Sphingosine-1-phosphate Receptor-1 Agonist Averts the De Novo Generation of Autoreactive T-cells in Murine Acute Graft-versus-Host Disease.
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ABSTRACT:
SUBMITTER: Vollmer M
PROVIDER: S-EPMC8274799 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P is linked to a pathological outcome with inflammation, cancer metastasis, or angiogenesis, etc. In this regard, SPHK/S1P axis regulation has been a specific issue in the anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhancing serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs, which eventually induced an unusual environment with a high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase), which contributes a partial increase in Cers. Collectively, a dansyl-modified DPF-543 relatively enhanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.
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Project description:Although IL-17 is a pro-inflammatory cytokine reportedly involved in various autoimmune inflammatory disorders, its role remains unclear in murine models of colitis. Acute colitis was induced by 2.5% dextran sodium sulfate (DSS) treatment for 5 days. A novel sphingosine-1-phosphate receptor agonist W-061, a prototype of ONO-4641, was orally administered daily, and histopathological analysis was performed on the colon. The number of lymphocytes and their cytokine production were also evaluated in spleen, mesenteric lymph node, Peyer's patch and lamina propria of the colon. Daily administration of W-061 resulted in improvement of DSS-induced colitis, and significantly reduced the number of CD4+ T cells in the colonic lamina propria. Numbers of both Th17 and Th1 cells were reduced by W-061 treatment. W-061, however, had no influence on the number of Treg cells in lamina propria. Thus, Th17 and Th1 cells in lamina propria were thought to be the key subsets in the pathogenesis of DSS-induced colitis. In conclusion, W-061 may be a novel therapeutic strategy to ameliorate acute aggravation of inflammatory bowel diseases.
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Project description:Aryl hydrocarbon receptor (AhR), a cellular chemical sensor, controls cellular homeostasis, and sphingosine-1-phosphate (S1P), a bioactive intermediate of sphingolipid metabolism, is believed to have a role in immunity and inflammation, but their potential crosstalk is currently unknown. We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism. We showed that AhR ligands, including an environmental polycyclic aromatic hydrocarbon (PAH), induced S1P generation, and inhibited S1P lyase (S1PL) activity in resting cells, antigen/IgE-activated mast cells, and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge. The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317, which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein, whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect. Furthermore, analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3-S1PL complex, which was confirmed by FRET analysis. This change increased the S1P levels, which in turn, induced mast cell degranulation via S1PR2 signaling. In addition, elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects. These results suggest a new regulatory pathway whereby the AhR-ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL, which may contribute to the expression of allergic diseases.
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Project description:Mammalian cells that have undergone gene amplification and/or gene rearrangement have been used as resources to gain insight into the questions of chromosome structure and dynamics. The multidrug resistant murine cell line J7.V2-1 has been shown previously to contain two distinct forms of the highly amplified mdr2 gene, a member of the mouse gene family responsible for the multidrug resistant (MDR) phenotype [Kirschner, L. S. (1995) DNA Cell Biol. 14, 47-59]. Characterization of both forms of the gene revealed that one form corresponded to the wild-type structure of the gene, whereas the other represented a rearrangement. Investigation of this altered gene demonstrated a deletion of 1.6 kb of the wild-type sequence, and replacement of this region with a poly(AT) tract that appears to have been generated de novo. Analysis of the native sequence in this region demonstrated the absence of repetitive elements, but was notable for the presence of two long stretches of polypurine: polypyrimidine strand asymmetry. Analysis of mdr2 transcripts in this cell line revealed that nearly all of the mRNA is transcribed from the rearranged form of the gene. This message is unable to code for a functional mdr2 gene product, owing to a deletion of the fourth exon during this event. Mechanisms of the rearrangement, as well as the significance of this curious effect on transcription, are discussed.
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Project description:Lung transplantation remains the only viable therapy for patients with end-stage lung disease. However, the full utilization of this strategy is severely compromised by a lack of donor lung availability. The vast majority of donor lungs available for transplantation are from individuals after brain death (BD). Unfortunately, the early autonomic storm that accompanies BD often results in neurogenic pulmonary edema (NPE), producing varying degrees of lung injury or leading to primary graft dysfunction after transplantation. We demonstrated that sphingosine 1-phosphate (S1P)/analogues, which are major barrier-enhancing agents, reduce vascular permeability via the S1P1 receptor, S1PR1. Because primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that the S1PR1 agonist, SEW-2871, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed after BD, with increases of approximately 60% in bronchoalveolar lavage (BAL) total protein, cell counts, and lung tissue wet/dry (W/D) weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after BD and assessed after 4 hours exhibited significant lung protection (? 50% reduction, P = 0.01), as reflected by reduced BAL protein/albumin, cytokines, cellularity, and lung tissue wet/dry weight ratio. Microarray analysis at 4 hours revealed a global impact of both BD and SEW on lung gene expression, with a differential gene expression of enriched immune-response/inflammation pathways across all groups. Overall, SEW served to attenuate the BD-mediated up-regulation of gene expression. Two potential biomarkers, TNF and chemokine CC motif receptor-like 2, exhibited gene array dysregulation. We conclude that SEW-2871 significantly attenuates BD-induced lung injury, and may serve as a potential candidate to improve human donor availability.
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Project description:Lung transplantation remains the only viable therapy for patients with end-stage lung disease; however, full utilization of this treatment strategy is severely compromised by the lack of donor lung availability. For example, the vast majority of donor lungs available for transplantation are obtained from brain death (BD) individuals. Unfortunately, the autonomic storm which accompanies BD often results in neurogenic pulmonary edema (NPE), thereby either producing irreversible lung injury or leading to primary graft dysfunction following lung transplantation. We previously demonstrated that sphingosine 1-phosphate (S1P), a phospholipid angiogenic factor and major barrier-enhancing agent, as well as S1P analogues serve to reduce vascular permeability and ischemia/reperfusion (I/R) lung injury in rodents via ligation of the S1P1 receptor, S1PR1. As primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that SEW-2871, a S1PR1 agonist, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed 4h after BD in a rat BD model with ~60% increases in BAL total protein, BAL cell counts, and lung tissue W/D weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after the induction of BD and assessed 4h later exhibited significant lung protection (~50% reduction, p=0.01) reflected by reduced BAL total protein, BAL cytokines concentrations, BAL albumin, BAL total cell count and lung tissue wet/dry (W/D) weights ratio. Microarray analysis at 4hrs revealed a global impact of both BD and SEW on lung gene expression with differential expression of a subclass of genes enriched in immune/inflammation response pathways across the 4 experimental groups. Overall, SEW served to attenuate the BD-mediated ie gene expression upregulation. Two potentially useful biomarkers, Tnf and Ccrl2, exhibited gene dysregulation by microarray analysis, which was validated by qPCR. We conclude that SEW-2871 significantly attenuates BD-induced lung injury and may serve as a potential candidate to improve human lung donor availability and transplantation outcomes. Animals were divided into four groups: sham, BD (A Fogarty catheter 4 Fr. was inserted and secured into the extradural space and inflated to induce BD), SEW (injection of SEW-2871), and BD/SEW. Three replicates each.
2010-07-30 | E-GEOD-22531 | biostudies-arrayexpress
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Project description:Traditional drug discovery is very laborious, expensive, and time-consuming, due to the huge combinatorial complexity of the discrete molecular search space. Researchers have turned to machine learning methods for help to tackle this difficult problem. However, most existing methods are either virtual screening on the available database of compounds by protein-ligand affinity prediction, or unconditional molecular generation, which does not take into account the information of the protein target. In this paper, we propose a protein target-oriented de novo drug design method, called AlphaDrug. Our method is able to automatically generate molecular drug candidates in an autoregressive way, and the drug candidates can dock into the given target protein well. To fulfill this goal, we devise a modified transformer network for the joint embedding of protein target and the molecule, and a Monte Carlo tree search (MCTS) algorithm for the conditional molecular generation. In the transformer variant, we impose a hierarchy of skip connections from protein encoder to molecule decoder for efficient feature transfer. The transformer variant computes the probabilities of next atoms based on the protein target and the molecule intermediate. We use the probabilities to guide the look-ahead search by MCTS to enhance or correct the next-atom selection. Moreover, MCTS is also guided by a value function implemented by a docking program, such that the paths with many low docking values are seldom chosen. Experiments on diverse protein targets demonstrate the effectiveness of our methods, indicating that AlphaDrug is a potentially promising solution to target-specific de novo drug design.
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