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181.
Huerta-García E Ventura-Gallegos JL Victoriano ME Montiél-Dávalos A Tinoco-Jaramillo G López-Marure R 《Steroids》2012,77(3):233-240
Dehydroepiandrosterone (DHEA), an adrenal steroid, has a protective role against diabetes; however, its mechanisms of action are unknown. Here, we focus on the effect of DHEA on the activation of endothelial cells induced by a high concentration of glucose. Adhesion on U937 cells, expression of adhesion molecules, production of ROS and NO, expression of eNOS, and translocation of NF-κB were evaluated in human umbilical vein endothelial cells (HUVEC) treated with high concentrations of glucose, DHEA, or both. High concentrations of glucose (>20mM) induced an increase in adhesion, an increment in mainly E-selectin and PECAM-1 expression, as well as in ROS and NO production, eNOS expression, translocation of NF-κB, and degradation of its inhibitor IκB-α. DHEA abolished adhesion and the increase of E-selectin, ICAM-1, VCAM-1, and PECAM-1 induced by glucose. In addition, DHEA completely blocked oxidative stress and decreased translocation of NF-κB and the degradation of IκB-α induced by glucose. These results suggest that DHEA protects against the activation of endothelial cells induced by high concentrations of glucose, indicating that DHEA could be useful in the treatment of hyperglycemia and diabetes. 相似文献
182.
Lombardi R Donini M Villani ME Brunetti P Fujiyama K Kajiura H Paul M Ma JK Benvenuto E 《Transgenic research》2012,21(5):1005-1021
We previously described the expression of a tumour-targeting antibody (mAb H10) in Nicotiana benthamiana by vacuum-agro-infiltration and the remarkable yields of highly pure protein achieved. The objective of the present work was to investigate different strategies for transient overexpression of the mAb H10 in which glycan configuration was modulated and assess how these strategies affect the accumulation yield and stability of the antibody. To this aim, three procedures have been assayed: (1) Site-directed mutagenesis to abolish the glycosylation site; (2) endoplasmic reticulum retention (C-terminal SEKDEL fusion) to ensure predominantly high-mannose type glycans; and (3) expression in a N. benthamiana RNAi down-regulated line in which β1,2-xylosyltransferase and α1,3-fucosyltransferase gene expression is silenced. The three antibody variants (H10-Mut) (H10-SEKDEL) (H10(XylT/FucT)) were transiently expressed, purified and characterised for their glycosylation profile, expression/purification yield and antibody degradation pattern. Glycosylation analysis of H10(XylT/FucT) demonstrated the absence of plant complex-type sugars, while H10-SEKDEL, although substantially retained in the ER, revealed the presence of β1,2-xylose and α1,3-fucose residues, indicating a partial escape from the ER retrieval system. Antibody accumulation and purification yields were not enhanced by ER retention. All H10 antibody glyco-forms revealed greater degradation compared to the original, resulting mostly in the formation of Fab fragments. In the case of aglycosylated H10-Mut, more than 95% of the heavy chain was cleaved, confirming the pivotal role of the sugar moiety in protein stability. Identification of possible 'fragile' sites in the H10 antibody hinge region could be of general interest for the development of new strategies to reduce antibody degradation and increase the yield of intact IgGs in plants. 相似文献
183.
184.
Monti DA Mitchell E Bazzan AJ Littman S Zabrecky G Yeo CJ Pillai MV Newberg AB Deshmukh S Levine M 《PloS one》2012,7(1):e29794
Background
Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy.Methods and Findings
14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease.Conclusions
These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration.Trial Registration
Clinicaltrials.gov NCT00954525相似文献185.
Gentilini D Castaldi D Mari D Monti D Franceschi C Di Blasio AM Vitale G 《Aging cell》2012,11(2):277-283
Recently, it has been proposed that age-related X chromosome inactivation (XCI) skewing can clinically result in late-onset X-linked disorders. This observation leads to hypothesize that age-related skewed XCI might also influence lifespan in women. To investigate this issue, we employed a new experimental model of longevity and healthy aging including 55 female centenarians, 40 of their offspring, 33 age-matched offspring of both non-long-lived parents and 41 young women. Peripheral blood DNA from 169 females was screened for heterozygosity at the HUMARA locus. We confirmed that skewing of XCI is an age-dependent phenomenon. However, skewed XCI was significantly less severe and frequent in centenarians' offspring [degree of skewing (DS) = 0.16 ± 0.02] compared to age-matched offspring of both non-long-lived parents (DS = 0.24 ± 0.02) (P < 0.05). A second goal was to assess whether changes in XCI pattern could be a consequence of loss of methylation on X chromosome. Using a methylation array evaluating 1085 CpG sites across X chromosome and eleven CpG sites located at HUMARA locus, no differences in methylation levels and profiles emerged between all groups analysed, thus suggesting that age-associated epigenetic changes could not influence HUMARA results. In conclusion, the results presented herein highlight for the first time an interesting link between skewing of XCI and healthy aging and longevity. We speculate that the allelic imbalance produced by XCI skewing may compromise the cooperative and compensatory organization occurring between the two cell populations that make up the female mosaic. 相似文献
186.
Background
Pulmonary embolism (PE) is a common and potentially fatal disease that is still underdiagnosed. The objective of our study was to reappraise the clinical presentation of PE with emphasis on the identification of the symptoms and signs that prompt the patients to seek medical attention.Methodology/Principal Findings
We studied 800 patients with PE from two different clinical settings: 440 were recruited in Pisa (Italy) as part of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISAPED); 360 were diagnosed with and treated for PE in seven hospitals of central Tuscany, and evaluated at the Atherothrombotic Disorders Unit, Firenze (Italy), shortly after hospital discharge. We interviewed the patients directly using a standardized, self-administered questionnaire originally utilized in the PISAPED. The two samples differed significantly as regards age, proportion of outpatients, prevalence of unprovoked PE, and of active cancer. Sudden onset dyspnea was the most frequent symptom in both samples (81 and 78%), followed by chest pain (56 and 39%), fainting or syncope (26 and 22%), and hemoptysis (7 and 5%). At least one of the above symptoms was reported by 756 (94%) of 800 patients. Isolated symptoms and signs of deep vein thrombosis occurred in 3% of the cases. Only 7 (1%) of 800 patients had no symptoms before PE was diagnosed.Conclusions/Significance
Most patients with PE feature at least one of four symptoms which, in decreasing order of frequency, are sudden onset dyspnea, chest pain, fainting (or syncope), and hemoptysis. The occurrence of such symptoms, if not explained otherwise, should alert the clinicians to consider PE in differential diagnosis, and order the appropriate objective test. 相似文献187.
Flavonoids have been reported to exert multiple biological effects that include acting as pro-oxidants at very high doses. The authors determined a structural alert to identify the clastogenic activity of a series of flavonoids with pro-oxidant activity. The methodology was based on a quantitative structure-activity relationship (QSAR) study. Specifically, the authors developed a virtual screening method for a clastogenic model using the topological substructural molecular design (TOPS-MODE) approach. It represents a useful platform for the automatic generation of structural alerts, based on the calculation of spectral moments of molecular bond matrices appropriately weighted, taking into account the hydrophobic, electronic, and steric molecular features. Therefore, it was possible to establish the structural criteria for maximal clastogenicity of pro-oxidant flavonoids: the presence of a 3-hydroxyl group and a 4-carbonyl group in ring C, the maximal number of hydroxyl groups in ring B, the presence of methoxyl and phenyl groups, the absence of a 2,3-double bond in ring C, and the presence of 5,7 hydroxyl groups in ring A. The presented clastogenic model may be useful for screening new pro-oxidant compounds. This alert could help in the design of new and efficient flavonoids, which could be used as bioactive compounds in nutraceuticals and functional food. 相似文献
188.
It is widely accepted that aerobic exercise enhances hippocampal plasticity. Often, this plasticity co-occurs with gains in hippocampal-dependent memory. Cross-sectional work investigating this relationship in preadolescent children has found behavioral differences in higher versus lower aerobically fit participants for tasks measuring relational memory, which is known to be critically tied to hippocampal structure and function. The present study tested whether similar differences would arise in a clinical intervention setting where a group of preadolescent children were randomly assigned to a 9-month after school aerobic exercise intervention versus a wait-list control group. Performance measures included eye-movements as a measure of memory, based on recent work linking eye-movement indices of relational memory to the hippocampus. Results indicated that only children in the intervention increased their aerobic fitness. Compared to the control group, those who entered the aerobic exercise program displayed eye-movement patterns indicative of superior memory for face-scene relations, with no differences observed in memory for individual faces. The results of this intervention study provide clear support for the proposed linkage among the hippocampus, relational memory, and aerobic fitness, as well as illustrating the sensitivity of eye-movement measures as a means of assessing memory. ? 2012 Wiley Periodicals, Inc. 相似文献
189.
Cyntia Anabel Amorosi Helena Myskóva Mariela Roxana Monti Carlos Enrique Argara?a Masashi Morita Stephan Kemp Raquel Dodelson de Kremer Lenka Dvoráková Ana María Oller de Ramírez 《PloS one》2012,7(12)
X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease associated with mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues, due to a defect in peroxisomal VLCFA β-oxidation. In the present study, we analyzed 10 male patients and 17 female carriers from 10 unrelated pedigrees with X-ALD from Argentina. By sequencing the ABCD1 we detected 9 different mutations, 8 of which were novel. These new mutations were verified by a combination of methods that included both functional (western blot and peroxisomal VLCFA β-oxidation) and bioinformatics analysis. The spectrum of novel mutations consists of 3 frameshift (p.Ser284fs*16, p.Glu380Argfs*21 and p.Thr254Argfs*82); a deletion (p.Ser572_Asp575del); a splicing mutation (c.1081+5G>C) and 3 missense mutations (p.Ala341Asp, p.His420Pro and p.Tyr547Cys). In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser). In vitro studies suggest that p.Ala19Ser is a polymorphism. Moreover, we identified two novel intronic polymorphisms and two amino acid polymorphisms. In conclusion, this study extends the spectrum of mutation in X-ALD and facilitates the identification of heterozygous females. 相似文献
190.
Eduardo Díaz-Rubio Auxiliadora Gómez-Espa?a Bartomeu Massutí Javier Sastre Margarita Reboredo José Luis Manzano Fernando Rivera MaJosé Safont Clara Montagut Encarnación González Manuel Benavides Eugenio Marcuello Andrés Cervantes Purificación Martínez de Prado Carlos Fernández-Martos Antonio Arrivi Inmaculada Bando Enrique Aranda Spanish Cooperative Group for the Treatment of Digestive Tumors 《PloS one》2012,7(10)