Arterial oxygen partial pressures reduce the insulin-dependent induction of the perivenously located glucokinase in rat hepatocyte cultures: mimicry of arterial oxygen pressures by H2O2.
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ABSTRACT:
SUBMITTER: Kietzmann T
PROVIDER: S-EPMC1218031 | biostudies-other | 1997 Jan
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Central venous oxygen saturation (ScvO2), venous-arterial blood carbon dioxide partial pressures difference (Pv-aCO2), venous-arterial blood carbon dioxide partial pressures difference/arterial-venous oxygen difference ratio (Pv-aCO2/Ca-vO2) and lactate are important parameters employed during shock resuscitation. We designed this study to confirm the effects of time delay and body temperature on measurements of these four parameters. METHODS:Arterial and central venous blood samples were simultaneously drawn by plastic syringes via indwelling intra-arterial and central venous catheters from critically ill patients. Blood gas analyses were performed on both samples and repeated after 10, 20, 30, 40, 50 and 60?min. Patients were divided into a control group and a high temperature group according to whether the body temperature was greater than 38?°C. RESULTS:A total of 30 critically ill patients were enrolled. There was a trend of increasing values for ScvO2, Pv-aCO2, Pv-aCO2/Ca-vO2 and lactate over time (P?<?0.001). The ScvO2 differences were all lower in high temperature group after 10, 20, 30, 40, 50 and 60?min when compared to the corresponding differences in the control group (P?<?0.05). The differences in lactate values were slightly higher in the high temperature group, relative to the control group after 20, 30, 40, 50 and 60?min (P?<?0.05). CONCLUSIONS:Measurements of ScvO2, Pv-aCO2, lactate and Pv-aCO2/Ca-vO2 were affected by time delay or body temperature. We recommend that arterial and central venous blood gas samples be analyzed quickly within 10?min, especially for patients with body temperature <38?°C. TRIAL REGISTRATION:ChiCTR, ChiCTR1800014484 . Registered 16 January 2018.
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Project description:Explaining the maintenance of adaptive diversity within populations is a long-standing goal in evolutionary biology, with important implications for conservation, medicine, and agriculture. Adaptation often leads to the fixation of beneficial alleles, and therefore it erodes local diversity so that understanding the coexistence of multiple adaptive phenotypes requires deciphering the ecological mechanisms that determine their respective benefits. Here, we show how antagonistic frequency-dependent selection (FDS), generated by natural and sexual selection acting on the same trait, maintains mimicry polymorphism in the toxic butterfly Heliconius numata Positive FDS imposed by predators on mimetic signals favors the fixation of the most abundant and best-protected wing-pattern morph, thereby limiting polymorphism. However, by using mate-choice experiments, we reveal disassortative mate preferences of the different wing-pattern morphs. The resulting negative FDS on wing-pattern alleles is consistent with the excess of heterozygote genotypes at the supergene locus controlling wing-pattern variation in natural populations of H. numata The combined effect of positive and negative FDS on visual signals is sufficient to maintain a diversity of morphs displaying accurate mimicry with other local prey, although some of the forms only provide moderate protection against predators. Our findings help understand how alternative adaptive phenotypes can be maintained within populations and emphasize the need to investigate interactions between selective pressures in other cases of puzzling adaptive polymorphism.
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Project description:P-Glycoprotein transporters encoded by mdr1 (multidrug resistance) genes mediate extrusion of an array of lipophilic xenobiotics from the cell. In rat liver, mdr transcripts have been shown to be expressed mainly in hepatocytes of the periportal region. Since gradients in oxygen tension (pO(2)) may contribute towards zonated gene expression, the influence of arterial and venous pO(2) on mRNA expression of the mdr1b isoform was examined in primary rat hepatocytes cultured for up to 3 days. Maximal mdr1b mRNA levels (100%) were observed under arterial pO(2) after 72 h, whereas less than half-maximal mRNA levels (40%) were attained under venous pO(2). Accordingly, expression of mdr protein and extrusion of the mdr1 substrate rhodamine 123 were maximal under arterial pO(2) and reduced under venous pO(2). Oxygen-dependent modulation of mdr1b mRNA expression was prevented by actinomycin D, indicating transcriptional regulation. Inhibition of haem synthesis by 25 microM CoCl(2) blocked mdr1b mRNA expression under both oxygen tensions, whereas 80 microM desferrioxamine abolished modulation by O(2). Haem (10 microM) increased mdr1b mRNA levels under arterial and venous pO(2). In hepatocytes treated with 50 microM H(2)O(2), mdr1b mRNA expression was elevated by about 1.6-fold at venous pO(2) and 1.5-fold at arterial pO(2). These results support the conclusion that haem proteins are crucial for modulation of mdr1b mRNA expression by O(2) in hepatocyte cultures and that reactive oxygen species may participate in O(2)-dependent signal transduction. Furthermore, the present study suggests that oxygen might be a critical modulator for zonated secretion of mdr1 substrates into the bile.
| S-EPMC1221271 | biostudies-other
Project description:Over the last decade HepaRG cells have emerged as a promising alternative to primary human hepatocytes (PHH) and have been featured in over 300 research publications. Most of these reports employed freshly differentiated HepaRG cells that require time-consuming culture (?28 days) for full differentiation. Recently, a cryopreserved, predifferentiated format of HepaRG cells (termed here "cryo-HepaRG") has emerged as a new model that improves global availability and experimental flexibility; however, it is largely unknown whether HepaRG cells in this format fully retain their hepatic characteristics. Therefore, we systematically investigated the hepatocyte functionality of cryo-HepaRG cultures in context with the range of interindividual variation observed with PHH in both sandwich-culture and suspension formats. These evaluations uncovered a novel adaptation period for the cryo-HepaRG format and demonstrated the impact of extracellular matrix on cryo-HepaRG functionality. Pharmacologically important drug-metabolizing alleles were genotyped in HepaRG cells and poor metabolizer alleles for CYP2D6, CYP2C9, and CYP3A5 were identified and consistent with higher frequency alleles found in individuals of Caucasian decent. We observed liver enzyme inducibility with aryl hydrocarbon receptor, constitutive androstane receptor (CAR), and pregnane X receptor activators comparable to that of sandwich-cultured PHH. Finally, we show for the first time that cryo-HepaRG supports proper CAR cytosolic sequestration and translocation to hepatocyte nuclei in response to phenobarbital treatment. Taken together, these data reveal important considerations for the use of this cell model and demonstrate that cryo-HepaRG are suitable for metabolism and toxicology screening.
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Project description:The jejunum is the segment of the small intestine responsible for several metabolism and biotransformation functions. In this report, we have cultured rat jejunum explants in vitro and integrated them with hepatocyte cultures. We have also investigated the changes in jejunum function at different locations since spatial variations in intestinal functions have been reported previously. We divided the length of the rat jejunum into three distinct regions of approximately 9 cm each. We defined the regions as proximal (adjacent to the duodenum), medial, and distal (adjacent to the ileum). Spatiotemporal variations in functions were observed between these regions within the jejunum. Alkaline phosphatase activity (a marker of enterocyte function), decreased twofold between the proximal and distal regions at 4 hr. Lysozyme activity (a marker of Paneth cell function) increased from the proximal to the distal jejunum by 40% at 24 hr. Mucin-covered areas, a marker of goblet cell function, increased by twofold between the proximal and distal segments of the jejunum at 24 hr. When hepatocytes were integrated with proximal jejunum explants, statistically higher urea (~2.4-fold) and mucin (57%) production were observed in the jejunum explants. The integrated intestine-liver cultures can be used as a platform for future investigations.
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Project description:End-tidal CO2 tension provides an accurate estimation of P aCO2 in healthy awake individuals over an extensive range of CO2 pressures induced by 17 environmental conditions combining different O2, CO2 and barometric pressures https://bit.ly/3YuKPAY.
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Project description:The liver plays a vital role in glucose homeostasis, the synthesis of bile acids and the detoxification of foreign substances. Liver culture systems are widely used to test adverse effects of drugs and environmental toxicants. The two most prevalent liver culture systems are hepatocyte monolayers (HMs) and collagen sandwiches (CS). Despite their wide use, comprehensive transcriptional programs and interaction networks in these culture systems have not been systematically investigated. We integrated an existing temporal transcriptional dataset for HM and CS cultures of rat hepatocytes with a functional interaction network of rat genes. We aimed to exploit the functional interactions to identify statistically significant linkages between perturbed biological processes. To this end, we developed a novel approach to compute Contextual Biological Process Linkage Networks (CBPLNs). CBPLNs revealed numerous meaningful connections between different biological processes and gene sets, which we were successful in interpreting within the context of liver metabolism. Multiple phenomena captured by CBPLNs at the process level such as regulation, downstream effects, and feedback loops have well described counterparts at the gene and protein level. CBPLNs reveal high-level linkages between pathways and processes, making the identification of important biological trends more tractable than through interactions between individual genes and molecules alone. Our approach may provide a new route to explore, analyze, and understand cellular responses to internal and external cues within the context of the intricate networks of molecular interactions that control cellular behavior.
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Project description:Leaf senescence, either as a natural stage of development or as an induced process under stress conditions, incorporates multiple intricate signaling pathways. At the cellular level, retrograde signals have been considered as important players during the initiation and progression of senescence in both animals and plants. The plant-specific single-strand DNA-binding protein WHIRLY1 (WHY1), a repressor of leaf natural senescence, is dually located in both nucleus and plastids. Despite many years of studies, the myth about its dual location and the underlying functional implications remain elusive. Here, we provide further evidence in Arabidopsis showing that alteration in WHY1 allocation between the nucleus and chloroplast causes perturbation in H2O2 homeostasis, resulting in adverse plant senescence phenotypes. The knockout of WHY1 increased H2O2 content at 37 days post-germination, coincident with an early leaf senescence phenotype, which can be rescued by ectopic expression of the nuclear isoform (nWHY1), but not by the plastid isoform (pWHY1). Instead, accumulated pWHY1 greatly provoked H2O2 in cells. On the other hand, exogenous H2O2 treatment induced a substantial plastid accumulation of WHY1 proteins and at the same time reduced the nuclear isoforms. This H2O2-induced loss of nucleus WHY1 isoform was accompanied by enhanced enrichments of histone H3 lysine 9 acetylation (H3K9ac) and recruitment of RNA polymerase II (RNAP II) globally, and specifically at the promoter of the senescence-related transcription factor WRKY53, which in turn activated WRKY53 transcription and led to a senescence phenotype. Thus, the distribution of WHY1 organelle isoforms and the feedback of H2O2 intervene in a circularly integrated regulatory network during plant senescence in Arabidopsis.
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Project description:A substantial shift in the field of pulmonary hypertension (PH) is ongoing, as the previous practice of mean pulmonary arterial wedge pressure (PAWPM ) is no longer supported. Instead, aiming for a better estimate of end-diastolic pressures (EDP), instantaneous PAWP at mid-A-wave (PAWPmid-A ) or, in the absence of an A-wave, at 130-160 ms following QRS onset has recently been recommended. Electrocardiogram-gated PAWP (PAWPQRS ) has also been proposed. The quantitative differences as well as the diagnostic and prognostic utility of these novel PAWP measurements have not been evaluated. We set out to address these issues. Pressure tracings of 141 patients with PH due to left heart disease (PH-LHD) and 43 with primary pulmonary arterial hypertension (PAH) were analysed. PAWP was measured as follows: (i) mean pressure (PAWPM ); (ii) per the latest consensus approach [PAWPmid-A , or in atrial fibrillation 130, 140, 150, and 160 ms following QRS onset (PAWP130-160 )]; (iii) at QRS onset (PAWPQRS ); and (iv) Z-point (PAWPZ ). For each PAWP, the corresponding pulmonary vascular resistance (PVR) and diastolic pressure gradient were calculated. The cohort comprised 45% female. Mean age was 66 ± 15. PAWPmid-A was in good agreement with PAWPZ (17.3 [14.5 to 21.2] vs. 17.6 [14.2 to 21.6] mmHg, P = 0.63), whereas PAWPQRS provided significantly lower values (15.3 [12.5 to 19.2] mmHg, P < 0.001). In atrial fibrillation, PAWP130 and PAWPQRS yielded the optimal temporal and quantitative analyses of EDPs. The ability to differentiate PAH from PH-LHD was similar for the various PAWP measurements [PAWPM : area under the curve (AUC) 0.98, confidence interval (CI) 0.96-0.99; PAWPmid-A/130 : AUC 0.94, CI 0.91-0.98; PAWPQRS : AUC 0.96, CI 0.94-0.99, P < 0.001 for all]. PVR based on instantaneous PAWP measurements failed to provide superior prognostic information in PH-LHD as compared with conventional PVR. Although instantaneous PAWP measurement might better represent EDP, they nevertheless fail to yield incremental diagnostic or prognostic information in PH-LHD as compared with conventional measurements.
| S-EPMC7754752 | biostudies-literature
Project description:Phase fluorimetry, unlike the more commonly used intensity-based measurement, is not affected by differences in light paths from culture vessels or by optical attenuation through dense 3D cell cultures and hydrogels thereby minimizing dependence on signal intensity for accurate measurements. This work describes the use of phase fluorimetry on oxygen-sensor microbeads to perform oxygen measurements in different microtissue culture environments. In one example, cell spheroids were observed to deplete oxygen from the cell-culture medium filling the bottom of conventional microwells within minutes, whereas oxygen concentrations remained close to ambient levels for several days in hanging-drop cultures. By dispersing multiple oxygen microsensors in cell-laden hydrogels, we also mapped cell-generated oxygen gradients. The spatial oxygen mapping was sufficiently precise to enable the use of computational models of oxygen diffusion and uptake to give estimates of the cellular oxygen uptake rate and the half-saturation constant. The results show the importance of integrated design and analysis of 3D cell cultures from both biomaterial and oxygen supply aspects. While this paper specifically tests spheroids and cell-laden gel cultures, the described methods should be useful for measuring pericellular oxygen concentrations in a variety of biomaterials and culture formats.
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