Dieter Leibfritz

University of Bremen | Uni Bremen · Institut für Organische und Analytische Chemie

Collagen 1 (Col1) fibers play an important role in tumor interstitial macromolecular transport and cancer cell dissemination. Our goal was to understand the influence of Col1 fibers on water diffusion, and to examine the potential of using noninvasive diffusion tensor imaging (DTI) to indirectly detect Col1 fibers in breast lesions. We previously o...

In this work, we illustrate a method to continuously hyperpolarize a biomolecule, nicotinamide, in water using parahydrogen and signal amplification by reversible exchange (SABRE). Building on the preparation procedure described recently by Truong et al. [J. Phys. Chem. B, 2014, 118,13882-13889], aqueous solutions of nicotinamide and an Ir-IMes cat...

Nuclear magnetic resonance spectroscopy and imaging (MRI) play an indispensable role in science and healthcare but use only a tiny fraction of their potential. No more than ≈10 p.p.m. of all (1)H nuclei are effectively detected in a 3-Tesla clinical MRI system. Thus, a vast array of new applications lays dormant, awaiting improved sensitivity. Here...

Hypoxic tumor microenvironments result in an aggressive phenotype and resistance to therapy that lead to tumor progression, recurrence, and metastasis. While poor vascularization and the resultant inadequate drug delivery are known to contribute to drug resistance, the effect of hypoxia on molecular transport through the interstitium, and the role...

Tumors display chaotic vasculature that leads to hypoxia. Hypoxia is associated with an aggressive phenotype and increased resistance to radiation and chemotherapy. Hypoxic tumor regions also contain very few collagen 1 fibers, which is a major component of the tumor extracellular matrix (ECM) and plays an important role in molecular movement throu...

Pure parahydrogen (pH(2) ) is the prerequisite for optimal pH(2) -based hyperpolarization experiments, promising approaches to access the hidden orders of magnitude of MR signals. pH(2) production on-site in medical research centers is vital for the proliferation of these technologies in the life sciences. However, previously suggested designs do n...

Collagen I (Col1) fibers are a major structural component in the extracellular matrix of human breast cancers. In a preliminary pilot study, we explored the link between Col1 fiber density in primary human breast cancers and the occurrence of lymph node metastasis. Col1 fibers were detected by second harmonic generation (SHG) microscopy in primary...

Cyclosporine (CsA) is a highly effective immunosuppressant used in patients after transplantation; however, its use is limited by nephrotoxicity. Salt depletion is known to enhance CsA-induced nephrotoxicity in the rat, but the underlying molecular mechanisms are not completely understood. The goal of our study was to identify the molecular effects...

Aims Dilated cardiomyopathies from chronic ischaemia (ISCM) or idiopathic (IDCM) pathological mechanisms are accompanied by similar clinical symptoms but may differ in protein expression, cell metabolism, and signalling processes at the cellular level. Using a combination of proteomic and metabolomic profiling, we sought to decipher the relationshi...

The hyperpolarization of nuclear spins holds great potential e.g. for biomedical research. Strong signal enhancements have been demonstrated e.g. by transforming the spin order of parahydrogen (pH(2)) to net polarization of a third nucleus (e.g. (13)C) by means of a spin-order-transfer (SOT) sequence. The polarization achieved is vitally dependent...

Altered choline phospholipid metabolism is a metabolic hallmark of cancer. Malignant transformation of breast can-cer cells results in a switch from high glycerophosphocholine (GPC) and low phosphocholine (PC) to low GPC and high PC. Glycerophosphocholine phosphodiesterase (GPC-PDE; E.C. 3.1.4.2) catalyzes the degradation of GPC to choline (Cho) an...

The combination of the principles of two fast spectroscopic imaging (SI) methods, spectroscopic missing pulse steady-state free precession and echo planar SI (EPSI) is described as an approach toward fast 3D SI. This method, termed missing pulse steady-state free precession echo planar SI, exhibits a considerably reduced minimum total measurement t...

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Altered choline phospholipid metabolism in breast cancers provides multiple targets for anticancer therapy. Malignant transformation of breast cancer cells results in a switch from high glycerophosphocholine (GPC) and low phosphocholine (PC) to low GPC and high PC. Glyce...

In respect of the manifold involvement of lipids in biochemical processes, the analysis of intact and underivatized lipids of body fluids as well as cell and tissue extracts is still a challenging task, if detailed molecular information is required. Therefore, the advantage of combined use of high-pressure liquid chromatography (HPLC), mass spectro...

In brain the amino acid L-aspartate serves roles as: (1) putative transmitter, (2) protein precursor, (3) donor of atoms for the biosynthesis of pyrimidine and purine bases, and (4) fuel for energy metabolism. Astrocytes dominate aspartate clearance in brain, and in culture they take up aspartate and quickly metabolize it. In brain, only astrocytes...

Application of the widely used immunosuppressant (ISS) cyclosporine (CsA) is severely limited by a number of serious side-effects such as kidney and neurotoxicity. As we have shown before, CsA exhibits metabolic toxicity in brain-models. The macrolide ISSs sirolimus (SRL) and everolimus (RAD) are capable of modulating these CsA-induced effects. It...

A new isocratic separation method was developed for separation of phospholipid (PL) classes based on a silica hydrophilic interaction liquid chromatography (HILIC) column with electrospray ionization (ESI) mass spectrometric detection. Although HILIC is typically used for polar compounds, also amphiphilic molecules like phospholipids can be separat...

Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT • Ciclosporin's nephrotoxicity initially targets the proximal tubule and is, at least in part, driven by increased formation of oxygen radicals. • ¹ H‐nuclear magnetic resonance spectroscopy (NMR)‐ and mass spectrometry (MS)‐based biochemical profiling (metabolomics) allows for the sensitive detection of meta...

Coadministration of the calcineurin inhibitor cyclosporine (CsA) and the mTOR inhibitors sirolimus (SRL) or everolimus (RAD) increases the efficacy of immunosuppression after organ transplantation. Neurotoxicity of CsA is a major clinical problem. Our goal was to assess the effects of CsA, SRL, and RAD on brain cell metabolism. The studies included...

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The basic mechanisms underlying calcineurin inhibitor (CI) nephrotoxicity and its enhancement by sirolimus are still largely unknown. We investigated the effects of CIs alone and in combination with sirolimus on the renal proteome and correlated these effects with urine metabolite pattern changes. Thirty-six male Wistar rats were assigned to six tr...

Oxidative stress and disrupted energy metabolism are common to many pathological conditions of the brain. Because astrocytes play an important role in the glucose metabolism of the brain, we have investigated whether sustained oxidative stress affects astroglial glucose metabolism with cultured primary rat astrocytes as a model system. Cultured ast...

Early detection of resistance development is crucial for imatinib-based treatment in chronic myeloid leukaemia (CML) patients. We aimed to distinguish metabolic markers of cell resistance to imatinib. Two human imatinib-sensitive CML cell lines: LAMA84-s and K562-s, and their resistant counterparts: LAMA84-r and K562-r (both resistant to 1 microM i...

Background: Cyclosporine and/or sirolimus impair recovery of renal transplants. This study examines the changes in urine metabolite profiles as surrogate markers of renal cell metabolism and function after cyclosporine and/or sirolimus treatment employing a rat kidney transplantation model. Methods: Using inbred Lewis rats, kidneys were transpla...

A recent report of detection of neural progenitor cells (NPCs) in living human brain by using in vivo proton MR spectroscopy ((1)H-MR spectroscopy) has sparked great excitement in the field of biomedicine because of its potential influence and utility in clinical neuroscience research. On the other hand, the method used and the findings described i...

The goal of this study was to evaluate the time course of metabolic changes in leukaemia cells treated with the Bcr-Abl tyrosine kinase inhibitor imatinib. Human Bcr-Abl(+) K562 cells were incubated with imatinib in a dose-escalating manner (starting at 0.1 microM with a weekly increase of 0.1 microM imatinib) for up to 5 weeks. Nuclear magnetic re...

The three essential amino acids, valine, leucine and isoleucine, constitute the group of branched-chain amino acids (BCAAs). BCAAs are rapidly taken up into the brain parenchyma, where they serve several distinct functions including that as fuel material in brain energy metabolism. As one function of astrocytes is considered the production of fuel...

The clinical use of the immunosuppressant calcineurin inhibitor cyclosporine is limited by its nephrotoxicity. This is enhanced when combined with the immunosuppressive mTOR inhibitor sirolimus. Nephrotoxicity of both drugs is not yet fully understood. The goal was to gain more detailed mechanistic insights into the time-dependent effects of cyclos...

The method of time averaging of distance restraints in molecular dynamics simulations is applied to Boc-Ala-Aib-Ala-OMe in order to demonstrate the improved sampling properties of this method compared to conventional distance restraining. Two conformational regions, β-turn type II and -turn, are seen during MD runs at a simulation temperature of 50...

The use of spectroscopic Missing Pulse--SSFP (spMP-SSFP) for fast three-dimensional (3D) proton MR spectroscopic imaging (MRSI) at 7 Tesla (T) is demonstrated. Sequence modifications were required regarding the limits of the specific absorption rate as well as hardware limitations with respect to maximum B(1) field strength and B(0) gradient slew r...

Isoleucine, together with leucine and valine, constitutes the group of branched-chain amino acids (BCAAs). BCAAs are transported from the blood into the brain parenchyma, where they can serve several distinct functions. Since brain tissue is known to oxidatively metabolize BCAAs to CO(2), they are considered as fuel material in brain energy metabol...

The analysis of intact and underivatised lipids in body fluids as well as in cell and tissue extracts is of utmost importance in the field of early diagnosis. Therefore, fast, reliable, and automated analytical methods are needed to detect known as well as unknown species. The combination of solid phase extraction, high-performance liquid chromatog...

Ammonia is a key factor in the pathogenesis of hepatic encephalopathy (HE). Acute ammonia treatment causes energy failure of astrocytes, which are able to compensate partly by increased anaerobic metabolism as a means of making up for the energetic shortfall. As hypothermia offers protection from severe encephalopathy and lactate accumulation in li...

Acute liver failure (ALF) is characterized by hepatic encephalopathy (HE) with brain edema as the main cause of death. The role of brain energy failure in ALF is still controversial. In the present study we investigated the association of encephalopathy with brain energy metabolism in rats with ALF induced by liver devascularization. Using [1–13]gl...

Thiamine deficiency (TD) results in region-selective impairment of brain metabolism. Since thiamine is a cofactor for enzymes involved in glucose metabolism, 1H and 13C-NMR was used to investigate metabolic fluxes through the major pathways of glucose metabolism in vulnerable (medial thalamus, MT; inferior colliculus, IC) and nonvulnerable brain st...

The genomic response to adaptation of IMCD3 cells to hypertonicity results in both upregulation and downregulation of a variety of genes. The present study was undertaken to assess the metabonomic and proteomic response of IMCD3 cells that have been chronically adapted to hypertonicity (600 and 900 mosm/kg H(2)O) as compared to cells under isotonic...

In patients with mesial temporal lobe epilepsy (MTLE) it remains an unresolved issue whether the interictal decrease in N-acetyl aspartate (NAA) detected by proton magnetic resonance spectroscopy ((1)H-MRS) reflects the epilepsy-associated loss of hippocampal pyramidal neurons or metabolic dysfunction. To address this problem, we applied high-resol...

A central question in manganese neurotoxicity concerns the focal neuronal damage in the globus pallidus. In the present study, we investigated specific pathways of [1-(13)C]glucose as well as of [2-(13)C]acetate in this brain region and the frontal cortex following 4-day manganese treatment by high-resolution NMR spectroscopy. Following administrat...

A unique quantitative high-performance liquid chromatography-mass spectrometry (HPLC-MS) method to investigate the energy state in cells and tissues was developed and validated using a chromatographic method designed to (i) separate and quantify more than 11 nucleotides without the use of phosphate buffer and (ii) minimize the potential ion suppres...

Sphingomyelins were characterized using a combination of a novel isocratic reversed-phase HPLC method with electrospray time-of-flight mass spectrometric detection and optional online MS/MS. The constitution of the sphingomyelins is determined by MS/MS experiments. Baseline separation of 17 compounds of a bovine brain extract (2 main compounds and...

A numerical simulation tool was developed to calculate the echo amplitudes of J-coupled resonances within a series of radiofrequency (RF) refocused echoes. The signal modulation due to J-coupling in rapid acquisition with relaxation enhancement (RARE) is suppressed only when the inverse of the pulse interval (tau) is large compared to both the chem...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. Visualizing corresponding metabolic changes in the brain of patients with ALS with proton magnetic resonance spectroscopy ((1)H-MRS) may provide surrogate markers for an early disease detection, for monitoring the progressi...

Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising eith...

The glutamine–glutamate cycle between astrocytes and neurons is an essential part of neuronal function and activity. However, this cycle is not stoichiometric and is modulated by different regulatory mechanisms. By this means, in particular, the astrocytes are flexible in their intracellular regulation of metabolism and their ability to support the...

Three-dimensional (3D) (1)H MR spectroscopic imaging (SI) allows metabolic changes in human tissue to be identified. In clinical practice, fast acquisition techniques are required to achieve an adequate spatial resolution within acceptable total measurement times. In this study a novel fast pulse sequence for 3D (1)H SI based on the condition of st...

The measurement of different urine components and their changes over time may provide comprehensive and early information about perinatal metabolic processes and physiological changes. We hypothesized that (1) H-NMR-spectroscopy generating a complex spectral profile without pre-selection of urinary metabolites could identify metabolites determining...

The influence of noise on the standard deviation of spectral integrals is examined. Calculations assuming discrete Fourier-transform data are compared with Monte-Carlo simulations. The effects of zero-filling and apodization are examined for free-induction-decay (FID) signals and for symmetric spin–echo signals in one and two dimensions, with parti...

Recently, new methods for fast (1)H spectroscopic imaging based on the condition of steady state free precession (SSFP) were introduced to achieve a high signal-to-noise ratio at short minimum measurement times. In this work, a major improvement is presented to overcome a crucial drawback in some of the former sequences: the lack of spatial selecti...

Global climate change is associated with a progressive rise in ocean CO(2) concentrations (hypercapnia) and, consequently, a drop in seawater pH. However, a comprehensive picture of the physiological mechanisms affected by chronic CO(2) stress in marine biota is still lacking. Here we present an analysis of protein biosynthesis rates in isolated mu...

A fast proton spectroscopic imaging pulse sequence based on the condition of steady-state free precession is presented. High 3D spatial and temporal resolution is achieved using simultaneous detection of both one spatial and one spectral dimension, with a time-dependent gradient cycle known from echo planar imaging. Additionally, in order to increa...

A methodological development for quantitative short-echo-time (TE) in vivo proton MR spectroscopy (MRS) without water suppression (WS) is described that integrates experimental and software approaches. Experimental approaches were used to eliminate frequency modulation sidebands and first-order phase errors. The dominant water signal was modeled an...

Over a period of several days, rhythmic changes in extracellular NH+4 concentration take place in cultures of the cyanobacterium Microcystis firma (Bré et Lenorm.) Schmidle, strain Gromov/St. Petersb. 398, under conditions of restricted CO2 supply and light/dark alternation. The changes are enhanced by nitrate supply. Among the various processes ge...

Multinuclear NMR spectroscopy is used to investigate the effect of glutamine on neuronal glucose metabolism. Primary neurons were incubated with [1-(13C)]glucose in the absence or presence of glutamine (2 mM) and/or NH4Cl (5 mM). After ammonia-treatment, the concentrations of high-energy phosphates decreased up to 84% of control, which was aggravat...

This study investigates how the metabolic activity and de novo synthesis of amino acids from glucose correlate with changes in intracellular organic osmolytes involved in astrocytic volume regulation during hyperammonemia and hyponatremia. Multinuclear (1H-, 31P-, 13C-) NMR spectra were recorded to quantify water-soluble metabolites, the cellular e...

A new two-scan method for localized 1H in vivo NMR spectroscopy (MRS) without water suppression (WS) is described. In one of the scans, two chemical shift selective 180 degrees pulses are applied prior to a standard localization sequence to invert all metabolite signals upfield and downfield from water, which remains unaffected. The difference spec...

Leucine is rapidly metabolized in astroglial primary cultures. Therefore, it is considered as valuable fuel in brain energy metabolism. Only few of the leucine metabolites generated and released by astroglial cells have been identified. Therefore, a more detailed study was performed analyzing by NMR techniques the 13C-labeled metabolites, which wer...

We previously reported that imatinib decreased glucose uptake in the BCR-ABL+ cells in a dose- and timedependent fashion by switching from glycolysis to Krebs cycle metabolism and improving the cell energy state. The goal of this study was to evaluate metabolic aspects of imatinib resistance in paired imatinib-sensitive and resistant clones of two...