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Synthetic glucocorticoids are potent anti-inflammatory drugs but show dose-dependent metabolic side effects such as the development of insulin resistance and obesity. The precise mechanisms involved in these glucocorticoid-induced side effects, and especially the participation of adipose tissue in this are not completely understood. We used a combination of transcriptomics, antibody arrays and bioinformatics approaches to characterize prednisolone-induced alterations in gene expression and adipokine secretion, which could underlie metabolic dysfunction in 3T3-L1 adipocytes. Several pathways, including cytokine signalling, Akt signalling, and Wnt signalling were found to be regulated at multiple levels, showing that these processes are targeted by prednisolone. These results suggest that mechanisms by which prednisolone induce insulin resistance include dysregulation of wnt signalling and immune response processes. These pathways may provide interesting targets for the development of improved glucocorticoids.
Background:In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19.Objective:Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19.Methods:This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand.Results:As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024.Conclusions:This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment.Trial Registration:ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359International Registered Report Identifier (IRRID):DERR1-10.2196/48183
MULTIFILE
The transition to a biobased economy necessitates utilizing renewable resources as a sustainable alternative to traditional fossil fuels. Bioconversion is a way to produce many green chemicals from renewables, e.g., biopolymers like PHAs. However, fermentation and bioconversion processes mostly rely on expensive, and highly refined pure substrates. The utilization of crude fractions from biorefineries, especially herbaceous lignocellulosic feedstocks, could significantly reduce costs. This presentation shows the microbial production of PHA from such a crude stream by a wild-type thermophilic bacterium Schlegelella thermodepolymerans [1]. Specifically, it uses crude xylose-rich fractions derived from a newly developed biorefinery process for grassy biomasses (the ALACEN process). This new stepwise mild flow-through biorefinery approach for grassy lignocellulosic biomass allows the production of various fractions: a fraction containing esterified aromatics, a monomeric xylose-rich stream, a glucose fraction, and a native-like lignin residue [2]. The crude xylose-rich fraction was free of fermentation-inhibiting compounds meaning that the bacterium S.thermodepolymerans could effectively use it for the production of one type of PHA, polyhydroxybutyrate. Almost 90% of the xylose in the refined wheat straw fraction was metabolized with simultaneous production of PHA, matching 90% of the PHA production per gram of sugars, comparable to PHA yields from commercially available xylose. In addition to xylose, S. thermodepolymerans converted oligosaccharides with a xylose backbone (xylans) into fermentable xylose, and subsequently utilized the xylose as a source for PHA production. Since the xylose-rich hydrolysates from the ALACEN process also contain some oligomeric xylose and minor hemicellulose-derived sugars, optimal valorization of the C5-fractions derived from the refinery process can be obtained using S. thermodepolymerans. This opens the way for further exploration of PHA production from C5-fractions out of a variety of herbaceous lignocellulosic biomasses using the ALACEN process combined with S. thermodepolymerans. Overall, the innovative utilization of renewable resources in fermentation technology, as shown herein, makes a solid contribution to the transition to a biobased economy.[1] W. Zhou, D.I. Colpa, H. Permentier, R.A. Offringa, L. Rohrbach, G.J.W. Euverink, J. Krooneman. Insight into polyhydroxyalkanoate (PHA) production from xylose and extracellular PHA degradation by a thermophilic Schlegelella thermodepolymerans. Resources, Conservation and Recycling 194 (2023) 107006, ISSN 0921-3449, https://doi.org/10.1016/j.resconrec.2023.107006. [2] S. Bertran-Llorens, W.Zhou. M.A.Palazzo, D.I.Colpa, G.J.W.Euverink, J.Krooneman, P.J.Deuss. ALACEN: a holistic herbaceous biomass fractionation process attaining a xylose-rich stream for direct microbial conversion to bioplastics. Submitted 2023.
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