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143
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Introduction
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January 2003 - present
Publications
Publications (143)
Although progress has been made in the therapy of pulmonary arterial hypertension (PAH), diagnosis is often late and therapy aims at vasoconstriction instead of the underlying mechanisms of pulmonary arterial (PA) remodeling. There is a need for biomarkers that are functional, diagnostic and prognostic and provide new targets for treatment.
We use...
Adaptive drug resistance, OGT, cancer cell reprogramming, epigenetics, metabolism, drug tolerant persisters
BACKGROUND
Orthotopic xenograft studies strongly promote the development of targeted/personalized cancer therapies to improve the still poor life expectancy of glioblastoma patients. In recent years, the tumor microenvironment has increasingly become subject of investigations, as it could have an impact on the progression of the cancer. However, ex...
Aims:
Drivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a...
Pulmonary hypertension (PH) is a severe hemodynamic, progressive condition associated with high morbidity and mortality where early and less invasive diagnostics could crucially improve management. There is a need for biomarkers in PH that are functional, diagnostic, and prognostic. We used a broad metabolomics approach with machine learning analys...
Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic param...
Coronavirus disease 2019 (COVID-19)-induced metabolic alterations have been proposed as a source for prognostic biomarkers and may harbor potential for therapeutic exploitation. However, the metabolic impact of COVID-19 in hemodialysis (HD), a setting of profound a priori alterations, remains unstudied. To evaluate potential COVID-19 biomarkers in...
Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days ( n...
(1) The cardio-reno-metabolic benefits of the SGLT2 inhibitors canagliflozin (cana), dapagliflozin (dapa), ertugliflozin (ertu), and empagliflozin (empa) have been demonstrated, but it remains unclear whether they exert different off-target effects influencing clinical profiles. (2) We aimed to investigate the effects of SGLT2 inhibitors on mitocho...
Context
The effect of liraglutide in C-peptide positive (C-pos) type 1 diabetes (T1D) patients during hypoglycaemia remains unclear.
Objective
To investigate the effect of a 12-week liraglutide-treatment on the body glucose fluxes during a hypoglycaemic clamp in C-pos T1D patients and its impact on the alpha and beta cell responses during hypoglyc...
Importance:
Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvemen...
BACKGROUND AND AIMS
The ongoing coronavirus disease 2019 (COVID-19) pandemic presents a major health and economical challenge. Chronic kidney disease (CKD) patients on haemodialysis (HDp) are at a particularly high risk of severe and fatal courses [1]. The COVID-19 metabolome is distinct [2] and may harbour potential prognostic markers and therapeu...
Spermidine is a natural polyamine which was shown to prolong lifespan of organisms and to improve cardiac and cognitive function. Spermidine was also reported to reduce inflammation and modulate T-cells. Autophagy is one of the mechanisms that spermidine exerts its effect. Autophagy is vital for β-cell homeostasis and autophagy deficiency was repor...
Background:
We aimed to gain insights in a co-culture of 10 bacteria and their postbiotic supernatant.
Methods:
Abundances and gene expression were monitored by shotgun analysis. The supernatant was characterized by liquid chromatography mass spectroscopy (LC-MS) and gas chromatography mass spectroscopy (GC-MS). Supernatant was harvested after 4...
Anchorage-independent growth of cancer cells in vitro is correlated to metastasis formation in vivo. Metformin use is associated with decreased breast cancer incidence and currently evaluated in cancer clinical trials. The combined treatment with metformin and 2-deoxy-D-glucose (2DG) in vitro induces detachment of viable MDA-MB-231 breast cancer ce...
PESI-MS enables with its greatly simplified handling and fast result delivery the application field for high-throughput use in routine settings. In health care and research, pre-analytical errors often remain undetected and disrupt diagnosis, treatment, clinical studies and biomarker validations incurring high costs. This proof-of-principle study i...
Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan- extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that die- tary spermidine passes the bloo...
Burn injuries initiate numerous processes such as heat shock response, inflammation and tissue regeneration. Reliable burn models are needed to elucidate the exact sequence of local events to be able to better predict when local inflammation triggers systemic inflammatory processes. In contrast to other ex vivo skin culture approaches, we used fres...
Objective:
To investigate the pharmacokinetic and pharmacodynamic properties, and safety of a novel formulation of insulin aspart (AT247) versus two currently marketed insulin aspart formulations (NovoRapid [IAsp] and Fiasp [faster IAsp]).
Research design and methods:
This single-center, randomized, double-blind, three-period, crossover study wa...
Obesity is associated with lung function impairment and respiratory diseases; however, the underlying pathophysiological mechanisms are still elusive and therapeutic options are limited. This study examined the effects of prolonged excess fat intake on lung mechanics and microstructure and tested spermidine supplementation and physical activity as...
Objectives: To evaluate the effect of SGLT2i on the development of DKA during insulin depletion in T1DM.
Methods: Sixteen male, C-peptide negative T1DM subjects were enrolled in this open, randomized, crossover, bicentric trial with two 7-day treatment periods (with/without SGLT2i). At the end of each treatment period, insulin was withdrawn for a m...
Background: AT247, an ultra-rapid acting formulation of insulin aspart designed for faster absorption following s.c. injection, will lead to better postprandial glycaemic control and is key to the development of closed-loop pump systems.
Method: Plasma glucose and serum insulin concentrations were measured in 19 adult male participants with T1DM fo...
N‐acetylaspartate (NAA) is synthesized by aspartate N‐acetyltransferase (gene: Nat8l) from acetyl‐coenzyme A and aspartate. In the brain, NAA is considered an important energy metabolite for lipid synthesis. However, the role of NAA in peripheral tissues remained elusive. Therefore, we characterized the metabolic phenotype of knockout (ko) and adip...
The present work demonstrates the utility of temperature controlled set up with pressurized headspace oxygen as an approach to effectively reduce the time required for solid-state drug-excipient compatibility study. To illustrate the utility, the incompatibility of polyethylene glycol (PEG) and polyethylene oxide (PEO) with Famotidine (Fam) was sho...
Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy,...
Rationale: Approximately 50% of heart failure patients are diagnosed with Heart Failure with preserved Ejection Fraction (HFpEF), but there are currently no effective treatments.
Hypothesis: Treatment of a feline HFpEF animal model with a pan HDAC inhibitor, SAHA, will improve the cardiopulmonary phenotype and mediate changes in the metabolome and...
Melanoma cells shift between epigenetic-metabolic states to adapt to stress and, particularly, to drugs. Here, we unraveled the metabolome of an H3K4 demethylase (KDM5B/JARID1B)-driven melanoma cell phenotype, which is known to be multi-drug resistant. We set up a fast protocol for standardized, high sensitive liquid-chromatography-high-resolution-...
Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4′-dimethoxychalcone (DMC...
The discovery of significant amounts of metabolically active brown adipose tissue (BAT) in adult humans renders it a promising target for anti-obesity therapies by inducing weight loss through increased energy expenditure. The components of the N-acetylaspartate (NAA) pathway are highly abundant in BAT. Aspartate N-acetyltransferase (Asp-NAT, encod...
Background/Objectives
Given their role in female reproduction, the effects of progesterone on arginine and related amino acids, polyamines and NF-κB p65 activation were studied across the menstrual cycle.
Methods
Arginine, ornithine and citrulline as well as putrescine, spermidine, spermine, and N-acetyl-putrescine were determined in plasma, NF-κB...
Introduction
Tyrosine kinase inhibitors (TKI) have dramatically changed the prognosis of patients with leukaemia. Unfortunately, they fail to achieve durable remissions for many patients with advanced BCR-Abl leukaemia or acute myelogenous leukaemia. Myeloid leukemic cells depend on mitochondrial oxidative phosphorylation (OxPhos) and/or glycolysis...
Context
Complete loss of beta-cell function in type 1 diabetes (T1DM) patients may lead to an increased risk of severe hypoglycaemia.
Objective
We aimed to determine the impact of C-peptide status on glucagon response and endogenous glucose production (EGP) during hypoglycaemia in T1DM patients.
Design/ Setting
We conducted an open, comparative t...
Lysosomal acid lipase (LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and triacylglycerols in lysosomes of multiple cells and tissues. Here, we explored the role of LAL in brown adipose tissue (BAT). LAL-deficient (Lal-/-) mice exhibit markedly reduced UCP1 expression in BAT, modified BAT morphology with accumulation of lysosome...
Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementatio...
Loss of cardiac macroautophagy/autophagy impairs heart function, and evidence accumulates that an increased autophagic flux may protect against cardiovascular disease. We therefore tested the protective capacity of the natural autophagy inducer spermidine in animal models of aging and hypertension, which both represent major risk factors for the de...
Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitoph...
Glucocorticoids (GCs) are important regulators of systemic energy metabolism, and aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiological energy metabolism depend on the GC receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR deficiency in mice significantly impac...
Bariatric surgery is currently one of the most effective treatments for obesity and leads to significant weight reduction, improved cardiovascular risk factors and overall survival in treated patients. To date, most studies focused on short-term effects of bariatric surgery on the metabolic profile and found high variation in the individual respons...
Metabolites with significant changes between high and low-weight loss patients.
(DOCX)
Demographical and clinical raw data from the study population.
(XLSX)
Final, processed data used for statistical analysis and annotated and identified metabolites.
(XLSX)
Median weight reduction.
(DOCX)
Non-remission patients (n) are significantly older than remission (c) (42(9) years vs (docx) 55(9)).
Nd = non-diabetes.
(DOCX)
Nutritional information: Supplements after bariatric surgery.
(DOCX)
Metabolites showing significant changes between diabetes remission and non-remission.
(DOCX)
Power-point file containing the consort-diagram of the clinical study.
(PPTX)
Detailed information about category of identification.
(XLSX)
Word-file, containing additional tables and figures of metabolites linked to clinical outcomes.
(DOCX)
Word-file, containing research plan of clinical study.
(DOCX)
Aims/hypothesis:
Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative...
H2O as nonradioactive, stable marker substance is commonly used in preclinical and clinical studies and the precise determination of ²H2O concentration in biological samples is crucial. However, aside from isotope ratio mass spectrometry (IRMS), only a very limited number of methods to accurately measure the ²H2O concentration in biological samples...
Although non-alcoholic and alcoholic fatty liver disease have been intensively studied, concerning pathophysiological mechanisms are still incompletely understood. This may be due to the use of different animal models and resulting model-associated variation. Therefore, this study aimed to compare three frequently used wild type mouse strains in th...
Medians and interquartile ranges of hepatic FA in 129Sv mice with respect to the different dietary regimens.
(DOCX)
Correlation of NAS and dietary regimen in C57BL/6, CD-1, and 129Sv mice.
(DOCX)
Histone acetylation depends on the abundance of nucleo-cytoplasmic acetyl-CoA. Here, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. N-acetylaspartate (NAA) is a highly abundant brain metabolite catabolized by aspartoacylase yielding aspartate and acetate. The latter can be further used for acetyl-CoA production....
Emerging evidence indicates that disruption of the gut microbial community (dysbiosis) impairs mental health. Germ-free mice and antibiotic-induced gut dysbiosis are two approaches to establish causality in gut microbiota-brain relationships. However, both models have limitations, as germ-free mice display alterations in blood-brain barrier and bra...
Investigations into sample preparation procedures usually focus on analyte recovery with no information provided about the fate of other components of the sample (matrix). For many analyses, however, and particularly those using liquid chromatography-mass spectrometry (LC-MS), quantitative measurements are greatly influenced by sample matrix. Using...
