Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Abstract: The IkappaB-Kinase (IKK) complex - consisting of the catalytic subunits IKKalpha and IKKbeta as well as the regulatory subunit NEMO - mediates activation of the NF-kappaB pathway, but previous studies suggested the existence of NF-kappaB-independent functions of IKK subunits with potential impact on liver physiology and disease. Programmed cell-death is a crucial factor in the progression of liver diseases, and Receptor-Interacting-Kinases (RIPKs) exerts strategic control over multiple pathways involved in regulating novel programmed cell-death pathways and inflammation. We hypothesized that RIPKs might be unrecognized targets of the catalytic IKK-complex subunits, thereby regulating hepatocarcinogenesis and cholestasis. In this present study, mice with specific genetic inhibition of catalytic IKK activity in liver parenchymal cells (LPC) (IKKalpha/betaLPC-KO ) were intercrossed with RIPK1LPC-KO or RIPK3-/- mice to examine if RIPK1 or RIPK3 might be downstream targets of IKKs. Moreover, we performed in vivo phospho-proteome analyses and in vitro kinase assays, mass spectrometry and mutagenesis experiments. These analyses revealed that IKKalpha and IKKbeta - in addition to their known function in NF-kappaB activation - directly phosphorylate RIPK1 at distinct regions of the protein, thereby regulating cell viability. Loss of this IKKalpha/beta-dependent RIPK1-phosphorylation in LPC inhibits compensatory proliferation of hepatocytes and intrahepatic biliary cells, thus impeding HCC development but promoting biliary cell paucity and lethal cholestasis. CONCLUSIONS: Collectively, these findings show that IKK-complex subunits transmits a previously unrecognized signal through RIPK1, which is fundamental for the long term consequences of chronic hepatic inflammation and might have potential implications for future pharmacological strategies against cholestatic liver disease and cancer. This article is protected by copyright. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 27396433
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Abstract: Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a form of programmed cell death that promotes inflammation in various pathological conditions, suggesting that it might be a privileged pharmacological target. However, its function in glucose homeostasis and obesity has been unknown. Here we show that RIPK3 is over expressed in the white adipose tissue (WAT) of obese mice fed with a choline-deficient high-fat diet. Genetic inactivation of Ripk3 promotes increased Caspase-8-dependent adipocyte apoptosis and WAT inflammation, associated with impaired insulin signalling in WAT as the basis for glucose intolerance. Similarly to mice, in visceral WAT of obese humans, RIPK3 is overexpressed and correlates with the body mass index and metabolic serum markers. Together, these findings provide evidence that RIPK3 in WAT maintains tissue homeostasis and suppresses inflammation and adipocyte apoptosis, suggesting that systemic targeting of necroptosis might be associated with the risk of promoting insulin resistance in obese patients.
    Type of Publication: Journal article published
    PubMed ID: 27323669
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Abstract: Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.
    Type of Publication: Journal article published
    PubMed ID: 28898696
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    ISSN: 0044-2313
    Keywords: Ternary rhenium chalcogenides ; rhenium clusters ; Chemistry ; Inorganic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Cs6Re6Se15, Synthesis, Atomic Arrangement, and the Classification in a System of Structural Design of Ternary Rhenium- and Technetium ChalcogenidesThe ternary selenide Cs6Re6Se15 was prepared via a reaction of caesium carbonate with rhenium in a seleniumcharged hydrogen stream at 850°C. The X-ray single crystal structure determination revealed an atomic arrangement in which, isotypic to the already described compound Cs6Re6S15, [Re6Se8] units are linked by diselenide bridges to a three-dimensional framework corresponding to the scheme {[Re6Se8](Se2)6/2}4-. In this framework six Cs+ ions and one Se2--ion are inserted with respect to the complete formula Cs6Se{[Re6Se8](Se2)6/2}. The classification of this atomic arrangement in a system of structural design of all so far known chalcogenides of rhenium and technetium AxM6Xz with A ≙ alkaline- or alkaline earth metal and X ≙ sulphur or selenium is demonstrated in this paper.
    Notes: Das ternäre Selenid Cs6Re6Se15 wurde durch Umsetzung von Cäsiumcarbonat mit Rhenium in einem mit Selen beladenen Wasserstoffstrom bei 850°C dargestellt. Röntgenographische Einkristallstrukturuntersuchungen führten zu einer Atomanordnung, in der, isotyp zu der bereits beschriebenen Verbindung Cs6Re6S15, [Re6Se8]-Baueinheiten dreidimensional über Diselenbrücken nach dem Schema {[Re6Se8](Se2)6/2}4- zu einer Gerüststruktur verknüpft sind. In diese sind sechs Cs+-Ionen und ein Se2--Ion eingelagert, so daß die vollständige Formel Cs6Se{[Re6Se8](Se2)6/2} lautet. Die Einordnung dieser Atomanordnung in eine Struktursystematik aller bisher bekannten ternären Chalkogenide des Rheniums und Technetiums AxM6Xz mit A ≙ Alkali- oder Erdalkalimetall und X ≙ Schwefel oder Selen wird dargelegt.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    ISSN: 0044-2313
    Keywords: Metal Chalcogenides ; Rhenium Osmium Clusters ; Chemistry ; Inorganic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Cs3Re5OsS11, a Compound Containing Mixed Rhenium Osmium ClustersThe sulphide Cs3Re5OsS11 was prepared via a reaction of cesium carbonate with rhenium- and osmium powder in a sulphur-charged hydrogen stream at 850°C. The X-ray single crystal structure determination revealed an atomic arrangement in which [Re5OsS8] units are linked by sulphurbridges to a three-dimensional framework (space group: Im 3, Z = 8, a = 16.222(2) Å). The (Re5Os)-octahedra are almost regular with respect to a 24 valence electron configuration. In agreement with this configuration a weak, nearly temperature independent paramagnetism was measured. The bond lengths between the bridging sulphur ligands and the (Re5Os)-clusters are shortened, compared to (Re6)-Clusters, because of the higher charge of the (Re5Os)-octahedra.
    Notes: Zur Darstellung von Cs3Re5OsS11 wurden Cäsiumcarbonat, Rhenium- und Osmiumpulver in einem mit Schwefel beladenen Wasserstoffstrom bei 850°C umgesetzt. Röntgenographische Strukturuntersuchungen an Einkristallen führten zu einer Atomanordnung, in der [(Re5Os)S8]-Baueinheiten dreidimensional über Schwefelbrücken verknüpft sind (Raumgruppe Im 3, Z = 8, a = 16,222(2) Å). Die (Re5Os)-Oktaeder sind nahezu regulär, entsprechend einer 24-Valenzelektronenkonfiguration. In Übereinstimmung damit wurde ein schwacher, weitgehend temperaturunabhängiger Paramagnetismus gemessen. Im Vergleich zu entsprechenden Verbindungen mit (Re6)-Clustern wird aufgrund der höheren Ladung des (Re5Os)-Clusters eine Verkürzung der Bindungsabstände zu den verbrückenden Schwefelliganden beobachtet.
    Additional Material: 5 Tab.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...