-derived metabolites protect mice against colonic inflammation.

Gut microbiota-derived metabolites play a pivotal role in the maintenance of intestinal immune homeostasis. Here, we demonstrate that the human commensal possesses a specific metabolic fingerprint, consisting predominantly of the tryptophan catabolite indole-3-propionic acid (IPA), the branched-chain acids (BCFAs) isobutyrate and isovalerate and the short-chain fatty acids (SCFAs) acetate and propionate. Mono-colonization of germ-free mice with (CS mice) affected colonic mucosal immune cell phenotypes, including up-regulation of gene expression, and increased abundance of transcriptionally active colonic tuft cells and Foxp3 regulatory T cells (Tregs).

A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1.

Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs).

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 (PGI) synthase (PTGIS) is of particular interest in this signaling network.

Arachidonic acid, a clinically adverse mediator in the ovarian cancer microenvironment, impairs JAK-STAT signaling in macrophages by perturbing lipid raft structures.

Survival of ovarian carcinoma is associated with the abundance of immunosuppressed CD163 CD206 tumor-associated macrophages (TAMs) and high levels of arachidonic acid (AA) in the tumor microenvironment. Here, we show that both associations are functionally linked. Transcriptional profiling revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signaling, mirrored by an impaired transcriptional response to interferons and IL-6 in monocyte-derived macrophages by AA.

An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products.

Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma.

α-Linolenic Acid-Rich Diet Influences Microbiota Composition and Villus Morphology of the Mouse Small Intestine.

α-Linolenic acid (ALA) is well-known for its anti-inflammatory activity. In contrast, the influence of an ALA-rich diet on intestinal microbiota composition and its impact on small intestine morphology are not fully understood. In the current study, we kept adult C57BL/6J mice for 4 weeks on an ALA-rich or control diet.

Overexpression of cyclooxygenase-2 in adipocytes reduces fat accumulation in inguinal white adipose tissue and hepatic steatosis in high-fat fed mice.

Cyclooxygenases are known as important regulators of metabolism and immune processes via conversion of C20 fatty acids into various regulatory lipid mediators, and cyclooxygenase activity has been implicated in browning of white adipose tissues. We generated transgenic (TG) C57BL/6 mice expressing the Ptgs2 gene encoding cyclooxygenase-2 (COX-2) in mature adipocytes. TG mice fed a high-fat diet displayed marginally lower weight gain with less hepatic steatosis and a slight improvement in insulin sensitivity, but no difference in glucose tolerance.

Urinary uromodulin independently predicts end-stage renal disease and rapid kidney function decline in a cohort of chronic kidney disease patients.

Data on risk factors predicting rapid progression to end-stage renal disease (ESRD) or short-term kidney function decline (i.e., within 1 year) in chronic kidney disease (CKD) are rare but urgently needed to plan treatment.

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.

Serum uromodulin-a marker of kidney function and renal parenchymal integrity.

Background: An ELISA to analyse uromodulin in human serum (sUmod) was developed, validated and tested for clinical applications.

Methods: We assessed sUmod, a very stable antigen, in controls, patients with chronic kidney disease (CKD) stages 1-5, persons with autoimmune kidney diseases and recipients of a renal allograft by ELISA.

Results: Median sUmod in 190 blood donors was 207 ng/mL (women: men, median 230 versus 188 ng/mL, P = 0.

Determination of red blood cell fatty acid profiles: Rapid and high-confident analysis by chemical ionization-gas chromatography-tandem mass spectrometry.

Cellular fatty acid (FA) profiles have been acknowledged as biomarkers in various human diseases. Nevertheless, common FA analysis by gas chromatography mass spectrometry (GC-MS) requires long analysis time. Hence, there is a need for feasible methods for high throughput analysis in clinical studies.

A new missense mutation in UMOD gene leads to severely reduced serum uromodulin concentrations - A tool for the diagnosis of uromodulin-associated kidney disease.

Background: Uromodulin-associated Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD) belongs to a group of autosomal dominant inherited diseases caused by mutations in the UMOD gene, which codes for uromodulin, a protein exclusively expressed in renal tubular cells of the ascending limb of the loop of Henle. The diagnosis is hampered by non-specific clinical, laboratory and histological findings. In this study, we evaluated serum uromodulin as diagnostic marker for ADTKD-UMOD in a family with a novel mutation in UMOD.

A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome.

Background: Soluble protein and lipid mediators play essential roles in the tumor environment, but their cellular origins, targets, and clinical relevance are only partially known. We have addressed this question for the most abundant cell types in human ovarian carcinoma ascites, namely tumor cells and tumor-associated macrophages.

Results: Transcriptome-derived datasets were adjusted for errors caused by contaminating cell types by an algorithm using expression data derived from pure cell types as references.

Plasma Uromodulin Correlates With Kidney Function and Identifies Early Stages in Chronic Kidney Disease Patients.

Uromodulin, released from tubular cells of the ascending limb into the blood, may be associated with kidney function. This work studies the relevance of plasma uromodulin as a biomarker for kidney function in an observational cohort of chronic kidney disease (CKD) patients and subjects without CKD (CKD stage 0). It should be further evaluated if uromodulin allows the identification of early CKD stages.

Design and Synthesis of Highly Active Peroxisome Proliferator-Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity.

Based on 3-(((4-(hexylamino)-2-methoxyphenyl)amino)sulfonyl)-2-thiophenecarboxylic acid methyl ester (ST247, compound 2), a recently described peroxisome proliferator-activated receptor (PPAR)β/δ-selective inverse agonist, we designed and synthesized a series of structurally related ligands. The structural modifications presented herein ultimately resulted in a series of ligands that display increased cellular activity relative to 2. Moreover, with methyl 3-(N-(2-(2-ethoxyethoxy)-4-(hexylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (PT-S264, compound 9 u), biologically relevant plasma concentrations in mice were achieved.

ω-3 fatty acids contribute to the asthma-protective effect of unprocessed cow's milk.

Background: Living on a farm has repeatedly been shown to protect children from asthma and allergies. A major factor involved in this effect is consumption of unprocessed cow's milk obtained directly from a farm. However, this phenomenon has never been shown in a longitudinal design, and the responsible milk components are still unknown.

Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment.

The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients.

[Metastasized renal cell carcinoma. Measurement of plasma levels of the tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib].

Background: Several tyrosine kinase inhibitors (TKI) are used in the treatment of metastasized renal cell carcinoma (mRCC). This article presents a feasibility study for the measurement of plasma levels of sunitinib, sorafenib and pazopanib using liquid chromatography tandem mass spectrometry (LC-MS/MS).

Methods: A total of 23 patients suffering from mRCC under treatment with sunitinib (n=16), sorafenib (n=3) and pazopanib (n=4) were included.

Nilotinib is more potent than imatinib for treating plexiform neurofibroma in vitro and in vivo.

Plexiform neurofibromas (PNFs) are benign nerve sheath tumors mostly associated with neurofibromatosis type 1. They often extend through multiple layers of tissue and therefore cannot be treated satisfactorily by surgery. Nilotinib is a tyrosine kinase inhibitor used to treat leukemia, with advantages over the prototype imatinib in terms of potency and selectivity towards BCR-ABL, and the DDR, PDGFR, and KIT receptor kinases.

Development and clinical application of a LC-MS/MS method for simultaneous determination of various tyrosine kinase inhibitors in human plasma.

Background: Increasing numbers of tyrosine kinase inhibitors (TKIs) were studied and approved for therapy of malignancies and other diseases. The aim of this study was to develop and validate a specific, simple and rapid quantification method for various TKIs in human plasma.

Methods: A simultaneous test for six TKIs (erlotinib, imatinib, lapatinib, nilotinib, sorafenib, sunitinib) was developed using liquid chromatography tandem mass spectrometry in a multiple reaction monitoring mode.

Clara cells drive eosinophil accumulation in allergic asthma.

Development of allergic asthma is a complex process involving immune, neuronal and tissue cells. In the lung, Clara cells represent a major part of the "immunomodulatory barrier" of the airway epithelium. To understand the contribution of these cells to the inflammatory outcome of asthma, disease development was assessed using an adjuvant-free ovalbumin model.

Nerve growth factor induces type III collagen production in chronic allergic airway inflammation.

Background: Excessive extracellular matrix deposition occurs as a result of repetitive injury-repair cycles and plays a central role in the pathogenesis of chronic inflammatory diseases, such as allergic asthma. The molecular mechanism leading to aberrant collagen deposition is not fully understood.

Objective: We sought to test the hypothesis that increased nerve growth factor (NGF) production contributes to collagen deposition in the airways during chronic allergic airway inflammation.

Development and validation of a combined method for the biomonitoring of omega-3/-6 fatty acids and conjugated linoleic acids in different matrices from human and nutritional sources.

Background: During the last decade, the contribution of omega-3 and -6 long chain-polyunsaturated fatty acids (LC-PUFA) and conjugated linoleic acids (CLA) to the prevention and development of many inflammatory and cardiovascular diseases has been of growing interest. In order to investigate the etiology of these diseases, rapid, combined and comparable methods are invaluable for monitoring both the intake and the incorporation of these fatty acids (FA).

Methods: The fatty acid methyl esters (FAME) were analyzed using a gas chromatography/flame ionization detector (GC-FID) system and quantified with an internal standard (C18:0 iso).

Nerve growth factor enhances Clara cell proliferation after lung injury.

The lung epithelia facilitate wound closure by secretion of various cytokines and growth factors. Nerve growth factor (NGF) has been well described in airway inflammation; however, its likely role in lung repair has not been examined thus far. To investigate the repair function of NGF, experiments were performed in vitro using cultured alveolar epithelial cells and in vivo using a naphthalene-induced model of Clara epithelial cell injury.

The effect of BDNF gene variants on asthma in German children.

Background: Allergic inflammation can trigger neuronal dysfunction and structural changes in the airways and the skin. Levels of brain-derived neurotrophic factor (BDNF) are strongly up regulated at the location of allergic inflammation.

Aim: We systematically investigated whether polymorphisms in the BDNF gene influence the development or severity of asthma and atopic diseases.