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131.
Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma 总被引:1,自引:0,他引:1
Heider U von Metzler I Kaiser M Rosche M Sterz J Rötzer S Rademacher J Jakob C Fleissner C Kuckelkorn U Kloetzel PM Sezer O 《European journal of haematology》2008,80(2):133-142
Objectives: Mantle cell lymphoma (MCL) is an incurable B cell lymphoma, and novel treatment strategies are urgently needed. We evaluated the effects of combined treatment with the proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) on MCL. Bortezomib acts by targeting the proteasome, and – among other mechanisms – results in a reduced nuclear factor-kappa B (NF-κB) activity. HDACi promote histone acetylation, and also interfere with NF-κB signaling.
Methods: Human MCL cell lines (JeKo-1, Granta-519 and Hbl-2) were exposed to bortezomib and/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H2 DCFDA. In addition, activated caspases, proteasome- and NF-κB activity were quantified.
Results: Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values <1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger N -acetyl- l -cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase-3, -8 and -9 activity, marked reduction of proteasome activity and decrease of NF-κB activity.
Conclusions: This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL. 相似文献
Methods: Human MCL cell lines (JeKo-1, Granta-519 and Hbl-2) were exposed to bortezomib and/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H
Results: Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values <1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger N -acetyl- l -cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase-3, -8 and -9 activity, marked reduction of proteasome activity and decrease of NF-κB activity.
Conclusions: This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL. 相似文献
132.
Warnholtz A Mollnau H Heitzer T Kontush A Möller-Bertram T Lavall D Giaid A Beisiegel U Marklund SL Walter U Meinertz T Munzel T 《Journal of the American College of Cardiology》2002,40(7):1356-1363
OBJECTIVE: With the present studies we sought to determine how treatment with nitroglycerin (NTG) affects endothelial function, oxidative stress and nitric oxide (NO)-downstream signaling in Watanabe heritable hyperlipidemic rabbits (WHHL). BACKGROUND: In vitro experiments have demonstrated potent antiatherosclerotic effects of NO suggesting that treatment with NO-donors such as NTG could compensate for the diminished availability of endothelial NO. Nitric oxide may, however, not only be scavenged by reaction with endothelium-derived superoxide but also form the potent oxidant and inhibitor of vascular function, peroxynitrite (ONOO(-)). METHODS: Watanabe heritable hyperlipidemic rabbits were treated for three days with NTG patches. Normolipidemic New Zealand White rabbits (NZWR) served as controls. Endothelial function was assessed ex vivo with organ chamber experiments and vascular superoxide was quantified using lucigenin (5 and 250 microM) and CLA-enhanced chemiluminescence. Vascular ONOO(-) formation was determined using nitrotyrosine antibodies. The activity of the cGMP-dependent kinase (cGK-I) was assessed by determining the phosphorylation of vasodilator-stimulated phosphoprotein VASP (P-VASP). RESULTS: Nitroglycerin treatment caused endothelial dysfunction in NZWR and WHHL, associated with an increase in superoxide and ONOO(-) production and a substantial drop in cGK-I activity. In vivo NTG-treatment decreased lipophilic antioxidants (alpha- and beta-carotene) in NZWR and WHHL. Treatment of NZWR with NTG also decreased plasma extracellular superoxide dismutase (EC-SOD)-activity. CONCLUSIONS: Nitroglycerin treatment of WHHL with exogenous NO worsens rather than improves endothelial dysfunction secondary to increased formation of superoxide and/or peroxynitrite leading to decreased cGK-I activity. The decrease in plasma levels of alpha- and beta-carotene may be at least in part due to a decrease in EC-SOD activity. 相似文献
133.
Majambere S Fillinger U Sayer DR Green C Lindsay SW 《The American journal of tropical medicine and hygiene》2008,79(1):19-27
We examined the distribution of aquatic stages of malaria vectors in a 400-km(2) area in rural Gambia to assess the practicality of targeting larval control. During the rainy season, the peak period of malaria transmission, breeding sites were 70% more likely to have anopheline larvae in the floodplain of the Gambia River than upland sites (P < 0.001). However, mosquitoes were found in some examples of all habitats, apart from moving water. Habitats most often colonized by anopheline larvae were the largest water bodies, situated near the landward edge of the flood-plain, where culicine larvae were present. In the wet season, 49% of sites had anophelines versus 19% in the dry season (P < 0.001). Larval control targeted at specific habitats is unlikely to be successful in this setting. Nonetheless, larval control initiated at the end of the dry season and run throughout the rainy season could help reduce transmission. 相似文献
134.
Although implantable glucose sensors have existed for over 30 years, their function deteriorates in hours to days, in large part as a result of tissue responses to the implanted sensor (i.e., acute and chronic inflammation, fibrosis, and vessel regression). Little is known about the mediators and mechanisms that control these tissue responses to implantable glucose sensors. In the present study, we developed and validated a murine model for implantable glucose sensors, which suitably parallel sensor function in humans. Using special care in implantation and implant retaining techniques, we demonstrated that (1) sensor function deteriorates rapidly within days post-implantation and (2) loss of glucose sensor function correlated with tissue reactions at the sites of sensor implantation, especially in the vicinity of the glucose oxidase-based working electrode. These studies establish a murine model that can be used to evaluate implantable glucose sensors in vivo. This model should provide the foundation for future studies to understand the factors and mechanisms that control sensor function in vivo. 相似文献
135.
Cell therapy is a novel promising option for treatment of ischemic diseases. Administered endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. However, the number of cells that home to ischemic tissues is restricted. The GTPase Rap1 plays an important role in the regulation of adhesion and chemotaxis. We investigated whether pharmacologic activation of Epac1, a nucleotide exchange protein for Rap1, which is directly activated by cAMP, can improve the adhesive and migratory capacity of distinct progenitor cell populations. Stimulation of Epac by a cAMP-analog increased Rap1 activity and stimulated the adhesion of human EPCs, CD34(+) hematopoietic progenitor cells, and mesenchymal stem cells (MSCs). Specifically, short-term stimulation with a specific Epac activator increased the beta2-integrin-dependent adhesion of EPCs to endothelial cell monolayers, and of EPC and CD34(+) cells to ICAM-1. Furthermore, the Epac activator enhanced the beta1-integrin-dependent adhesion of EPCs and MSCs to the matrix protein fibronectin. In addition, Epac1 activation induced the beta1- and beta2-integrin-dependent migration of EPCs on fibronectin and fibrinogen. Interestingly, activation of Epac rapidly increased lateral mobility of beta1- and beta2-integrins, thereby inducing integrin polarization, and stimulated beta1-integrin affinity, whereas the beta2-integrin affinity was not increased. Furthermore, prestimulation of EPCs with the Epac activator increased homing to ischemic muscles and neovascularization-promoting capacity of intravenously injected EPCs in the model of hind limb ischemia. These data demonstrate that activation of Epac1 increases integrin activity and integrin-dependent homing functions of progenitor cells and enhances their in vivo therapeutic potential. These results may provide a platform for the development of novel therapeutic approaches to improve progenitor cell homing. 相似文献
136.
137.
Ulrike Baranyi Martina Gattringer Andreas M. Farkas Karin Hock Nina Pilat John Iacomini Thomas Wekerle 《European journal of immunology》2013,43(9):2451-2460
The transplantation of allergens (e.g. Phl p 5 or Bet v 1) expressed on BM cells as membrane‐anchored full‐length proteins leads to permanent tolerance at the T‐cell, B‐cell, and effector‐cell levels. Since the exposure of complete allergens bears the risk of inducing anaphylaxis, we investigated here whether expression of Phl p 5 in the cytoplasm (rather than on the cell surface) is sufficient for tolerance induction. Transplantation of BALB/c BM retrovirally transduced to express Phl p 5 in the cytoplasm led to stable and durable molecular chimerism in syngeneic recipients (~20% chimerism at 6 months). Chimeras showed allergen‐specific T‐cell hyporesponsiveness. Further, Phl p 5‐specific TH1‐dependent humoral responses were tolerized in several chimeras. Surprisingly, Phl p 5‐specific IgE and IgG1 levels were significantly reduced but still detectable in sera of chimeric mice, indicating incomplete B‐cell tolerance. No Phl p 5‐specific sIgM developed in cytoplasmic chimeras, which is in marked contrast to mice transplanted with BM expressing membrane‐anchored Phl p 5. Thus, the expression site of the allergen substantially influences the degree and quality of tolerance achieved with molecular chimerism in IgE‐mediated allergy. 相似文献
138.
Ulrike Schliesser Martin Chopra Andreas Beilhack Christine Appelt Simone Vogel Julia Schumann Ivo Panov Katrin Vogt Stephan Schlickeiser Sven Olek Kathryn Wood Christine Brandt Hans‐Dieter Volk Birgit Sawitzki 《European journal of immunology》2013,43(12):3291-3305
The transfer of alloreactive regulatory T (aTreg) cells into transplant recipients represents an attractive treatment option to improve long‐term graft acceptance. We recently described a protocol for the generation of aTreg cells in mice using a nondepleting anti‐CD4 antibody (aCD4). Here, we investigated whether adding TGF‐β and retinoic acid (RA) or rapamycin (Rapa) can further improve aTreg‐cell generation and function. Murine CD4+ T cells were cultured with allogeneic B cells in the presence of aCD4 alone, aCD4+TGF‐β+RA or aCD4+Rapa. Addition of TGF‐β+RA or Rapa resulted in an increase of CD25+Foxp3+‐expressing T cells. Expression of CD40L and production of IFN‐γ and IL‐17 was abolished in aCD4+TGF‐β+RA aTreg cells. Additionally, aCD4+TGF‐β+RA aTreg cells showed the highest level of Helios and Neuropilin‐1 co‐expression. Although CD25+Foxp3+ cells from all culture conditions displayed complete demethylation of the Treg‐specific demethylated region, aCD4+TGF‐β+RA Treg cells showed the most stable Foxp3 expression upon restimulation. Consequently, aCD4+TGF‐β+RA aTreg cells suppressed effector T‐cell differentiation more effectively in comparison to aTreg cells harvested from all other cultures, and furthermore inhibited acute graft versus host disease and especially skin transplant rejection. Thus, addition of TGF‐β+RA seems to be superior over Rapa in stabilising the phenotype and functional capacity of aTreg cells. 相似文献
139.
William S. Helton Ulrike Ossowski Sanna Malinen 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2013,226(3):357-362
The present study was designed to explore the relationships between post-disaster self-reports of depression, vigilance task performance, and frontal cerebral oxygenation. Forty participants (20 women) performed vigilance tasks following a magnitude 7.1 earthquake in Christchurch, New Zealand. In addition to performance, we measured self-reports of depression, anxiety, and stress anchored to the initial earthquake event, and frontal cerebral activity with functional near-infrared spectroscopy. Among the participants, one case may have been an outlier with extremely elevated levels of self-reported depressivity. Excluding the extreme case, there was a correlation between change in response time (response slowing) and depressivity. Including the case there was a correlation between depressivity and right hemisphere oxygenation. These results provide some support for a relationship between moderate depressivity and sustained attention difficulties. 相似文献
140.
Niki Antypa Raffaella Calati Daniel Souery Silvia Pellegrini Othman Sentissi Daniela Amital Ulrike Moser Stuart Montgomery Siegfried Kasper Joseph Zohar Diana De Ronchi Julien Mendlewicz Alessandro Serretti 《Journal of affective disorders》2013