Biomedical subjects

P Jost

Publications and source records attributed to P Jost.

15 recordsLinked to original sources

PubMed2006

The Bcl10/Malt1 signaling pathway as a drug target in lymphoma.

The development of lymphomas and leukemias is frequently caused by chromosomal translocations that deregulate cellular pathways of differentiation, proliferation or survival. The molecules that are involved in these aberrations provide rational targets for selective drug therapies. Recently, several disease specific translocations have been identified in human MALT lymphoma. These aberrations either upregulate the expression of BCL10 or MALT1 or induce the formation of API2-MALT1 fusion proteins. Genetic and biochemical experiments identified BCL10 and MALT1 as central components of an oligomerization-ubiquitinylation-phosphorylation cascade that activates the transcription factor NF-kappaB in response to antigen receptor ligation. Deregulation of the signaling cascade is directly associated with antigen independent MALT lymphoma growth. Here we provide an overview of the physiological and pathological functions of BCL10/MALT1 signal transduction and discuss the potential of this pathway as a drug target.

Adaptor Proteins, Signal Transducing↗

PubMed2005

The beta3-adrenergic agonist CL316,243 inhibits insulin signaling but not glucose uptake in primary human adipocytes.

Insulin resistance and obesity are central components of the metabolic syndrome which has become the leading cause of cardiovascular morbidity and mortality worldwide. Direct interactions of the beta (3)-adrenoceptor system with adipocyte signaling and function in humans remain poorly understood. However, this might have important consequences for the regulation of energy homeostasis and insulin resistance in states of hyperinsulinemia and sympatho-adrenergic overactivity. We therefore investigated beta (3)-adrenoceptor-mediated effects on insulin signaling and glucose uptake in mammary adipocytes of healthy women that underwent breast reduction surgery. Glucose uptake was strongly induced by insulin stimulation. This was paralleled by robust induction of insulin receptor kinase activity, insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity, and protein kinase B phosphorylation. Treatment with the beta (3)-adrenoceptor-selective agonist CL316,243 alone, neither induced alterations in the early insulin signaling cascade nor changed the basal level of glucose uptake. By contrast, pretreatment with the beta (3)-adrenoceptor agonist inhibited the insulin-induced insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity by 50 % and protein kinase B phosphorylation by 40 % without affecting insulin receptor kinase activity upstream. However, on the functional level insulin-induced glucose uptake remained unchanged by beta (3)-adrenoceptor stimulation. Our data demonstrate an insulin receptor-independent negative influence of beta (3)-adrenoceptor stimulation on proximal insulin signaling. This inhibition is apparently dissociated from glucose uptake in human adipocytes.

Acrylates↗

PubMed2000

Halide anion recognition in water by a hexaprotonated octaaza-cryptand: a molecular dynamics investigation.

Based on molecular dynamics simulations, we describe the F- versus Cl- complexation by an hexaprotonated cryptand L6+ in aqueous solution, in order to elucidate their structures, solvation properties and the status of external halide counterions. In water, F- and Cl- simulated inclusive complexes adopt a structure somewhat different from the solid state structure of the F- complex: The anion binding involves two diammonium bridges only, and the accompanying counterions are dissociated from the +5 charged complex. A remarkable result is obtained for the dissociated L6+,3F- ,3Cl- system, where spontaneous complexation of F- (the anion which forms the most stable complex with L6+) takes place during the dynamics. The resulting complex is of facial type; this suggests that the equilibrium involves multiple binding modes and structures in aqueous solution. The question of F-/Cl- binding selectivity is investigated by free energy perturbations simulations which nicely reproduce the spectacular preference for F- over Cl-. Two different methodologies used for the treatment of electrostatics (standard versus Ewald calculations) yield similar conclusions.

Journal Article↗

PubMed1999

Targeted gene delivery into alpha9beta1-integrin-displaying cells by a synthetic peptide.

We have investigated the usefulness of two small synthetic peptides comprising either a linear or a cyclic PLAEIDGIEL domain and a DNA-binding moiety of 16 lysine residues to mediate gene transfer selectively into alpha9beta1-integrin-displaying cells. Such specific gene delivery could only be achieved with the peptide containing the cyclic PLAEIDGIEL domain. However, inclusion of the cationic liposome Lipofect-AMINE into the peptide/DNA complexes resulted for both peptides in efficient gene transfer with significant targeting specificity. Naturally, the integrin alpha9beta1 is present only in a few highly specialised tissues and abundant throughout the human airway epithelia in vivo. Targeting gene vectors to this integrin therefore appears a useful approach to gene therapy of lung diseases such as cystic fibrosis. As the integrin alpha9beta1 is associated with tissue differentiation during foetal development and may cause resurgence of the foetal phenotype in colon cancers, such vectors may also be applicable for prenatal and cancer gene therapy.

Cation Exchange Resins↗

PubMed1988

The role of antidysrhythmics in cardiac arrest.

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Anti-Arrhythmia Agents↗

PubMed1981

Photosuicide inactivation of acetylcholinesterase by nitrosamine derivatives.

Methyl(acetoxymethyl)nitrosamine and methyl-(butyroxymethyl)nitrosamine are respectively substrate (KM - 10(-2) M) and competitive inhibitor (Ki = 2 x 10(-3) M) of electric eel acetylcholinesterase (EC 3.1.1.7). Irradiation of an incubation mixture of this enzyme with either nitrosamine leads to an irreversible loss of enzyme activity. The inactivation rates are dependent on photolysis wavelength, light intensity, and inhibitor concentration. Experiments where acetylcholinesterase was radioactively labeled by [14C]-methyl(acetoxymethyl)nitrosamine show that the incorporation of 1 mol of radioactive label per active site is sufficient to cause complete enzyme inactivation irrespective of the reaction conditions used. Methyl(acetoxymethyl)nitrosamine shows no affinity for horse serum butyrylcholinesterase (EC 3.1.1.8) while methyl(butyroxymethyl)nitrosamine is a competitive inhibitor (Ki = 2 x 10(-3) M), but no irreversible inhibition is induced by the action of light. We propose that a suicide type of inhibition [Bloch, K. (1969) Acc. Chem. Res. 2, 193-198] is responsible for the inactivation of acetylcholinesterase, based on photoactivation of nitrosamines only when associated with an acidic hydrogen of the active site.

Animals↗

PubMed1973