Funktionelle Aspekte biologisch aktiver Komponenten aus dem Regurgitat von Spondoptera littoralis-Larven

Im Regurgitat (Vorderdarminhalt) von Spodoptera-Larven befinden sich zahlreiche biologisch aktive Substanzen, welche in verschiedenen multitrophen Interaktionen eine Rolle spielen können. N-Acylaminosäure-Konjugate induzieren beispielsweise indirekte Verteidigungsstrategien einiger Pflanzen. Spodoptera-Darmbakterien sind in der Lage diese Konjugate zu synthetisieren. Einer dieser Bakterienstämme, Microbacterium arborescens, besitzt ein Konjugationsenzym (AAH), das Homologien zu DPS-Proteinen (DNA-protecting protein under starved conditions) zeigt. Hier konnte gezeigt werden, dass AAH in anderen konjugationsaktiven Bakterien nicht vorkommt. Die Suche nach weiteren bakteriellen Konjugationsenzymen ergab Hinweise auf eine Glutamatdehydrogenase und eine Putrescinoxidase. Die bislang bekannten Konjugationsenzyme bilden somit keine homogene Gruppe. Die Untersuchung der Regulation von AAH ergab, dass es wie andere DPS-Proteine vorwiegend in der stationären Wachstumsphase gebildet wird. AAH wird über Eisen (II) reguliert. Siderophore oder FeSO4 induzierten die Expression von AAH, während Chelatoren seine Expression inhibierten. Neben den N-Acylaminosäure-Konjugaten findet man im Regurgitat die 8-Hydroxychinolin-2-carbonäure (8-HQA) in hoher Konzentration. Hier konnte gezeigt werden, dass diese Komponente von der Larve selbst gebildet wird und nicht von ihren Darmbakterien. 8-HQA ist ein Stoffwechselprodukt von Tryptophan. Mit der Aufklärung des Biosyntheseweges wurde gezeigt, dass das reaktive 3-Hydroxykynurenin eine Vorstufe ist. Analog zur strukturell ähnlichen Xanthurensäure in Aedes aegypti könnte die Aufgabe von 8-HQA in Spodoptera-Larven die Eliminierung dieser toxischen Vorstufe sein. Zudem hemmte 8-HQA bakterielles Wachstum über Eisenkomplexierung und die Aktivität eisenhaltiger Enzyme wurde inhibiert

Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy

Though peanut oral immunotherapy (OIT) is a promising investigational therapy, its potential is limited by substantial adverse events (AEs), which are relatively understudied

Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy

Although peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy

Prostacyclin Released by Cancer-Associated Fibroblasts Promotes Immunosuppressive and Pro-Metastatic Macrophage Polarization in the Ovarian Cancer Microenvironment

Metastasis of high-grade ovarian carcinoma (HGSC) is orchestrated by soluble mediators of the tumor microenvironment. Here, we have used transcriptomic profiling to identify lipid-mediated signaling pathways encompassing 41 ligand-synthesizing enzymes and 23 cognate receptors in tumor, immune and stroma cells from HGSC metastases and ascites. Due to its strong association with a poor clinical outcome, prostacyclin (PGI2) synthase (PTGIS) is of particular interest in this signaling network. PTGIS is highly expressed by cancer-associated fibroblasts (CAF), concomitant with elevated PGI2 synthesis, whereas tumor-associated macrophages (TAM) exhibit the highest expression of its surface receptor (PTGIR). PTGIR activation by PGI2 agonists triggered cAMP accumulation and induced a mixed-polarization macrophage phenotype with altered inflammatory gene expression, including CXCL10 and IL12A repression, as well as reduced phagocytic capability. Co-culture experiments provided further evidence for the interaction of CAF with macrophages via PGI2, as the effect of PGI2 agonists on phagocytosis was mitigated by cyclooxygenase inhibitors. Furthermore, conditioned medium from PGI2-agonist-treated TAM promoted tumor adhesion to mesothelial cells and migration in a PTGIR-dependent manner, and PTGIR activation induced the expression of metastasis-associated and pro-angiogenic genes. Taken together, our study identifies a PGI2/PTGIR-driven crosstalk between CAF, TAM and tumor cells, promoting immune suppression and a pro-metastatic environment

Cell type‐selective pathways and clinical associations of lysophosphatidic acid biosynthesis and signaling in the ovarian cancer microenvironment

The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show that the levels of multiple acyl‐LPA species are strongly elevated in ascites versus plasma and are associated with short relapse‐free survival. Data derived from transcriptome and secretome analyses of primary ascite‐derived cells indicate that (a) the major route of LPA synthesis is the consecutive action of a secretory phospholipase A2 (PLA2) and autotaxin, (b) that the components of this pathway are coordinately upregulated in ascites, and (c) that CD163+CD206+ tumor‐associated macrophages play an essential role as main producers of PLA2G7 and autotaxin. The latter conclusion is consistent with mass spectrometry‐based metabolomic analyses of conditioned medium from ascites cells, which showed that tumor‐associated macrophages, but not tumor cells, are able to produce 20:4 acyl‐LPA in lipid‐free medium. Furthermore, our transcriptomic data revealed that LPA receptor (LPAR) genes are expressed in a clearly cell type‐selective manner: While tumor cells express predominantly LPAR1‐3, macrophages and T cells also express LPAR5 and LPAR6 at high levels, pointing to cell type‐selective LPA signaling pathways. RNA profiling identified cytokines linked to cell motility and migration as the most conspicuous class of LPA‐induced genes in macrophages, suggesting that LPA exerts protumorigenic properties at least in part via the tumor secretome

Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy

Though peanut oral immunotherapy (OIT) is a promising investigational therapy, its potential is limited by substantial adverse events (AEs), which are relatively understudied