NMI Technology Transfer GmbH

Reutlingen, Germany

NMI Technology Transfer GmbH

Reutlingen, Germany
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Beissner M.,Max Planck Institute for Brain Research | Dutertre S.,University of Queensland | Schemm R.,Max Planck Institute for Biophysical Chemistry | Danker T.,NMI Technology Transfer GmbH | And 4 more authors.
Molecular Pharmacology | Year: 2012

α-Conotoxins are subtype-selective nicotinic acetylcholine receptor (nAChR) antagonists. Although potent α3β2 nAChR-selective α-conotoxins have been identified, currently characterized α-conotoxins show no or only weak affinity for α4β2 nAChRs, which are, besides α7 receptors, the most abundant nAChRs in the mammalian brain. To identify the determinants responsible for this difference, we substituted selected amino acid residues in the ligand-binding domain of the α4 subunit by the corresponding residues in the α3 subunit. Two-electrode voltage clamp analysis of these mutants revealed increased affinity of α-conotoxins MII, TxIA, and [A10L]TxIA at the α4(R185I)β2 receptor. Conversely, α-conotoxin potency was reduced at the reverse α3(I186R)β2 mutant. Replacement of α4Arg185 by alanine, glutamate, and lysine demonstrated that a positive charge in this position prevents α-conotoxin binding. Combination of the R185I mutation with a P195Q mutation outside the binding site but in loop C completely transferred high α-conotoxin potency to the α4β2 receptor. Molecular dynamics simulations of homology models with docked α-conotoxin indicate that these residues control access to the α-conotoxin binding site. Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics.


Girndt M.,Martin Luther University of Halle Wittenberg | Fiedler R.,Martin Luther University of Halle Wittenberg | Martus P.,University of Tübingen | Pawlak M.,NMI Technology Transfer GmbH | And 11 more authors.
European Journal of Clinical Investigation | Year: 2015

Background: Haemodialysis patients suffer from chronic systemic inflammation and high incidence of cardiovascular disease. One cause for this may be the failure of diseased kidneys to eliminate immune mediators. Current haemodialysis treatment achieves insufficient elimination of proteins in the molecular weight range 15-45 kD. Thus, high cut-off dialysis might improve the inflammatory state. Design: In this randomized crossover trial, 43 haemodialysis patients were treated for 3 weeks with high cut-off or high-flux dialysis. Inflammatory plasma mediators, monocyte subpopulation distribution and leucocyte gene expression were quantified. Results: High cut-off dialysis supplemented by a low-flux filter did not influence the primary end-point, expression density of CD162 on monocytes. Nevertheless, treatment reduced multiple immune mediators in plasma. Such reduction proved - at least for some markers - to be a sustained effect over the interdialytic interval. Thus, for example, soluble TNF-receptor 1 concentration predialysis was reduced from median 13·3 (IQR 8·9-17·2) to 9·7 (IQR 7·5-13·2) ng/mL with high cut-off while remaining constant with high-flux treatment. The expression profile of multiple proinflammatory genes in leucocytes was significantly dampened. Treatment was well tolerated although albumin losses in high cut-off dialysis would be prohibitive against long-term use. Conclusions: The study shows for the first time that a dampening effect of high cut-off dialysis on systemic inflammation is achievable. Earlier studies had failed due to short study duration or insufficient dialysis efficacy. Removal of soluble mediators from the circulation influences cellular activation levels in leucocytes. Continued development of less albumin leaky membranes with similar cytokine elimination is justified. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.


PubMed | University of Tübingen, Martin Luther University of Halle Wittenberg, Gambro Dialysatoren GmbH, Charité - Medical University of Berlin and NMI Technology Transfer GmbH
Type: Journal Article | Journal: European journal of clinical investigation | Year: 2016

Haemodialysis patients suffer from chronic systemic inflammation and high incidence of cardiovascular disease. One cause for this may be the failure of diseased kidneys to eliminate immune mediators. Current haemodialysis treatment achieves insufficient elimination of proteins in the molecular weight range 15-45kD. Thus, high cut-off dialysis might improve the inflammatory state.In this randomized crossover trial, 43 haemodialysis patients were treated for 3weeks with high cut-off or high-flux dialysis. Inflammatory plasma mediators, monocyte subpopulation distribution and leucocyte gene expression were quantified.High cut-off dialysis supplemented by a low-flux filter did not influence the primary end-point, expression density of CD162 on monocytes. Nevertheless, treatment reduced multiple immune mediators in plasma. Such reduction proved - at least for some markers - to be a sustained effect over the interdialytic interval. Thus, for example, soluble TNF-receptor 1 concentration predialysis was reduced from median 133 (IQR 89-172) to 97 (IQR 75-132) ng/mL with high cut-off while remaining constant with high-flux treatment. The expression profile of multiple proinflammatory genes in leucocytes was significantly dampened. Treatment was well tolerated although albumin losses in high cut-off dialysis would be prohibitive against long-term use.The study shows for the first time that a dampening effect of high cut-off dialysis on systemic inflammation is achievable. Earlier studies had failed due to short study duration or insufficient dialysis efficacy. Removal of soluble mediators from the circulation influences cellular activation levels in leucocytes. Continued development of less albumin leaky membranes with similar cytokine elimination is justified.


PubMed | University of Tübingen, Martin Luther University of Halle Wittenberg, Charité - Medical University of Berlin, Gambro Dialysatoren GmbH and NMI Technology Transfer GmbH
Type: Journal Article | Journal: PloS one | Year: 2017

To increase the removal of middle-sized uremic toxins a new membrane with enhanced permeability and selectivity, called Medium Cut-Off membrane (MCO-Ci) has been developed that at the same time ensures the retention of albumin. Because many middle-sized substances may contribute to micro-inflammation we hypothesized that the use of MCO-Ci influences the inflammatory state in hemodialysis patients.The randomized crossover trial in 48 patients compared MCO-Ci dialysis to High-flux dialysis of 4 weeks duration each plus 8 weeks extension phase. Primary endpoint was the gene expression of TNF- and IL-6 in peripheral blood mononuclear cells (PBMCs), secondary endpoints were plasma levels of specified inflammatory mediators and cytokines.After four weeks of MCO-Ci the expression of TNF- mRNA (Relative quantification (RQ) from 0.92 0.34 to 0.75 0.31, -18.5%, p<0.001)- and IL-6 mRNA (RQ from 0.78 0.80 to 0.60 0.43, -23.1%, p<0.01) was reduced to a significantly greater extent than with High-flux dialyzers (TNF mRNA-RQ: -14.3%; IL-6 mRNA-RQ: -3.5%). After retransformation of logarithmically transformed data, measurements after MCO were reduced to 82% of those after HF (95% CI 74%-91%). 4 weeks use of MCO-Ci resulted in long-lasting change in plasma levels of several cytokines and other substances with a significant decrease for sTNFR1, kappa and lambda free light chains, urea and an increase for Lp-PLA2 (PLA2G7) compared to High-flux. Albumin levels dropped significantly after 4 weeks of MCO dialysis but increased after additional 8 weeks of MCO dialysis. Twelve weeks treatment with MCO-Ci was well tolerated regarding the number of (S)AEs. In the extension period levels of CRP, TNF--mRNA and IL-6 mRNA remained stable in High-flux as well as in MCO-Ci.MCO-Ci dialyzers modulate inflammation in chronic HD patients to a greater extent compared to High-flux dialyzers. Transcription of pro-inflammatory cytokines in peripheral leukocytes is markedly reduced and removal of soluble mediators is enhanced with MCO dialysis. Serum albumin concentrations stabilize after an initial drop. These results encourage further trials with longer treatment periods and clinical endpoints.


PubMed | University of Tübingen, Martin Luther University of Halle Wittenberg, NMI Technology Transfer GmbH, Charité - Medical University of Berlin and Gambro Dialysatoren GmbH
Type: | Journal: Hemodialysis international. International Symposium on Home Hemodialysis | Year: 2016

Introduction Patients with chronic kidney disease maintained on intermittent hemodialysis suffer from systemic chronic inflammation which is causally associated with high mortality. Inflammation mediators of 15-45 kDa range cannot be effectively removed by conventional dialysis membranes. In this study, we tested the influence of serum and dialysates obtained from patients maintained on High cut-off or High flux membranes on the inflammation profile of THP-1 monocytes. Methods THP-1 monocytes were treated with serum or dialysates obtained from patients maintained on High cut-off and High flux membranes within a randomized crossover pilot trial. Serum-treated cells were subjected to qPCR analyses with TaqMan probes specific for IL6, TNFa, osteopontin and osteocalcin, and transcriptional screening with Inflammatory Array. Apoptosis assay was performed flow cytometrically with 7-AAD and Annexin V staining. Findings Treatment of the cells with High cut-off serum led to significant reduction of TNFa and IL-6 expression as well as inflammation-related osteopontin and osteocalcin as compared to High flux membrane treatment. As a complementary finding, treatment with High cut-off dialysates induced a pro-apoptotic phenotype in the cells as demonstrated by a significantly increased percentage of 7-AAD and Annexin V positivity. Global screening of serum-treated cells revealed noticeably decreased inflammation profile under High cut-off serum as compared to High flux treatment. Discussion Taken together, these data demonstrate that High cut-off -membranes eliminate a spectrum of mediators from serum into the dialysate that possess proinflammatory properties and may impair cellular viability.


Steuer H.,NMI Technology Transfer GmbH | Krastev R.,University of Tübingen | Lembert N.,NMI Technology Transfer GmbH
Journal of Biomedical Materials Research - Part B Applied Biomaterials | Year: 2014

Positively charged metallic oxides prevent blood coagulation whereas negatively charged metallic oxides are thrombogenic. This study was performed to examine whether this effect extends to metallic oxide nanoparticles. Oscillation shear rheometry was used to study the effect of zinc oxide and silicon dioxide nanoparticles on thrombus formation in human whole blood. Our data show that oscillation shear rheometry is a sensitive and robust technique to analyze thrombogenicity induced by nanoparticles. Blood without previous contact with nanoparticles had a clotting time (CT) of 16.7 ± 1.0 min reaching a maximal clot strength (CS) of 16 ± 14 Pa (G') after 30 min. ZnO nanoparticles (diameter 70 nm, +37 mV zeta-potential) at a concentration of 1 mg/mL prolonged CT to 20.8 ± 3.6 min and provoked a weak clot (CS 1.5 ± 1.0 Pa). However, at a lower concentration of 100 μg/mL the ZnO particles dramatically reduced CT to 6.0 ± 0.5 min and increased CS to 171 ± 63 Pa. This procoagulant effect decreased at lower concentrations reaching the detection limit at 10 ng/mL. SiO2 nanoparticles (diameter 232 nm, -28 mV zeta-potential) at high concentrations (1 mg/mL) reduced CT (2.1 ± 0.2 min) and stimulated CS (249 ± 59 Pa). Similar to ZnO particles, this procoagulant effect reached a detection limit at 10 ng/mL. Nanoparticles in high concentrations reproduce the surface charge effects on blood coagulation previously observed with large particles or solid metal oxides. However, nanoparticles with different surface charges equally well stimulate coagulation at lower concentrations. This stimulation may be an effect which is not directly related to the surface charge. © 2013 Wiley Periodicals, Inc.


PubMed | NMI Technology Transfer GmbH
Type: Journal Article | Journal: Journal of biomedical materials research. Part B, Applied biomaterials | Year: 2014

Positively charged metallic oxides prevent blood coagulation whereas negatively charged metallic oxides are thrombogenic. This study was performed to examine whether this effect extends to metallic oxide nanoparticles. Oscillation shear rheometry was used to study the effect of zinc oxide and silicon dioxide nanoparticles on thrombus formation in human whole blood. Our data show that oscillation shear rheometry is a sensitive and robust technique to analyze thrombogenicity induced by nanoparticles. Blood without previous contact with nanoparticles had a clotting time (CT) of 16.71.0 min reaching a maximal clot strength (CS) of 1614 Pa (G) after 30 min. ZnO nanoparticles (diameter 70 nm, +37 mV zeta-potential) at a concentration of 1 mg/mL prolonged CT to 20.83.6 min and provoked a weak clot (CS 1.51.0 Pa). However, at a lower concentration of 100 g/mL the ZnO particles dramatically reduced CT to 6.00.5 min and increased CS to 17163 Pa. This procoagulant effect decreased at lower concentrations reaching the detection limit at 10 ng/mL. SiO2 nanoparticles (diameter 232 nm, -28 mV zeta-potential) at high concentrations (1 mg/mL) reduced CT (2.10.2 min) and stimulated CS (24959 Pa). Similar to ZnO particles, this procoagulant effect reached a detection limit at 10 ng/mL. Nanoparticles in high concentrations reproduce the surface charge effects on blood coagulation previously observed with large particles or solid metal oxides. However, nanoparticles with different surface charges equally well stimulate coagulation at lower concentrations. This stimulation may be an effect which is not directly related to the surface charge.

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