Publications by authors named "Dominique Thomas"

138 Publications

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice.

Neurotherapeutics 2021 Apr 12. Epub 2021 Apr 12.

Institute of Clinical Pharmacology, Medical Faculty, Goethe-University, Frankfurt, Germany.

Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4), in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice, suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 drug (sapropterin) might increase the risk of autoimmune diseases. The present study assessed the implications for multiple sclerosis (MS) as an exemplary CNS autoimmune disease. Plasma levels of biopterin were persistently low in MS patients and tended to be lower with high Expanded Disability Status Scale (EDSS). Instead, the bypass product, neopterin, was increased. The deregulation suggested that BH4 replenishment might further drive the immune response or beneficially restore the BH4 balances. To answer this question, mice were treated with sapropterin in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood. Mechanistically, sapropterin treatment was associated with increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood-brain barrier in EAE mice. Indeed, RNA data analyses revealed upregulations of genes involved in ceramide synthesis in brain endothelial cells of EAE mice (LASS6/CERS6, LASS3/CERS3, UGCG, ELOVL6, and ELOVL4). The results support the view that BH4 fortifies autoimmune CNS disease, mechanistically involving lipid deregulations that are known to contribute to the EAE pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-021-01043-4DOI Listing
April 2021

Bacterial and Fungal Toll-Like Receptor Activation Elicits Type I IFN Responses in Mast Cells.

Front Immunol 2020 12;11:607048. Epub 2021 Feb 12.

Institute of Clinical Pharmacology, University Hospital Goethe-University Frankfurt, Frankfurt, Germany.

Next to their role in IgE-mediated allergic diseases and in promoting inflammation, mast cells also have antiinflammatory functions. They release pro- as well as antiinflammatory mediators, depending on the biological setting. Here we aimed to better understand the role of mast cells during the resolution phase of a local inflammation induced with the Toll-like receptor (TLR)-2 agonist zymosan. Multiple sequential immunohistology combined with a statistical neighborhood analysis showed that mast cells are located in a predominantly antiinflammatory microenvironment during resolution of inflammation and that mast cell-deficiency causes decreased efferocytosis in the resolution phase. Accordingly, FACS analysis showed decreased phagocytosis of zymosan and neutrophils by macrophages in mast cell-deficient mice. mRNA sequencing using zymosan-induced bone marrow-derived mast cells (BMMC) revealed a strong type I interferon (IFN) response, which is known to enhance phagocytosis by macrophages. Both, zymosan and lipopolysaccharides (LPS) induced IFN-β synthesis in BMMCs in similar amounts as in bone marrow derived macrophages. IFN-β was expressed by mast cells in paws from naïve mice and during zymosan-induced inflammation. As described for macrophages the release of type I IFNs from mast cells depended on TLR internalization and endosome acidification. In conclusion, mast cells are able to produce several mediators including IFN-β, which are alone or in combination with each other able to regulate the phagocytotic activity of macrophages during resolution of inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.607048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907501PMC
February 2021

Inhibition of mPGES-1 attenuates efficient resolution of acute inflammation by enhancing CX3CL1 expression.

Cell Death Dis 2021 Feb 2;12(2):135. Epub 2021 Feb 2.

Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.

Despite the progress to understand inflammatory reactions, mechanisms causing their resolution remain poorly understood. Prostanoids, especially prostaglandin E (PGE), are well-characterized mediators of inflammation. PGE is produced in an inducible manner in macrophages (Mϕ) by microsomal PGE-synthase-1 (mPGES-1), with the notion that it also conveys pro-resolving properties. We aimed to characterize the role of mPGES-1 during resolution of acute, zymosan-induced peritonitis. Experimentally, we applied the mPGES-1 inhibitor compound III (CIII) once the inflammatory response was established and confirmed its potent PGE-blocking efficacy. mPGES-1 inhibition resulted in an incomplete removal of neutrophils and a concomitant increase in monocytes and Mϕ during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating Mϕ upon mPGES-1 inhibition. Besides elevated Cx3cr1 expression, its ligand CX3CL1 was enriched in the peritoneal lavage of the mice, produced by epithelial cells upon mPGES-1 inhibition. CX3CL1 not only increased adhesion and survival of Mϕ but its neutralization also completely reversed elevated inflammatory cell numbers, thereby normalizing the cellular, peritoneal composition during resolution. Our data suggest that mPGES-1-derived PGE contributes to the resolution of inflammation by preventing CX3CL1-mediated retention of activated myeloid cells at sites of injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-021-03423-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862376PMC
February 2021

C6 Ceramide (d18:1/6:0) as a Novel Treatment of Cutaneous T Cell Lymphoma.

Cancers (Basel) 2021 Jan 13;13(2). Epub 2021 Jan 13.

Department of Dermatology, Venerology and Allergology, Goethe University Hospital, 60590 Frankfurt am Main, Germany.

Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of T cell lymphomas that primarily affect the skin. The most frequent forms of CTCL are mycosis fungoides and Sézary syndrome. Both are characterized by frequent recurrence, developing chronic conditions and high mortality with a lack of a curative treatment. In this study, we evaluated the effect of short-chain, cell-permeable C6 Ceramide (C6Cer) on CTCL cell lines and keratinocytes. C6Cer significantly reduced cell viability of CTCL cell lines and induced cell death via apoptosis and necrosis. In contrast, primary human keratinocytes and HaCaT keratinocytes were less affected by C6Cer. Both keratinocyte cell lines showed higher expressions of ceramide catabolizing enzymes and HaCaT keratinocytes were able to metabolize C6Cer faster and more efficiently than CTCL cell lines, which might explain the observed protective effects. Along with other existing skin-directed therapies, C6Cer could be a novel well-tolerated drug for the topical treatment of CTCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13020270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828274PMC
January 2021

Sphingosine 1-phosphate levels in cerebrospinal fluid after subarachnoid hemorrhage.

Neurol Res Pract 2020 23;2:49. Epub 2020 Nov 23.

Frankfurt University Hospital, Department of Neurology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.

Background And Purpose: Sphingosin-1-phosphate (S1P) plays a crucial role as a signaling molecule in the immune system and the vasculature. Previous studies suggested a role as a vasoconstrictor of cerebral arteries via the S1P3-Receptor. Cerebral vasospasm (VS) following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of disability and poor neurological outcome. Early detection of vasospasm could facilitate the prevention of cerebral ischemia in SAH patients. The aim of this prospective case-control study was to characterize the dynamics of S1P in the cerebrospinal fluid (CSF) of patients with SAH in relation to hemorrhage volume, the occurrence of VS, and neurological outcome.

Methods: S1P levels in CSF of 18 control subjects and 18 SAH patients with placement of an external ventricular drainage (EVD) were determined by high sensitivity mass spectrometry from day 1 through 14 after SAH onset. Hemorrhage volume, development of asymptomatic vasospasm (aVS) and symptomatic vasospasm (sVS), and neurological outcome were correlated to day 1 S1P levels.

Results: The intrathecal S1P levels of SAH patients were higher than those of the control subjects, and correlated with hemorrhage volume. There was no significant difference in S1P levels between patients with aVS and those with sVS. S1P levels significantly correlated with neurological outcome on a sliding modified Rankin scale.

Conclusion: S1P levels were highest directly after placement of the EVD and correlated strongly with hemorrhage volume, which may be caused by the intrathecal clot and subsequent lysis of red blood cells, an important source of S1P. We did not detect a second peak of S1P release over the course of the intensive care period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s42466-020-00093-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684722PMC
November 2020

TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly.

Hum Mol Genet 2021 Feb;29(23):3757-3764

IRIBHM, Université Libre de Bruxelles, 1070 Brussels, Belgium.

Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddaa245DOI Listing
February 2021

Serum Sphingosine-1-Phosphate Is Decreased in Patients With Acute-on-Chronic Liver Failure and Predicts Early Mortality.

Hepatol Commun 2020 Oct 12;4(10):1477-1486. Epub 2020 Aug 12.

Departement of Internal Medicine 1 University Hospital Frankfurt Goethe University Frankfurt am Main Germany.

Sphingosine-1-phosphate (S1P) regulates pathophysiological processes, including liver regeneration, vascular tone control, and immune response. In patients with liver cirrhosis, acute deterioration of liver function is associated with high mortality rates. The present study investigated whether serum S1P concentrations are associated with disease severity in patients with chronic liver disease from compensated cirrhosis (CC), acute decompensation (AD), or acute-on-chronic liver failure (ACLF). From August 2013 to October 2017, patients who were admitted to the University Hospital Frankfurt with CC, AD, or ACLF were enrolled in our cirrhosis cohort study. Tandem mass spectrometry was performed on serum samples of 127 patients to assess S1P concentration. Our study comprised 19 patients with CC, 55 with AD, and 51 with ACLF, aged 29 to 76 years. We observed a significant decrease of S1P according to advanced liver injury from CC and AD up to ACLF ( < 0.001). S1P levels further decreased with progression to ACLF grade 3 ( < 0.05), and S1P highly inversely correlated with the Model for End-Stage Liver Disease score ( = -0.508;  < 0.001). In multivariate analysis, S1P remained an independent predictor of 7-day mortality with high diagnostic accuracy (area under the curve, 0.874;  < 0.001). In patients with chronic liver disease, serum S1P levels dramatically decreased with advanced stages of liver disease and were predictive of early mortality. Because S1P is a potent regulator of endothelial integrity and immune response, low S1P levels may significantly influence progressive multiorgan failure. Our data justify further elucidation of the diagnostic and therapeutic role of S1P in ACLF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527696PMC
October 2020

Consistent alteration of chain length-specific ceramides in human and mouse fibrotic kidneys.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 01 1;1866(1):158821. Epub 2020 Oct 1.

Institute of General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt am Main, Germany.

Background: Several studies revealed alterations of single sphingolipid species, such as chain length-specific ceramides, in plasma and serum of patients with kidney diseases. Here, we investigated whether such alterations occur in kidney tissue from patients and mice suffering from renal fibrosis, the common endpoint of chronic kidney diseases.

Methods: Human fibrotic kidney samples were collected from nephrectomy specimens with hydronephrosis and/or pyelonephritis. Healthy parts from tumor nephrectomies served as nonfibrotic controls. Mouse fibrotic kidney samples were collected from male C57BL/6J mice treated with an adenine-rich diet for 14 days or were subjected to 7 days of unilateral ureteral obstruction (UUO). Kidneys of untreated mice and contralateral kidneys (UUO) served as respective controls. Sphingolipid levels were detected by LC-MS/MS. Fibrotic markers were analyzed by TaqMan® analysis and immunohistology.

Results: Very long-chain ceramides Cer d18:1/24:0 and Cer d18:1/24:1 were significantly downregulated in both fibrotic human kidney cortex and fibrotic murine kidney compared to respective control samples. These effects correlate with upregulation of COL1α1, COL3α1 and αSMA expression in fibrotic human kidney cortex and fibrotic mouse kidney.

Conclusion: We have shown that very long-chain ceramides Cer d18:1/24:0 and Cer d18:1/24:1 are consistently downregulated in fibrotic kidney samples from human and mouse. Our findings support the use of in vivo murine models as appropriate translational means to understand the involvement of ceramides in human kidney diseases. In addition, our study raises interesting questions about the possible manipulation of ceramide metabolism to prevent progression of fibrosis and the use of ceramides as potential biomarkers of chronic kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2020.158821DOI Listing
January 2021

S1P Lyase siRNA Dampens Malignancy of DLD-1 Colorectal Cancer Cells.

Lipids 2021 03 24;56(2):155-166. Epub 2020 Sep 24.

Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt/ZAFES, Hospital of the Goethe University, Frankfurt am Main, Germany.

Sphingosine-1-phosphate lyase 1 (S1P lyase or SGPL1) is an essential sphingosine-1-phosphate-degrading enzyme. Its manipulation favors onset and progression of colorectal cancer and others in vivo. Thus, SGPL1 is an important modulator of cancer initiation. However, in established cancer, the impact of retrospective SGPL1 modulation is elusive. Herein, we analyzed how SGPL1 siRNA affects malignancy of the human colorectal cancer cells DLD-1 and found that in parallel to the reduction of SGPL1 expression levels, migration, invasion, and differentiation status changed. Diminished SGPL1 expression was accompanied with reduced cell migration and cell invasion in scratch assays and transwell assays, whereas metabolic activity and proliferation was not altered. Decreased migration was attended by increased cell-cell-adhesion through upregulation of E-cadherin and formation of cadherin-actin complexes. Spreading cell islets showed lower vimentin abundance in border cells. Furthermore, SGPL1 siRNA treatment induced expression of epithelial cell differentiation markers, such as intestinal alkaline phosphatase and cytokeratin 20. Hence, interference with SGPL1 expression augmented a partial redifferentiation of colorectal cancer cells toward normal colon epithelial cells. Our investigation showed that SGPL1 siRNA influenced tumorigenic activity of established colorectal cancer cells. We therefore suggest SGPL1 as a target for lowering malignant potential of already existing cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lipd.12282DOI Listing
March 2021

Exercise-Induced Changes in Bioactive Lipids Might Serve as Potential Predictors of Post-Exercise Hypotension. A Pilot Study in Healthy Volunteers.

Cells 2020 09 16;9(9). Epub 2020 Sep 16.

Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.

Post-exercise hypotension (PEH) is the phenomenon of lowered blood pressure after a single bout of exercise. Only a fraction of people develops PEH but its occurrence correlates well with long-term effects of sports on blood pressure. Therefore, PEH has been suggested as a suitable predictor for the effectivity of exercise as therapy in hypertension. Local vascular bioactive lipids might play a potential role in this context. We performed a cross-over clinical pilot study with 18 healthy volunteers to investigate the occurrence of PEH after a single short-term endurance exercise. Furthermore, we investigated the plasma lipid profile with focus on arachidonic acid (AA)-derived metabolites as potential biomarkers of PEH. A single bout of ergometer cycling induced a significant PEH in healthy volunteers with the expected high inter-individual variability. Targeted lipid spectrum analysis revealed significant upregulation of several lipids in the direct post-exercise phase. Among these changes, only 15- hydroxyeicosatetranoic acid (HETE) correlated significantly with the extent of PEH but in an AA-independent manner, suggesting that 15-HETE might act as specific PEH-marker. Our data indicate that specific lipid modulation might facilitate the identification of patients who will benefit from exercise activity in hypertension therapy. However, larger trials including hypertonic patients are necessary to verify the clinical value of this hypothesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9092111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563406PMC
September 2020

Alox12/15 Deficiency Exacerbates, While Lipoxin A Ameliorates Hepatic Inflammation in Murine Alcoholic Hepatitis.

Front Immunol 2020 14;11:1447. Epub 2020 Jul 14.

Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany.

Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A (LXA), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15 and Alox12/15 mice, with or without supplementation of LXA. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA significantly lowered transaminase levels only in Alox12/15 mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA injection attenuated selected parameters of disease progression in Alox12/15 mice, its beneficial impact on immunity was also apparent in Alox12/15 mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371948PMC
April 2021

High Glucosylceramides and Low Anandamide Contribute to Sensory Loss and Pain in Parkinson's Disease.

Mov Disord 2020 10 11;35(10):1822-1833. Epub 2020 Jul 11.

Institute of Clinical Pharmacology, Goethe-University, Medical Faculty, Frankfurt, Germany.

Background: Parkinson's disease (PD) causes chronic pain in two-thirds of patients, in part originating from sensory neuropathies. The aim of the present study was to describe the phenotype of PD-associated sensory neuropathy and to evaluate its associations with lipid allostasis, the latter motivated by recent genetic studies associating mutations of glucocerebrosidase with PD onset and severity. Glucocerebrosidase catalyzes the metabolism of glucosylceramides.

Methods: We used quantitative sensory tests, pain ratings, and questionnaires and analyzed plasma levels of multiple bioactive lipid species using targeted lipidomic analyses. The study comprised 2 sets of patients and healthy controls: the first 128 Israeli PD patients and 224 young German healthy controls for exploration, the second 50/50 German PD patients and matched healthy controls for deeper analyses.

Results: The data showed a 70% prevalence of PD pain and sensory neuropathies with a predominant phenotype of thermal sensory loss plus mechanical hypersensitivity. Multivariate analyses of lipids revealed major differences between PD patients and healthy controls, mainly originating from glucosylceramides and endocannabinoids. Glucosylceramides were increased, whereas anandamide and lysophosphatidic acid 20:4 were reduced, stronger in patients with ongoing pain and with a linear relationship with pain intensity and sensory losses, particularly for glucosylceramide 18:1 and glucosylceramide 24:1.

Conclusions: Our data suggest that PD-associated sensory neuropathies and PD pain are in part caused by accumulations of glucosylceramides, raising the intriguing possibility of reducing PD pain and sensory loss by glucocerebrosidase substituting or refolding approaches. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.28186DOI Listing
October 2020

Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation.

Cancers (Basel) 2020 Jul 1;12(7). Epub 2020 Jul 1.

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.

Ceramide synthase 5 is one of six enzymes that catalyze the production of ceramides from sphingosine or sphinganine. Ceramides are important components of cell membranes and act as signaling molecules. Previously it has been shown that ceramide synthase 6 and 2 influence colitis in several animal models with sometimes opposite effects. Here, we investigated the disease course of dextran sodium sulfate-induced acute colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer in mice with global ceramide synthase 5 knockout (CerS5-ko) or with ceramide synthase 5 knockout restricted to the colon epithelium (CerS5fl/fl VilCre). We monitored disease development and analyzed colon barrier function as well as the immune cell status in these mice. CerS5-ko mice but not CerS5fl/fl-VilCre mice were more susceptible to acute and chronic inflammation. However, the cell barrier function of colon epithelial cells was not disturbed by downregulation of ceramide synthase 5. Instead, untreated CerS5-ko mice displayed reduced numbers of CD3 immune cells in the spleen, colon, and blood, especially of intraepithelial CD8 T-cells, which was not obvious in CerS5fl/fl Vil Cre mice. Reduced T-cell number in colon tissue of CerS5-ko mice was accompanied by a reduced expression of IL-1β, IFNγ, and IL-4. In vitro investigations revealed that knockdown of ceramide synthase 5 in T-cells impaired T-cell activation. In summary, we show that CerS5-ko mice were more susceptible to dextran sodium sulfate-induced colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer. A reduced number of T-cells in the colon epithelium that was already the case in untreated CerS5-ko mice might have contributed to this effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12071753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409364PMC
July 2020

Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

J Allergy Clin Immunol 2021 Feb 12;147(2):587-599. Epub 2020 Jun 12.

Center of Allergy and Environment, Technical University of Munich and Helmholtz Zentrum München, Munich, Germany. Electronic address:

Background: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD.

Objective: This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD.

Methods: Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD.

Results: This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages.

Conclusions: Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.04.064DOI Listing
February 2021

Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2.

Cell Mol Life Sci 2021 Feb 28;78(3):1029-1050. Epub 2020 May 28.

Institute of Clinical Pharmacology, Goethe-University Frankfurt, Faculty of Medicine, Frankfurt, Germany.

Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2 mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2 mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2 mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2 mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2 were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2 phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better  performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00018-020-03553-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897625PMC
February 2021

UGCG overexpression leads to increased glycolysis and increased oxidative phosphorylation of breast cancer cells.

Sci Rep 2020 05 18;10(1):8182. Epub 2020 May 18.

Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Theodor Stern-Kai 7, 60590, Frankfurt am Main, Germany.

The only enzyme in the glycosphingolipid (GSL) metabolic pathway, which produces glucosylceramide (GlcCer) de novo is UDP-glucose ceramide glucosyltransferase (UGCG). UGCG is linked to pro-cancerous processes such as multidrug resistance development and increased proliferation in several cancer types. Previously, we showed an UGCG-dependent glutamine metabolism adaption to nutrient-poor environment of breast cancer cells. This adaption includes reinforced oxidative stress response and fueling the tricarboxylic acid (TCA) cycle by increased glutamine oxidation. In the current study, we investigated glycolytic and oxidative metabolic phenotypes following UGCG overexpression (OE). UGCG overexpressing MCF-7 cells underwent a metabolic shift from quiescent/aerobic to energetic metabolism by increasing both glycolysis and oxidative glucose metabolism. The energetic metabolic phenotype was not associated with increased mitochondrial mass, however, markers of mitochondrial turnover were increased. UGCG OE altered sphingolipid composition of the endoplasmic reticulum (ER)/mitochondria fractions that may contribute to increased mitochondrial turnover and increased cell metabolism. Our data indicate that GSL are closely connected to cell energy metabolism and this finding might contribute to development of novel therapeutic strategies for cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-65182-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234995PMC
May 2020

In-vitro safety and off-target profile of the anti-parasitic arylmethylaminosteroid 1o.

Sci Rep 2020 05 5;10(1):7534. Epub 2020 May 5.

Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology (TMP), Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.

Parasite-mediated diseases like malaria and schistosomiasis are growing health problems worldwide and novel drug candidates are urgently needed. In this study, the in-vitro safety profile of steroid compound 1o (sc1o), effective against the parasites Plasmodium falciparum and Schistosoma mansoni with an IC value of 5 nM, was characterized. We assessed viability/proliferation, apoptosis and cell cycle tests to determine the cytotoxic profile of sc1o in cancer cells. The mutagenic potential was determined with the AMES test. To identify off-target effects we investigated whether sc1o interacts with safety-relevant molecules such as cytochrome P450 (CYP) enzymes, phosphodiesterases (PDE), histone deacteylases (HDAC) and human ether-a-go-go related gene (hERG). Furthermore, to predict the potential bioavailability of sc1o, its effect on Caco-2 cell barrier integrity, by measurement of the transepithelial electrical resistance (TEER), was determined. Sc1o at 25 µM reduced cell viability, probably through cell-cycle arrest, but did not induce apoptosis in cancer cells. No adverse off-target effects nor mutagenic potential of sc1o were observed. Furthermore, sc1o did not disturb the integrity of the cell barrier, but exhibited low membrane permeability, apparently due to cell adherence. In conclusion, sc1o up to 10 µM showed a good in-vitro safety profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-64382-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200784PMC
May 2020

The endocannabinoid anandamide has an anti-inflammatory effect on CCL2 expression in vascular smooth muscle cells.

Basic Res Cardiol 2020 04 22;115(3):34. Epub 2020 Apr 22.

Fachbereich Medizin, Institute for Cardiovascular Physiology, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.

Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00395-020-0793-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176595PMC
April 2020

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

Sci Transl Med 2020 04;12(540)

Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, 80802 Munich, Germany.

Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth (), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the -driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E (PGE) and IL-10] and suppressed chemotaxis. also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with extract attenuated allergic airway inflammation in mice, and intranasal transfer of -conditioned macrophages led to reduced airway eosinophilia in a COX/PGE-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in GDH activity was required for anti-inflammatory effects of in macrophages, and local administration of recombinant GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aay0605DOI Listing
April 2020

Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro.

Int J Mol Sci 2020 Mar 31;21(7). Epub 2020 Mar 31.

Medizinische Klinik 1, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany.

Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, which is the most widely used systemic HCC medication, on the sphingolipid pathway as well as the effects of inhibiting the sphingolipid pathway in HCC. Huh7.5 and HepG2 cells were stimulated with sorafenib, and inhibitors of the sphingolipid pathway and cell proliferation, viability, and concentrations of bioactive metabolites were assessed. We observed a significant downregulation of cell proliferation and viability and a simultaneous upregulation of dihydroceramides upon sorafenib stimulation. Interestingly, fumonisin B1 (FB1) and the general sphingosine kinase inhibitor SKI II were able to inhibit cell proliferation more prominently in HepG2 and Huh7.5 cells, whereas there were no consistent effects on the formation of dihydroceramides, thus implying an involvement of distinct metabolic pathways. In conclusion, our study demonstrates a significant downregulation of HCC proliferation upon sorafenib, FB1, and SKI II treatment, whereas it seems they exert antiproliferative effects independently from sphingolipids. Certainly, further data would be required to elucidate the potential of FB1 and SKI II as putative novel therapeutic targets in HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21072409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177910PMC
March 2020

S1P d20:1, an endogenous modulator of S1P d18:1/S1P -dependent signaling.

FASEB J 2020 03 15;34(3):3932-3942. Epub 2020 Jan 15.

Department of Neurology, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.

Sphingosine 1-phosphate (S1P) signaling influences numerous cell biological mechanisms such as differentiation, proliferation, survival, migration, and angiogenesis. Intriguingly, our current knowledge is based solely on the role of S1P with an 18-carbon long-chain base length, S1P d18:1. Depending on the composition of the first and rate-limiting enzyme of the sphingolipid de novo metabolism, the serine palmitoyltransferase, other chain lengths have been described in vivo. While cells are also able to produce S1P d20:1, its abundance and function remains elusive so far. Our experiments are highlighting the role of S1P d20:1 in the mouse central nervous system (CNS) and human glioblastoma. We show here that S1P d20:1 and its precursors are detectable in both healthy mouse CNS-tissue and human glioblastoma. On the functional level, we focused our work on one particular, well-characterized pathway, the induction of cyclooxygenase (COX)-2 expression via the S1P receptor 2 (S1P ). Intriguingly, S1P d20:1 only fairly induces COX-2 expression and can block the S1P d18:1-induced COX-2 expression mediated via S1P activation in the human glioblastoma cell line LN229. This data indicates that S1P d20:1 might act as an endogenous modulator of S1P signaling via a partial agonism at the S1P receptor. While our findings might stimulate further research on the relevance of long-chain base lengths in sphingolipid signaling, the metabolism of S1P d20:1 has to be considered as an integral part of S1P signaling pathways in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201902391RDOI Listing
March 2020

Implementation of lipidomics in clinical routine: Can fluoride/citrate blood sampling tubes improve preanalytical stability?

Talanta 2020 Mar 26;209:120593. Epub 2019 Nov 26.

Pharmazentrum Frankfurt/ ZAFES, Institute of Clinical Pharmacology, Goethe University, Frankfurt, Germany. Electronic address:

The impact of preanalytical sample handling on lipid stability has been assessed in human plasma using targeted LC-MS/MS quantification of endocannabinoids, sphingolipids and LPA, complemented by non-targeted lipidomics screening with LC-QTOFMS. The study involved incubation of whole blood and plasma from healthy volunteers at room temperature or in ice water for time periods ranging from 20 min to 24 h. The impact of two different anticoagulants, K3EDTA and sodium fluoride/citrate, on lipid stability was evaluated. It was found that the concentrations determined for several endogenous lipids vary when whole blood and plasma samples are processed at room temperature, whereas the concentrations of most lipids were stable for 4 h in ice water. Surprisingly, the detected amounts of endocannabinoids 1- and 2-arachidonoyl glycerol and arachidonoyl ethanolamide increased markedly by 60, 95, and 30% in K3EDTA whole blood after storage in ice water for only 20 min. When using sodium fluoride/citrate blood collection tubes, the stability of several lipids, including that of the endocannabinoids, was improved. Accordingly, it is absolutely necessary to keep the blood sampling and plasma processing time below 1 h to avoid ex-vivo formation of endocannabinoids. It is worth mentioning that baseline lipid levels differ when using K3EDTA or sodium fluoride/citrate blood sampling tubes, which emphasizes the importance of traceability of reported plasma concentrations to the used anticoagulant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.talanta.2019.120593DOI Listing
March 2020

Stearoylethanolamide interferes with retrograde endocannabinoid signalling and supports the blood-brain barrier integrity under acute systemic inflammation.

Biochem Pharmacol 2020 04 25;174:113783. Epub 2019 Dec 25.

Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University Graz, Universitätsplatz 4, 8010 Graz, Austria. Electronic address:

Neuroinflammation plays a prominent role in the onset of demyelinating diseases, major depressive disorder and delayed neurodegeneration. An open question remains whether pharmacological suppression of inflammation can effectively reduce the progression of these states. Bioactive lipid mediators such as N-acylethanolamines (NAEs) have an anti-inflammatory activity and are of pharmacological interest due to their endogenous on-demand production and the existence of distinct biological targets in humans and animals. Here we demonstrate for the first time, that treatment with stearoylethanolamide (SEA), a prevailing endogenously formed NAE, is neuroprotective against LPS-induced neuroinflammation in C57BL/6 male mice. SEA restricted the spreading of peripheral inflammation to the brain, and averted the activation of resident microglia and leukocyte trafficking to the brain parenchyma. Treatment with SEA per se increased the neuronal expression of cannabinoid receptors CB and brain levels of the most potent endogenous CB agonist 2-arachidonoylglycerol in vivo. SEA enhanced the amplitude of synaptic vesicle release, supported the balanced signal-to-noise ratio in glutamate- and GABAergic neurotransmission and decreased the excitotoxic risk associated with higher extracellular glutamate levels under neuroinflammation. The interference of SEA with the endocannabinoid system and presynaptic neurotransmitter release may represent an intrinsic neuroprotective mechanism that is triggered by inflammation and glutamate excitotoxicity. Thus, our data allows to consider SEA for the preventive therapy of acute and late-onset neuroinflammation-associated synaptic dysfunction and neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2019.113783DOI Listing
April 2020

Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome.

J Peripher Nerv Syst 2020 03 2;25(1):9-18. Epub 2020 Jan 2.

Department of Neurology, University of Würzburg, Würzburg, Germany.

In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age-matched female controls. After screening for dry eye disease, corneal LC were counted and sub-classified as dendritic (dLC) and non-dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jns.12360DOI Listing
March 2020

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue.

J Allergy Clin Immunol 2020 03 5;145(3):818-833.e11. Epub 2019 Dec 5.

Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE metabolism under the control of TGF-β and microRNA 218.

Objective: We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue.

Methods: In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis.

Results: We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro.

Conclusions: These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2019.11.032DOI Listing
March 2020

The role of photovaporization of the prostate in small volume benign prostatic hyperplasia and review of the literature.

Asian J Urol 2019 Oct 25;6(4):353-358. Epub 2019 Jan 25.

Department of Urology, Weill Cornell Medical College/New York Presbyterian, New York, NY, USA.

Objective: Our objective was to characterize the safety and efficacy of the 180 W XPS-GreenLight laser in men with lower urinary tract symptoms secondary to a small volume benign prostatic hyperplasia (BPH).

Methods: A retrospective analysis was performed for all patients who underwent 180 W XPS-laser photoselective vaporization of the prostate (PVP) vaporization of the prostate between 2012 and 2016 at two-tertiary medical centers. Data collection included baseline comorbidities, disease-specific quality of life scores, maximum urinary flow rate (Q), postvoid residual (PVR), complications, prostate volume and prostate-specific antigen (PSA). The secondary endpoints were the incidence of intraoperative and postoperative adverse events. Complications were stratified using the Clavien-Dindo grading system up to 90 days after surgery.

Results: Mean age of men was 67.8 years old, with a mean body mass index of 29.7 kg/m. Mean prostate volume as measured by transrectal ultrasound was 29 mL. Anticoagulation use was 47% and urinary retention with catheter at time of surgery was 17%. Mean hospital stay and catheter time were 0.5 days. Median follow-up time was 6 months with the longest duration of follow-up being 22.5 months (interquartile range, 3-22.5 months). The International Prostate Symptom Score improved from 22.8 ± 7.0 at baseline to 10.7 ± 7.4 ( < 0.01) and 6.3 ± 4.4 ( < 0.01) at 1 and 6 months, respectively. The Q improved from 7.70 ± 4.46 mL/s at baseline to 17.25 ± 9.30 mL/s ( < 0.01) and 19.14 ± 7.19 mL/s ( < 0.001) at 1 and 6 months, respectively, while the PVR improved from 216.0 ± 271.0 mL preoperatively to 32.8 ± 45.3 mL ( < 0.01) and 26.2 ± 46.0 mL ( < 0.01) at 1 and 6 months, respectively. The PSA dropped from 1.97 ± 1.76 ng/mL preoperatively to 0.71 ± 0.61 ng/mL ( < 0.01) and 0.74 ± 0.63 ng/mL at 1 and 6 months, respectively. No patient had a bladder neck contracture postoperatively and no capsular perforations were noted intraoperatively.

Conclusion: The 180 W GreenLight XPS system is safe and effective for men with small volume BPH. PVP produced improvements in symptomatic and clinical parameters without any safety concern. It represents a safe surgical option in this under studied population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajur.2019.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872824PMC
October 2019

Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis.

PLoS One 2019 23;14(10):e0222840. Epub 2019 Oct 23.

Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.

Background: Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated.

Methods: Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein.

Results: While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001).

Conclusions: Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis.

Trial Registration: ClinicalTrials.gov identifier: NCT03584204.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222840PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808498PMC
March 2020

Inhibitors of Oxidative Phosphorylation Modulate Astrocyte Inflammatory Responses through AMPK-Dependent Ptgs2 mRNA Stabilization.

Cells 2019 10 1;8(10). Epub 2019 Oct 1.

Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.

Inflammatory activation of astroglia adds to the pathology of various neurological diseases. Astrocytes respond to microglia-derived cytokines such as interleukin-1α (IL-1α) with enhanced inflammatory signaling. This provokes pro-inflammatory gene expression of, among others, the eicosanoid-generating enzyme prostaglandin endoperoxide synthase 2 (Ptgs2). Whereas metabolic regulation of innate immune cell inflammatory responses is intensely studied, pathways related to how metabolism modulates inflammatory signaling in astrocytes are underexplored. Here, we examined how mitochondrial oxidative phosphorylation affects inflammatory responses towards IL-1α and tumor necrosis factor α in neonatal rat astrocytes. Blocking respiratory complex I and III or adenosine triphosphate (ATP) synthase did not affect activation of inflammatory signaling by IL-1α, but did elicit differential effects on inflammatory gene mRNA expression. Remarkably, mRNA and protein expression of Ptgs2 by IL-1α was consistently up-regulated when oxidative phosphorylation was inhibited. The increase of Ptgs2 resulted from mRNA stabilization. Mitochondrial inhibitors also increased IL-1α-triggered secretion of eicosanoids, such as prostaglandin E, prostaglandin F, and 6-keto-prostaglandin F, as assessed by liquid chromatography/mass spectrometry. Mechanistically, attenuating oxidative phosphorylation elevated adenosine monophosphate (AMP) and activated AMP-activated protein kinase (AMPK). AMPK silencing prevented Ptgs2 up-regulation by mitochondrial inhibitors, while AMPK activators recapitulated Ptgs2 mRNA stability regulation. Our data indicate modulation of astrocyte inflammatory responses by oxidative metabolism, with relevance towards eicosanoid production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells8101185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829456PMC
October 2019

Ejaculatory Preserving Middle Lobe Onl-Transurethral Resection and Vaporization of the Prostate: 12-Year Experience.

Urology 2019 12 26;134:199-202. Epub 2019 Sep 26.

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Objective: To report long-term safety and efficacy data on middle lobe only-transurethral resection of the prostate (TURP) (MLO-TURP).

Materials And Methods: We evaluated: (1) efficacy: International Prostate Symptom Score, Quality of Life, peak flow rate (Qmax), postvoid residual urine, International Index of Erectile Function and ejaculatory function, which was assessed by the Male Sexual Health Questionnaire. Men were evaluated at 1 month, 6 months, and yearly thereafter.

Results: A total 312 men (mean age 61.3 ± 8.6) with significant lower urinary tract symptoms (n = 147) or urinary retention (n = 175 were treated with MLO-TURP from 2005 to 2017. Mean baseline prostate volume was 79.8 g (30-178 g); mean baseline intravesical-prostatic protrusion was 13.6. Improvements in International Prostate Symptom Score, Quality of Life, Qmax and postvoid residual urine were durable throughout the study period. There was no difference in outcomes between monopolar and bipolar MLO-TURPs. Postoperatively, the incidence of ejaculatory dysfunction was 2.6% (N = 8) and there was 1 case of new onset ED (0.3%). There were modest improvement in bother due to ejaculatory function (baseline: 2.4 and at 5 years: 1.27).

Conclusion: MLO-TURP is a safe and effective treatment for men with lower urinary tract symptoms. Patients experience long-term improvement of symptoms and preserve antegrade ejaculation. In select men with prominent middle lobes, MLO-- should be considered a therapeutic, ejaculation-sparing option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2019.07.042DOI Listing
December 2019

First trimester ultrasound prediction of velamentous cord insertions: a prospective study.

J Matern Fetal Neonatal Med 2019 Sep 26:1-7. Epub 2019 Sep 26.

Department of Obstetrics and Gynecology, Hôpital Universitaire Saint Pierre , Bruxelles , Belgium.

The marginal and velamentous cord insertions complicate around 8% of pregnancies and are at higher risk of adverse perinatal outcomes. Their visualisation seems to decrease with advancing gestational age. Our aim was to analyse whether an umbilical cord insertion in the lower third of the uterus during the first trimester could predict abnormal cord insertions later in pregnancy. This was a prospective multicentre study in two hospitals. During the first trimester, the cord insertions were inspected as well as their location (lower third of the uterus or not). Finally, all cord insertions were described at delivery. During the study period the cord insertion was described in 1620 patients of which 87.7% had a normal cord insertion, 11.9% ( = 192) a low cord insertion, and in 3.8% the insertion could not be situated. We find that 4.7% of those who have a low-lying cord insertion versus 0.7% in the normal cord insertion group during the first trimester will have a velamentous cord insertion subsequently (OR = 6.67; 95% CI = 2.67-16.63). The detection of a low lying umbilical cord insertion during the first-trimester ultrasound can help to predict an abnormal cord insertion at delivery particularly a velamentous cord insertion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14767058.2019.1670797DOI Listing
September 2019