouts stored for 6 d under simulated microgravity conditions maintained higher thickness levels than the vegetable samples stored under normal gravity conditions (9.8 m s-2) for the same duration. The mass of all three items decreased with time without regard to the gravity environment, though the samples stored within the simulated microgravity environment displayed significant mass retention on and after 3 d for mung bean sprout samples and 1 d for white radish sprout samples. In contrast, the mass retention effect was not observed in the vegetable soybean samples. Hence, it was confirmed that the mass retention effect of microgravity was limited to sprout vegetables. As a result of analysis harnessing a mathematical model, assuming that the majority of the mass loss is due to moisture loss, a significant difference in mass reduction coefficient occurs among mung bean sprouts and white radish sprouts due to the microgravity environment, and the mass retention effect of simulated microgravity is quantitatively evaluated utilizing mathematical models. Simulated microgravity, which varies significantly from conventional refrigeration, ethylene control, and modified atmosphere, was demonstrated effective as a novel method for preserving and maintaining the freshness of sprout vegetables. This founding will support long-term space flight missions by prolonging shelf life of sprout vegetables.
| S-EPMC7561153 | biostudies-literature
Project description:Simulated microgravity (SMG) is regarded as a suitable environment to produce recombinant proteins. This study showed that β-glucuronidase expressing Escherichia coli had higher productivity of recombinant protein and higher plasmid copy number under SMG compared with the normal gravity condition. The cellular changes were analyzed at both transcriptomic and proteomic levels. The upregulation of a group of ribosome/RNA polymerase genes and a cluster of genes involving energy metabolism at transcriptomic level stood out for improved production of recombinant protein under SMG. The protein folding modulators such as chaperones were upregulated at proteomic level, which could be a result of the increased activity of protein synthesis and can help recombinant protein production. Protein export was also strengthened, which was revealed at both transcriptomic and proteomic levels. The results demonstrated that SMG is a favorable environment for recombinant protein production arousing the upregulation of protein synthesis, protein folding, and protein export.
| S-EPMC7044180 | biostudies-literature
Project description:RNAseq analysis of Hypomontagnella monticulosum under production and non-production conditions
2020-07-17 | E-MTAB-8948 | biostudies-arrayexpress
Project description:Two species of microcolonial fungi - Cryomyces antarcticus and Knufia perforans - and a species of black yeasts-Exophiala jeanselmei - were exposed to thermo-physical Mars-like conditions in the simulation chamber of the German Aerospace Center. In this study the alterations at the protein expression level from various fungi species under Mars-like conditions were analyzed for the first time using 2D gel electrophoresis. Despite of the expectations, the fungi did not express any additional proteins under Mars simulation that could be interpreted as stress induced HSPs. However, up-regulation of some proteins and significant decreasing of protein number were detected within the first 24 hours of the treatment. After 4 and 7 days of the experiment protein spot number was increased again and the protein patterns resemble the protein patterns of biomass from normal conditions. It indicates the recovery of the metabolic activity under Martian environmental conditions after one week of exposure.
| S-EPMC4037706 | biostudies-other
Project description:To reveal the potential mechanisms involved in the dysfunction of antiviral immune responses under simulated microgravity conditions, we investigated the transcriptional changes related to the status of innate immune responses by RNA-seq with poly I:C or mock PBS treatment under Normal gravity or simulated microgravity conditions. Our results indicate that the retinoic acid inducible gene (RIG)-I-like receptor (RLR) and Toll-like receptor (TLR) signal pathways, which are both involved in the type-I interferon induction, are significantly inhibited by simulated microgravity effects.
2020-12-22 | GSE145967 | GEO
Project description:Background:To objectively investigate accommodative response to various refractive stimuli in subjects with normal accommodation. Methods:This prospective, non-randomized clinical trial included 64 eyes of 32 subjects with a mean spherical equivalent -1.4 diopters (D). We evaluated changes in accommodative power, pupil diameter, astigmatic value, and axis when visual stimuli were applied to binocular, monocular (dominant eye, non-dominant eye, ipsilateral, and contralateral), and pinhole conditions. Visual stimuli were given at 0.25 D (4 m), 2 D (50 cm), 3 D (33 cm), and 4 D (25 cm) and accommodative response was evaluated using open view binocular autorefractor/keratometer. Results:The accommodative response to binocular stimulus was 90.9% of the actual refractive stimulus, while that of the monocular stimulus was 84.6%. The binocular stimulus induced a smaller pupil diameter than did the monocular stimulus. There was no difference in accommodative response between the dominant eye and non-dominant eye or between ipsilateral and contralateral stimuli. As the refractive stimuli became stronger, the absolute astigmatic value increased and the direction of the astigmatism axis became more horizontal. Pinhole glasses required 10%-15% less accommodative power compared with the monocular condition. Conclusion:Binocular stimuli enable more precise and effective accommodation than do monocular stimuli. Accommodative response is composed of 90% true accommodation and 10% pseudo-accommodation, and the refractive stimulus in one eye affects the contralateral eye to the same extent. This should be taken into account when developing guidelines for wearing smart glasses while driving, as visual stimulation is applied to only one eye, but far distance attention is constantly needed. Trial Registration:ClinicalTrials.gov Identifier: NCT03557346.
| S-EPMC6345635 | biostudies-literature