Publications by authors named "Uwe Lendeckel"

139 Publications

Expression of canonical transient receptor potential channels in U-2 OS and MNNG-HOS osteosarcoma cell lines.

Oncol Lett 2021 Apr 21;21(4):307. Epub 2021 Feb 21.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, D-17475 Greifswald, Germany.

In U-2 OS and MNNG-HOS osteosarcoma cells, small interfering RNA-mediated knockdown of the angiotensin-(1-7) receptor, Mas, increases cell proliferation. Whether alterations in canonical transient receptor potential channels (TRPC) expression contribute to this effect is not clear. In the present study, a basic description of TRPC subtype expression in osteosarcoma cell lines was provided. The pharmacological modulators of the angiotensin-(1-7) receptor, Mas, AVE0991 (agonist), or D-Ala-Ang-(1-7) (antagonist) were applied to elucidate a possible role of Mas in the regulation of TRPC mRNA levels. The contribution of other G-protein coupled receptors (GPCR) or receptor tyrosine kinases to TRCP expression was studied by applying the selective pharmacological blockers of either PI3 kinase or MEK/Erk1/2 signaling, Ly294002 and PD98059. AVE0991 and D-Ala-Ang-(1-7) exhibited no or marginal effects on TRPC mRNA expression. Ly294002 provoked a 9.6- and 5.9-fold increase in the amounts of TRPC5 mRNA in MNNG-HOS and U-2 OS cells, respectively. Additionally, Ly294002 increased TRPC6 mRNA levels; however, it had no effect on TRPCs 1, 3 and 4. Administration of PD98059 increased the amounts of TRPC6 and TRPC4 ~2-fold. In conclusion, the present study demonstrated that Mas-dependent alterations in osteosarcoma cell line proliferation were not mediated by any changes in TRPC subtype gene expression. The data shows in principle, and consistent with the literature, that the signaling pathways examined can regulate the expression of TRPCs at the mRNA level. Therefore, direct and signaling pathway-specific pharmacological targeting of TRPC subtypes may represent an option for improving the treatment of osteosarcoma.
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http://dx.doi.org/10.3892/ol.2021.12568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905632PMC
April 2021

The effects of the chemical environment of menaquinones in lipid monolayers on mercury electrodes on the thermodynamics and kinetics of their electrochemistry.

Eur Biophys J 2021 Mar 17. Epub 2021 Mar 17.

Institute of Biochemistry, University of Greifswald, Felix-Hausdorff-Str. 4, 17487, Greifswald, Germany.

The effects of the chemical environment of menaquinones (all-trans MK-4 and all-trans MK-7) incorporated in lipid monolayers on mercury electrodes have been studied with respect to the thermodynamics and kinetics of their electrochemistry. The chemical environment relates to the composition of lipid films as well as the adjacent aqueous phase. It could be shown that the addition of all-trans MK-4 to TMCL does not change the phase transition temperatures of TMCL. In case of DMPC monolayers, the presence of cholesterol has no effect on the thermodynamics (formal redox potentials) of all-trans MK-7, but the kinetics are affected. Addition of an inert electrolyte (sodium perchlorate; change of ionic strength) to the aqueous phase shifts the redox potentials of all-trans MK-7 only slightly. The formal redox potentials of all-trans MK-4 were determined in TMCL and nCL monolayers and found to be higher in nCL monolayers than in TMCL monolayers. The apparent electron transfer rate constants, transfer coefficients and activation energies of all-trans MK-4 in cardiolipins have been also determined. Most surprisingly, the apparent electron transfer rate constants of all-trans MK-4 exhibit an opposite pH dependence for TMCL and nCL films: the rate constants increase in TMCL films with increasing pH, but in nCL films they increase with decreasing pH. This study is a contribution to understand environmental effects on the redox properties of membrane bond redox systems.
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http://dx.doi.org/10.1007/s00249-021-01512-wDOI Listing
March 2021

WNT signaling in atrial fibrillation.

Exp Biol Med (Maywood) 2021 May 27;246(9):1112-1120. Epub 2021 Feb 27.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald D-17475, Germany.

The Wnt signaling pathway regulates physiological processes such as cell proliferation and differentiation, cell fate decisions, and stem cell maintenance and, thus, plays essential roles in embryonic development, but also in adult tissue homeostasis and repair. The Wnt signaling pathway has been associated with heart development and repair and has been shown to be crucially involved in proliferation and differentiation of progenitor cells into cardiomyocytes. The investigation of the role of the Wnt signaling pathway and the regulation of its expression/activity in atrial fibrillation has only just begun. The present minireview (I) provides original data regarding the expression of Wnt signaling components in atrial tissue of patients with atrial fibrillation or sinus rhythm and (II) summarizes the current state of knowledge of the regulation of Wnt signaling components' expression/activity and the contribution of the various levels of the Wnt signal transduction pathway to the processes of the development, maintenance, and progression of atrial fibrillation.
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http://dx.doi.org/10.1177/1535370221994086DOI Listing
May 2021

Possible New Strategies for the Treatment of Congenital Hyperinsulinism.

Front Endocrinol (Lausanne) 2020 27;11:545638. Epub 2020 Oct 27.

Department of Pharmacology, Institute of Pharmacy, University of Tübingen, Tübingen, Germany.

Objective: Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence β-cells and thus attenuate insulin secretion.

Research Design And Methods: In the scope of our research, we tested substances more selective and more potent than the gold standard diazoxide that also interact with neuroendocrine ATP-sensitive K (K) channels. Additionally, K channel-independent targets as Ca-activated K channels of intermediate conductance (K3.1) and L-type Ca channels were investigated. Experiments were performed using human islet cell clusters isolated from tissue of CHI patients (histologically classified as pathological) and islet cell clusters obtained from C57BL/6N (WT) or SUR1 knockout (SUR1) mice. The cytosolic Ca concentration ([Ca]) was used as a parameter for the pathway regulated by electrical activity and was determined by fura-2 fluorescence. The mitochondrial membrane potential (ΔΨ) was determined by rhodamine 123 fluorescence and single channel currents were measured by the patch-clamp technique.

Results: The selective K channel opener NN414 (5 µM) diminished [Ca] in isolated human CHI islet cell clusters and WT mouse islet cell clusters stimulated with 10 mM glucose. In islet cell clusters lacking functional K channels (SUR1) the drug was without effect. VU0071063 (30 µM), another K channel opener considered to be selective, lowered [Ca] in human CHI islet cell clusters. The compound was also effective in islet cell clusters from SUR1 mice, showing that [Ca] is influenced by additional effects besides K channels. Contrasting to NN414, the drug depolarized ΔΨ in murine islet cell clusters pointing to severe interference with mitochondrial metabolism. An opener of K3.1 channels, DCEBIO (100 µM), significantly decreased [Ca] in SUR1 and human CHI islet cell clusters. To target L-type Ca channels we tested two already approved drugs, dextromethorphan (DXM) and simvastatin. DXM (100 µM) efficiently diminished [Ca] in stimulated human CHI islet cell clusters as well as in stimulated SUR1 islet cell clusters. Similar effects on [Ca] were observed in experiments with simvastatin (7.2 µM).

Conclusions: NN414 seems to provide a good alternative to the currently used K channel opener diazoxide. Targeting K3.1 channels by channel openers or L-type Ca channels by DXM or simvastatin might be valuable approaches for treatment of CHI caused by mutations of K channels not sensitive to K channel openers.
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http://dx.doi.org/10.3389/fendo.2020.545638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653201PMC
October 2020

From putative brain tumor marker to high cognitive abilities: Emerging roles of a disintegrin and metalloprotease (ADAM) 12 in the brain.

J Chem Neuroanat 2020 11 2;109:101846. Epub 2020 Jul 2.

Department of Psychiatry, Otto-von-Guericke University, Magdeburg, Germany.

ADAM (a disintergin and metalloprotease) 12 is a member of the large family of multidomain metalloprotease-disintegrins, which possess cell-binding and metalloprotease properties. The enzyme is responsible for the shedding of a number of membrane-bound proteins (heparin-binding-EGF, insulin-like growth factor 2-binding proteins 3 and 5, oxytocinase, glycoprotein non-metastatic melanoma protein B and basigin). In rat and human CNS, ADAM12 is predominantly localized in white and gray matter oligodendrocytes. In addition it can be detected in astrocytes, neurons and endothelial cells. Its function in healthy brain is not well established yet, but prominent roles in CNS development, myelination and high cognitive abilities are discussed. There is increasing evidence that ADAM12 is involved in numerous major diseases of the CNS, which are summarized in the present review (brain tumors, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer´s disease, stroke, schizophrenia, autism and bipolar disorder).
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http://dx.doi.org/10.1016/j.jchemneu.2020.101846DOI Listing
November 2020

The acid-base and redox properties of menaquinone MK-4, MK-7, and MK-9 (vitamin K) in DMPC monolayers on mercury.

Eur Biophys J 2020 May 5;49(3-4):279-288. Epub 2020 May 5.

Institute of Biochemistry, University of Greifswald, Felix-Hausdorff-Str. 4, 17487, Greifswald, Germany.

The acid-base and redox properties of the menaquinones MK-4, MK-7, and MK-9 (vitamin K) have been studied in DMPC monolayers on mercury electrodes. The monolayers were prepared by adhesion-spreading of menaquinone-spiked DMPC liposomes on a stationary mercury drop electrode. All three menaquinones possess [Formula: see text] constants outside the experimentally accessible range, i.e., they are higher than about 12. The standard potentials of MK-4, MK-7, and MK-9 in the DMPC monolayers are very similar, i.e., 0.351, 0.326, and 0.330 V (corresponding to the biochemical standard potentials - 0.063, - 0.088, and - 0.085 V).
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http://dx.doi.org/10.1007/s00249-020-01433-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244470PMC
May 2020

Proliferation of C6 glioma cells requires the phospholipid remodeling enzyme tafazzin independent of cardiolipin composition.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 03 26;1865(3):158596. Epub 2019 Dec 26.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, University of Greifswald, Ferdinand-Sauerbruch-Str., D-17475 Greifswald, Germany. Electronic address:

The mitochondrial phospholipid (CL) has been linked to mitochondrial and cellular functions. It has been postulated that the composition of CL is of impact for mitochondrial energy metabolism and cell proliferation. Although a correlation between CL composition and proliferation could be demonstrated for several cell types, evidence for a causal relationship remains obscure. Here, we applied two independent approaches, i) supplementation of fatty acids and ii) knock-out of the phospholipid remodeling enzyme tafazzin, to manipulate CL composition and analyzed the response on proliferation of C6 glioma cells. Both strategies caused substantial changes in the distribution of cellular fatty acids as well as in the distribution of fatty acids incorporated in CL that were accompanied by changes of the composition of molecular CL species. These changes did not correlate with cell proliferation. However, knock-out of tafazzin caused dramatic reduction in proliferation of C6 glioma cells independent of CL composition. The mechanism of tafazzin-dependent restriction of proliferation remains unclear. Among the various fatty acids administered only palmitic acid restricted cell proliferation by induction of cell death.
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http://dx.doi.org/10.1016/j.bbalip.2019.158596DOI Listing
March 2020

Vitamin B6 deficiency in new born rats affects hepatic cardiolipin composition and oxidative phosphorylation.

Exp Biol Med (Maywood) 2019 12 21;244(18):1619-1628. Epub 2019 Nov 21.

Department of Pathological Biochemistry, Otto-von-Guericke University Magdeburg, Magdeburg D-39120, Germany.

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http://dx.doi.org/10.1177/1535370219889880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963376PMC
December 2019

Tafazzin-dependent cardiolipin composition in C6 glioma cells correlates with changes in mitochondrial and cellular functions, and cellular proliferation.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 04 9;1864(4):452-465. Epub 2019 Jan 9.

Institute of Clinical Chemistry, Department of Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany.

The mitochondrial phospholipid cardiolipin (CL) has been implicated with mitochondrial morphology, function and, more recently, with cellular proliferation. Tafazzin, an acyltransferase with key functions in CL remodeling determining actual CL composition, affects mitochondrial oxidative phosphorylation. Here, we show that the CRISPR-Cas9 mediated knock-out of tafazzin (Taz) is associated with substantial alterations of various mitochondrial and cellular characteristics in C6 glioma cells. The knock-out of tafazzin substantially changed the profile of fatty acids incorporated in CL and the distribution of molecular CL species. Taz knock-out was further associated with decreased capacity of oxidative phosphorylation that mainly originates from impaired complex I associated energy metabolism in C6 glioma cells. The lack of tafazzin switched energy metabolism from oxidative phosphorylation to glycolysis indicated by lower respiration rates, membrane potential and higher levels of mitochondria-derived reactive oxygen species but keeping the cellular ATP content unchanged. The impact of tafazzin on mitochondria was also indicated by altered morphology and arrangement in tafazzin deficient C6 glioma cells. In the cells we observed tafazzin-dependent changes in the distribution of cellular fatty acids as an indication of altered lipid metabolism as well as in stability/morphology. Most impressive is the dramatic reduction in cell proliferation in tafazzin deficient C6 glioma cells that is not mediated by reactive oxygen species. Our data clearly indicate that defects in CL phospholipid remodeling trigger a cascade of events including modifications in CL linked to subsequent alterations in mitochondrial and cellular functions.
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http://dx.doi.org/10.1016/j.bbalip.2019.01.006DOI Listing
April 2019

BDNF: mRNA expression in urine cells of patients with chronic kidney disease and its role in kidney function.

J Cell Mol Med 2018 11 21;22(11):5265-5277. Epub 2018 Aug 21.

Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.

Podocyte loss and changes to the complex morphology are major causes of chronic kidney disease (CKD). As the incidence is continuously increasing over the last decades without sufficient treatment, it is important to find predicting biomarkers. Therefore, we measured urinary mRNA levels of podocyte genes NPHS1, NPHS2, PODXL and BDNF, KIM-1, CTSL by qRT-PCR of 120 CKD patients. We showed a strong correlation between BDNF and the kidney injury marker KIM-1, which were also correlated with NPHS1, suggesting podocytes as a contributing source. In human biopsies, BDNF was localized in the cell body and major processes of podocytes. In glomeruli of diabetic nephropathy patients, we found a strong BDNF signal in the remaining podocytes. An inhibition of the BDNF receptor TrkB resulted in enhanced podocyte dedifferentiation. The knockdown of the orthologue resulted in pericardial oedema formation and lowered viability of zebrafish larvae. We found an enlarged Bowman's space, dilated glomerular capillaries, podocyte loss and an impaired glomerular filtration. We demonstrated that BDNF is essential for glomerular development, morphology and function and the expression of BDNF and KIM-1 is highly correlated in urine cells of CKD patients. Therefore, BDNF mRNA in urine cells could serve as a potential CKD biomarker.
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http://dx.doi.org/10.1111/jcmm.13762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201371PMC
November 2018

Integration of "omics" techniques: Dronedarone affects cardiac remodeling in the infarction border zone.

Exp Biol Med (Maywood) 2018 07;243(11):895-910

1 Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald D-17475, Germany.

Dronedarone improves microvascular flow during atrial fibrillation and reduces the infarct size in acute models of myocardial infarction. However, dronedarone might be harmful in patients with recent decompensated heart failure and increases mortality in patients with permanent atrial fibrillation. A pathophysiological explanation for these discrepant data is lacking. This study investigated the effects of dronedarone on gene and protein expression in the infarcted area and border zone in pigs subjected to anterior ischemia/reperfusion myocardial infarction. The ischemia/reperfusion myocardial infarction was induced in 16 pigs. Eight pigs were treated with dronedarone for 28 days after myocardial infarction, the remaining pigs served as control. Microarray-based transcriptome profiling and 2D-DIGE-based proteome analysis were used to assess the effects of dronedarone on left ventricular gene expression in healthy (LV), infarcted (MI), and border zone tissue. Selected targets were validated by RT-qPCR or immunoblot analyses, with special emphasize given to the transcriptome/proteome overlap. Combined "omics" analysis was performed to identify most significant disease and function charts affected by dronedarone and to establish an integrated network. The levels of 879 (BZ) or 7 (MI) transcripts and 51 (LV) or 15 (BZ) proteins were significantly altered by dronedarone, pointing to a substantial efficacy of dronedarone in the border zone. Transcriptome and proteome data indicate that dronedarone influences post-infarction remodeling processes and identify matricellular proteins as major targets of dronedarone in this setting. This finding is fully supported by the disease and function charts as well as by the integrated network established by combined "omics". Dronedarone therapy alters myocardial gene expression after acute myocardial infarction with pronounced effects in the border zone. Dronedarone promotes infarct healing via regulation of periostin and might contribute to the limitation of its expansion as well as cardiac rupture. Thus, there are no experimental hints that dronedarone per se has direct harmful effects after MI in ventricular tissue. Impact statement Dronedarone reduced the infarct size in models of acute myocardial infarction (MI). Here, we show that dronedarone attenuates many of the substantial changes in gene expression that are provoked by acute myocardial infarction (AMI) in pigs. Dronedarone modifies the expression of gene panels related to post-infarction cardiac healing and remodeling processes and, most remarkably, this occurs predominantly in the infarction border-zone and much less so in the vital or infarcted myocardium. Combined "omics" identified matricellular proteins and ECM as major dronedarone-regulated targets and emphasizes their relevance for Disease Charts and Tox Function Charts associated with tissue remodeling and cellular movement. The results demonstrate dronedarone's capability of regulating cardiac repair and remodeling processes specifically in the infarction border zone and identify underlying mechanisms and pathways that might be employed in future therapeutic strategies to improve long-term cardiac tissue function and stability.
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http://dx.doi.org/10.1177/1535370218788517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108048PMC
July 2018

Effects of siRNA-dependent knock-down of cardiolipin synthase and tafazzin on mitochondria and proliferation of glioma cells.

Biochim Biophys Acta Mol Cell Biol Lipids 2018 Apr 9;1863(4):379-387. Epub 2018 Jan 9.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, D-17475 Greifswald, Germany.

The mitochondrial phospholipid cardiolipin (CL) has been implicated with mitochondrial morphology, function, and cell proliferation. Changes in CL are often paralleled by changes in the lipid environment of mitochondria that may contribute to mitochondrial function and proliferation. This study aimed to separate the effects of CL content and CL composition from cellular free fatty acid distribution on bioenergetics and proliferation in C6 glioma cells. To this end, cardiolipin synthase and the CL remodelling enzyme, tafazzin, were knocked-down by siRNA in C6 cells. After 72 h of cultivation, we analysed CL composition by means of LC/MS/MS, distribution of cellular fatty acids by means of gas chromatography, and determined oxygen consumption and proliferation. Knock-down of cardiolipin synthase affected the cellular CL content in the presence of linoleic acid (LA) in the culture medium. Knock-down of tafazzin had no consequence with respect to the pattern of cellular fatty acids but caused a decrease in cell proliferation. It significantly changed the distribution of molecular CL species, increased CL content, decreased oxygen consumption, and decreased cell proliferation when cultured in the presence of linoleic acid (LA). The addition of linoleic acid to the culture medium caused significant changes in the pattern of cellular fatty acids and the composition of molecular CL species. These data suggest that tafazzin is required for efficient bioenergetics and for proliferation of glioma cells. Supplementation of fatty acids can be a powerful tool to direct specific changes in these parameters.
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http://dx.doi.org/10.1016/j.bbalip.2018.01.003DOI Listing
April 2018

Proteomics and transcriptomics in atrial fibrillation.

Herzschrittmacherther Elektrophysiol 2018 Mar 9;29(1):70-75. Epub 2018 Jan 9.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.

Atrial fibrillation (AF) is the most common tachyarrhythmia. AF, due to substantial remodeling processes initiated in the atria, is a typically self-sustaining and progressive disease. Atrial remodeling has been intensively investigated at the molecular level in recent decades. Although the application of "omics" technologies has already significantly contributed to our current understanding of the pathophysiology of AF, the complexity of the latter and the large heterogeneity of AF patients remained a major limitation. With the advent of novel "omics" and by applying integrative approaches, it will be possible to extract more information and push boundaries. The present review will summarize the contribution of transcriptomics and proteomics to our understanding of the pathophysiology of AF.
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http://dx.doi.org/10.1007/s00399-017-0551-xDOI Listing
March 2018

Identification of miR-16 as an endogenous reference gene for the normalization of urinary exosomal miRNA expression data from CKD patients.

PLoS One 2017 31;12(8):e0183435. Epub 2017 Aug 31.

Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.

Chronic kidney disease (CKD) is a severe disorder with an increasing incidence worldwide. An early detection may help to prevent its progression and to minimize the risk of cardiovascular diseases as one of the major comorbidities. Recently, extracellular miRNAs like urinary exosomal miRNAs became of great interest as non-invasive biomarkers which can be determined by RT-qPCR. But until now, there is no consensus regarding the normalization of miRNAs isolated from body fluids. The present study analyzed the miRNAs miR-16, miR-92a, miR-21, miR-124a and the small nuclear RNA RNU6B for their applicability as an endogenous reference gene in expression studies of exosomal miRNAs isolated from CKD patients. For this purpose, miRNA expression levels were determined by RT-qPCR after the isolation of urinary exosomes from 33 CKD patients and from 5 healthy controls. Expression data was analyzed with the normalization determination software NormFinder, BestKeeper, GeNorm and DeltaCt. Our results revealed an abundant expression of the four candidate miRNAs in urinary exosomes and no detectable expression of RNU6B. We identified miR-16 as the most stable endogenous reference gene in our data set, making it a suitable endogenous reference gene for miRNA studies of urinary exosomes derived from CKD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183435PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578666PMC
October 2017

The LXR Ligand T0901317 Acutely Inhibits Insulin Secretion by Affecting Mitochondrial Metabolism.

Endocrinology 2017 07;158(7):2145-2154

Institute of Pharmacy, Department of Pharmacology, University of Tübingen, 72076 Tübingen, Germany.

The role of liver X receptor (LXR) in pancreatic β-cell physiology and pathophysiology is still unclear. It has been postulated that chronic LXR activation in β-cells induces lipotoxicity, a key step in the development of β-cell dysfunction, which accompanies type 2 diabetes mellitus. In most of these studies, the LXR ligand T0901317 has been administered chronically in the micromolar range to study the significance of LXR activation. In the current study, we have evaluated acute effects of T0901317 on stimulus-secretion coupling of β-cells. We found that 10 µM T0901317 completely suppressed oscillations of the cytosolic Ca2+ concentration induced by 15 mM glucose. Obviously, this effect was due to inhibition of mitochondrial metabolism. T0901317 markedly depolarized the mitochondrial membrane potential, thus inhibiting adenosine triphosphate (ATP) production and reducing the cytosolic ATP concentration. This led in turn to a huge increase in KATP current and hyperpolarization of the cell membrane potential. Eventually, T0901317 inhibited glucose-induced insulin secretion. These effects were rapid in on-set and not compatible with the activation of a nuclear receptor. In vivo, T0901317 acutely increased the blood glucose concentration after intraperitoneal application. In summary, these data clearly demonstrate that T0901317 exerts acute effects on stimulus-secretion coupling. This observation questions the chronic use of T0901317 and limits the interpretation of results obtained under these experimental conditions.
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http://dx.doi.org/10.1210/en.2016-1941DOI Listing
July 2017

Structuring (right) atrial fibrillation: location matters.

Europace 2018 06;20(6):906-907

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, Greifswald D-17475, Germany.

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http://dx.doi.org/10.1093/europace/eux076DOI Listing
June 2018

Urinary Angiotensinogen and Renin Excretion are Associated with Chronic Kidney Disease.

Kidney Blood Press Res 2017 11;42(1):145-155. Epub 2017 Apr 11.

Institute of Physiology, Greifswald, Germany.

Background/aims: Several studies sought to identify new biomarkers for chronic kidney disease (CKD). As the renal renin-angiotensin system is activated in CKD, urinary angiotensinogen or renin excretion may be suitable candidates. We tested whether urinary angiotensinogen or renin excretion is elevated in CKD and whether these parameters are associated with estimated glomerular filtration rate (eGFR). We further tested whether urinary angiotensinogen or renin excretion may convey additional information beyond that provided by albuminuria.

Methods: We measured urinary and plasma angiotensinogen, renin, albumin and creatinine in 177 CKD patients from the Greifswald Approach to Individualized Medicine project and in 283 healthy controls from the Study of Health in Pomerania. The urinary excretion of specific proteins is given as protein-to-creatinine ratio. Receiver operating characteristic (ROC) curves, spearman correlation coefficients and linear regression models were calculated.

Results: Urinary angiotensinogen [2,511 (196-31,909) vs. 18.6 (8.3-44.0) pmol/g, *P<0.01] and renin excretion [0.311 (0.135-1.155) vs. 0.069 (0.045-0.148) pmol/g, *P<0.01] were significantly higher in CKD patients than in healthy controls. The area under the ROC curve was significantly larger when urinary angiotensinogen, renin and albumin excretion were combined than with urinary albumin excretion alone. Urinary angiotensinogen (ß-coefficient -2.405, standard error 0.117, P<0.01) and renin excretion (ß-coefficient -0.793, standard error 0.061, P<0.01) were inversely associated with eGFR. Adjustment for albuminuria, age, sex, systolic blood pressure and body mass index did not significantly affect the results.

Conclusion: Urinary angiotensinogen and renin excretion are elevated in CKD patients. Both parameters are negatively associated with eGFR and these associations are independent of urinary albumin excretion. In CKD patients urinary angiotensinogen and renin excretion may convey additional information beyond that provided by albuminuria.
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http://dx.doi.org/10.1159/000474932DOI Listing
March 2018

Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort.

Exp Biol Med (Maywood) 2017 03 30;242(5):554-563. Epub 2016 Dec 30.

1 Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald D-17475, Germany.

Serum or plasma proteases have been associated with various diseases including cancer, inflammation, or reno-cardiovascular diseases. We aimed to investigate whether the enzymatic activities of serum proteases are associated with the estimated glomerular filtration rate (eGFR) in patients with different stages of chronic kidney disease (CKD). Our study population comprised 268 participants of the "Greifswald Approach to Individualized Medicine" (GANI_MED) cohort. Enzymatic activity of aminopeptidase A, aminopeptidase B, alanyl (membrane) aminopeptidase, insulin-regulated aminopeptidase, puromycin-sensitive aminopeptidase, leucine aminopeptidase 3, prolyl-endopeptidase (PEP), dipeptidyl peptidase 4 (DPP4), angiotensin I-converting enzyme, and angiotensin I-converting enzyme 2 (ACE2) proteases was measured in serum. Linear regression of the respective protease was performed on kidney function adjusted for age and sex. Kidney function was modeled either by the continuous Modification of Diet in Renal Disease (MDRD)-based eGFR or dichotomized by eGFR < 15 mL/min/1.73 m or <45 mL/min/1.73 m, respectively. Results with a false discovery rate below 0.05 were deemed statistically significant. Among the 10 proteases investigated, only the activities of ACE2 and DPP4 were correlated with eGFR. Patients with lowest eGFR exhibited highest DPP4 and ACE2 activities. DPP4 and PEP were correlated with age, but all other serum protease activities showed no associations with age or sex. Our data indicate that ACE2 and DPP4 enzymatic activity are associated with the eGFR in patients with CKD. This finding distinguishes ACE2 and DPP4 from other serum peptidases analyzed and clearly indicates that further analyses are warranted to identify the precise role of these serum ectopeptidases in the pathogenesis of CKD and to fully elucidate underlying molecular mechanisms. Impact statement • Renal and cardiac diseases are very common and often occur concomitantly, resulting in increased morbidity and mortality. Understanding of molecular mechanisms linking both diseases is limited, available fragmentary data point to a role of the renin-angiotensin system (RAS) and, in particular, Ras-related peptidases. • Here, a comprehensive analysis of serum peptidase activities in patients with different stages of chronic kidney disease (CKD) is presented, with special emphasis given to RAS peptidases • The serum activities of the peptidases angiotensin I-converting enzyme 2 and dipeptidyl peptidase 4 were identified as closely associated with kidney function, specifically with the estimated glomerular filtration rate. The findings are discussed in the context of available data suggesting protective roles for both enzymes in reno-cardiac diseases. • The data add to our understanding of pathomechanisms underlying development and progression of CKD and indicate that both enzymes might represent potential pharmacological targets for the preservation of renal function.
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http://dx.doi.org/10.1177/1535370216684040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367655PMC
March 2017

Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia.

Eur Arch Psychiatry Clin Neurosci 2017 Aug 29;267(5):427-443. Epub 2016 Dec 29.

Department of Psychiatry and Psychotherapy, Medical Faculty, University of Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany.

The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.
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http://dx.doi.org/10.1007/s00406-016-0757-7DOI Listing
August 2017

The Angiotensin-(1-7)/Mas Axis Improves Pancreatic β-Cell Function in Vitro and in Vivo.

Endocrinology 2016 Dec 7;157(12):4677-4690. Epub 2016 Oct 7.

Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.

The angiotensin-converting enzyme 2/angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system often opposes the detrimental effects of the angiotensin-converting enzyme/Ang II/Ang II type 1 receptor axis and has been associated with beneficial effects on glucose homeostasis, whereas underlying mechanisms are mostly unknown. Here we investigate the effects of Ang-(1-7) and its receptor Mas on β-cell function. Isolated islets from Mas-deficient and wild-type mice were stimulated with Ang-(1-7) or its antagonists and effects on insulin secretion determined. Islets' cytoplasmic calcium and cAMP concentrations, mRNA amounts of Ins1, Ins2, Pdx1, and Mafa and effects of inhibitors of cAMP downstream signaling were determined. Ang-(1-7) was also applied to mice by osmotic pumps for 14 days and effects on glucose tolerance and insulin secretion were assessed. Ang-(1-7) increased insulin secretion from wild-type islets, whereas antagonists and genetic Mas deficiency led to reduced insulin secretion. The Mas-dependent effects of Ang-(1-7) on insulin secretion did not result from changes in insulin gene expression or changes in the excitation-secretion coupling but from increased intracellular cAMP involving exchange protein activated directly by cAMP. Administration of Ang-(1-7) in vivo had only marginal effects on glucose tolerance in wild-type mice but still resulted in improved insulin secretion from islets isolated of these mice. Interestingly, although less pronounced than in wild types, Ang-(1-7) still affected insulin secretion in Mas-deficient islets. The data indicate a significant function of Ang-(1-7) in the regulation of insulin secretion from mouse islets in vitro and in vivo, mainly, but not exclusively, by Mas-dependent signaling, modulating the accessory pathway of insulin secretion via increase in cAMP.
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http://dx.doi.org/10.1210/en.2016-1247DOI Listing
December 2016

The mitochondrial phospholipid cardiolipin is involved in the regulation of T-cell proliferation.

Biochim Biophys Acta 2016 Aug 7;1861(8 Pt A):748-54. Epub 2016 May 7.

Department of Pathological Biochemistry, Otto-von-Guericke University, D-39120 Magdeburg, Germany. Electronic address:

Challenge of the immune system with antigens induces a cascade of processes including activation of naïve T cells, induction of proliferation, differentiation into effector cells and finally contraction via apoptosis. To meet the dynamic requirements of an adequate immune response, T cells must metabolically adapt to actual situations by switching between catabolic and anabolic metabolism. In this context mitochondria are hubs of metabolic regulation. The phospholipid cardiolipin (CL) is crucial for the structural and functional integrity and, thus, the metabolism of mitochondria. The aim of this study was to verify a possible interrelationship between T cell proliferation and CL composition. For this purpose, we adjusted the proliferation of peripheral human T cells from volunteers by stimulation with different concentrations of the mitogen phytohaemagglutinin (PHA), inhibition with Cyclosporin A (CsA) and exposure of cells to different free fatty acids and subsequently analysed the composition of CL by LC/MS/MS spectroscopy. All of the treatments had significant effects on CL composition. Correlation analysis of the proliferation rate and CL composition revealed that only the amount of incorporated palmitoleic acid and the content of tetralinoleoyl-CL are significantly associated with the proliferation rate. This observation is strongly suggestive of a regulatory function of these particular CL components/species in the process of T cell proliferation. As CL is crucially involved in mitochondrial function one can speculate that changes in CL composition contribute to vital mitochondria-dependent adaptations of energy metabolism in T cells during immune response.
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http://dx.doi.org/10.1016/j.bbalip.2016.05.001DOI Listing
August 2016

Exosomal particles secreted by prostate cancer cells are potent mRNA and protein vehicles for the interference of tumor and tumor environment.

Prostate 2016 Mar 8;76(4):409-24. Epub 2015 Dec 8.

Department of Urology, University Medicine Greifswald, Greifswald, Germany.

Background: Remodeling of the tumor environment and the modulation of tumor associated non-malignant cells are essential events in tumor progression. Exosomes are small membranous vesicles of 50-150 nm in diameter, which are secreted into the extracellular space and supposedly serve as vehicles for signal and effector molecules to modulate adjacent target cells. We characterized the mRNA and protein composition as well as cellular functions of prostate cancer cell-derived exosomes.

Methods: Exosomes were prepared from prostate cancer cell culture supernatant by ultracentrifugation and subsequently characterized by dynamic light scattering and electron microscopy. Exosomal mRNA and protein composition were analyzed by DNA microarrays and gel electrophoresis coupled with mass spectrometry. Physiological effects of exosomes were studied by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release cell assays. Using a SILAC approach, putative uptake of exosomal human proteins in canine cells and canine de novo synthesis of proteins specified by exosome-transferred human mRNA was analyzed in MDCK cells via mass spectrometry.

Results: Preparations of exosomes revealed typical cup shaped particles of 150 nm in diameter. Analysis of mRNA and protein composition of exosomes exhibited a wide range of mRNA and protein species. Interestingly, the packaging of at least small proteins into exosomes was apparently unspecific, as shown with the example of two model proteins. In cell culture incubation experiments exosomal preparations of prostate cancer cells caused anti-proliferative effects. MS analysis revealed the uptake of exosomal human proteins into canine cells after 6 hr of incubation.

Conclusions: The results reveal a distinct exosomal functionality in the modulation of the prostatic tumor adjacent environment. The multitude of translocated factors implies the induction of numerous effects in tumor-associated target cells, including impact on cellular growth.
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http://dx.doi.org/10.1002/pros.23132DOI Listing
March 2016

Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.

Diabetes 2016 Mar 2;65(3):803-17. Epub 2015 Dec 2.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
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http://dx.doi.org/10.2337/db15-1313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764151PMC
March 2016

Atrial fibrillation is associated with the fibrotic remodelling of adipose tissue in the subepicardium of human and sheep atria.

Eur Heart J 2017 01 26;38(1):53-61. Epub 2015 Nov 26.

Sorbonne Université Paris 06, UMR_S1166 team Cardiac Electrophysiology, Paris, France

Aims: Accumulation of atrial adipose tissue is associated with atrial fibrillation (AF). However, the underlying mechanisms remain poorly understood. We examined the relationship between the characteristics of fatty infiltrates of the atrial myocardium and the history of AF.

Methods And Results: Atrial samples, collected in 92 patients during cardiac surgery and in a sheep model of persistent AF, were subjected to a detailed histological analysis. In sections of human right atrial samples, subepicardial fatty infiltrations were commonly observed in the majority of patients. A clear difference in the appearance and fibrotic content of these fatty infiltrations was observed. Fibro-fatty infiltrates predominated in patients with permanent AF (no AF: 37 ± 24% vs. paroxysmal AF: 50 ± 21% vs. permanent AF: 64 ± 23%, P < 0.001). An inverse correlation between fibrotic remodelling and the amount of subepicardial adipose tissue suggested the progressive fibrosis of fatty infiltrates with permanent AF. This hypothesis was tested in a sheep model of AF. In AF sheep, an increased accumulation of peri-atrial fat depot was observed on cardiac magnetic resonance imaging and dense fibro-fatty infiltrations predominated in the left atria of AF sheep. Cellular inflammation, mainly consisting of functional cytotoxic T lymphocytes, was observed together with adipocyte cell death in human atria.

Conclusion: Atrial fibrillation is associated with the fibrosis of subepicardial fatty infiltrates, a process in which cytotoxic lymphocytes might be involved. This remodelling of the atrial subepicardium could contribute to structural remodelling forming a substrate for AF.
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http://dx.doi.org/10.1093/eurheartj/ehv625DOI Listing
January 2017

The European Network for Translational Research in Atrial Fibrillation (EUTRAF): objectives and initial results.

Europace 2015 Oct 12;17(10):1457-66. Epub 2015 Sep 12.

St. George's University of London, London, UK.

Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population. As an age-related arrhythmia AF is becoming a huge socio-economic burden for European healthcare systems. Despite significant progress in our understanding of the pathophysiology of AF, therapeutic strategies for AF have not changed substantially and the major challenges in the management of AF are still unmet. This lack of progress may be related to the multifactorial pathogenesis of atrial remodelling and AF that hampers the identification of causative pathophysiological alterations in individual patients. Also, again new mechanisms have been identified and the relative contribution of these mechanisms still has to be established. In November 2010, the European Union launched the large collaborative project EUTRAF (European Network of Translational Research in Atrial Fibrillation) to address these challenges. The main aims of EUTRAF are to study the main mechanisms of initiation and perpetuation of AF, to identify the molecular alterations underlying atrial remodelling, to develop markers allowing to monitor this processes, and suggest strategies to treat AF based on insights in newly defined disease mechanisms. This article reports on the objectives, the structure, and initial results of this network.
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http://dx.doi.org/10.1093/europace/euv252DOI Listing
October 2015

Dronedarone does not affect infarct volume as assessed by magnetic resonance imaging in a porcine model of myocardial infarction.

Mol Med Rep 2015 Oct 13;12(4):5169-78. Epub 2015 Jul 13.

Institute of Physiology, University Medicine Greifswald, Ernst‑Moritz‑Arndt‑University, Karlsburg D‑17495, Germany.

Dronedarone has been demonstrated to be harmful in patients with recent decompensated heart failure. Furthermore, a PALLAS study reported that dronedarone therapy increases mortality rates in patients with permanent atrial fibrillation. Although a pathophysiological explanation for these finding remains to be elucidated, the long term effects of dronedarone on myocardial structure and stability have been suggested. The aim of the present study was to determine whether dronedarone therapy affects left ventricular (LV) function in a chronic model of myocardial infarction (MI). An anterior MI was induced in 16 pigs. Of these animals, eight pigs were then treated with dronedarone for 1 week prior to, and 4 weeks following MI, the remaining pigs served as controls. LV angiography was performed 4 weeks after MI to determine the LV ejection fraction (LVEF). A post‑mortem magnetic resonance imaging scan of the LV was then performed on the two groups (n=6) to determine the volume and size of the induced MI. Dronedarone therapy did not affect systemic and intracardiac hemodynamic parameters or LVEF during the follow‑up assessment. Of note, dronedarone had no negative effect on the total infarct volume and size and did not induce lethal proarrhythmic effects following the induced anterior MI. Therefore, the results suggested that dronedarone did not increase the volume or size of induced anterior MI and did not affect LV performance. Thus, dronedarone therapy was observed to be safe in a porcine model of anterior MI.
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http://dx.doi.org/10.3892/mmr.2015.4077DOI Listing
October 2015

Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples.

Mol Med Rep 2015 Aug 17;12(2):2253-62. Epub 2015 Apr 17.

Institute of Biochemistry and Cell Biology, Otto‑von‑Guericke University, Magdeburg D‑39120, Germany.

A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) belongs to the ADAM family of transmembrane proteins. Via proteolysis, cell adhesion, cell-cell fusion, cell-matrix interaction and membrane protein shedding, ADAM proteins are involved in normal brain development, and also in cancer genesis and progression, and in inflammation. Therefore, neurobiological research focusing on this protein is increasing. Nitric oxide (NO), which is endogenously produced by NO synthases (NOS), is associated with glial tumors. However, knock-out of NOS produces only limited antitumor effects. The present study analyzed the expression of ADAM12 in the cortex and hippocampus of C57/BL6 wild-type mice, and endothelial NOS-, neuronal NOS-(nNOS) or inducible NOS (iNOS)-deficient (-/-) mice, at different stages of development. Expression of ADAM12 was quantified using immunoblot analysis of cortical and hippocampal tissue samples from fetal, neonatal (5 days postnatal), adult (12 weeks old) or >1 year old mice. Using reverse transcription-quantitative polymerase chain reaction, ADAM12 expression was analyzed in cultured N9, OLN93, C6 and PC12 cells, representing the four main cell types in the brain, following NOS inhibition. ADAM12 expression was low in all mouse genotypes and regions of the brain, and in fetal and neonatal mice, an increase in expression was observed with increasing age. The highest levels of expression were observed in the cortex of adult mice, iNOS(-/-) mice of >1 year and wild-type mice, and in the hippocampus of adult and iNOS(-/-) mice of >1 year. By contrast, ADAM12 expression was lowest in adult nNOS(-/-) mice. Inhibition of NOS using N(ω)-Nitro-L-arginine methyl ester hydrochloride, induced ADAM12 mRNA expression in N9 and PC12 cell lines. Inhibition of NOS using L-N(6)-(1-Iminoethyl)lysine dihydrochloride, induced ADAM12 mRNA expression in N9 and C6 cell lines. No change in ADAM12 expression was observed in OLN93 cells following NOS inhibition. ADAM12 expression in mouse hippocampus and cortex samples demonstrated considerable variation during development, with a marked increase observed in adult and >1 year old mice, compared with that in fetal and neonatal mice.
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http://dx.doi.org/10.3892/mmr.2015.3643DOI Listing
August 2015

Redox control of cardiac remodeling in atrial fibrillation.

Biochim Biophys Acta 2015 Aug 13;1850(8):1555-65. Epub 2014 Dec 13.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, D-17487 Greifswald, Germany. Electronic address:

Background: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is a potential cause of thromboembolic events. AF induces significant changes in the electrophysiological properties of atrial myocytes and causes alterations in the structure, metabolism, and function of the atrial tissue. The molecular basis for the development of structural atrial remodeling of fibrillating human atria is still not fully understood. However, increased production of reactive oxygen or nitrogen species (ROS/RNS) and the activation of specific redox-sensitive signaling pathways observed both in patients with and animal models of AF are supposed to contribute to development, progression and self-perpetuation of AF.

Scope Of Review: The present review summarizes the sources and targets of ROS/RNS in the setting of AF and focuses on key redox-sensitive signaling pathways that are implicated in the pathogenesis of AF and function either to aggravate or protect from disease.

Major Conclusions: NADPH oxidases and various mitochondrial monooxygenases are major sources of ROS during AF. Besides direct oxidative modification of e.g. ion channels and ion handling proteins that are crucially involved in action potential generation and duration, AF leads to the reversible activation of redox-sensitive signaling pathways mediated by activation of redox-regulated proteins including Nrf2, NF-κB, and CaMKII. Both processes are recognized to contribute to the formation of a substrate for AF and, thus, to increase AF inducibility and duration.

General Significance: AF is a prevalent disease and due to the current demographic developments its socio-economic relevance will further increase. Improving our understanding of the role that ROS and redox-related (patho)-mechanisms play in the development and progression of AF may allow the development of a targeted therapy for AF that surpasses the efficacy of previous general anti-oxidative strategies. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.
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http://dx.doi.org/10.1016/j.bbagen.2014.12.012DOI Listing
August 2015

Cohort profile: Greifswald approach to individualized medicine (GANI_MED).

J Transl Med 2014 May 23;12:144. Epub 2014 May 23.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ellernholzstraße 1-2, Greifswald 17475, Germany.

Background: Individualized Medicine aims at providing optimal treatment for an individual patient at a given time based on his specific genetic and molecular characteristics. This requires excellent clinical stratification of patients as well as the availability of genomic data and biomarkers as prerequisites for the development of novel diagnostic tools and therapeutic strategies. The University Medicine Greifswald, Germany, has launched the "Greifswald Approach to Individualized Medicine" (GANI_MED) project to address major challenges of Individualized Medicine. Herein, we describe the implementation of the scientific and clinical infrastructure that allows future translation of findings relevant to Individualized Medicine into clinical practice.

Methods/design: Clinical patient cohorts (N > 5,000) with an emphasis on metabolic and cardiovascular diseases are being established following a standardized protocol for the assessment of medical history, laboratory biomarkers, and the collection of various biosamples for bio-banking purposes. A multi-omics based biomarker assessment including genome-wide genotyping, transcriptome, metabolome, and proteome analyses complements the multi-level approach of GANI_MED. Comparisons with the general background population as characterized by our Study of Health in Pomerania (SHIP) are performed. A central data management structure has been implemented to capture and integrate all relevant clinical data for research purposes. Ethical research projects on informed consent procedures, reporting of incidental findings, and economic evaluations were launched in parallel.
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http://dx.doi.org/10.1186/1479-5876-12-144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040487PMC
May 2014