Time filter

Source Type

Vienna, Austria

Herman S.,Medical University of Vienna | Fischer A.,Medical University of Vienna | Presumey J.,Montpellier University | Hoffmann M.,Medical University of Vienna | And 4 more authors.
Arthritis and Rheumatology | Year: 2015

Objective The nuclear protein heterogeneous nuclear RNP A2/B1 (hnRNP A2/B1) is involved in posttranscriptional regulation of gene expression. It is constitutively expressed in lymphoid organs and highly up-regulated in the synovial tissue of patients with rheumatoid arthritis (RA), who may also generate autoantibodies to this protein. This study was undertaken to investigate the potential involvement of hnRNP A2/B1 in the pathogenesis of autoimmune arthritis, by silencing hnRNP A2/B1 expression in 2 animal models of RA. Methods Collagen-induced arthritis (CIA) and the K/BxN serum-transfer model were used as animal models of RA. Efficient silencing of hnRNP A2/B1 was achieved using a liposome-based carrier system for delivery of small interfering RNAs. Expression of hnRNP A2/B1 was analyzed by flow cytometry, reverse transcription-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The number of osteoclasts was determined by tartrate-resistant acid phosphatase staining. Cytokine levels and anticollagen antibody levels were measured by enzyme-linked immunosorbent assay. Results Efficient silencing of hnRNP A2/B1 was achieved in all lymphoid organs. In both experimental models, the incidence and severity of arthritis were largely reduced and bone erosion was not detectable as compared to the control groups. Down-modulation of hnRNP A2/B1 significantly interfered with the production of proinflammatory cytokines from monocyte/macrophages, but not from T cells. Consistent with these findings, production of T cell cytokines was not impaired when cells were restimulated in vitro with type II collagen. Furthermore, levels of anticollagen antibodies were not affected by hnRNP A2/B1 silencing. Conclusion Our findings suggest that hnRNP A2/B1 has an important role in regulation of the innate immune system, especially at the level of monocyte/macrophage activation. Therefore, down-modulation of hnRNP A2/B1 seems to affect primarily the effector phase of autoimmune arthritis. © 2015, American College of Rheumatology. Source

Riha J.,University of Vienna | Brenner S.,University of Vienna | Srovnalova A.,Palacky University | Klameth L.,Ludwig Boltzmann Society | And 3 more authors.
Food and Function | Year: 2015

Anthocyans (anthocyanins and their aglycones anthocyanidins) are colorful pigments, naturally occurring in fruits. They exhibit many biological effects and have potent health benefits. Anthocyans are widely used as dietary supplements and the safety of products containing them is of great importance. To investigate whether anthocyans influence the expression of hepatic uptake transporters from the organic anion transporting polypeptide (SLCO gene/OATP protein) family, we carried out studies on primary cultures of human hepatocytes. The hepato-cellular accumulation of widely used drugs such as statins and some anticancer drugs is mediated by the liver-specific OATP1B1 and OATP1B3, thus any interference with expression of these particular transporters might influence therapeutic outcomes. We evaluated the effects of 21 anthocyanins and their corresponding 6 anthocyanidins on the expression levels of SLCO1B1/SLCO1B3 by RT-qPCR. Changes in OATP protein levels were confirmed by western blotting. Our data show that OATP1B1 responds differently to anthocyans compared with OATP1B3. We observed the induction of SLCO1B1 gene and OATP1B1 protein in four hepatocyte samples by the anthocyanins malvin chloride, malvidin-3-O-galactoside chloride and cyanidin-3-O-sophoroside chloride. For SLCO1B3, a reduction in the expression levels was seen with delphin chloride and the anthocyanidin pelargonidin. Although the values varied considerably between primary hepatocyte isolates from different individuals, a mean induction of SLCO1B1 (up to 60%) and reduction of SLCO1B3 (by less than 25%) were detected. We propose that the effects of anthocyans derived from high dose dietary supplements may have to be taken into account in patients undergoing a therapy with drugs transported by OATP1B1 and OATP1B3. This journal is © The Royal Society of Chemistry 2015. Source

Olszewski U.,Ludwig Boltzmann Society | Zeillinger R.,Ludwig Boltzmann Society | Kars M.D.,Selcuk University | Zalatnai A.,Semmelweis University | And 2 more authors.
Anti-Cancer Agents in Medicinal Chemistry | Year: 2012

1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis{3-[1(4-butylpiperazinyl)]-propyl}-disiloxan-tetrahydrochlorid (SILA 421) is a compound that was developed as modulator of the ABC cassette transporter P-glycoprotein. Furthermore, it exerted antimicrobial toxicity, vascular effects, downregulation of chaperone induction and plasmid curing in bacterial cells. Here, this drug was found to possess cytotoxic activity against a panel of human cancer cell lines that do not overexpress P-gp, with 50% inhibitory concentrations ranging between 1.75±0.38 μM for GLC14 small cell lung cancer and 34.00±4.75 μM for PC-3 prostate cancer cells. HL-60 leukemia and MDA-MB-435 breast cancer cells exhibited cell cycle arrest and apoptotic cell death in response to SILA 421. Assessment of global gene expression of SILA 421-treated HL-60 cells was employed to identify cellular pathways affected by the compound and revealed disturbance of DNA replication, transcription and production of apparently misfolded proteins. Endoplasmatic reticulum stress and downregulation of cell cycle, cellular repair mechanisms and growth factor-related signaling cascades eventually resulted in induction of apoptosis in this cell line. In addition to the well established P-gp inhibitory effect of SILA compounds, reversal of resistance to taxanes, which had been reported for SILA 421 and the related molecule SILA 409, may be linked to downregulation of gene expression of kinesins. Interference with DNA replication and transcription seems to be the common denominator of antimicrobial activity and plasmid curing, as well as anticancer toxicity in human cell lines. Thus, in consideration of the full range of putative cellular targets found in the present work, the application of these SILA compounds for treatment of tumors should be further evaluated. © 2012 Bentham Science Publishers. Source

Olszewski U.,Ludwig Boltzmann Society | Deally A.,University College Dublin | Tacke M.,University College Dublin | Hamilton G.,Ludwig Boltzmann Society | Hamilton G.,Medical University of Vienna
Neoplasia (United States) | Year: 2012

First-line treatment of small cell lung cancer (SCLC) with combination chemotherapy consisting of cisdiamminedichloroplatinum(II) (cisplatin) and etoposide is frequently followed by early relapses and a dismal prognosis. Survival of a fraction of tumor cells and development of chemoresistance may be influenced by an initial cellular stress response against the administered xenobiotics. Therefore, we compared the short-term effects of cisplatin and non-cross-resistant bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) on phosphorylation of 46 sites of a total of 38 signaling proteins in tumor suppressor protein 53 (p53)-wild-type NCI-H526 SCLC cells. The functional significance of selected kinases for the cytotoxicity of both drugs was tested using specific inhibitors and an activator. The cisplatin-induced cellular stress response involved activation of p38α mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N-terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase α1 (AMPKα1) was increased by both drugs, which promoted cell survival, as indicated by results obtained using AMPK inhibitor compound C and AMPK activator 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside. This is in good agreement with previous reports, where AMPKα1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPKα1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds. © 2012 Neoplasia Press, Inc. All rights reserved. Source

Theyer G.,Hospital Kittsee | Holub S.,Wilhelminenspital | Olszewski U.,Ludwig Boltzmann Society | Hamilton G.,Ludwig Boltzmann Society
Open Access Journal of Urology | Year: 2010

Purpose: Reports on clinical measurements of bone mineral density (BMD) in prostate cancer patients undergoing intermittent androgen suppression therapy (IAS) that allows for hormonal recovery between treatment cycles indicate decreased osteoporosis compared to continuous androgen suppression therapy (CAS). In the present study the effect of IAS on bone metabolism by determinations of CrossLaps, a biochemical marker of collagen degradation, were examined. Method: In total 100 IAS treatment cycles of 75 patients with prostate cancer stages ≥pT2 were studied. Clinical data and monthly laboratory tests (testosterone, prostate-specific antigen; PSA) of these patients were monitored together with measurements of C-terminal telopeptide collagen fragments using CrossLaps® ELISA assays. Results: During phases of androgen suppression (AS) lasting for 9 months serum testosterone (<1 ng/mL) and PSA (>2 ng/mL) levels were reversibly reduced, indicating partial growth arrest and apoptotic regression of the prostatic tumors. Serum CrossLaps concentrations peaked at the last 2 months of the AS phases (0.91 ± 0.25 μg/L; mean ± SEM) and were reduced below initial values (0.21 ± 0.43 versus baseline of 0.43 ± 0.06 μg/L) during therapy cessation periods until tumor progression-related increases. Conclusion: Measurements of the serum concentration of CrossLaps in prostate cancer patients receiving IAS indicated that treatment cessation phases rapidly reversed increased bone degradation associated with AS phases, in strong agreement with the clinical observations reporting reduced loss of BMD in IAS when compared to CAS. In terms of clinical outcomes, IAS seems to be as effective as CAS while showing reduced side effects, as demonstrated here by the reduction of androgen-induced bone matrix degradation. © 2010 Theyer et al. Source

Discover hidden collaborations