73 research outputs found
Cytokine hemoadsorption with CytoSorb<sup>Âź</sup> in post-cardiac arrest syndrome, a pilot randomized controlled trial.
Hemoadsorption (HA) might mitigate the systemic inflammatory response associated with post-cardiac arrest syndrome (PCAS) and improve outcomes. Here, we investigated the feasibility, safety and efficacy of HA with CytoSorb <sup>Âź</sup> in cardiac arrest (CA) survivors at risk of PCAS.
In this pilot randomized controlled trial, we included patients admitted to our intensive care unit following CA and likely to develop PCAS: required norepinephrine (> 0.2 ”g/kg/min), and/or had serum lactate > 6 mmol/l and/or a time-to-return of spontaneous circulation (ROSC) > 25 min. Those requiring ECMO or renal replacement therapy were excluded. Eligible patients were randomly allocated to either receive standard of care (SOC) or SOC plus HA. Hemoadsorption was performed as stand-alone therapy for 24 h, using CytoSorb <sup>Ÿ</sup> and regional heparin-protamine anticoagulation. We collected feasibility, safety and clinical data as well as serial plasma cytokines levels within 72 h of randomization.
We enrolled 21 patients, of whom 16 (76%) had out-of-hospital CA. Median (IQR) time-to-ROSC was 30 (20, 45) minutes. Ten were assigned to the HA group and 11 to the SOC group. Hemoadsorption was initiated in all patients allocated to the HA group within 18 (11, 23) h of ICU admission and conducted for a median duration of 21 (14, 24) h. The intervention was well tolerated except for a trend for a higher rate of aPTT elevation (5 (50%) vs 2 (18%) p = 0.18) and mild (100-150 G/L) thrombocytopenia at day 1 (5 (50%) vs 2 (18%) p = 0.18). Interleukin (IL)-6 plasma levels at randomization were low (< 100 pg/mL) in 10 (48%) patients and elevated (> 1000 pg/mL) in 6 (29%). The median relative reduction in IL-6 at 48 h was 75% (60, 94) in the HA group versus 5% (- 47, 70) in the SOC group (p = 0.06).
In CA survivors at risk of PCAS, HA was feasible, safe and was associated with a nonsignificant reduction in cytokine plasma levels. Future trials are needed to further define the role of HA after CA. Those studies should include cytokine assessment to enrich the study population.
NCT03523039, registered 14 May 2018
Respiratory distress and perinatal lethality in Nedd4-2-deficient mice
The epithelial sodium channel (ENaC) is essential for sodium homoeostasis in many epithelia. ENaC activity is required for lung fluid clearance in newborn animals and for maintenance of blood volume and blood pressure in adults. In vitro studies show that the ubiquitin ligase Nedd4-2 ubiquitinates ENaC to regulate its cell surface expression. Here we show that knockout of Nedd4-2 in mice leads to increased ENaC expression and activity in embryonic lung. This increased ENaC activity is the likely reason for premature fetal lung fluid clearance in Nedd4-2â/â animals, resulting in a failure to inflate lungs and perinatal lethality. A small percentage of Nedd4-2â/â animals survive up to 22 days, and these animals also show increased ENaC expression and develop lethal sterile inflammation of the lung. Thus, we provide critical in vivo evidence that Nedd4-2 is essential for correct regulation of ENaC expression, fetal and postnatal lung function and animal survival
Antiviral activity of the mineralocorticoid receptor NR3C2 against Herpes simplex virus Type 1 (HSV-1) infection
Abstract Analysis of a genome-scale RNA interference screen of host factors affecting herpes simplex virus type 1 (HSV-1) revealed that the mineralocorticoid receptor (MR) inhibits HSV-1 replication. As a ligand-activated transcription factor the MR regulates sodium transport and blood pressure in the kidney in response to aldosterone, but roles have recently been elucidated for the MR in other cellular processes. Here, we show that the MR and other members of the mineralocorticoid signalling pathway including HSP90 and FKBP4, possess anti-viral activity against HSV-1 independent of their effect on sodium transport, as shown by sodium channel inhibitors. Expression of the MR is upregulated upon infection in an interferon (IFN) and viral transcriptional activator VP16-dependent fashion. Furthermore, the MR and VP16, together with the cellular co-activator Oct-1, transactivate the hormone response element (HRE) present in the MR promoter and those of its transcriptional targets. As the MR induces IFN expression, our data suggests the MR is involved in a positive feedback loop that controls HSV-1 infection
A Splice Isoform of DNedd4, DNedd4-Long, Negatively Regulates Neuromuscular Synaptogenesis and Viability in Drosophila
Neuromuscular (NM) synaptogenesis is a tightly regulated process. We previously showed that in flies, Drosophila Nedd4 (dNedd4/dNedd4S) is required for proper NM synaptogenesis by promoting endocytosis of commissureless from the muscle surface, a pre-requisite step for muscle innervation. DNedd4 is an E3 ubiquitin ligase comprised of a C2-WW(x3)-Hect domain architecture, which includes several splice isoforms, the most prominent ones are dNedd4-short (dNedd4S) and dNedd4-long (dNedd4Lo).We show here that while dNedd4S is essential for NM synaptogenesis, the dNedd4Lo isoform inhibits this process and causes lethality. Our results reveal that unlike dNedd4S, dNedd4Lo cannot rescue the lethality of dNedd4 null (DNedd4(T121FS)) flies. Moreover, overexpression of UAS-dNedd4Lo specifically in wildtype muscles leads to NM synaptogenesis defects, impaired locomotion and larval lethality. These negative effects of dNedd4Lo are ameliorated by deletion of two regions (N-terminus and Middle region) unique to this isoform, and by inactivating the catalytic activity of dNedd4Lo, suggesting that these unique regions, as well as catalytic activity, are responsible for the inhibitory effects of dNedd4Lo on synaptogenesis. In accord with these findings, we demonstrate by sqRT-PCR an increase in dNedd4S expression relative to the expression of dNedd4Lo during embryonic stages when synaptogenesis takes place.Our studies demonstrate that splice isoforms of the same dNedd4 gene can lead to opposite effects on NM synaptogenesis
Effects of dietary Na+ deprivation on epithelial Na+ channel (ENaC), BDNF, and TrkB mRNA expression in the rat tongue
<p>Abstract</p> <p>Background</p> <p>In rodents, dietary Na<sup>+ </sup>deprivation reduces gustatory responses of primary taste fibers and central taste neurons to lingual Na<sup>+ </sup>stimulation. However, in the rat taste bud cells Na<sup>+ </sup>deprivation increases the number of amiloride sensitive epithelial Na<sup>+ </sup>channels (ENaC), which are considered as the "receptor" of the Na<sup>+ </sup>component of salt taste. To explore the mechanisms, the expression of the three ENaC subunits (α, ÎČ and Îł) in taste buds were observed from rats fed with diets containing either 0.03% (Na<sup>+ </sup>deprivation) or 1% (control) NaCl for 15 days, by using <it>in situ </it>hybridization and real-time quantitative RT-PCR (qRT-PCR). Since BDNF/TrkB signaling is involved in the neural innervation of taste buds, the effects of Na<sup>+ </sup>deprivation on BDNF and its receptor TrkB expression in the rat taste buds were also examined.</p> <p>Results</p> <p><it>In situ </it>hybridization analysis showed that all three ENaC subunit mRNAs were found in the rat fungiform taste buds and lingual epithelia, but in the vallate and foliate taste buds, only α ENaC mRNA was easily detected, while ÎČ and Îł ENaC mRNAs were much less than those in the fungiform taste buds. Between control and low Na<sup>+ </sup>fed animals, the numbers of taste bud cells expressing α, ÎČ and Îł ENaC subunits were not significantly different in the fungiform, vallate and foliate taste buds, respectively. Similarly, qRT-PCR also indicated that Na<sup>+ </sup>deprivation had no effect on any ENaC subunit expression in the three types of taste buds. However, Na<sup>+ </sup>deprivation reduced BDNF mRNA expression by 50% in the fungiform taste buds, but not in the vallate and foliate taste buds. The expression of TrkB was not different between control and Na<sup>+ </sup>deprived rats, irrespective of the taste papillae type.</p> <p>Conclusion</p> <p>The findings demonstrate that dietary Na<sup>+ </sup>deprivation does not change ENaC mRNA expression in rat taste buds, but reduces BDNF mRNA expression in the fungiform taste buds. Given the roles of BDNF in survival of cells and target innervation, our results suggest that dietary Na<sup>+ </sup>deprivation might lead to a loss of gustatory innervation in the mouse fungiform taste buds.</p
High Salt Intake Down-Regulates Colonic Mineralocorticoid Receptors, Epithelial Sodium Channels and 11ÎČ-Hydroxysteroid Dehydrogenase Type 2
Besides the kidneys, the gastrointestinal tract is the principal organ responsible for sodium homeostasis. For sodium transport across the cell membranes the epithelial sodium channel (ENaC) is of pivotal relevance. The ENaC is mainly regulated by mineralocorticoid receptor mediated actions. The MR activation by endogenous 11ÎČ-hydroxy-glucocorticoids is modulated by the 11ÎČ-hydroxysteroid dehydrogenase type 2 (11ÎČ-HSD2). Here we present evidence for intestinal segment specific 11ÎČ-HSD2 expression and hypothesize that a high salt intake and/or uninephrectomy (UNX) affects colonic 11ÎČ-HSD2, MR and ENaC expression. The 11ÎČ-HSD2 activity was measured by means of 3H-corticosterone conversion into 3H-11-dehydrocorticosterone in Sprague Dawley rats on a normal and high salt diet. The activity increased steadily from the ileum to the distal colon by a factor of about 3, an observation in line with the relevance of the distal colon for sodium handling. High salt intake diminished mRNA and protein of 11ÎČ-HSD2 by about 50% (p<0.001) and reduced the expression of the MR (p<0.01). The functionally relevant ENaC-ÎČ and ENaC-Îł expression, a measure of mineralocorticoid action, diminished by more than 50% by high salt intake (p<0.001). The observed changes were present in rats with and without UNX. Thus, colonic epithelial cells appear to contribute to the protective armamentarium of the mammalian body against salt overload, a mechanism not modulated by UNX
Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants
The relative concentrations of ions and solutes inside cells are actively maintained by several classes of transport proteins, in many cases against their concentration gradient. These transport processes, which consume a large portion of cellular energy, must be constantly regulated. Many structurally distinct families of channels, carriers, and pumps have been characterized in considerable detail during the past decades and defects in the function of some of these proteins have been linked to a growing list of human diseases. The dynamic regulation of the transport proteins present at the cell surface is vital for both normal cellular function and for the successful adaptation to changing environments. The composition of proteins present at the cell surface is controlled on both the transcriptional and post-translational level. Post-translational regulation involves highly conserved mechanisms of phosphorylation- and ubiquitylation-dependent signal transduction routes used to modify the cohort of receptors and transport proteins present under any given circumstances. In this review, we will summarize what is currently known about one facet of this regulatory process: the endocytic regulation of alkali metal transport proteins. The physiological relevance, major contributors, parallels and missing pieces of the puzzle in mammals, yeast and plants will be discussed.This work was supported by grant BFU2011-30197-C03-03 from the Ministerio de Ciencia e Innovacion (Spain). V.L.-T. is supported by a fellowship from the Universidad Politecnica de Valencia. C. P. is supported by a fellowship from the Consejo Superior de Investigaciones Cientificas (Spain).Mulet Salort, JM.; Llopis Torregrosa, V.; Primo Planta, C.; Marques Romero, MC.; Yenush, L. (2013). 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Regulation of the epithelial sodium channel (ENaC) by the serum and glucocorticoid-induced kinase 1 (Sgk1) and the ubiquitin-conjugating enzyme UBE2E3
The role of Nedd4/Nedd4-like dependant ubiquitylation in epithelial transport processes
Ubiquitylation has emerged as an important mechanism for controlling surface expression of membrane proteins. This post-translational modification involves the sequential action of several enzymes including a ubiquitin-activating enzyme E1, a ubiquitin-conjugating enzyme E2 and a ubiquitin-protein ligase E3. E3s are responsible for substrate recognition. Here we describe the role of the Nedd4/Nedd4-like family of ubiquitin-protein ligases in the regulation of proteins involved in epithelial transport. The Nedd4/Nedd4-like proteins are composed of a N-terminal C2 domain, several WW domains and a catalytic HECT domain. The epithelial Na(+) channel ENaC is the best studied example of a Nedd4/Nedd4-like substrate. Its cell surface expression is regulated by the ubiquitin-protein ligase Nedd4-2 via direct PY motif/WW domain interaction. This regulatory mechanism is impaired in Liddle's disease, an inherited form of human hypertension, and is controlled by Sgk1, an aldosterone-inducible kinase which phosphorylates Nedd4-2. The regulation of ENaC by Nedd4-2 is a paradigm for the control of epithelial membrane proteins, as evidenced by the regulation of the ClC-5 chloride channel by the ubiquitin-protein ligase WWP2 or the tight junction protein Occludin by Itch
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