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Heinrich Sauer

Publications and source records attributed to Heinrich Sauer.

At least 37 records · Page 2Linked to original sources
PubMed2005

Reactive oxygen species-linked regulation of the multidrug resistance transporter P-glycoprotein in Nox-1 overexpressing prostate tumor spheroids.

Expression of the multidrug resistance (MDR) transporter P-glycoprotein (P-gp) has been demonstrated to be regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibited by intracellular reactive oxygen species (ROS). Herein, P-gp and HIF-1alpha expression were investigated in multicellular prostate tumor spheroids overexpressing the ROS-generating enzyme Nox-1 in comparison to the mother cell line DU-145. In Nox-1-overexpressing tumor spheroids (DU-145Nox1) generation of ROS as well as expression of Nox-1 was significantly increased as compared to DU-145 tumor spheroids. ROS generation was significantly inhibited in the presence of the NADPH-oxidase antagonists diphenylen-iodonium chloride (DPI) and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF). Albeit growth kinetic of DU-145Nox1 tumor spheroids was decreased as compared to DU-145 spheroids, elevated expression of Ki-67 was observed indicating increased cell cycle activity. In DU-145Nox1 tumor spheroids, expression of HIF-1alpha as well as P-gp was significantly decreased as compared to DU-145 spheroids, which resulted in an increased retention of the anticancer agent doxorubicin. Pretreatment with the free radical scavengers vitamin E and vitamin C increased the expression of P-gp as well as HIF-1alpha in Nox-1-overexpressing cells, whereas no effect of free radical scavengers was observed on mdr-1 mRNA expression. In summary, the data of the present study demonstrate that the development of P-gp-mediated MDR is abolished under conditions of elevated ROS levels, suggesting that the MDR phenotype can be circumvented by modest increase of intracellular ROS generation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Decreased sensitivity to experimental pain in adjustment disorder.

An altered perception of pain has been described for several psychiatric disorders. To date the influence of adjustment disorders (AD) on pain perception has not been described. Here, we investigated perception of experimentally induced pain in 15 patients suffering from AD (subtype with depressive symptoms) and controls matched for age and sex. Thresholds and tolerances were assessed for thermal and electrical pain on both sides of the body. We found an overall increase of pain thresholds and tolerances in AD patients as compared to controls, predominately on the right side of the body. Analogue findings have been reported for pain perception in major depressive disorder (MDD). Of the data obtained, only thermal pain threshold on the right arm correlated with the severity of depressive symptoms. Although the underlying pathology is elusive it is likely that the mechanisms for reduced pain sensitivity are comparable in MDD and AD.

Adjustment Disorders↗
PubMed2005

Intracellular redox state: towards quantitative description.

Redox state is a widely used term for the description of redox phenomena in biological systems. The regulating mechanisms responsible for maintaining the redox state are not yet fully known. But it was shown that changes in the redox state might lead to a cascade of intracellular events, beneficial or deleterious to the cell. There are several methods for the description of the intracellular redox state. These methods are based on using measured intracellular concentrations of reduced and oxidized glutathione in the Nernst equation. However, glutathione is not always a basic redox component in biological fluids, organelles, cells or tissues. As a result, changes in the intracellular redox state are not always accompanied by considerable changes of glutathione concentration. In this work it was proposed to use the concept of effective reduction potential for the quantitative characteristic of the intracellular redox state. The effective reduction potential was substantiated on the basis of a thermodynamic description. A new equation for the calculation of the effective reduction potential was derived. This equation summarizes the contribution of different oxidizing and reducing agents in the formation of an effective redox potential. The theoretical estimation of the effective reduction potential values for the different biological fluids and cells was carried out with the use of a method developed.

Animals↗
PubMed2005

Increased calcium-independent phospholipase A2 activity in first but not in multiepisode chronic schizophrenia.

BACKGROUND: Increased activity of calcium independent phospholipase A2 (iPLA2) has repeatedly been found in the serum of unmedicated first-episode schizophrenia patients and assumed to reflect a pertubation of phospholipid metabolism. Previous studies in chronic schizophrenia were less conclusive. To explore whether iPLA2 changes are stage dependent, we investigated serum iPLA2 activity in various stages of schizophrenia. METHODS: iPLA2 activity was assessed in the serum of 30 first-episode and 23 multiepisode schizophrenia patients and 53 healthy control subjects matched for age and gender. A fluorimetric assay was applied using the PLA2 specific substrate NBDC6-HPC, thin-layer chromatography of reaction products, and digital image scanning for signal detection. RESULTS: Group comparison between first-episode and multiepisode patients and corresponding control groups revealed significantly increased iPLA2 activity only in first-episode patients. Enzyme activity in first-episode patients was also markedly increased, compared with chronic patients. iPLA2 changes observed were irrespective of neuroleptic medication, age, or gender. CONCLUSIONS: Our results suggest increased lipid turnover in the acute early phase of schizophrenia that is less obvious in chronic stages. Future longitudinal studies involving iPLA2 activity and phosphorous magnetic resonance spectroscopy need to address the relation between perturbed brain lipid metabolism and iPLA2 increment in the course of schizophrenia.

Adolescent↗
PubMed2005

Regulation of the multidrug resistance transporter P-glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species.

Hyperthermia is an important component of many cancer treatment protocols. In our study the regulation of the multidrug resistance (MDR) transporter P-glycoprotein by hyperthermia was studied in multicellular prostate tumor spheroids. Hyperthermia treatment of small (50-100 microm) tumor spheroids significantly increased P-glycoprotein and mdr-1 mRNA expression with a maximum effect at 42 degrees C, whereas only moderate elevation of P-glycoprotein was found in large (350-450 microm) tumor spheroids. Hyperthermia caused an elevation of intracellular reactive oxygen species (ROS). Inhibition of ROS generation with NADPH-oxidase inhibitors diphenylen iodonium (DPI) and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF) abolished P-glycoprotein expression but did not affect its transcript levels following heat treatment. This indicates that P-glycoprotein levels are controlled by regulating its translation rate or stability. Hyperthermia incubation resulted in a differential activation of p38 mitogen-activated protein kinase (MAPK), extracellular regulated kinase 1,2 (ERK1,2), and c-jun N-terminal kinase (JNK) immediately, 4 hr and 24 hr after treatment. Furthermore, upregulation of hypoxia-inducible factor 1alpha (HIF-1alpha) was observed. Elevation of HIF-1alpha and P-glycoprotein expression following hyperthermia treatment were abolished upon coadministration of the p38 inhibitor SB203580. In contrast the JNK inhibitor SP600125 and the ERK1,2 inhibitor UO126 resulted in increase of HIF-1alpha and P-glycoprotein in the control as well as the hyperthermia-treated samples, indicating negative regulation of intrinsic HIF-1alpha and P-glycoprotein expression by ERK1,2 and JNK signaling cascades. In summary our data demonstrate that hyperthermia-induced upregulation of P-glycoprotein and HIF-1alpha is mediated by activation of p38, whereas ERK1,2 and JNK are involved in repression of P-glycoprotein and HIF-1alpha under control conditions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Redox control of angiogenic factors and CD31-positive vessel-like structures in mouse embryonic stem cells after direct current electrical field stimulation.

The molecular mechanisms driving angiogenesis in tissues derived from embryonic stem (ES) cells are currently unknown. Herein we investigated the effects of direct current (DC) electrical field treatment on endothelial cell differentiation and angiogenesis of mouse ES cells. Treatment of ES cell-derived embryoid bodies with field strengths ranging from 250 V/m to 750 V/m, applied for 60 s, dose-dependently increased the capillary area staining positive for the endothelial-specific marker platelet endothelial cell adhesion molecule-1 (PECAM-1), indicating stimulation of endothelial cell differentiation and angiogenesis. Consequently, increased expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) within 24 h was observed. Electric field treatment raised reactive oxygen species (ROS) generation for at least 48 h, which was blunted by NADPH-oxidase inhibitors diphenylen iodonium chloride (DPI) as well as 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), and increased the expression of NADPH-oxidase subunits p22-phox, p47-phox, p67-phox, and gp91-phox within 24 h. Electrical field treatment resulted in activation of extracellular regulated kinase 1,2 (ERK1,2), p38, as well as c-Jun NH2-terminal kinase (JNK). Pretreatment with the JNK inhibitor SP600125 resulted in a significant decrease in capillary areas under control conditions as well as under conditions of electrical field treatment, whereas the p38 inhibitor SB203580 was without effects. By contrast, the ERK1,2 antagonist UO126 inhibited electrical field-induced angiogenesis, whereas angiogenesis under control conditions was unimpaired. The increase in capillary areas and VEGF expression as well as activation of JNK and ERK1,2 was significantly inhibited in the presence of the free radical scavenger vitamin E underscoring the role of ROS in electrical field-induced angiogenesis of ES cells.

Angiogenesis Inducing Agents↗
PubMed2005

Pain perception in major depression depends on pain modality.

One frequently described feature of depression is an increased vulnerability to pain complaints, and chronic pain is frequently accompanied by symptoms of depression. In contrast to this, a decreased sensitivity to experimental pain has been described in major depression. The physiological basis of this phenomenon is yet elusive. We investigated 30 patients suffering from a major depressive disorder and matched controls. Pain testing (threshold and tolerance) was performed on both sides of the body and included assessment of thermal, electrical and ischemic pain. While confirming hypoalgesia to heat and electrical pain in comparison to controls, we found hyperalgesia to ischemic muscle pain. Furthermore, thermal pain tolerance and electrical pain tolerance were significantly increased on the right hand side confirming previous results of a lateralized perception of pain in depression. Our main finding suggests that painful stimuli are processed differentially depending on the localization of pain induction in depression. This knowledge may enable us to understand and ultimately treat pain complaints more appropriately in depressed patients.

Adult↗
PubMed2004

Lateralization of pupillary light reflex parameters.

OBJECTIVE: The aim of this study was to determine differing reactions of the left and right eyes with regard to pupillary light reflex (PLR) parameters. METHODS: All together 90 healthy subjects were included. In the first test series, 34 subjects were investigated on both eyes (left eye was tested first, three tests per day and one reliability test). In the second test series, 32 subjects were studied while changing the beginning side. In the last test series, 29 subjects were investigated 12 times each within 1h (beginning side changed, without spoken advice). Infrared pupillometry was used to study pupil diameter, latency time, relative amplitude, contraction/dilation velocity, and pupil redilation time. RESULTS: The study demonstrated significant differences of PLR parameters between both eyes. In contrast to the pupil diameter of the left eye the parasympathetically-dominated right eye was not influenced by vocal instructions or by changing the beginning side. CONCLUSIONS: PLR parameters might indicate functional lateralization of autonomic function in the central nervous system. High sensitivity of the procedure (arousal due to spoken advice, time of day) is advantageous for various psychophysiological investigations. SIGNIFICANCE: Differences between both eyes might point towards cortical lateralization of central autonomic function.

Adult↗
PubMed2004

Olfactory impairment in monozygotic twins discordant for schizophrenia.

OBJECTIVE: Several studies demonstrated olfactory dysfunction in patients with schizophrenia, some reported deficient olfaction in unaffected relatives of schizophrenics as well. This study differentially assessed olfactory acuity as well as smell identification and smell discrimination in monozygotic twins discordant for schizophrenia and healthy, monozygotic control twins, to determine the genetic basis of different olfactory modalities and their association to schizophrenia. METHOD: The Sniffin'Sticks test,a comprehensive and standardized olfactory test, was employed to assess the olfactory function of 10 monozygotic twin pairs discordant for schizophrenia versus 10 age- and sexmatched healthy,monozygotic twin pairs. RESULTS: Olfaction of affected monozygotic twins was globally impaired. Partial olfactory impairment of their unaffected co-twins may point to a genetic cause of olfactory impairment in schizophrenia. The influence of genetic factors was most evident for olfactory acuity and least evident for smell identification. All olfactory functions declined with duration of illness. Side of stimulus presentation did not influence olfactory performance. CONCLUSIONS: Genetic factors associated with olfactory dysfunction may contribute to schizophrenia. The degree of the genetic influence on olfaction depends on the olfactory domain under examination.

Adult↗
PubMed2004

The influence of major depression and its treatment on heart rate variability and pupillary light reflex parameters.

BACKGROUND: The link between depression and autonomic dysfunction has attracted more attention since epidemiological studies have revealed that depressed patients have an augmented risk of cardiovascular morbidity and mortality. Former studies of autonomic dysfunction in major depression have shown inconclusive results. AIMS: To further elucidate the effect of depression and medication on autonomic function, 18 patients and 18 matched control subjects were comprehensively assessed once medicated and once non-medicated as well as after full clinical recovery. METHODS: Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters, and central autonomic tone was investigated by obtaining parameters of the pupillary light reflex (PLR). RESULTS: Acutely depressed patients who had not taken antidepressant medication for 8 weeks prior to the investigation differed significantly neither in heart rate parameters nor in parameters of the PLR from their controls. However, after 2 days of antidepressant treatment (SSRI and NaSSRI), parameters of heart rate analysis and PLR (except relative amplitude) changed significantly and remained significantly different after clinical recovery. LIMITATIONS: The study needs to be repeated using larger patient groups. Long-term studies are absolutely essential. CONCLUSION: The state of depression did not influence autonomic parameters significantly. In fact, treatment influenced autonomic function far more than the disease itself. Other branches of the autonomic nervous system (ANS), as well as new techniques should be applied to elucidate whether small changes in autonomic function exist. This might clarify whether disease or treatment might influence cardiac mortality in depression.

Adult↗
PubMed2004

Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells.

Cardiotrophin-1 (CT-1) is a cytokine that is involved in the growth and survival of cardiac cells. In the present study, we demonstrate that treatment of embryoid bodies grown from pluripotent murine embryonic stem (ES) cells with CT-1 significantly stimulated cardiomyogenesis and increased nuclear expression of the proliferation marker Ki-67. The increase in Ki-67 expression was inhibited upon pretreatment with the free radical scavenger vitamin E, indicating a role for reactive oxygen species (ROS) in the signaling cascade. CT-1 treatment of cardiac cells raised intracellular ROS in ES cell-derived cardiomyocytes. ROS were presumably generated by an NADPH-oxidase since ROS generation was down-regulated upon preincubation with the NADPH-oxidase inhibitor diphenylen iodonium chloride (DPI) and LY294002, which inhibits phosphatidylinositol 3 kinase (PI3-kinase). CT-1 activated nuclear factor-kappaB (NF-kappaB) and induced phosphorylation of the Janus kinase signal transducer-2 (Jak-2), the signal transducer and activator of transcription-3 (STAT-3) as well as the extracellular signal-regulated kinase 1,2 (ERK1/2). STAT-3 and ERK1/2 phosphorylation as well as NF-kappaB activation were inhibited by pretreatment with the Jak-2 antagonist AG490, the ERK1/2 inhibitor PD98059, the free radical scavenger vitamin E, the NADPH-oxidase inhibitor DPI, as well as by LY294002. PD98059 failed to inhibit Jak-2 phosphorylation, indicating that the ERK and the Jak/STAT signaling cascade interact on a level downstream of Jak-2. It is concluded that CT-1 stimulates the proliferation of ES cell-derived cardiomyocytes by signaling pathways that involve ROS as signaling molecules in the signal transduction cascade.

Animals↗
PubMed2004

Reliability of brain volumes from multicenter MRI acquisition: a calibration study.

Multicenter studies can provide additional information over single center studies because of their increased statistical power. Because similar acquisition protocols are being used internationally for structural magnetic resonance imaging (MRI) studies of the human brain, volumetric MRI data studies seem suitable for this purpose. Possible systematic differences between sites should be avoided, however, particularly when subtle differences in tissue volume are being searched for, such as in neuropsychiatric diseases. In this calibration study, the brains of six healthy volunteers were (re)scanned with MR scanners from four different manufacturers at five different sites, using the local acquisition protocols. The images were segmented at a central reference site. The intraclass correlation coefficient (ICC) was determined for the whole brain, gray and white matter, cerebellum, and lateral and third ventricle volumes. When required, the processing algorithms were calibrated for each site. Calibration of the histogram analysis was needed for segmentation of total brain volume at one site and for gray and white matter volume at all sites. No (additional) calibration was needed for cerebellum and ventricle volumes. The ICCs were > or = 0.96 for total brain, > or = 0.92 for cerebellum, > or = 0.96 for lateral ventricle, > or = 0.21 for third ventricle, > or = 0.84 for gray matter, and > or = 0.78 for white matter volume. Calibration of segmentation procedures allows morphologic MRI data acquired at different research sites to be combined reliably in multicenter studies.

Adult↗
PubMed2004

Effects of lorazepam on the neuromagnetic mismatch negativity (MMNm) and auditory evoked field component N100m.

The mismatch negativity (MMN) as an auditory evoked potential is thought to reflect an early, preconscious attention process. While this component has gained great importance in studies on clinical populations and in basic research on auditory information processing, the involvement of different neurotransmitters in the generation of this component is less well understood. We investigated the impact of the benzodiazepine lorazepam as a GABA agonist on the neuromagnetic MMN (MMNm) and auditory evoked field component N100m. A group of 12 healthy subjects was studied in single blind trials under the following three conditions: after the intake of 1.25 mg lorazepam, 100 mg caffeine or placebo. Neuromagnetic recordings were obtained before drug intake and three times after it. Controlled visual attention was tested additionally using a version of the Continuous Performance Test (CPT). The neuromagnetic activity was reconstructed by a single moving dipole, and the dipole moment and its latency were compared between conditions and time points of measurement. Lorazepam diminished the signal detection performance in the CPT 25 min after drug intake. The source of the field component N100m was attenuated, most significantly in the recording 105 min after lorazepam intake. The attenuation of the MMNm under lorazepam became significant at 105 min, but was visually less apparent, because in all conditions a decrease of the MMNm dipole moment within the course of a session was observed. Besides the already known effects of benzodiazepines on controlled attention functions, preconscious attention functions as reflected in the MMN are impaired by acute benzodiazepine intake. MMN studies on clinical populations have to be controlled for the recording time because of the strong habituation of this component.

Adult↗
PubMed2004

Neuroanatomy of "hearing voices": a frontotemporal brain structural abnormality associated with auditory hallucinations in schizophrenia.

Auditory hallucinations are a frequent symptom in schizophrenia. While functional imaging studies have suggested the association of certain patterns of brain activity with sub-syndromes or single symptoms (e.g. positive symptoms such as hallucinations), there has been only limited evidence from structural imaging or post-mortem studies. In this study, we investigated the relation of local brain structural deficits to severity of auditory hallucinations, particularly in perisylvian areas previously reported to be involved in auditory hallucinations. In order to overcome certain limitations of conventional volumetric methods, we used deformation-based morphometry (DBM), a novel automated whole-brain morphometric technique, to assess local gray and white matter deficits in structural magnetic resonance images of 85 schizophrenia patients. We found severity of auditory hallucinations to be significantly correlated (P < 0.001) with volume loss in the left transverse temporal gyrus of Heschl (primary auditory cortex) and left (inferior) supramarginal gyrus, as well as middle/inferior right prefrontal gyri. This demonstrates a pattern of distributed structural abnormalities specific for auditory hallucinations and suggests hallucination-specific alterations in areas of a frontotemporal network for processing auditory information and language.

Adult↗
PubMed2003

Regulation of intrinsic prion protein by growth factors and TNF-alpha: the role of intracellular reactive oxygen species.

Function and regulation of the intrinsic prion protein (PrPc) are largely unknown. In the present study the regulation of PrPc expression by growth factors and cytokines that increase intracellular reactive oxygen species (ROS) levels was studied in glioma and neuroblastoma cells grown as multicellular tumor spheroids. PrPc protein was significantly increased when glioma spheroids were treated with either ATP, nerve growth factor (NGF), epidermal growth factor (EGF), or tumor necrosis factor alpha (TNF-alpha), whereas mRNA levels as evaluated by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) remained unchanged. ATP, NGF, EGF, and TNF-alpha raised intracellular ROS levels as evaluated using the redox-sensitive fluorescence dye 2'7'-dichlorodihydrofluorescein diacetate (H2DCFDA). The observed elevation in PrPc was completely abolished in the presence of the free radical scavengers vitamin E and ebselen, as well as following pretreatment with the NADPH-oxidase inhibitor diphenylen iodonium chloride (DPI), indicating that PrPc levels are regulated by intracellular ROS. The correlation of PrPc expression to the intracellular ROS levels was investigated by the use of neuroblastoma cells overexpressing either mutant V210I PrP, or wild-type PrPc. It was observed that the intracellular redox state was significantly reduced in PrPc as well as V210I PrP overexpressing cells as compared to non-transfected cells. Consequently, the observed elevation of ROS following treatment with ATP was completely abolished in PrP overexpressing cells. Our data are in line with the assumption that PrPc plays a role as free radical scavenger and/or sensor molecule for oxidative stress.

Adenosine Triphosphate↗
PubMed2003

T lymphoid differentiation in human bone marrow.

The unique role of the thymus in the development of T cells was established >4 decades ago. To elucidate how uncommitted lymphoid progenitor cells are instructed to migrate from bone marrow to the thymus to undergo T lymphoid differentiation, we generated and analyzed a genome-wide gene expression profile of CD7+ CD10+ human bone marrow T cell lineage precursors (TLPs) by using the serial analysis of gene expression technique. Unexpectedly, the serial analysis of gene expression profile identified a high number of (pre-) T cell receptor antigen (TCR)-related transcripts in bone marrow TLPs. To determine the configuration of the TCRbeta locus in these cells at a quantitative level, we sorted and analyzed bone marrow TLPs from five donors by single-cell PCR. Similar proportions of TLPs harbored TCRbeta germ-line alleles, D-J, or V-DJ gene rearrangements. Thus, bone marrow TLPs are heterogenous with respect to TCRbeta rearrangement status, suggesting an active recombination machinery that is consistent with the expression of RAG1, RAG2, and TdT in this population. As a hallmark of ongoing TCRbeta V-DJ rearrangement, we could amplify broken-ended recombination-signal sequence DNA intermediates from bone marrow TLPs, but not from mature T cells by ligation-mediated PCR. Approximately half of the TCRbeta rearrangements were compatible with the expression of a functional pre-TCR, which is in agreement with surface expression of pre-Talpha on bone marrow TLPs as shown by confocal laser microscopy and flow cytometry. At a frequency <0.5% of mononucleated cells in human bone marrow, this population is rare, yet it exemplifies T lymphoid differentiation in the human already before immigration into the thymus.

Base Sequence↗
PubMed2003

Cardiac specific differentiation of mouse embryonic stem cells.

Embryonic stem (ES) cells may represent an alternative source of functionally intact cardiomyocytes for the causal treatment of cardiovascular diseases. However, this requires cardiac-specific differentiation of stem cells and the selection of pure lineages consisting of early embryonic cardiomyocytes. Therefore, an understanding of the basic mechanisms of heart development is essential for selective differentiation of embryonic stem cells into cardiac cells. The development of cardiac cells from embryonic stem cells is regulated by several soluble factors and signalling molecules together with cardiac specific transcription factors such as the zinc-finger GATA proteins and Nkx-2.5. GATA-4 and Nkx-2.5 seem to be essential for heart development. The use of enhanced green fluorescent protein (EGFP) under the control of cardiac-specific promoters in combination with the ES cell system has allowed for the functional characterisation of cardiac precursor cells. Embryonic stem cell-derived cardiomyocytes developmentally express similar cardiac-specific proteins, ion channels and signalling molecules to that of adult cardiomyocytes. Furthermore, identification of growth factors and signalling molecules under cell culture conditions is crucial for the selective cardiac differentiation of embryonic stem cells. Therefore, serum-free culture conditions have to be established in order to examine the influence of different growth factors and signalling molecules on cardiac development and/or formation from ES cells. Although significant progress has been made in generating cardiac cell lineage by the combination of genetically manipulative methods with selective culture conditions for cell transplantation therapy, one of the remaining future challenges for transplantation in humans is the immunological rejection of the engrafted cardiomyocytes.

Animals↗