FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Tubular Epithelial NF-kappaB Activity Regulates Ischemic AKI
Marko(*), L., Vigolo(*), E., Hinze(*), C., Park(*), J. K., Roel(*), G., Balogh(*), A., Choi(*), M., Wübken(*), A., Cording, J., Blasig, I. E., Luft(*), F. C., Scheidereit(*), C., Schmidt-Ott(*), K. M., Schmidt-Ullrich(*), R.; Müller(*), D. N.
Journal of the American Society of Nephrology : JASN, 27:2658-2669
(2016)

Tags: Molecular Cell Physiology (Blasig, I.E.)

Abstract: NF-kappaB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of AKI. The cell type-specific functions of NF-kappaB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF-kappaB signaling in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-kappaB reporter activity and nuclear localization of phosphorylated NF-kappaB subunit p65 analyses in mice revealed that IRI induced widespread NF-kappaB activation in renal tubular epithelia and in interstitial cells that peaked 2-3 days after injury. To genetically antagonize tubular epithelial NF-kappaB activity, we generated mice expressing the human NF-kappaB super-repressor IkappaBalphaDeltaN in renal proximal, distal, and collecting duct epithelial cells. Compared with control mice, these mice exhibited improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration after IRI-induced AKI. Furthermore, tubular NF-kappaB-dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IkappaBalphaDeltaN-expressing mice and exposed to hypoxia-mimetic agent cobalt chloride exhibited less apoptosis and expressed lower levels of chemokines than cells from control mice did. Our results indicate that postischemic NF-kappaB activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response.

Inhibition of the key enzyme of sialic acid biosynthesis by C6-Se modified N-acetylmannosamine analogs
Nieto-Garcia, O., Wratil(*), P. R., Nguyen(*), L. D., Bohrsch(*), V., Hinderlich(*), S., Reutter(*), W.; Hackenberger, C. P. R.
Chem Sci, 7:3928-3933
(2016)

Tags: Chemical Biology II (Hackenberger)

Abstract: Synthetically accessible C6-analogs of N-acetylmannosamine (ManNAc) were tested as potential inhibitors of the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE/MNK), the key enzyme of sialic acid biosynthesis. Enzymatic experiments revealed that the modification introduced at the C6 saccharide position strongly influences the inhibitory potency. A C6-ManNAc diselenide dimer showed the strongest kinase inhibition in the low mu M range among all the substrates tested and successfully reduced cell surface sialylation in Jurkat cells.

Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2
Preisitsch(*), M., Heiden(*), S. E., Beerbaum, M., Niedermeyer(*), T. H., Schneefeld(*), M., Herrmann(*), J., Kumpfmüller(*), J., Thürmer(*), A., Neidhardt(*), I., Wiesner(*), C., Daniel(*), R., Müller(*), R., Bange(*), F. C., Schmieder, P., Schweder(*), T.; Mundt(*), S.
Mar Drugs, 14:21
(2016)

Tags: Solution NMR (Schmieder)

Abstract: In this study, the influence of halide ions on [7.7]paracyclophane biosynthesis in the cyanobacterium Nostoc sp. CAVN2 was investigated. In contrast to KI and KF, supplementation of the culture medium with KCl or KBr resulted not only in an increase of growth but also in an up-regulation of carbamidocyclophane production. LC-MS analysis indicated the presence of chlorinated, brominated, but also non-halogenated derivatives. In addition to 22 known cylindrocyclophanes and carbamidocyclophanes, 27 putative congeners have been detected. Nine compounds, carbamidocyclophanes M-U, were isolated, and their structural elucidation by 1D and 2D NMR experiments in combination with HRMS and ECD analysis revealed that they are brominated analogues of chlorinated carbamidocyclophanes. Quantification of the carbamidocyclophanes showed that chloride is the preferably utilized halide, but incorporation is reduced in the presence of bromide. Evaluation of the antibacterial activity of 30 [7.7]paracyclophanes and related derivatives against selected pathogenic Gram-positive and Gram-negative bacteria exhibited remarkable effects especially against methicillin- and vancomycin-resistant staphylococci and Mycobacterium tuberculosis. For deeper insights into the mechanisms of biosynthesis, the carbamidocyclophane biosynthetic gene cluster in Nostoc sp. CAVN2 was studied. The gene putatively coding for the carbamoyltransferase has been identified. Based on bioinformatic analyses, a possible biosynthetic assembly is discussed.

Liquid storage of boar semen: Current and future perspectives on the use of cationic antimicrobial peptides to replace antibiotics in semen extenders
Schulze(*), M., Dathe, M., Waberski(*), D.; Müller(*), K.
Theriogenology, 85:39-46
(2016)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: Antibiotics are of great importance in boar semen extenders to ensure long shelf life of spermatozoa and to reduce transmission of pathogens into the female tract. However, the use of antibiotics carries a risk of developing resistant bacterial strains in artificial insemination laboratories and their spread via artificial insemination. Development of multiresistant bacteria is a major concern if mixtures of antibiotics are used in semen extenders. Minimal contamination prevention techniques and surveillance of critical hygiene control points proved to be efficient in reducing bacterial load and preventing development of antibiotic resistance. Nevertheless, novel antimicrobial concepts are necessary for efficient bacterial control in extended boar semen with a minimum risk of evoking antibiotic resistance. Enhanced efforts have been made in recent years in the design and use of antimicrobial peptides (AMPs) as alternatives to conventional antibiotics. The male genital tract harbors a series of endogenic substances with antimicrobial activity and additional functions relevant to the fertilization process. However, exogenic AMPs often exert dose- and time-dependent toxic effects on mammalian spermatozoa. Therefore, it is important that potential newly designed AMPs have only minor impacts on eukaryotic cells. Recently, synthetic magainin derivatives and cyclic hexapeptides were tested for their application in boar semen preservation. Bacterial selectivity, proteolytic stability, thermodynamic resistance, and potential synergistic interaction with conventional antibiotics propel predominantly cyclic hexapeptides into highly promising, leading candidates for further development in semen preservation. The time scale for the development of resistant pathogens cannot be predicted at this moment.

Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus
Stempel(*), A. V., Stumpf(*), A., Zhang(*), H. Y., Ozdogan(*), T., Pannasch(*), U., Theis(*), A. K., Otte(*), D. M., Wojtalla(*), A., Racz(*), I., Ponomarenko, A., Xi(*), Z. X., Zimmer(*), A.; Schmitz(*), D.
Neuron, 90:795-809
(2016)

Tags: Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
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