Bioaktive Kollagenfragmente : Neue strukturbiologische Studien an Kollagen-Integrin-Komplexen belegen Justus Liebigs wegweisende Ideen

In seinem bahnbrechenden Werk „Thierchemie“ von 1843 beschreibt Justus Liebig Ge latine, das Abbauprodukt von Kollagen, als Leim gebendes Gebilde. Bis heute ist in der Human- wie in der Veterinärmedizin umstritten, ob die Verabreichung von Kollagenfragmenten in Form von Nahrungsergänzungsmitteln eine wirksame Strategie darstellt, um einem Gelenkverschleiß vorzubeugen, der sich z.B. in einer Arthrose manifestieren kann. Die Arbeitsgruppe von Prof. Hans-Christian Siebert kombiniert nanotechnologische Analysemethoden mit Bioinformatikalgorithmen, um die submolekularen Mechanismen zu ergründen, die die hochkomplexen Wechselwirkungen bestimmter Rezeptoren in der extra-zellulären Matrix mit unterschiedlichen bioaktiven Kollagenfragmenten ermöglichen

Gauge copies in the Landau-DeWitt gauge: a background invariant restriction

The Landau background gauge, also known as the Landau-DeWitt gauge, has found renewed interest during the past decade given its usefulness in accessing the confinement-deconfinement transition via the vacuum expectation value of the Polyakov loop, describable via an appropriate background. In this Letter, we revisit this gauge from the viewpoint of it displaying gauge (Gribov) copies. We generalize the Gribov-Zwanziger effective action in a BRST and background invariant way; this action leads to a restriction on the allowed gauge fluctuations, thereby eliminating the infinitesimal background gauge copies. The explicit background invariance of our action is in contrast with earlier attempts to write down and use an effective Gribov-Zwanziger action. It allows to address certain subtleties arising in these earlier works, such as a spontaneous and thus spurious Lorentz symmetry breaking, something which is now averted.Comment: 14 pages. v2: version to appear in Phys.Lett.B, with minor modifications and extra reference

Transfusion of Target Antigens to Pre-Immunized Recipients:A New Mechanism in Transfusion-Related Acute Lung Injury

Transfusion-related lung injury (TRALI) is a serious side effect of blood transfusion. Exclusion of antibody carriers from the donor pool has significantly decreased the number of cases, but TRALI remains the leading cause of transfusion-related morbidity and mortality in industrialized countries. Here, we show that proteins released from donor cells during processing of blood components are capable of inducing a new type of reverse TRALI when transfused to preimmunized recipients. First, we show that soluble neutrophil surface protein CD177 in complex with proteinase 3 (sCD177/PR3) is not only present in human plasma but also in packed red blood cell (PRBC) supernatant. Filtration or storage enhances the concentration of sCD177/PR3 in PRBCs. Second, we show that sCD177/PR3 specifically binds to PECAM-1 on stimulated (but not on unstimulated) endothelial cells (ECs). Third, we provide evidence that the sCD177/PR3/PECAM-1 complex is functional. In the presence of monoclonal or human antibodies against CD177 or PR3, ECs produce reactive oxygen species and become apoptotic. Albumin flux through an EC monolayer increases significantly whenever antibodies and the cognate antigens are present. Finally, we describe a clinical case in which anti-CD177 present in a transfusion recipient precipitated TRALI after the transfusion of CD177-positive, but not CD177-negative, PRBCs. In conclusion, we introduce a new TRALI mechanism based on the specific binding of transfused, soluble antigens to activated ECs in preimmunized recipients. We suggest that further studies and clinical work-up of TRALI should also include antibody investigation of the recipient

Efficacy of Chondroprotective Food Supplements Based on Collagen Hydrolysate and Compounds Isolated from Marine Organisms †

Osteoarthritis belongs to the most common joint diseases in humans and animals and shows increased incidence in older patients. The bioactivities of collagen hydrolysates, sulfated glucosamine and a special fatty acid enriched dog-food were tested in a dog patient study of 52 dogs as potential therapeutic treatment options in early osteoarthritis. Biophysical, biochemical, cell biological and molecular modeling methods support that these well-defined substances may act as effective nutraceuticals. Importantly, the applied collagen hydrolysates as well as sulfated glucosamine residues from marine organisms were strongly supported by both an animal model and molecular modeling of intermolecular interactions. Molecular modeling of predicted interaction dynamics was evaluated for the receptor proteins MMP-3 and ADAMTS-5. These proteins play a prominent role in the maintenance of cartilage health as well as innate and adapted immunity. Nutraceutical data were generated in a veterinary clinical study focusing on mobility and agility. Specifically, key clinical parameter (MMP-3 and TIMP-1) were obtained from blood probes of German shepherd dogs with early osteoarthritis symptoms fed with collagen hydrolysates. Collagen hydrolysate, a chondroprotective food supplement was examined by high resolution NMR experiments. Molecular modeling simulations were used to further characterize the interaction potency of collagen fragments and glucosamines with protein receptor structures. Potential beneficial effects of collagen hydrolysates, sulfated glycans (i.e., sulfated glucosamine from crabs and mussels) and lipids, especially, eicosapentaenoic acid (extracted from fish oil) on biochemical and physiological processes are discussed here in the context of human and veterinary medicine

Circulating Adipokines and Hepatokines Serve as Diagnostic Markers during Obesity Therapy

Deutsche Forschungsgemeinschaft (DFG); ROR-ID:018mejw6

Transfusion of Soluble Target Antigens to Pre-Immunized Recipients: A Previously Overlooked Mechanism in Transfusion-Related Acute Lung Injury

Abstract Transfusion related lung injury (TRALI) is a leading cause for transfusion related morbidity and mortality in industrialized countries. The majority of cases is induced by antibodies present in donor plasma, and exclusion of antibody carriers from the donor pool has decreased the number of TRALI cases significantly. However, TRALI is still reported. We have identified a new and previously overlooked mechanism in which soluble antigens present in the blood component become the target of pre-existing antibodies present in the recipient. Some of us have recently reported a case of TRALI in a female patient precipitating after the transfusion of 120 mL of leuko-reduced packed red blood cells (PRBC). Immediate serologic work-up revealed no antibody in the donor material; but anti-CD177 was detected in the recipient's blood. The following transfusions with two units of PRBCs from CD177 negative donors were uneventful. CD177 is a glycosylphosphatidylinositol-anchored protein exclusively expressed on neutrophils. Only a small minority of Caucasians (&lt;5%) do not express CD177 and can form antibodies when challenged with CD177 during pregnancy or blood transfusions. CD177 functions as a major surface carrier protein for proteinase-3 (PR3), one key contributor to PECAM-1 dependent neutrophil extravasation. Using a sandwich ELISA, we could demonstrate the presence of soluble CD177 in complex with PR3 (sCD177/PR3) in human plasma. As demonstrated by surface plasmon resonance analysis (SPR), PR3 (KD 4.98e-8 M) and the CD177/PR3 complex (KD 7.39e-9 M) specifically bind to immobilized PECAM-1, whereas CD177 does not interact with PECAM-1. In vitro, TNF-alpha pre-treated endothelial cells were negative with anti-CD177 or anti-PR3 antibodies by flow cytometry, but became positive after incubation with sCD177/PR3. Subsequent stimulation with monoclonal anti-CD177 or anti-PR3 induced the production of reactive oxygen species (ROS) in sCD177/PR3 positive (+EC), but not negative (-EC), endothelial cells. The same results were obtained after incubation with human anti-CD177 IgG (hIgG) isolated from plasma. If pre-treated ECs were incubated with recombinant PR3, only monoclonal anti-PR3, but not anti-CD177 or anti-CD177 hIgG induced ROS production. When experiments were repeated with F(ab)2 fragments, overall effects were still present, but diminished. To study the effects of this interaction on EC barrier integrity, ECs were grown on a transwell system, and pre-treated as outlined above. Monoclonal anti-CD177 or anti-PR3 as well as anti-CD177 hIgG significantly increased the albumin-FITC flux through +EC, but not -EC. In the presence of recombinant PR3 only, anti-PR3, but not anti-CD177, increased the albumin flux. Finally, we could demonstrate that the filtration process of buffy coat-reduced red blood cells by standard blood bank technology enhances the concentration of sCD177/PR3 in the storage solution almost 6-fold. In summary, our data demonstrate the presence of sCD177/PR3 in plasma and PRBC storage solution following filtration. When sCD177/PR3 is transfused, it has the capacity to bind to PECAM-1 on the EC surface of the transfusion recipient. The exposure of sCD177/PR3 positive endothelial cells to antibodies against CD177 or PR3 induces endothelial activation and barrier dysfunction in a partially Fcgamma-receptor dependent mechanism, comparable to the mechanism described for "classical" antibody-dependent TRALI. The relevance of soluble target proteins in transfused blood components has previously been overlooked. Furthermore, we assume that the identified new pathway might also be involved in endothelial dysfunction present in Wegener's granulomatosis. Disclosures No relevant conflicts of interest to declare. </jats:sec