Die Bedeutung von freien Radikalen für die Toxizität proinflammatorischer Zytokine und die Apoptoseinduktion in insulinproduzierenden Zellen

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Induction of the intrinsic apoptosis pathway in insulin-secreting cells is dependent on oxidative damage of mitochondria but independent of caspase-12 activation

AbstractPro-inflammatory cytokine-mediated beta cell apoptosis is activated through multiple signaling pathways involving mitochondria and endoplasmic reticulum. Activation of organelle-specific caspases has been implicated in the progression and execution of cell death. This study was therefore performed to elucidate the effects of pro-inflammatory cytokines on a possible cross-talk between the compartment-specific caspases 9 and 12 and their differential contribution to beta cell apoptosis. Moreover, the occurrence of ROS-mediated mitochondrial damage in response to beta cell toxic cytokines has been quantified. ER-specific caspase-12 was strongly activated in response to pro-inflammatory cytokines; however, its inhibition did not abolish cytokine-induced mitochondrial caspase-9 activation and loss of cell viability. In addition, there was a significant induction of oxidative mitochondrial DNA damage and elevated cardiolipin peroxidation in insulin-producing RINm5F cells and rat islet cells. Overexpression of the H2O2 detoxifying enzyme catalase effectively reduced the observed cytokine-induced oxidative damage of mitochondrial structures. Taken together, the results strongly indicate that mitochondrial caspase-9 is not a downstream substrate of ER-specific caspase-12 and that pro-inflammatory cytokines cause apoptotic beta cell death through activation of caspase-9 primarily by hydroxyl radical-mediated mitochondrial damage

Facial cellulitis caused by Candida guilliermondi in an immunocompetent patient: a rare case report

Background: Candida cellulitis is a rare disease, primarily reported in immunocompromised patients. Atypical Candida spp. infections are increasing, largely due to the growing number of immunocompromised patients. This case report describes a 52-year-old immunocompetent patient with facial cellulitis caused by Candida guilliermondi. Candida guilliermondi has not previously been reported as a cause of facial cellulitis in either immunocompromised or immunocompetent patients. Case presentation: A 52-year-old, otherwise healthy, male patient presented with facial cellulitis that did not respond to intravenous antibiotics. Culture of the drained pus revealed Candida guilliermondi. The patient was successfully treated with intravenous fluconazole. Conclusion: This case highlights the possibility of atypical Candida spp. causing deep facial infections in immunocompetent patients. Candida guilliermondi has not been previously reported as a cause of facial cellulitis in either immunocompromised or immunocompetent patients. Healthcare providers should consider atypical Candida spp. infections in the differential diagnosis of deep facial infections in both immunocompromised and immunocompetent patients

Characteristics of farming systems in Albania

This report is based on information collected from a face-to-face survey of more than 1 000 farmers from three regions of Albania (namely Berat, Elbasan and Lezhë To identify a representative sample of Albanian farming systems, a three-step sample design was used. A group of 11 variables dealing with the socio-economic characteristics of farms was selected to build up the farming system typology. Two typologies are used: one for the whole sample (three regions) and a second one for each region. The differences between the two typologies are considered to be a proxy indicator of different characteristics of farming systems in each region. The farm types identified are (1) poly-culture, mainly for the market; (2) leisure farms; (3) arable crops; (4) fruit trees; (5) self-sufficient; and (6) livestock. The farm typology is slightly different for the regions of Berat and Lezhë. The farm types’ strategies are constructed according to the land, infrastructure facilities and the investment availability of farms. Non-agricultural incomes (remittances, income from the construction, trade, pensions, etc.) appear to provide an important economic support for the farm household. Farming structures in rural areas are characterised by the use of more labour and lower inputs. The farm types that tend to specialise in one activity are not always those that make the best use of labour and land. Farming does not provide enough income to repay the work put in at the official minimum wage level. Non-agricultural work is better paid. Albanian farms provide at least a minimal income that is enough to keep the household members above the threshold of extreme poverty. The farm types that base their incomes on agricultural activities are poorer than those that base their income on non-agricultural activities. Income structures and the low incomes generated by work in agriculture suggests that rural migration towards urban areas and abroad is a phenomenon that will persist into the future.JRC.J.4-Agriculture and Life Sciences in the Econom

An ER source for H2O2

The endoplasmic reticulum (ER)-localized peroxiredoxin 4 (PRDX4) supports disulfide bond formation in eukaryotic cells lacking endoplasmic reticulum oxidase 1 (ERO1). The source of peroxide that fuels PRDX4-mediated disulfide bond formation has remained a mystery, because ERO1 is believed to be a major producer of hydrogen peroxide (H2O2) in the ER lumen. We report on a simple kinetic technique to track H2O2 equilibration between cellular compartments, suggesting that the ER is relatively isolated from cytosolic or mitochondrial H2O2 pools. Furthermore, expression of an ER-adapted catalase to degrade lumenal H2O2 attenuated PRDX4-mediated disulfide bond formation in cells lacking ERO1, whereas depletion of H2O2 in the cytosol or mitochondria had no similar effect. ER catalase did not effect the slow residual disulfide bond formation in cells lacking both ERO1 and PRDX4. These observations point to exploitation of a hitherto unrecognized lumenal source of H2O2 by PRDX4 and a parallel slow H2O2-independent pathway for disulfide formation.Supported by grants from the Wellcome Trust (Wellcome 084812) the European Commission (EU FP7 Beta-Bat No: 277713) and Fundação para a Ciência e Tecnologia, Portugal (PTDC/QUI-BIQ/119677/2010) and, a Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research (Wellcome 100140). DR is a Wellcome Trust Principal Research Fellow. TK was supported by Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation, Japan Society for the Promotion of Science (JSPS)This is the author accepted manuscript. The final version is available from Rockefeller University Press via http://dx.doi.org/10.1083/jcb.20150612

Modulation of Bcl-2-related protein expression in pancreatic beta cells by pro-inflammatory cytokines and its dependence on the antioxidative defense status. Mol Cell Endocrinol 332: 88–96

a b s t r a c t Pro-inflammatory cytokines are key mediators in the selective and progressive destruction of insulinproducing beta cells during type 1 diabetes development. However, the mechanisms of cytokine-induced beta cell apoptosis are not fully understood. This study demonstrates that pro-inflammatory cytokines strongly modified the expression of the antiapoptotic protein Bcl-2 and the pro-apoptotic BH3-only proteins Bad, Bim, and Bid in primary rat islets and insulin-producing RINm5F cells. Overexpression of mitochondrially located catalase (MitoCatalase) specifically increased basal Bcl-2 and decreased basal Bax expression, suppressed cytokine-mediated reduction of Bcl-2, and thereby prevented the release of cytochrome c, Smac/DIABLO and the activation of caspase-9 and -3. Thus, cytokine-mediated decrease of Bcl-2 expression and the sequentially changed Bax/Bcl-2 ratio are responsible for the release of pro-apoptotic mitochondrial factors, activation of caspase-9, and ultimately caspase-3. These results indicate that activation of the intrinsic/mitochondrial apoptosis pathway is essential for cytokine-induced beta cell death and the mitochondrial generation of reactive oxygen species, in particular mitochondrial hydrogen peroxide, differentially regulates the Bax/Bcl-2 ratio

Cytokine toxicity in insulin-producing cells is mediated by nitro-oxidative stressinduced hydroxyl radical formation in mitochondria

Abstract Although nitric oxide (NO) and oxidative stress both contribute to proinflammatory cytokine toxicity in pancreatic β-cells during type 1 diabetes mellitus (T1DM) development, the interactions between NO and reactive oxygen species (ROS) in cytokine-mediated β-cell death have not been clarified. Exposure of insulin-producing RINm5F cells to IL-1β generated NO, while exposure to a combination of IL-1β, TNF-α, and IFN-γ, which simulates T1DM conditions, generated both NO and ROS. In theory, two reactions between NO and ROS are possible, one with the superoxide radical yielding peroxynitrite, and the other with hydrogen peroxide (H 2 O 2 ) yielding hydroxyl radicals. Results of the present work exclude peroxynitrite involvement in cytokine toxicity to β-cells because its generation did not correlate with the toxic action of cytokines. On the other hand, we show that H 2 O 2 , produced upon exposure of insulin-producing cell clones and primary rat islet cells to cytokines almost exclusively in the mitochondria, reacted in the presence of trace metal (Fe ++ ) with NO forming highly toxic hydroxyl radicals, thus explaining the severe toxicity that causes apoptotic β-cell death. Expression of the H 2 O 2 -inactivating enzyme catalase in mitochondria protected against cytokine toxicity by preventing hydroxyl radical formation. We therefore conclude that proinflammatory cytokine-mediated β-cell death is due to nitro-oxidative stress-mediated hydroxyl radical formation in the mitochondria

Brucellosis associated with deep vein thrombosis

Over the past 10 years more than 700 cases of brucellosis have been reported in Kosovo, which is heavily oriented towards agriculture and animal husbandry. Here, brucellosis is still endemic and represents an uncontrolled public health problem. Human brucellosis may present with a broad spectrum of clinical manifestations; among them, vascular complications are uncommon. Hereby we describe the case of a 37-year-old male patient with brucellosis complicated by deep vein thrombosis on his left leg