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51.
Brian Ponnaiya Sally A. Amundson Shanaz A. Ghandhi Lubomir B. Smilenov Charles R. Geard Manuela Buonanno David J. Brenner 《Radiation and environmental biophysics》2013,52(4):523-530
While gene expression studies have proved extremely important in understanding cellular processes, it is becoming more apparent that there may be differences in individual cells that are missed by studying the population as a whole. We have developed a qRT-PCR protocol that allows us to assay multiple gene products in small samples, starting at 100 cells and going down to a single cell, and have used it to study radiation responses at the single-cell level. Since the accuracy of qRT-PCR depends greatly on the choice of “housekeeping” genes used for normalization, initial studies concentrated on determining the optimal panel of such genes. Using an endogenous control array, it was found that for IMR90 cells, common housekeeping genes tend to fall into one of two categories—those that are relatively stably expressed regardless of the number of cells in the sample, e.g., B2M, PPIA, and GAPDH, and those that are more variable (again regardless of the size of the population), e.g., YWHAZ, 18S, TBP, and HPRT1. Further, expression levels in commonly studied radiation-response genes, such as ATF3, CDKN1A, GADD45A, and MDM2, were assayed in 100, 10, and single-cell samples. It is here that the value of single-cell analyses becomes apparent. It was observed that the expression of some genes such as FGF2 and MDM2 was relatively constant over all irradiated cells, while that of others such as FAS was considerably more variable. It was clear that almost all cells respond to ionizing radiation but the individual responses were considerably varied. The analyses of single cells indicate that responses in individual cells are not uniform and suggest that responses observed in populations are not indicative of identical patterns in all cells. This in turn points to the value of single-cell analyses. 相似文献
52.
53.
Cláudia Marques Diana Teixeira Ana Cunha Manuela Meireles Diogo Pestana Elisa Keating Conceição Calhau Rosário Monteiro Ana Faria 《Cell biology and toxicology》2013,29(4):293-302
Methotrexate (MTX) is broadly used in the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA). The prevalence of metabolic syndrome (MeS) in patients with this condition is relatively high. Given the importance of adipose tissue in the development of obesity metabolic complications, this study aimed to investigate the effect of methotrexate on preadipocyte proliferation, adipogenesis, and glucose uptake by adipocytes. 3T3-L1 preadipocytes proliferation was evaluated by sulforhodamine B staining and 3H-thymidine incorporation, after 24 or 48 h of treatment with MTX (0.1 and 10 μM). Preadipocytes were induced to differentiate with an appropriate adipogenic cocktail in the presence or absence of MTX. Adipogenesis was determined by measuring lipid accumulation after staining with oil red O. 3H-Deoxyglucose (3H-DG) uptake was determined by liquid scintillation counting. MTX treatment reduced culture protein content in a concentration-dependent manner and 3H-thymidine incorporation (P?<?0.05). MTX (0.1 μM) treatment increased lipid accumulation and basal 3H-DG uptake by adipocytes (P?<?0.05). In 0.1 μM MTX-treated adipocytes, insulin stimulation did not result in an increase of 3H-DG uptake, contrarily to what was observed in control cells. These results demonstrate that methotrexate interferes with adipocyte proliferation and promotes the hypertrophic growth of adipocytes. These molecular effects may have implications on metabolic profile of RA patients treated with MTX. 相似文献
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55.
Manuela Gellert Simone Venz Jessica Mitl?hner Catherine Cott Eva-Maria Hanschmann Christopher Horst Lillig 《The Journal of biological chemistry》2013,288(49):35117-35125
Vertebrate-specific glutaredoxin 2 (Grx2) is expressed in at least two isoforms, mitochondrial Grx2a and cytosolic Grx2c. We have previously shown that cytosolic Grx2 is essential for embryonic development of the brain. In particular, we identified collapsin response mediator protein 2 (CRMP2/DPYSL2), a mediator of the semaphorin-plexin signaling pathway, as redox-regulated target of Grx2c and demonstrated that this regulation is required for normal axonal outgrowth. In this study, we demonstrate the molecular mechanism of this regulation, a specific and reversible intermolecular Cys-504-Cys-504 dithiol-disulfide switch in homotetrameric CRMP2. This switch determines two conformations of the quaternary CRMP2 complex that controls axonal outgrowth and thus neuronal development. 相似文献
56.
Ellen Preuss Manuela Hugle Romy Reimann Marcel Schlecht Simone Fulda 《The Journal of biological chemistry》2013,288(49):35287-35296
The PI3K/mammalian Target of Rapamycin (mTOR) pathway is often aberrantly activated in rhabdomyosarcoma (RMS) and represents a promising therapeutic target. Recent evaluation of AZD8055, an ATP-competitive mTOR inhibitor, by the Preclinical Pediatric Testing Program showed in vivo antitumor activity against childhood solid tumors, including RMS. Therefore, in the present study, we searched for AZD8055-based combination therapies. Here, we identify a new synergistic lethality of AZD8055 together with ABT-737, a BH3 mimetic that antagonizes Bcl-2, Bcl-xL, and Bcl-w but not Mcl-1. AZD8055 and ABT-737 cooperate to induce apoptosis in alveolar and embryonal RMS cells in a highly synergistic fashion (combination index < 0.2). Synergistic induction of apoptosis by AZD8055 and ABT-737 is confirmed on the molecular level, as AZD8055 and ABT-737 cooperate to trigger loss of mitochondrial membrane potential, activation of caspases, and caspase-dependent apoptosis that is blocked by the pan-caspase inhibitor Z-VAD-fmk. Similar to AZD8055, the PI3K/mTOR inhibitor NVP-BEZ235, the PI3K inhibitor NVP-BKM120 and Akt inhibitor synergize with ABT-737 to trigger apoptosis, whereas no cooperativity is found for the mTOR complex 1 inhibitor RAD001. Interestingly, molecular studies reveal a correlation between the ability of different PI3K/mTOR inhibitors to potentiate ABT-737-induced apoptosis and to suppress Mcl-1 protein levels. Importantly, knockdown of Mcl-1 increases ABT-737-induced apoptosis similar to AZD8055/ABT-737 cotreatment. This indicates that AZD8055-mediated suppression of Mcl-1 protein plays an important role in the synergistic drug interaction. By identifying a novel synergistic interaction of AZD8055 and ABT-737, our findings have important implications for the development of molecular targeted therapies for RMS. 相似文献
57.
Cleoni Alves Mendes de Lima Harrison Magdinier Gomes Maraníbia Aparecida Cardoso Oelemann Jesus Pais Ramos Paulo Cezar Caldas Carlos Eduardo Dias Campos Márcia Aparecida da Silva Pereira Fátima Fandinho Onofre Montes Maria do Socorro Calixto de Oliveira Philip Noel Suffys Maria Manuela da Fonseca Moura 《Memórias do Instituto Oswaldo Cruz》2013,108(4):457-462
The main cause of pulmonary tuberculosis (TB) is infection with
Mycobacterium tuberculosis (MTB). We aimed to evaluate the
contribution of nontuberculous mycobacteria (NTM) to pulmonary disease in
patients from the state of Rondônia using respiratory samples and
epidemiological data from TB cases. Mycobacterium isolates were identified using
a combination of conventional tests, polymerase chain reaction-based restriction
enzyme analysis of hsp65 gene and hsp65 gene
sequencing. Among the 1,812 cases suspected of having pulmonary TB, 444 yielded
bacterial cultures, including 369 cases positive for MTB and 75 cases positive
for NTM. Within the latter group, 14 species were identified as
Mycobacterium abscessus, Mycobacterium
avium, Mycobacterium fortuitum,
Mycobacterium intracellulare, Mycobacterium
gilvum, Mycobacterium gordonae,
Mycobacterium asiaticum, Mycobacterium
tusciae, Mycobacterium porcinum,
Mycobacterium novocastrense, Mycobacterium
simiae, Mycobacterium szulgai,
Mycobacterium phlei and Mycobacterium
holsaticum and 13 isolates could not be identified at the species
level. The majority of NTM cases were observed in Porto Velho and the relative
frequency of NTM compared with MTB was highest in Ji-Paraná. In approximately
half of the TB subjects with NTM, a second sample containing NTM was obtained,
confirming this as the disease-causing agent. The most frequently observed NTM
species were M. abscessus and M. avium and
because the former species is resistant to many antibiotics and displays
unsatisfactory cure rates, the implementation of rapid identification of
mycobacterium species is of considerable importance. 相似文献
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59.
Federica Prati Manuela Bartolini Elena Simoni Angela De Simone Antonella Pinto Vincenza Andrisano Maria Laura Bolognesi 《Bioorganic & medicinal chemistry letters》2013,23(23):6254-6258
The anti-amyloid properties shared by several quinones inspired the design of a new series of hybrids derived from the multi-target drug candidate memoquin (1). The hybrids consist of a central benzoquinone core and a fragment taken from non-steroidal anti-inflammatory drugs, connected through polyamine linkers. The new hybrids retain the potent anti-aggregating activity of the parent 1, while exhibiting micromolar AChE inhibitory activities. Remarkably, 2, 4, (R)-6 and (S)-6 were Aβ aggregation inhibitors even more potent than 1. The balanced amyloid/cholinesterase inhibitory profile is an added value that makes the present series of compounds promising leads against Alzheimer’s disease. 相似文献