Publications (3)2.48 Total impact
Article: Deficient heat shock protein 70 response to stress in leukocytes at onset of type 1 diabetes.[show abstract] [hide abstract]
ABSTRACT: Type 1 diabetes is caused by the immune-mediated destruction of pancreatic beta cells. Animal models of the disease demonstrate an increased susceptibility of beta cells to immunological attacks due to their defective stress-responsiveness. To investigate the stress-responsiveness in human type 1 diabetes we analyzed the heat-inducibility of the dominant stress protein heat shock protein (Hsp)70 in diabetic patients at different disease stages. At diabetes-manifestation heat-induced Hsp70 levels in peripheral blood mononuclear cells (PBMC) reached only about 25% of the levels expressed by heat-treated PBMC from non-diabetic subjects (p<0.05). Heat-responsiveness improved with disease duration and was re-established at more than eight months after disease-manifestation. Hyperthermia-induced Hsp70 expression was decreased by the T-helper 1-associated cytokine interferon-gamma and increased by the T-helper 2-associated transforming growth factor-beta. We conclude that impaired cellular stress-responsiveness, aggravated by the inflammatory milieu at the onset of type 1 diabetes, contributes to disease manifestation.Biochemical and Biophysical Research Communications 06/2008; 369(2):421-5. · 2.48 Impact Factor
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ABSTRACT: We show here that preincubation of pancreatic islet cells with α-tocopherol significantly improves their resistance to toxic doses of nitric oxide (NO). No protection was afforded by other antioxidants such as vitamin C or glutathione-monoethyl ester. The pathway of NO induced islet cell death involves DNA damage and excessive activation of poly(ADP-ribose)polymerase leading to irreversible depletion of intracellular NAD+. α-Tocopherol was found to interfere at early steps of this pathway, by preventing the occurrence of DNA strand breaks. This indicates that α-tocopherol directly interacts with NO or its reactive intermediates. We conclude that α-tocopherol is not only part of the cellular defence system against oxygen radicals but also protects eukaryotic cells from NO toxicity.FEBS Letters.
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ABSTRACT: Earlier preclinical and clinical trials indicate that fusidic acid, a triterpenoid compound originally described as an antimicrobial drug may protect islet beta cells from destruction in type I (insulin-dependent) diabetes mellitus. Since nitric oxide appears to be an important mediator of inflammatory islet cell death we analysed whether fusidic acid interferes with nitric oxide production or action. We report here that fusidic acid dose-dependently inhibits lysis of isolated islet cells by activated macrophages, a process mediated by nitric oxide. In the presence of 100 μM fusidic acid macrophage-mediated islet cell lysis was reduced from 52.5 to 1.7% (P<0.001). Fusidic acid only slightly affected macrophage function and did not inhibit the release of nitric oxide. We therefore tested whether fusidic acid suppresses nitric oxide toxicity in target cells. Isolated islet cells were exposed to the nitric oxide donor nitroprusside which led to DNA strand breaks and plasma membrane lysis. DNA strand breaks were reduced from 54.6 to 34.9% (P<0.001) in the presence of 100 μM fusidic acid and cell lysis was reduced from 60.1 to 27.5% with 100 μM (P<0.001). In the presence of 500 μM fusidic acid DNA strand breaks and cell lysis were reduced further to 27.1 and 10.7%, respectively (P<0.001). No protection by fusidic acid was observed when cells were exposed to oxygen radicals or the alkylating beta cell toxin streptozotocin. The suppression of nitric oxide toxicity by fusidic acid was not due to its known inhibitory action on protein biosynthesis and thus represents a hitherto unknown activity of this drug.Biochemical Pharmacology.